FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Neckers, L Ricketts, CJ Linehan, WM AF Neckers, Len Ricketts, Christopher J. Linehan, W. Marston TI New Insights into von Hippel-Lindau Function Highlighted by Investigation of the Trichloroethylene-Induced p.P81S Hotspot Mutation SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID RENAL-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; CANCER; EXPOSURE C1 [Neckers, Len; Ricketts, Christopher J.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, CRC Room 1W-5940,9000 Rockville Pike, Bethesda, MD 20892 USA. EM WML@nih.gov FU Intramural NIH HHS NR 14 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2013 VL 105 IS 18 BP 1339 EP 1340 DI 10.1093/jnci/djt240 PG 2 WC Oncology SC Oncology GA 232GH UT WOS:000325479900003 PM 23990664 ER PT J AU Amiri-Kordestani, L Kamangar, F Zujewski, JA AF Amiri-Kordestani, Laleh Kamangar, Farin Zujewski, Jo Anne TI Inflammatory Breast Cancer: Yet Another Risk of the Obesity Epidemic? SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID EXPRESSION; CARCINOMA; SUBTYPES; DENSITY C1 [Amiri-Kordestani, Laleh; Zujewski, Jo Anne] NCI, Med Oncol Branch, Ctr Canc Res, Rockville, MD 20850 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. RP Zujewski, JA (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM zujewskj@mail.nih.gov NR 21 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2013 VL 105 IS 18 BP 1340 EP 1342 DI 10.1093/jnci/djt236 PG 4 WC Oncology SC Oncology GA 232GH UT WOS:000325479900004 PM 24046389 ER PT J AU Schmitz, KH Neuhouser, ML Agurs-Collins, T Zanetti, KA Cadmus-Bertram, L Dean, LT Drake, BF AF Schmitz, Kathryn H. Neuhouser, Marian L. Agurs-Collins, Tanya Zanetti, Krista A. Cadmus-Bertram, Lisa Dean, Lorraine T. Drake, Bettina F. TI Impact of Obesity on Cancer Survivorship and the Potential Relevance of Race and Ethnicity SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID QUALITY-OF-LIFE; BODY-MASS INDEX; STAGE BREAST-CANCER; POPULATION-BASED SAMPLE; IOWA WOMENS HEALTH; LONG-TERM BREAST; AFRICAN-AMERICAN; PROSTATE-CANCER; PHYSICAL-ACTIVITY; RISK-FACTORS AB Evidence that obesity is associated with cancer incidence and mortality is compelling. By contrast, the role of obesity in cancer survival is less well understood. There is inconsistent support for the role of obesity in breast cancer survival, and evidence for other tumor sites is scant. The variability in findings may be due in part to comorbidities associated with obesity itself rather than with cancer, but it is also possible that obesity creates a physiological setting that meaningfully alters cancer treatment efficacy. In addition, the effects of obesity at diagnosis may be distinct from the effects of weight change after diagnosis. Obesity and related comorbid conditions may also increase risk for common adverse treatment effects, including breast cancer-related lymphedema, fatigue, poor health-related quality of life, and worse functional health. Racial and ethnic groups with worse cancer survival outcomes are also the groups for whom obesity and related comorbidities are more prevalent, but findings from the few studies that have addressed these complexities are inconsistent. We outline a broad theoretical framework for future research to clarify the specifics of the biological-social-environmental feedback loop for the combined and independent contributions of race, comorbid conditions, and obesity on cancer survival and adverse treatment effects. If upstream issues related to comorbidities, race, and ethnicity partly explain the purported link between obesity and cancer survival outcomes, these factors should be among those on which interventions are focused to reduce the burden of cancer. C1 [Schmitz, Kathryn H.; Dean, Lorraine T.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Agurs-Collins, Tanya; Zanetti, Krista A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Cadmus-Bertram, Lisa] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Drake, Bettina F.] Washington Univ, Dept Surg, St Louis, MO USA. RP Schmitz, KH (reprint author), Univ Penn, Perelman Sch Med, 423 Guardian Dr,8th Fl Blockley Hall, Philadelphia, PA 19104 USA. EM schmitz@upenn.edu OI Drake, Bettina/0000-0001-9340-5848 FU National Institutes of Health [U54-CA155850, U01CA116850, 1U54CA155435, U54 CA155496] FX This work was supported by grants from the National Institutes of Health (U54-CA155850 at University of Pennsylvania [KHS, LTD]; U01CA116850 at the Fred Hutchinson Cancer Research Center [MLN]; 1U54CA155435 at University of California at San Diego [LC-B]; and U54 CA155496 at Washington University [BFD]). NR 138 TC 35 Z9 35 U1 3 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2013 VL 105 IS 18 BP 1344 EP 1354 DI 10.1093/jnci/djt223 PG 11 WC Oncology SC Oncology GA 232GH UT WOS:000325479900006 PM 23990667 ER PT J AU Schairer, C Li, Y Frawley, P Graubard, BI Wellman, RD Buist, DSM Kerlikowske, K Onega, TL Anderson, WF Miglioretti, DL AF Schairer, Catherine Li, Yan Frawley, Peter Graubard, Barry I. Wellman, Robert D. Buist, Diana S. M. Kerlikowske, Karla Onega, Tracy L. Anderson, William F. Miglioretti, Diana L. TI Risk Factors for Inflammatory Breast Cancer and Other Invasive Breast Cancers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BODY-MASS INDEX; DENSITY AB Background We investigated risk factors for inflammatory breast cancer (IBC), a rare, aggressive, and poorly understood breast cancer that is characterized by diffuse breast skin erythema and edema. Methods We included 617 IBC case subjects in a nested case-control study from the Breast Cancer Surveillance Consortium database (1994-2009). We also included 1151 noninflammatory, locally advanced, invasive breast cancers with chest wall/breast skin involvement (LABC), 7600 noninflammatory invasive case subjects without chest wall/breast skin involvement (BC), and 93 654 control subjects matched to case subjects on age and year at diagnosis and mammography registry. We present estimates of rate ratios (RRs) and 95% confidence intervals (CI) from conditional logistic regression analyses for each case group vs control subjects based on multiply imputed datasets. Results First-degree family history of breast cancer and high mammographic breast density increased risk of IBC, LABC, and BC. High body mass index (BMI) increased IBC risk irrespective of menopausal status and estrogen receptor (ER) expression; rate ratios for BMI 30 and greater vs BMI less than 25 were 3.90 (95% CI = 1.50 to 10.14) in premenopausal women and 3.70 (95% CI = 1.98 to 6.94) in peri/postmenopausal women not currently using hormones. BMI 30 and greater slightly increased risk of ER-positive BC (RR = 1.40; 95% CI = 1.11 to 1.76). Statistically significant reductions in risk of ER-negative IBC with older age at first birth and of ER-positive IBC with higher education were not seen for LABC and BC of the same ER status. Conclusions Different associations with BMI, age at first birth, and education between IBC and/or LABC and BC suggest a distinct etiology for IBC. C1 [Li, Yan] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Frawley, Peter; Wellman, Robert D.; Buist, Diana S. M.; Miglioretti, Diana L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Schairer, Catherine; Graubard, Barry I.; Anderson, William F.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol Biostat, San Francisco, CA 94143 USA. [Onega, Tracy L.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. [Miglioretti, Diana L.] Univ Calif Davis Sch Med, Dept Publ Hlth Sci, Davis, CA USA. RP Schairer, C (reprint author), NCI, 9609 Med Ctr Dr,Rm 7E612, Bethesda, MD 20892 USA. EM schairec@exchange.nih.gov FU National Cancer Institute [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, HHSN261201100031C]; Intramural Research Program at the National Cancer Institute, National Institutes of Health FX This work was supported by the National Cancer Institute-funded BCSC (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, HHSN261201100031C) and by the Intramural Research Program at the National Cancer Institute, National Institutes of Health. NR 23 TC 14 Z9 15 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2013 VL 105 IS 18 BP 1373 EP 1384 DI 10.1093/jnci/djt206 PG 12 WC Oncology SC Oncology GA 232GH UT WOS:000325479900009 PM 24046390 ER PT J AU Ellis, RJ Boufraqech, M Jain, M Patel, D Nilubol, N He, M Zhang, LS Kebebew, E AF Ellis, Ryan J. Boufraqech, Myriem Jain, Meenu Patel, Dhaval Nilubol, Naris He, Mei Zhang, Lisa Kebebew, Electron TI Programmed Death-Ligand 1 as a prognostic marker in papillary thyroid cancer SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 99th Annual Clinical Congress of the American-College-of-Surgeons / 68th Annual Sessions of the Owen H Wangensteen Surgical Forum on Fundamental Surgical Problems CY OCT 06-10, 2013 CL Washington, DC SP Amer Coll Surg C1 [Ellis, Ryan J.; Boufraqech, Myriem; Jain, Meenu; Patel, Dhaval; Nilubol, Naris; He, Mei; Zhang, Lisa; Kebebew, Electron] NCI, Bethesda, MD 20892 USA. RI Boufraqech, Myriem/E-4823-2016 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 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2013 VL 217 IS 3 SU S BP S30 EP S30 PG 1 WC Surgery SC Surgery GA 233OG UT WOS:000325577900044 ER PT J AU Upham, TC Rao, M Atay, SM Siddiqui, MM Hong, YK Raiji, MT Hong, JA Zhang, MR Linehan, WM Schrump, DS AF Upham, Trevor C. Rao, Mahadev Atay, Scott M. Siddiqui, M. Minhaj Hong, Young K. Raiji, Manish T. Hong, Julie A. Zhang, Mary R. Linehan, W. Martson Schrump, David S. TI Cigarette smoke modulates glucose utilization in human lung cancer cells SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 99th Annual Clinical Congress of the American-College-of-Surgeons / 68th Annual Sessions of the Owen H Wangensteen Surgical Forum on Fundamental Surgical Problems CY OCT 06-10, 2013 CL Washington, DC SP Amer Coll Surg C1 [Upham, Trevor C.; Rao, Mahadev; Atay, Scott M.; Siddiqui, M. Minhaj; Hong, Young K.; Raiji, Manish T.; Hong, Julie A.; Zhang, Mary R.; Linehan, W. Martson; Schrump, David S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2013 VL 217 IS 3 SU S BP S40 EP S41 PG 4 WC Surgery SC Surgery GA 233OG UT WOS:000325577900069 ER PT J AU O'Seaghdha, CM Hwang, SJ Ho, JE Vasan, RS Levy, D Fox, CS AF O'Seaghdha, Conall M. Hwang, Shih-Jen Ho, Jennifer E. Vasan, Ramachandran S. Levy, Daniel Fox, Caroline S. TI Elevated Galectin-3 Precedes the Development of CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; PLASMA TOTAL HOMOCYSTEINE; ALL-CAUSE MORTALITY; HEART-FAILURE; RENAL-INSUFFICIENCY; DIABETES-MELLITUS; CARDIOVASCULAR-DISEASE; GENERAL-POPULATION; BLOOD-PRESSURE AB Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal models and inversely correlates with GFR in humans, but whether galectin-3 predicts incident kidney disease is unknown. Here, we assessed renal outcomes for 2450 Framingham Offspring participants who attended examination 6 (1995-1998) and had follow-up data at examination 8 (2005-2008). Renal outcomes of interest included rapid decline in renal function (3 ml/min per 1.73 m(2) per year decline in estimated GFR [eGFR]), CKD (eGFR < 60 ml/min per 1.73 m(2)), and albuminuria (albumin-to-creatinine ratio 17 mg/g in men or 25 mg/g in women). We used multivariable logistic regression models to evaluate associations between galectin-3 with incident renal outcomes at examination 8. During a mean follow-up of 10.1 years, GFR declined rapidly in 241 (9.2%) participants, incident CKD developed in 277 (11.3%), and albuminuria developed in 194 (10.1%). Higher plasma levels of galectin-3 were associated with rapid decline in eGFR (per 1-SD log-galectin-3; adjusted odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28 to 1.73]) and a higher risk of incident CKD (OR, 1.47; 95% CI, 1.27 to 1.71), but not with the risk of incident albuminuria. The addition of galectin-3 to clinical predictors improved the C-statistic (0.837-0.845; P=0.02) but did not reach predefined thresholds for clinically significant improvements to risk prediction based on reclassification indices. In conclusion, elevated levels of plasma galectin-3 are associated with increased risks of rapid GFR decline and of incident CKD in the community, which calls for further study in higher-risk groups. C1 [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Ho, Jennifer E.; Vasan, Ramachandran S.; Levy, Daniel; Fox, Caroline S.] NHLBI, Intramural Res Program, Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Ho, Jennifer E.; Vasan, Ramachandran S.; Levy, Daniel; Fox, Caroline S.] Ctr Populat Studies, Bethesda, MD USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Boston, MA 02114 USA. [Ho, Jennifer E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [O'Seaghdha, Conall M.] Beaumont Hosp, Div Nephrol & Transplantat, Dublin 9, Ireland. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Cardiol & Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Epidemiol Sect, Boston, MA 02118 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute [N01-HC-25195]; American Heart Association FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195). J.E.H. is supported by an American Heart Association Clinical Research Program award. NR 69 TC 42 Z9 46 U1 0 U2 11 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2013 VL 24 IS 9 BP 1470 EP 1477 DI 10.1681/ASN.2012090909 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 227EO UT WOS:000325092900018 PM 23766533 ER PT J AU Miller, LR AF Miller, Lara R. TI Lymphatic Function and the Immune Response to Microbial or Viral Infection SO LYMPHATIC RESEARCH AND BIOLOGY LA English DT Article AB The National Institute of Allergy and Infectious Diseases (NIAID) is the primary institute within the National Institutes of Health (NIH) that conducts and supports basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases. For more than 60 years, NIAID research has led to new therapies, vaccines, diagnostic tests, and other technologies that have improved the health of millions of people in the United States and around the world. C1 [Miller, Lara R.] NIAID, Basic Immunol Branch, Div Allergy Immunol & Transplantat, NIH,DHHS, Bethesda, MD 20892 USA. RP Miller, LR (reprint author), NIAID, Basic Immunol Branch, Div Allergy Immunol & Transplantat, 6610 Rockledge Dr,Room 6307, Bethesda, MD 20892 USA. EM lrmiller@niaid.nih.gov FU The National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) FX The National Institute of Allergy and Infectious Diseases (NIAID) is the primary institute within the National Institutes of Health (NIH) that conducts and supports basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases. For more than 60 years, NIAID research has led to new therapies, vaccines, diagnostic tests, and other technologies that have improved the health of millions of people in the United States and around the world. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1539-6851 EI 1557-8585 J9 LYMPHAT RES BIOL JI Lymphat. Res. Biol. PD SEP 1 PY 2013 VL 11 IS 3 SI SI BP 116 EP 116 DI 10.1089/lrb.2013.0010 PG 1 WC Medicine, Research & Experimental; Physiology SC Research & Experimental Medicine; Physiology GA 219AY UT WOS:000324477300002 PM 24024575 ER PT J AU Nutman, TB AF Nutman, Thomas B. TI Insights into the Pathogenesis of Disease in Human Lymphatic Filariasis SO LYMPHATIC RESEARCH AND BIOLOGY LA English DT Article ID HUMAN BANCROFTIAN FILARIASIS; ADULT WUCHERERIA-BANCROFTI; PARASITE-SPECIFIC ANERGY; BRUGIA-MALAYI; ENDEMIC AREA; T-CELLS; ULTRASONOGRAPHIC EVIDENCE; INFLAMMATORY RESPONSES; TISSUE-FLUID; SCROTAL AREA AB Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, approximate to 40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce lymphatic dilatation. Progressive lymphatic damage and pathology results primarily from the host inflammatory response to the parasites but also perhaps from the host inflammatory response to the parasite's Wolbachia endosymbiont and as a consequence of superimposed bacterial or fungal infections. This review will attempt to shed light on disease pathogenesis in lymphatic filariasis. C1 [Nutman, Thomas B.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), Bldg 4,Room B1-03,4 Ctr Dr, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health 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. NR 59 TC 11 Z9 11 U1 1 U2 17 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1539-6851 EI 1557-8585 J9 LYMPHAT RES BIOL JI Lymphat. Res. Biol. PD SEP 1 PY 2013 VL 11 IS 3 SI SI BP 144 EP 148 DI 10.1089/lrb.2013.0021 PG 5 WC Medicine, Research & Experimental; Physiology SC Research & Experimental Medicine; Physiology GA 219AY UT WOS:000324477300007 PM 24044755 ER PT J AU Samuel-Hodge, CD Garcia, BA Johnston, LF Gizlice, Z Ni, A Cai, JW Kraschnewski, JL Gustafson, AA Norwood, AF Glasgow, RE Gold, AD Graham, JW Evenson, KR Trost, S Keyserling, TC AF Samuel-Hodge, Carmen D. Garcia, Beverly A. Johnston, Larry F. Gizlice, Ziya Ni, Andy Cai, Jianwen Kraschnewski, Jennifer L. Gustafson, Alison A. Norwood, Arnita F. Glasgow, Russell E. Gold, Alison D. Graham, John W. Evenson, Kelly R. Trost, Stewart Keyserling, Thomas C. TI Translation of a Behavioral Weight Loss Intervention for Mid-life, Low-Income Women in Local Health Departments SO OBESITY LA English DT Article ID PHYSICAL-ACTIVITY; RANDOMIZED-TRIAL; PRIMARY-CARE; RURAL COMMUNITIES; CLINICAL-TRIAL; RISK-FACTORS; OBESITY; ADULTS; MANAGEMENT; US AB Objective: To translate a behavioral weight loss intervention for mid-life, low-income women in real world settings. Design and Methods: In this pragmatic clinical trial, we randomly selected six North Carolina county health departments and trained their current staff to deliver a 16-session evidence-based behavioral weight loss intervention (special intervention, SI). SI weight loss outcomes were compared to a delayed intervention (DI) control group. Results: Of 432 women expressing interest, 189 completed baseline measures and were randomized within health departments to SI (N = 126) or DI (N = 63). At baseline, average age was 51 years, 53% were African American, mean weight was 100 kg, and BMI averaged 37 kg/m(2). A total of 96 (76%) SI and 55 (87%) DI participants returned for 5-month follow-up measures. The crude weight change was -3.1 kg in the SI and -0.4 kg in the DI group, for a difference of 2.8 kg (95% CI 1.4 to 4.1, p = 0.0001). Diet quality and physical activity improved significantly more in the SI group, and estimated intervention costs were $327 per participant. Conclusion: This pragmatic short-term weight loss intervention targeted to low-income mid-life women yielded meaningful weight loss when translated to the county health department setting. C1 [Samuel-Hodge, Carmen D.] Univ N Carolina, Dept Nutr, Gillings Sch Publ Hlth, Chapel Hill, NC 27599 USA. [Samuel-Hodge, Carmen D.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Samuel-Hodge, Carmen D.; Garcia, Beverly A.; Johnston, Larry F.; Gizlice, Ziya; Norwood, Arnita F.; Keyserling, Thomas C.] Univ N Carolina, UNC Ctr Hlth Promot & Dis Prevent, Chapel Hill, NC USA. [Cai, Jianwen] Univ N Carolina, Dept Biostat, Gillings Sch Publ Hlth, Chapel Hill, NC USA. [Kraschnewski, Jennifer L.] Penn State Coll Med, Div Gen Internal Med, Hershey, PA USA. [Gustafson, Alison A.] Univ Kentucky, Dept Nutr, Lexington, KY USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Gold, Alison D.] Hudson River Healthcare Inc, New York, NY USA. [Graham, John W.] Univ N Carolina, NC Inst Publ Hlth, Chapel Hill, NC USA. [Evenson, Kelly R.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Trost, Stewart] Oregon State Univ, Dept Nutr & Exercise Sci, Corvallis, OR 97331 USA. [Keyserling, Thomas C.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. RP Samuel-Hodge, CD (reprint author), Univ N Carolina, Dept Nutr, Gillings Sch Publ Hlth, Chapel Hill, NC 27599 USA. EM carmen_samuel@unc.edu RI Trost, Stewart/B-5948-2012 OI Trost, Stewart/0000-0001-9587-3944 FU Centers for Disease Control and Prevention (CDC) [5R18DP001144]; University of North Carolina Center for Health Promotion and Disease Prevention (a CDC prevention research center) through by CDC cooperative agreement [U48/DP000059] FX This study was supported through funding by the Centers for Disease Control and Prevention (CDC) grant No. 5R18DP001144. Other support was provided by the University of North Carolina Center for Health Promotion and Disease Prevention (a CDC prevention research center) through funding by CDC cooperative agreement No. U48/DP000059. These funding sources had no involvement with the preparation of this manuscript or the decision to submit for publication. Dr. Glasgow is now with the National Cancer Institute (NCI). This article does not necessarily reflect the opinions of the CDC or the NCI. We are grateful for the participation of the six county health departments in North Carolina that participated in the study: Davidson, Forsyth, Lincoln, Nash, Pasquotank, and Warren. NR 41 TC 5 Z9 5 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2013 VL 21 IS 9 BP 1764 EP 1773 DI 10.1002/oby.20317 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 231ON UT WOS:000325426600033 PM 23408464 ER PT J AU Nielsen, S Sumner, AE Miller, BV Turkova, H Klein, S Jensen, MD AF Nielsen, Soren Sumner, Anne E. Miller, Bernard V., III Turkova, Hana Klein, Samuel Jensen, Michael D. TI Free Fatty Acid Flux in African-American and Caucasian Adults-Effect of Sex and Race SO OBESITY LA English DT Article ID SUBCUTANEOUS ADIPOSE-TISSUE; X-RAY ABSORPTIOMETRY; INSULIN-RESISTANCE; WHITE WOMEN; BODY-FAT; ENERGY-EXPENDITURE; VISCERAL OBESITY; GLYCEROL RELEASE; METABOLISM; GLUCOSE AB Objective: Obesity, insulin resistance, and diabetes disproportionately affect African-American (AA) women. Abnormal adipose tissue free fatty acid (FFA) release is associated with these conditions. Resting energy expenditure (REE) and sex predict FFA release in Caucasians, but whether this is true in AA is unknown. The sex-specific relationships between FFA release, REE, and race was compared. Design and Methods: 100 adults (47% AA, 50% male, age 32 +/- 8 years [mean +/- SD]) from three different centers underwent duplicate measures of FFA release ([U-C-13] palmitate) and REE (indirect calorimetry). Body composition was determined by DXA and abdominal imaging. Results: AA participants had lower REE, but similar FFA concentrations and flux compared with Caucasian participants. The significant predictors of palmitate release were REE, sex, and race. REE and FFA flux were correlated in both sexes and both races. In a multiple linear regression analysis with palmitate flux as the dependent variable and REE, sex, race, total fat mass, fat-free mass, and insulin as independent variables, REE was the only independent predictor of FFA release in men. Both REE and race predicted palmitate flux in women. Conclusions: FFA flux is related to REE, but the relationship differs in AA and Caucasian women. C1 [Nielsen, Soren] Aarhus Univ Hosp, Dept Endocrinol & Internal Med, DK-8000 Aarhus, Denmark. [Nielsen, Soren; Jensen, Michael D.] Mayo Clin, Endocrine Res Unit, Rochester, MN 55905 USA. [Sumner, Anne E.; Miller, Bernard V., III] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MA USA. [Miller, Bernard V., III; Klein, Samuel] Washington Univ, Sch Med, Ctr Human Nutr, St Louis, MO USA. [Miller, Bernard V., III; Klein, Samuel] Washington Univ, Sch Med, Atkins Ctr Excellence Obes Med, St Louis, MO USA. [Turkova, Hana] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Jensen, MD (reprint author), Mayo Clin, Endocrine Res Unit, Rochester, MN 55905 USA. EM jensen@mayo.edu FU U.S. Public Health Service [K40484, DK50456, UL1 RR024150, DK 37948, DK 56341, UL1 RR024992]; Novo Nordic Foundation; Mayo Foundation; NIDDK; NICHD FX We acknowledge the technical assistance of the staff of the Mayo Clinic GCRC. This work was supported by grants DK40484, DK50456, and UL1 RR024150 from the U.S. Public Health Service; by DK 37948, DK 56341, UL1 RR024992 (SK) from the U.S. Public Health Service; by grants from the Novo Nordic Foundation (to SN), and by the Mayo Foundation. Anne E. Sumner and Bernard V. Miller III were supported by the intramural program of NIDDK. Hana Turkova was supported by the intramural program of NICHD. NR 28 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2013 VL 21 IS 9 BP 1836 EP 1842 DI 10.1002/oby.20322 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 231ON UT WOS:000325426600043 PM 23418014 ER PT J AU Ebong, IA Goff, DC Rodriguez, CJ Chen, HY Bluemke, DA Szklo, M Bertoni, AG AF Ebong, Imo A. Goff, David C., Jr. Rodriguez, Carlos J. Chen, Haiying Bluemke, David A. Szklo, Moyses Bertoni, Alain G. TI The Relationship Between Measures of Obesity and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis SO OBESITY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; CORONARY-ARTERY CALCIUM; INDEPENDENT RISK-FACTOR; BODY-MASS INDEX; CARDIOVASCULAR-DISEASE; WAIST CIRCUMFERENCE; METABOLIC SYNDROME; PHYSICAL-ACTIVITY; ABDOMINAL OBESITY; ASSOCIATION AB Objective: To evaluate the strength of association of body mass index (BMI) and waist circumference (WC) with incident heart failure (HF), exploring our associations by ethnicity and age. Design and Methods: 6,809 participants, aged 45-84 years old, without clinical cardiovascular disease (2000-2002), from the Multi-Ethnic Study of Atherosclerosis were included. Cox-Proportional hazards models were used to examine associations of BMI and WC with incident HF. The predictive abilities of BMI and WC were compared using receiver operating characteristic curves. Results: Over a median follow-up of 7.6 years, there were 176 cases. BMI and WC were associated with incident HF in men (1.33 [1.10-1.61] and 1.38 [1.18-1.62], respectively] and women (1.70 [1.33-2.17] and 1.64 [1.29-2.08], respectively). These associations became non-significant after adjusting for obesity-related conditions (hypertension, dysglycemia, hypercholesterolemia, left ventricular hypertrophy, kidney disease, and inflammation). The associations of BMI and WC did not vary significantly by ethnicity or age-group, but were inverse in Hispanic men. The area under the curve for BMI and WC was 0.749 and 0.750, respectively, in men and 0.782 and 0.777, respectively, in women. Conclusions: The association between obesity and incident HF is largely mediated by obesity-related conditions. BMI and WC have similar predictive abilities for incident HF. C1 [Ebong, Imo A.] Univ So Calif, Dept Med, Los Angeles, CA USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Aurora, CO USA. [Rodriguez, Carlos J.; Bertoni, Alain G.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Rodriguez, Carlos J.; Bertoni, Alain G.] Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Winston Salem, NC 27103 USA. [Chen, Haiying] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Szklo, Moyses] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Ebong, IA (reprint author), Univ So Calif, Dept Med, Los Angeles, CA USA. EM ebong@usc.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung and Blood Institute (NHLBI) [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, N01-HC-95168, N01-HC-95169]; NHLBI [5 T32 HL087730-03] FX The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The MESA study was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung and Blood Institute (NHLBI). The T32 training grant was supported by grant 5 T32 HL087730-03 from the NHLBI. Imo Ebong proposed the study, analyzed data and drafted the manuscript. David Goff, Carlos Rodriguez, and Alain Bertoni contributed to study design and proposal development. Haiying Chen analyzed data and supervised data analysis. Moyses Szklo and David Bluemke contributed to manuscript writing and reviewed the draft for intellectual content. All authors contributed to data interpretation, revision of the manuscript draft, and approved the final version of the manuscript. NR 40 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2013 VL 21 IS 9 BP 1915 EP 1922 DI 10.1002/oby.20298 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 231ON UT WOS:000325426600053 PM 23441088 ER PT J AU Bray, M Pomeroy, J Knowler, WC Bersamin, A Hopkins, S Brage, S Stanhope, K Havel, PJ Boyer, BB AF Bray, Maria Pomeroy, Jeremy Knowler, William C. Bersamin, Andrea Hopkins, Scarlett Brage, Soren Stanhope, Kimber Havel, Peter J. Boyer, Bert B. TI Simple Anthropometrics Are More Correlated with Health Variables Than Are Estimates of Body Composition in Yup'ik People SO OBESITY LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; X-RAY ABSORPTIOMETRY; WAIST CIRCUMFERENCE; METABOLIC SYNDROME; MASS INDEX; ADOLESCENTS; ADIPOSITY; BMI; FAT AB Objectives: To (1) evaluate the relationships between several indices of obesity with obesity-related risk factors; (2) compare the accuracy of body composition estimates derived from anthropometry and bioimpedance analysis (BIA) to estimates of body composition assessed by doubly-labeled water (DLW); and (3) establish equations for estimating fat mass (FM), fat-free mass (FFM), and percent body fat (PBF) in Yup'ik people. Design and Methods: Participants included 1,056 adult Yup'ik people from 11 communities in Southwestern Alaska. In a sub-study of 30 participants, we developed population-specific linear regression models for estimating FM, FFM, and PBF from anthropometrics, age, sex, and BIA against criterion measures derived from total body water assessed with DLW. These models were then used with the population cohort and we analyzed the relationships between obesity indices and several health-related and disease status variables: (1) fasting plasma lipids, (2) glucose, (3) HbA1c, (4) adiponectin, (5) blood pressure, (6) diabetes (DM), and (7) cerebrocoronary vascular disease (CCVD) which includes stroke and heart disease. Results: The best model for estimating FM in the sub-study used only three variables-sex, waist circumference (WC), and hip circumference and had multiple R-2=0.9730. FFM and PBF were calculated from FM and body weight. Conclusion: WC and other anthropometrics were more highly correlated with a number of obesity-elated risk factors than were direct estimates of body composition. Body composition in Yup'ik people can be accurately estimated from simple anthropometrics. C1 [Bray, Maria; Knowler, William C.; Bersamin, Andrea; Hopkins, Scarlett; Boyer, Bert B.] Univ Alaska Fairbanks, Ctr Alaska Native Hlth Res, Fairbanks, AK 99775 USA. [Pomeroy, Jeremy; Knowler, William C.] NIDDK, NIH, Phoenix, AZ USA. [Brage, Soren] MRC, Epidemiol Unit, Cambridge, England. [Stanhope, Kimber; Havel, Peter J.] Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, Davis, CA 95616 USA. [Stanhope, Kimber; Havel, Peter J.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. RP Boyer, BB (reprint author), Univ Alaska Fairbanks, Ctr Alaska Native Hlth Res, Fairbanks, AK 99775 USA. EM bboyer@alaska.edu FU National Institutes of Health [R01DK074842, P20RR016430]; Intramural Research Program of the National Institute of Diabetes; Digestive and Kidney Diseases and funding to the University of Alaska President FX This study was supported by Award Number R01DK074842 and P20RR016430 (Boyer). Dr. Peter Havel's laboratory receives support from National Institutes of Health grants HL075675, HL091333, HL107256, AT003545, and DK097307. This work was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and funding to the University of Alaska President for dedicating unrestricted funds from British Petroleum and ConocoPhillips. NR 13 TC 1 Z9 1 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2013 VL 21 IS 9 BP E435 EP E438 DI 10.1002/oby.20125 PG 4 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 231ON UT WOS:000325426600013 PM 23666898 ER PT J AU Pan, Q Delahanty, LM Jablonski, KA Knowler, WC Kahn, SE Florez, JC Franks, PW AF Pan, Qing Delahanty, Linda M. Jablonski, Kathleen A. Knowler, William C. Kahn, Steven E. Florez, Jose C. Franks, Paul W. CA Diabet Prevention Program Res Grp TI Variation at the Melanocortin 4 Receptor Gene and Response to Weight-Loss Interventions in the Diabetes Prevention Program SO OBESITY LA English DT Article ID LIFE-STYLE INTERVENTION; BODY-MASS INDEX; COMMON VARIANTS; PIMA-INDIANS; MC4R GENE; BASE-LINE; OBESITY; METFORMIN; COHORT; RISK AB Objective: To assess associations and genotype x treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits. Design and Methods: Diabetes prevention program (DPP) participants (N = 3,819, of whom 3,356 were genotyped for baseline and 3,234 for longitudinal analyses) were randomized into intensive lifestyle modification (diet, exercise, weight loss), metformin or placebo control. Adiposity was assessed in a subgroup (n = 909) using computed tomography. All analyses were adjusted for age, sex, ethnicity and treatment. Results: The rs1943218 minor allele was nominally associated with short-term (6 month; P = 0.032) and long-term (2 year; P = 0.038) weight change. Eight SNPs modified response to treatment on short-term (rs17066856, rs9966412, rs17066859, rs8091237, rs17066866, rs7240064) or long-term (rs12970134, rs17066866) reduction in body weight, or diabetes incidence (rs17066829) (all P-interaction < 0.05). Conclusion: This is the first study to comprehensively assess the role of MC4R variants and weight regulation in a weight loss intervention trial. One MC4R variant was directly associated with obesity-related traits or diabetes; numerous other variants appear to influence body weight and diabetes risk by modifying the protective effects of the DPP interventions. C1 [Pan, Qing; Jablonski, Kathleen A.] George Washington Univ, Biostat Ctr, Dept Biostat & Epidemiol, Dept Stat, Rockville, MD USA. [Delahanty, Linda M.] Massachusetts Gen Hosp, Diabet Res Ctr, MGH Diabet Ctr, Dept Med, Boston, MA 02114 USA. [Delahanty, Linda M.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Franks, Paul W.] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. RP Franks, PW (reprint author), Lund Univ, Dept Clin Sci, Malmo, Sweden. EM paul.franks@med.lu.se OI Franks, Paul/0000-0002-0520-7604; Kahn, Steven/0000-0001-7307-9002 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; Office of Research on Women's Health; Department of Veterans Affairs; American Diabetes Association; McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation; Novo Nordisk; Swedish Research Council; Swedish Heart-Lung Foundation; Swedish Diabetes Association; [R01 DK072041-02] FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; collection, management, analysis, and interpretation of the data (U01 DK048489). The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, the Department of Veterans Affairs, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. This work was funded by R01 DK072041-02 to JCF and KAJ (PWF and WCK are unpaid co-investigators). PWF was supported by grants from Novo Nordisk, the Swedish Research Council, the Swedish Heart-Lung Foundation and the Swedish Diabetes Association. SEK is supported in part by the Department of Veterans Affairs. JCF has received consulting honoraria from Novartis, Lilly and Pfizer. No other potential conflict of interest is declared by any author. NR 28 TC 11 Z9 11 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD SEP PY 2013 VL 21 IS 9 BP E520 EP E526 DI 10.1002/oby.20459 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 231ON UT WOS:000325426600026 PM 23512951 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Genome as a stochastic evolutionary machine Comment on "How life changes itself: The Read-Write (RW) genome" by James Shapiro SO PHYSICS OF LIFE REVIEWS LA English DT Editorial Material ID ELEMENTS; SYSTEM; PHAGE C1 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 Intramural NIH HHS NR 18 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1571-0645 EI 1873-1457 J9 PHYS LIFE REV JI Phys. Life Rev. PD SEP PY 2013 VL 10 IS 3 BP 341 EP 343 DI 10.1016/j.plrev.2013.07.017 PG 3 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA 231UW UT WOS:000325444900018 PM 23933228 ER PT J AU Lugassy, C Peault, B Wadehra, M Kleinman, HK Barnhill, RL AF Lugassy, Claire Peault, Bruno Wadehra, Madhuri Kleinman, Hynda K. Barnhill, Raymond L. TI Could pericytic mimicry represent another type of melanoma cell plasticity with embryonic properties? SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article ID EXON-15 BRAF MUTATIONS; CUTANEOUS MELANOMA; NRAS MUTATIONS; SUBTYPES; FREQUENCIES; UNCOMMON; SITES AB We hypothesize that the interaction between angiotropic melanoma cells and the abluminal vascular surface can induce or sustain embryonic and/or stem cell migratory properties in these tumor cells. As a result, such angiotropic melanoma cells may migrate along the abluminal vascular surface, demonstrating pericytic mimicry. Through these cellular interactions, melanoma cells may migrate toward secondary sites. C1 [Lugassy, Claire; Wadehra, Madhuri; Barnhill, Raymond L.] Univ Calif Los Angeles, Med Ctr, Jonsson Comprehens Canc Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90024 USA. [Peault, Bruno] Univ Edinburgh, Queens Med Res Inst, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Peault, Bruno] Univ Calif Los Angeles, Med Ctr, Orthopaed Hosp Res Ctr, Los Angeles, CA 90024 USA. [Kleinman, Hynda K.] NIDCR, NIH, Bethesda, MD USA. RP Barnhill, RL (reprint author), Univ Calif Los Angeles, Med Ctr, Jonsson Comprehens Canc Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90024 USA. EM RBarnhill@mednet.ucla.edu FU Medical Research Council [G1000816] NR 11 TC 11 Z9 11 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD SEP PY 2013 VL 26 IS 5 BP 746 EP 754 DI 10.1111/pcmr.12120 PG 9 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 204TG UT WOS:000323391700021 PM 23789776 ER PT J AU Stokes, W Srinivas, G McFarland, R Kulpa-Eddy, J Casey, W Walker, A Draayer, H Sebring, R Brown, K Balks, E Stirling, C Klaasen, E Hill, R Rippke, B Ruby, K Alt, D Mukhopadhyay, S Kojima, H Johnson, N Rinckel, L Doelling, V Jones, B AF Stokes, William Srinivas, Geetha McFarland, Richard Kulpa-Eddy, Jodie Casey, Warren Walker, Angela Draayer, Hans Sebring, Randy Brown, Karen Balks, Elisabeth Stirling, Catrina Klaasen, Eric Hill, Richard Rippke, Byron Ruby, Kevin Alt, David Mukhopadhyay, Suman Kojima, Hajime Johnson, Nelson Rinckel, Lori Doelling, Vivian Jones, Brett TI Report on the international workshop on alternative methods for Leptospira vaccine potency testing: State of the science and the way forward SO BIOLOGICALS LA English DT Article DE Leptospira vaccines; Alternative methods; Potency; Replacement; Refinement; Reduction ID RELATIVE POTENCY; LETHAL INFECTION; DISEASE; ASSAY; BUPRENORPHINE; INTERROGANS; BACTERINS; PATHOGEN; POMONA AB Routine potency testing of Leptospira vaccines is mostly conducted using a vaccination challenge test that involves large numbers of hamsters and unrelieved pain and distress. NICEATM, ICCVAM, and their international partners organized a workshop to review the state of the science of alternative methods that might replace, reduce, and refine the use of animals for veterinary Leptospira vaccine potency testing and to identify ways to advance improved alternative methods. Vaccine manufacturers were encouraged to initiate or continue product-specific validation using in vitro enzyme-linked immunosorbent assays as replacements for potency testing of four common Leptospira serogroups. Participants discussed the potential for eliminating the back-titration procedure in the hamster challenge assay, which could reduce animal use by 50% for each individual potency test. Further animal reduction may also be possible by using cryopreserved Leptospira stock to replace continual passaging through hamsters. Serology assays were identified as a way to further reduce and refine animal use but should be considered only after attempting in vitro assays. Workshop participants encouraged consideration of analgesics and use of earlier humane endpoints when the hamster vaccination challenge potency assay is used. International harmonization of alternative potency methods was recommended to avoid duplicative potency testing to meet regionally different requirements. C1 [Stokes, William; Casey, Warren] NIEHS, Natl Toxicol Program Interagcy Ctr Evaluat Altern, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Srinivas, Geetha; Walker, Angela; Hill, Richard; Rippke, Byron; Ruby, Kevin] USDA, Ctr Vet Biol, Ames, IA 50010 USA. [McFarland, Richard] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Kulpa-Eddy, Jodie] USDA, Anim & Plant Hlth Inspect Serv, Riverdale, MD 20737 USA. [Draayer, Hans] Gourdneck View Consulting LLC, Portage, MI 49002 USA. [Sebring, Randy] Colorado Serum Co, Denver, CO 80216 USA. [Brown, Karen] Pair ODocs Consultants, Parkville, MO 64152 USA. [Balks, Elisabeth] Paul Ehrlich Inst, D-63225 Langen, Germany. [Stirling, Catrina] Pfizer Ltd, Sandwich CT13 9NJ, Kent, England. [Klaasen, Eric] MSD Anim Hlth, NL-5830 AA Boxmeer, Netherlands. [Alt, David] USDA ARS, Ames, IA 50010 USA. [Mukhopadhyay, Suman] NIAID, Bethesda, MD 20892 USA. [Kojima, Hajime] Natl Inst Hlth Sci, Japanese Ctr Validat Alternat Methods, Setagaya Ku, Tokyo 1585801, Japan. [Johnson, Nelson; Rinckel, Lori; Doelling, Vivian; Jones, Brett] Integrated Lab Syst Inc, Morrisville, NC 27560 USA. RP Casey, W (reprint author), NIEHS, Natl Toxicol Program Interagcy Ctr Evaluat Altern, Div Natl Toxicol Program, NIH, POB 12233,MD K2-16, Res Triangle Pk, NC 27709 USA. EM warren.casey@nih.gov FU NICEATM; ICCVAM; EURL ECVAM; JaCVAM FX The authors extend their sincere appreciation to all participants in the international workshop for their contributions leading to the workshop conclusions and recommendations. The members of the Leptospira Workshop Organizing Committee, ICCVAM Interagency Biologics Working Group, and NICEATM staff are acknowledged for their contributions to the planning of the workshop, and all the invited experts are acknowledged for their presentations and contributions to breakout group discussions and workshop proceedings. Participating national/international validation organizations from the International Cooperation on Alternative Test Methods, including NICEATM, ICCVAM, EURL ECVAM, and JaCVAM, are also gratefully acknowledged for their scientific contributions and financial support. Finally, the authors gratefully acknowledge Dr. Raymond Tice and Dr. John Bucher from the National Institute of Environmental Health Sciences, National Institutes of Health, USA for their review of the manuscript. NR 62 TC 0 Z9 0 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 J9 BIOLOGICALS JI Biologicals PD SEP PY 2013 VL 41 IS 5 SI SI BP 279 EP 294 DI 10.1016/j.biologicals.2013.06.013 PG 16 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 231VU UT WOS:000325447300001 PM 23890729 ER PT J AU Qin, L Smith, BD Tsai, HL Yaghi, NK Neela, PH Moake, M Fu, J Kasamon, YL Prince, GT Goswami, M Rosner, GL Levitsky, HI Hourigan, CS AF Qin, L. Smith, B. D. Tsai, H-L Yaghi, N. K. Neela, P. H. Moake, M. Fu, J. Kasamon, Y. L. Prince, G. T. Goswami, M. Rosner, G. L. Levitsky, H. I. Hourigan, C. S. TI Induction of high-titer IgG antibodies against multiple leukemia-associated antigens in CML patients with clinical responses to K562/GVAX immunotherapy SO BLOOD CANCER JOURNAL LA English DT Article DE leukemia; chronic myeloid; cancer vaccines; immunotherapy; K562 cells ID CHRONIC MYELOID-LEUKEMIA; BONE-MARROW TRANSPLANTATION; CHRONIC MYELOGENOUS LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; DONOR LYMPHOCYTE INFUSION; CD8(+) T-CELLS; CELLULAR IMMUNOTHERAPY; CANCER-IMMUNOTHERAPY; PEPTIDE VACCINATION; IMMUNE-RESPONSES AB The ability to target myeloid leukemia with immunotherapy would represent a significant therapeutic advance. We report here immunological analysis of clinical trials of primary and secondary vaccination with K562/GM-CSF immunotherapy in adult chronic phase chronic myeloid leukemia patients (CML-CP) with suboptimal responses to imatinib mesylate. Using serological analysis of recombinant cDNA expression libraries of K562 with autologous vaccinated patient serum, we have identified 12 novel chronic myeloid leukemia-associated antigens (LAAs). We show that clinical responses following K562/GM-CSF vaccination are associated with induction of high-titer antibody responses to multiple LAAs. We observe markedly discordant patterns of baseline and induced antibody responses in these identically vaccinated patients. No single antigen was recognized in all responses to vaccination. We demonstrate that an additional 'booster' vaccination series can be given safely to those with inadequate responses to initial vaccination, and is associated with more frequent induction of IgG responses to antigens overexpressed in K562 vaccine compared with primary CML-CP. Finally, those with induced immune responses to the same LAAs often shared HLA subtypes and patients with clinical responses following vaccination recognized a partially shared but non-identical spectrum of antigens; both findings have potentially significant implications for cancer vaccine immunotherapy. C1 [Qin, L.; Smith, B. D.; Tsai, H-L; Yaghi, N. K.; Neela, P. H.; Moake, M.; Fu, J.; Kasamon, Y. L.; Prince, G. T.; Rosner, G. L.; Levitsky, H. I.; Hourigan, C. S.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Goswami, M.; Hourigan, C. S.] NHLBI, Myeloid Malignancies Sect, Hematol Branch, Bethesda, MD 20892 USA. [Levitsky, H. I.] Roche Glycart AG, Schlieren, Switzerland. RP Hourigan, CS (reprint author), NHLBI, Myeloid Malignancies Sect, Hematol Branch, Room 6C 103C,10 Ctr Dr, Bethesda, MD 20892 USA. EM hourigan@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU National Institutes of Health [5R01CA142620, 5T32AI007247, P30CA006973]; Intramural Research Program of the NIH, National Heart, Lung and Blood Institute; Samuel Smith Award for Leukemia Research FX We wish to thank Jerry Radich (Seattle), Nancy Hensel and A John Barrett (Bethesda) for the gift of CML samples and Mary S Leffell of the Clinical Immunogenetics Laboratory at the Johns Hopkins University School of Medicine for molecular HLA typing results. This research was supported by the National Institutes of Health grants 5R01CA142620, 5T32AI007247, P30CA006973 and the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. BDS and CSH were also supported in part by the Samuel Smith Award for Leukemia Research. NR 60 TC 9 Z9 9 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2044-5385 J9 BLOOD CANCER J JI Blood Cancer J. PD SEP PY 2013 VL 3 AR UNSP e145 DI 10.1038/bcj.2013.44 PG 11 WC Oncology SC Oncology GA 229PW UT WOS:000325280500006 PM 24013666 ER PT J AU Fann, DYW Lee, SY Manzanero, S Tang, SC Gelderblom, M Chunduri, P Bernreuther, C Glatzel, M Cheng, YL Thundyil, J Widiapradja, A Lok, KZ Foo, SL Wang, YC Li, YI Drummond, GR Basta, M Magnus, T Jo, DG Mattson, MP Sobey, CG Arumugam, TV AF Fann, D. Yang-Wei Lee, S-Y Manzanero, S. Tang, S-C Gelderblom, M. Chunduri, P. Bernreuther, C. Glatzel, M. Cheng, Y-L Thundyil, J. Widiapradja, A. Lok, K-Z Foo, S. L. Wang, Y-C Li, Y-I Drummond, G. R. Basta, M. Magnus, T. Jo, D-G Mattson, M. P. Sobey, C. G. Arumugam, T. V. TI Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke SO CELL DEATH & DISEASE LA English DT Article DE IVIg; ischemic stroke; inflammasome; cell death; caspase ID GLYCATION END-PRODUCTS; ANTHRAX LETHAL TOXIN; SPINAL-CORD-INJURY; CELL-DEATH; BRAIN-INJURY; CEREBRAL-ISCHEMIA; MOLECULAR PLATFORM; ACTIVATION; MECHANISMS; INHIBITION AB Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen-glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1 beta and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1 beta and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity. C1 [Fann, D. Yang-Wei; Lee, S-Y; Manzanero, S.; Chunduri, P.; Cheng, Y-L; Thundyil, J.; Widiapradja, A.; Lok, K-Z; Foo, S. L.; Arumugam, T. V.] Univ Queensland, Sch Biomed Sci, St Lucia, Qld, Australia. [Tang, S-C; Wang, Y-C; Li, Y-I] Natl Taiwan Univ Hosp, Stroke Ctr, Dept Neurol, Taipei, Taiwan. [Gelderblom, M.; Magnus, T.] Univ Clin Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [Bernreuther, C.; Glatzel, M.] Univ Clin Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany. [Drummond, G. R.; Sobey, C. G.] Monash Univ, Dept Pharmacol, Clayton, Vic 3168, Australia. [Basta, M.] Biovisions Inc, Potomac, MD USA. [Jo, D-G; Arumugam, T. V.] Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea. [Mattson, M. P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Arumugam, T. V.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117595, Singapore. RP Arumugam, TV (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, MD9, Singapore 117595, Singapore. EM chris.sobey@monash.edu; phstva@nus.edu.sg RI Sobey, Christopher/A-2786-2008; Chunduri, Prasad/J-2141-2014; Glatzel, Markus/G-3356-2011; Arumugam, Thiruma/B-4898-2011; OI Glatzel, Markus/0000-0002-7720-8817; Tang, Sung-Chun/0000-0003-3731-5973; Basta, Milan/0000-0001-5958-9241; Drummond, Grant/0000-0001-8556-9738; Chunduri, Prasad/0000-0001-7297-7580; LI, YU-I/0000-0002-9888-1541; Manzanero, Silvia/0000-0002-5294-7082 FU The ARC Future Fellowship [FT100100427]; Academia Sinica, Biosignature grant [BM102021169]; National Institute on Aging Intramural Research Program FX The ARC Future Fellowship (FT100100427) awarded to TVA, Academia Sinica, Biosignature grant (BM102021169) to SCT and the National Institute on Aging Intramural Research Program supported this work. CGS and GRD are Senior Research Fellows of the National Health and Medical Research Council of Australia. NR 53 TC 70 Z9 72 U1 7 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD SEP PY 2013 VL 4 AR e790 DI 10.1038/cddis.2013.326 PG 10 WC Cell Biology SC Cell Biology GA 230VC UT WOS:000325370300007 PM 24008734 ER PT J AU Moss, B AF Moss, Bernard TI Poxvirus DNA Replication SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID VACCINIA VIRUS-DNA; TEMPERATURE-SENSITIVE MUTANTS; HOLLIDAY JUNCTION RESOLVASES; THREONINE PROTEIN-KINASE; I3L GENE-PRODUCT; VIRAL-DNA; CYTOPLASMIC FACTORIES; POLYMERASE GENE; INFECTED CELLS; A20R PROTEIN AB Poxviruses are large, enveloped viruses that replicate in the cytoplasm and encode proteins for DNA replication and gene expression. Hairpin ends link the two strands of the linear, double-stranded DNA genome. Viral proteins involved in DNA synthesis include a 117-kDa polymerase, a helicase-primase, a uracil DNA glycosylase, a processivity factor, a single-stranded DNA-binding protein, a protein kinase, and a DNA ligase. A viral FEN1 family protein participates in double-strand break repair. The DNA is replicated as long concatemers that are resolved by a viral Holliday junction endonuclease. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX I thank George Katsafanas for help with the figures. The review was written with the support of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 109 TC 15 Z9 15 U1 3 U2 13 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD SEP PY 2013 VL 5 IS 9 AR a010199 DI 10.1101/cshperspect.a010199 PG 12 WC Cell Biology SC Cell Biology GA 228EO UT WOS:000325168700006 ER PT J AU Mueller, F Stasevich, TJ Mazza, D McNally, JG AF Mueller, Florian Stasevich, Timothy J. Mazza, Davide McNally, James G. TI Quantifying transcription factor kinetics: At work or at play? SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Competition-ChIP; kinetic modeling; live-cell imaging; non-specific binding; specific binding; transcription; transcription factor dynamics ID FLUORESCENCE CORRELATION SPECTROSCOPY; SINGLE-MOLECULE LEVEL; PROTEIN-DNA INTERACTIONS; TATA-BINDING PROTEIN; LIVING CELLS; GENE-EXPRESSION; IN-VIVO; GLUCOCORTICOID-RECEPTOR; ANOMALOUS DIFFUSION; LIVE CELLS AB Transcription factors (TFs) interact dynamically in vivo with chromatin binding sites. Here we summarize and compare the four different techniques that are currently used to measure these kinetics in live cells, namely fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), single molecule tracking (SMT) and competition ChIP (CC). We highlight the principles underlying each of these approaches as well as their advantages and disadvantages. A comparison of data from each of these techniques raises an important question: do measured transcription kinetics reflect biologically functional interactions at specific sites (i.e. working TFs) or do they reflect non-specific interactions (i.e. playing TFs)? To help resolve this dilemma we discuss five key unresolved biological questions related to the functionality of transient and prolonged binding events at both specific promoter response elements as well as non-specific sites. In support of functionality, we review data suggesting that TF residence times are tightly regulated, and that this regulation modulates transcriptional output at single genes. We argue that in addition to this site-specific regulatory role, TF residence times also determine the fraction of promoter targets occupied within a cell thereby impacting the functional status of cellular gene networks. Thus, TF residence times are key parameters that could influence transcription in multiple ways. C1 [Mueller, Florian] Inst Pasteur, CNRS, Computat Imaging & Modeling Unit, Paris, France. [Mueller, Florian] Ecole Normale Super, Inst Biol, F-75231 Paris, France. [Stasevich, Timothy J.] Osaka Univ, Grad Sch Frontier Biosci, Osaka, Japan. [Mazza, Davide] Univ Milan, Osped San Raffaele, Ist Sci, Ctr Imaging Sperimentale, I-20127 Milan, Italy. [Mazza, Davide] Univ Vita Salute San Raffaele, Milan, Italy. [McNally, James G.] NCI, Fluorescence Imaging Grp, NIH, Bethesda, MD 20892 USA. RP McNally, JG (reprint author), NCI, Fluorescence Imaging Grp, NIH, Bethesda, MD 20892 USA. EM mcnallyj@exchange.nih.gov RI Mueller, Florian/C-9075-2012; Mazza, Davide/R-5340-2016 OI Mueller, Florian/0000-0002-9622-4396; Mazza, Davide/0000-0003-2776-4142 FU Fondation pour la Recherche Medicale en France (FRM); Japan Society for the Promotion of Science (JSPS); Marie Curie international incoming fellowship [GA: 27432]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX FM was supported by the Fondation pour la Recherche Medicale en France (FRM). TS was supported by the Japan Society for the Promotion of Science (JSPS). DM was supported by Marie Curie international incoming fellowship (GA: 27432). JM was supported by the intramural program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 138 TC 27 Z9 27 U1 5 U2 44 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD SEP-OCT PY 2013 VL 48 IS 5 BP 492 EP 514 DI 10.3109/10409238.2013.833891 PG 23 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 229PY UT WOS:000325280700006 PM 24025032 ER PT J AU Wang, MY Wang, HJH Lakatta, EG AF Wang, Mingyi Wang, Hejia H. Lakatta, Edward G. TI Milk Fat Globule Epidermal Growth Factor VIII Signaling in Arterial Wall Remodeling SO CURRENT VASCULAR PHARMACOLOGY LA English DT Article DE Milk fat globule epidermal growth factor VIII; arterial remodeling; intervention ID SMOOTH-MUSCLE-CELLS; COMPARATIVE PROTEOMIC ANALYSIS; CIRCULATING MICROPARTICLES; METABOLIC SYNDROME; ENDOTHELIAL-CELLS; ELDERLY-PATIENTS; APOPTOTIC CELLS; FACTOR RECEPTOR; MAJOR PROTEINS; MOUSE MODEL AB Arterial inflammation and remodeling, important sequellae of advancing age, are linked to the pathogenesis of age-associated arterial diseases e.g. hypertension, atherosclerosis, and metabolic disorders. Recently, high-throughput proteomic screening has identified milk fat globule epidermal growth factor VIII (MFG-E8) as a novel local biomarker for aging arterial walls. Additional studies have shown that MFG-E8 is also an element of the arterial inflammatory signaling network. The transcription, translation, and signaling levels of MFG-E8 are increased in aged, atherosclerotic, hypertensive, and diabetic arterial walls in vivo as well as activated vascular smooth muscle cells (VSMC) and a subset of macrophages in vitro. In VSMC, MFG-E8 increases proliferation and invasion as well as the secretion of inflammatory molecules. In endothelial cells (EC), MFG-E8 facilitates apoptosis. In addition, MFG-E8 has been found to be an essential component of the endothelial-derived microparticles that relay biosignals and modulate arterial wall phenotypes. This review mainly focuses upon the landscape of MFG-E8 expression and signaling in adverse arterial remodeling. Recent discoveries have suggested that MFG-E8 associated interventions are novel approaches for the retardation of the enhanced rates of VSMC proliferation and EC apoptosis that accompany arterial wall inflammation and remodeling during aging and age-associated arterial disease. C1 [Wang, Mingyi; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Wang, Hejia H.] Univ Penn, Sch Arts & Sci, Philadelphia, PA 19104 USA. RP Wang, MY (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mingyiw@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 82 TC 7 Z9 9 U1 0 U2 9 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1611 J9 CURR VASC PHARMACOL JI Current Vascular Pharmacology PD SEP PY 2013 VL 11 IS 5 BP 768 EP 776 PG 9 WC Pharmacology & Pharmacy; Peripheral Vascular Disease SC Pharmacology & Pharmacy; Cardiovascular System & Cardiology GA 224EJ UT WOS:000324865000014 PM 22272902 ER PT J AU Cupul-Uicab, LA Klebanoff, MA Brock, JW Longnecker, MP AF Cupul-Uicab, Lea A. Klebanoff, Mark A. Brock, John W. Longnecker, Matthew P. TI Prenatal Exposure to Persistent Organochlorines and Childhood Obesity in the US Collaborative Perinatal Project SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BODY-MASS INDEX; ENDOCRINE-DISRUPTING CHEMICALS; POLYCHLORINATED-BIPHENYLS; CAUSAL-DIAGRAMS; IN-UTERO; GROWTH; OVERWEIGHT; CHILDREN; BIRTH; RISK AB Background: In some previous studies, prenatal exposure to persistent organochlorines such as 1,1,-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p' -DDE), polychlorinated biphenyls (PCBs), and hexachlorobenzene (HCB) has been associated with higher body mass index (BMI) in children. Objective: Our goal was to evaluate the association of maternal serum levels of beta-hexachlorocyclohexane (beta-HCH), p,p' -DDE, dichlorodiphenyltrichloroethane (p,p' -DDT), dieldrin, heptachlor epoxide, HCB, trans-nonachlor, oxychlordane, and PCBs with offspring obesity during childhood. Methods: The analysis was based on a subsample of 1,915 children followed until 7 years of age as part of the U.S. Collaborative Perinatal Project (CPP). The CPP enrolled pregnant women in 1959-1965; exposure levels were measured in third-trimester maternal serum that was collected before these organochlorines were banned in the United States. Childhood overweight and obesity were defined using age-and sex-specific cut points for BMI as recommended by the International Obesity Task Force. Results: Adjusted results did not show clear evidence for an association between organochlorine exposure and obesity; however, a suggestive finding emerged for dieldrin. Compared with those in the lowest quintile (dieldrin, <0.57 mu g/L), odds of obesity were 3.6 (95% CI: 1.3, 10.5) for the fourth and 2.3 (95% CI: 0.8, 7.1) for the highest quintile. Overweight and BMI were unrelated to organochlorine exposure. Conclusions: In this population with relatively high levels of exposure to organochlorines, no clear associations with obesity or BMI emerged. C1 [Cupul-Uicab, Lea A.; Longnecker, Matthew P.] Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Epidemiol Branch, Res Triangle Pk, NC USA. [Cupul-Uicab, Lea A.] Natl Inst Publ Hlth, Ctr Populat Hlth Res, Cuernavaca 62100, Morelos, Mexico. [Klebanoff, Mark A.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Klebanoff, Mark A.] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Brock, John W.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. RP Cupul-Uicab, LA (reprint author), Natl Inst Publ Hlth, Ctr Populat Hlth Res, Ave Univ 655, Cuernavaca 62100, Morelos, Mexico. EM lea.cupul@insp.mx RI CUPUL UICAB, LEA/C-8699-2014; OI CUPUL UICAB, LEA/0000-0001-6190-4474; Longnecker, Matthew/0000-0001-6073-5322 FU National Institute of Environmental Health Sciences; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 41 TC 19 Z9 19 U1 1 U2 12 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2013 VL 121 IS 9 BP 1103 EP 1109 DI 10.1289/ehp.1205901 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227XS UT WOS:000325149600027 PM 23799652 ER PT J AU Schmidt, LS AF Schmidt, Laura S. TI Birt-Hogg-Dube syndrome: from gene discovery to molecularly targeted therapies SO FAMILIAL CANCER LA English DT Article DE Birt-Hogg-Dube syndrome; BHD; FLCN; Folliculin; FNIP1; FNIP2; Tumor suppressor; Inherited kidney cancer; Fibrofolliculoma ID ACTIVATED PROTEIN-KINASE; RENAL TUMORS; BHD GENE; SPONTANEOUS PNEUMOTHORAX; INTESTINAL POLYPOSIS; POLYCYSTIC KIDNEYS; SUPPRESSOR GENE; MTOR ACTIVATION; CELL-LINE; FLCN AB Since the hallmark dermatologic features of Birt-Hogg-Dub, (BHD) syndrome were first described by three Canadian physicians in 1977, the clinical manifestations of BHD have been expanded to include hamartomas of the hair follicle, lung cysts, increased risk for spontaneous pneumothorax and kidney neoplasia. Twenty-five years later the causative gene FLCN was identified, and the mutation spectrum has now been defined to include mainly protein truncating mutations, but also rare missense mutations and large gene deletions/duplication. Second "hit" FLCN mutations in BHD kidney tumors and loss of tumorigenic potential of the FLCN-null UOK257 tumor cell line when FLCN is re-expressed underscore a tumor suppressor role for FLCN. The identification of novel FLCN interacting proteins FNIP1 and FNIP2/L and their interaction with 5'-AMP activated protein kinase (AMPK) has provided a link between FLCN and the AMPK-mTOR axis and suggested molecular targets for therapeutic intervention to treat BHD kidney cancer and fibrofolliculomas. The generation of FLCN-null cell lines and in vivo animal models in which FLCN (or FNIP1) has been inactivated have provided critical reagents to facilitate mechanistic studies of FLCN function. Research efforts utilizing these critical FLCN-deficient cell lines and mice have begun to uncover important signaling pathways in which FLCN and its protein partners may play a role, including TGF-beta signaling, TFE3 transcriptional regulation, PGC1-alpha driven mitochondrial biogenesis, apoptotic response to cell stress, and vesicular transport. As the mechanisms by which FLCN inactivation leads to BHD manifestations are clarified, we can begin to develop therapeutic agents that target the pathways dysregulated in FLCN-deficient fibrofolliculomas and kidney tumors, providing improved prognosis and quality of life for BHD patients. C1 [Schmidt, Laura S.] SAIC Frederick Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Schmidt, Laura S.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Schmidt, LS (reprint author), NCI, Urol Oncol Branch, NIH, Bldg 10 CRC Rm 1-3961,10 Ctr Dr MSC 1107, Bethesda, MD 20892 USA. EM schmidtl@mail.nih.gov FU NIH, Frederick National Lab, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, 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, not does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. NR 45 TC 16 Z9 16 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD SEP PY 2013 VL 12 IS 3 SI SI BP 357 EP 364 DI 10.1007/s10689-012-9574-y PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 231OJ UT WOS:000325426200002 PM 23108783 ER PT J AU Stamatakis, L Metwalli, AR Middelton, LA Linehan, WM AF Stamatakis, Lambros Metwalli, Adam R. Middelton, Lindsay A. Linehan, W. Marston TI Diagnosis and management of BHD-associated kidney cancer SO FAMILIAL CANCER LA English DT Article DE Birt-Hogg-Dube; Clinical; Management; Syndrome; Kidney cancer; BHD; Renal cell carcinoma ID HOGG-DUBE-SYNDROME; RENAL TUMORS; SPONTANEOUS PNEUMOTHORAX; THERMAL ABLATION; GENE; MUTATIONS; IDENTIFICATION; NEOPLASMS; FAMILIES; PROTEIN AB In addition to the associated cutaneous and pulmonary manifestations, individuals with the Birt-Hogg-Dub, (BHD) syndrome have an increased risk of developing kidney cancer, which is often bilateral and multifocal. The risk of developing a renal tumor in this population does not decrease with age and therefore warrants a lifelong screening approach. We recommend abdominal imaging every 36 months in individuals without renal lesions at initial screening. Once renal tumors are identified, they should be followed with interval imaging studies until the largest tumor reaches 3 cm in maximal diameter, at which point nephron-sparing surgery should be ideally pursued. While the histology of renal tumors can vary in the BHD syndrome, most tumors possess a relatively indolent natural history and do not require adjuvant therapy if resected when localized to the kidney. With this approach, the vast majority of patients will achieve a curative oncologic outcome and avoid the medical sequelae of chronic renal insufficiency that could otherwise result from total nephrectomy. C1 [Stamatakis, Lambros; Metwalli, Adam R.; Middelton, Lindsay A.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 10 Ctr Dr MSC 1107,CRC Room 1W-5940, Bethesda, MD 20892 USA. EM WML@nih.gov 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. The authors wish to thank Georgia Shaw (editorial and graphics support), Dr. Maria J. Merino (for providing the BHD kidney cancer histology images), and Rabindra Gautam (for providing the radiologic images). NR 22 TC 17 Z9 17 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD SEP PY 2013 VL 12 IS 3 SI SI BP 397 EP 402 DI 10.1007/s10689-013-9657-4 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 231OJ UT WOS:000325426200007 PM 23703644 ER PT J AU Middelton, LA AF Middelton, Lindsay A. TI Birt-Hogg-Dube: beyond the clinical manifestations (vol 12, pg 97, 2013) SO FAMILIAL CANCER LA English DT Correction C1 NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Middelton, LA (reprint author), NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. EM middeltl@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD SEP PY 2013 VL 12 IS 3 SI SI BP 403 EP 403 DI 10.1007/s10689-013-9663-6 PG 1 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 231OJ UT WOS:000325426200008 ER PT J AU Thambisetty, M Metter, J Yang, A Dolan, H Marano, C Zonderman, AB Troncoso, JC Zhou, Y Wong, DF Ferrucci, L Egan, J Resnick, SM O'Brien, RJ AF Thambisetty, Madhav Metter, Jeffrey Yang, An Dolan, Hillary Marano, Christopher Zonderman, Alan B. Troncoso, Juan C. Zhou, Yun Wong, Dean F. Ferrucci, Luigi Egan, Josephine Resnick, Susan M. O'Brien, Richard J. TI Glucose Intolerance, Insulin Resistance, and Pathological Features of Alzheimer Disease in the Baltimore Longitudinal Study of Aging SO JAMA NEUROLOGY LA English DT Article ID COGNITIVE DECLINE; DIABETES-MELLITUS; TOLERANCE TEST; RISK; DEMENTIA; COMMUNITY; BRAIN; IMPAIRMENT; ROTTERDAM; HISAYAMA AB IMPORTANCE Peripheral glucose homeostasis has been implicated in the pathogenesis of Alzheimer disease (AD). The relationship among diabetes mellitus, insulin, and AD is an important area of investigation. However, whether cognitive impairment seen in those with diabetes is mediated by excess pathological features of AD or other related abnormalities, such as vascular disease, remains unclear. OBJECTIVE To investigate the association between serial measures of glucose intolerance and insulin resistance and in vivo brain beta-amyloid burden, measured with carbon 11-labeled Pittsburgh Compound B (11C-PiB), and AD pathology at autopsy. DESIGN Scores calculated from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and Braak criteria were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance in 197 participants who underwent autopsy after death and who had undergone 2 or more oral glucose tolerance tests (OGTT) using grouped analyses and a continuous mixed-models analysis. The same measures of glucose intolerance and insulin resistance were also correlated with brain 11C-PiB retention in an additional 53 living subjects from the Baltimore Longitudinal Study of Aging neuroimaging study. SETTING Prospective, serially assessed cohort of community-dwelling subjects. PARTICIPANTS Cohort 1 consisted of 197 participants enrolled in the Baltimore Longitudinal Study of Aging who had 2 or more OGTTs during life and a complete brain autopsy after death. Cohort 2 consisted of 53 living subjects who had 2 or more OGTTs and underwent brain 11C-PiB positron emission tomography. EXPOSURES Autopsy and 11C-PiB positron emission tomography. MAIN OUTCOMES AND MEASURES The correlation of brain markers of AD, including CERAD score, Braak score, and 11C-PiB retention, with serum markers of glucose homeostasis using grouped and continuous mixed-models analyses. RESULTS We found no significant correlations between measures of brain AD pathology or 11C-PiB beta-amyloid load and glucose intolerance or insulin resistance in subjects who had a mean (SD) of 6.4 (3.2) OGTTs during 22.1 (8.0) years of follow-up. Thirty subjects with frank diabetes mellitus who received medications also had AD pathology scores that were similar to those of the cohort as a whole. CONCLUSIONS AND RELEVANCE In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis are not associated with AD pathology and likely play little role in AD pathogenesis. Long-term therapeutic trials are important to elucidate this issue. C1 [Thambisetty, Madhav; Metter, Jeffrey; Yang, An; Zonderman, Alan B.; Ferrucci, Luigi; Egan, Josephine; Resnick, Susan M.] NIA, Res Program, Baltimore, MD 21224 USA. [Dolan, Hillary; O'Brien, Richard J.] Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. [Marano, Christopher] Johns Hopkins Bayview Med Ctr, Dept Psychiat, Baltimore, MD 21224 USA. [Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Zhou, Yun; Wong, Dean F.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP O'Brien, RJ (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, Mason Lord Ctr Tower,Ste 5100, Baltimore, MD 21224 USA. EM robrien@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging (NIA) [P50 AG05146, U01 AG033655]; Burroughs Wellcome Fund for Translational Research; Intramural Research Program, NIA, National Institutes of Health FX This study was supported by grants P50 AG05146 and U01 AG033655 from the National Institute on Aging (NIA); by the Burroughs Wellcome Fund for Translational Research; and by the Intramural Research Program, NIA, National Institutes of Health. NR 35 TC 44 Z9 45 U1 2 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6149 J9 JAMA NEUROL JI JAMA Neurol. PD SEP PY 2013 VL 70 IS 9 BP 1167 EP 1172 DI 10.1001/jamaneurol.2013.284 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 228TB UT WOS:000325211600013 PM 23897112 ER PT J AU Chattaraj, P Reimold, FR Muskett, JA Shmukler, BE Chien, WW Madeo, AC Pryor, SP Zalewski, CK Butman, JA Brewer, CC Kenna, MA Alper, SL Griffith, AJ AF Chattaraj, Parna Reimold, Fabian R. Muskett, Julie A. Shmukler, Boris E. Chien, Wade W. Madeo, Anne C. Pryor, Shannon P. Zalewski, Christopher K. Butman, John A. Brewer, Carmen C. Kenna, Margaret A. Alper, Seth L. Griffith, Andrew J. TI Use of SLC26A4 Mutation Testing for Unilateral Enlargement of the Vestibular Aqueduct SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID GENOTYPE-PHENOTYPE CORRELATION; NONSYNDROMIC HEARING-LOSS; PENDRED-SYNDROME; ALLELIC VARIANTS; GENE; DEAFNESS; DOMAIN; EVA; PDS AB IMPORTANCE Approximately one-half of all subjects with unilateral or bilateral hearing loss with enlargement of the vestibular aqueduct (EVA) will have SLC26A4 gene mutations. The number (0, 1, or 2) of mutant alleles of SLC26A4 detected in an individual subject with EVA is each associated with a distinct combination of diagnostic and prognostic information as well as probability of recurrence of EVA in siblings. OBJECTIVE To evaluate the results of SLC26A4 mutation testing in subjects with unilateral EVA. (The study objective was formulated before data were collected.) DESIGN Prospective cross-sectional study of cohort ascertained between 1998 and 2012. SETTING National Institutes of Health Clinical Center, a federal biomedical research facility. PARTICIPANTS Twenty-four subjects (10 males, 14 females) with unilateral EVA, defined as a midpoint diameter greater than 1.5 mm, who were referred or self-referred to participate in a study about the clinical and molecular analysis of EVA. Twenty-one (87.5%) of 24 subjects were white. Mean age was 10.3 years (age range, 5-39 years). INTERVENTION SLC26A4 mutation analysis. MAIN OUTCOMES AND MEASURES Audiometric results, the presence or absence of EVA, and the number of mutant alleles of SLC26A4. RESULTS Approximately 8.3% of the subjects with unilateral EVA had 2 mutant SLC26A4 alleles, 16.7% had 1 mutant allele, and 75.0% had 0 mutant alleles. CONCLUSIONS AND RELEVANCE Unilateral EVA can be associated with all possible SLC26A4 genotype results. The distinct combination of prognoses and recurrence probability associated with each genotype supports the clinical use of testing for SLC26A4 mutations in subjects with unilateral EVA. C1 [Chattaraj, Parna; Muskett, Julie A.; Madeo, Anne C.; Pryor, Shannon P.; Zalewski, Christopher K.; Brewer, Carmen C.; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. [Reimold, Fabian R.; Shmukler, Boris E.; Alper, Seth L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA USA. [Chien, Wade W.] Natl Inst Deafness & Other Commun Disorders, Off Clin Director, NIH, Bethesda, MD USA. [Butman, John A.] NIH, Radiol & Imaging Sci Clin Ctr, Bethesda, MD 20892 USA. [Kenna, Margaret A.] Boston Childrens Hosp, Dept Otolaryngol, Boston, MA USA. [Kenna, Margaret A.] Boston Childrens Hosp, Dept Commun Enhancement, Boston, MA USA. [Kenna, Margaret A.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Ct,Room 2B28, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU National Institutes of Health [Z01-DC-000082, Z01-DC-000060, Z01-DC-000064, R01 DK43495, R30 DK34854]; Robert Bosch Foundation FX This study was supported by intramural research funds Z01-DC-000082 (Dr Chien) and Z01-DC-000060 and Z01-DC-000064 (Dr Griffith), by grants R01 DK43495 and R30 DK34854 (The Harvard Digestive Diseases Center) (Dr Alper) from the National Institutes of Health, and by the Robert Bosch Foundation (Dr Reinmold). NR 20 TC 7 Z9 7 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6181 J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD SEP PY 2013 VL 139 IS 9 BP 907 EP 913 DI 10.1001/jamaoto.2013.4185 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 228IZ UT WOS:000325180700005 PM 24051746 ER PT J AU Blasi, G De Virgilio, C Papazacharias, A Taurisano, P Gelao, B Fazio, L Ursini, G Sinibaldi, L Andriola, I Masellis, R Romano, R Rampino, A Di Giorgio, A Lo Bianco, L Caforio, G Piva, F Popolizio, T Bellantuono, C Todarello, O Kleinman, JE Gadaleta, G Weinberger, DR Bertolino, A AF Blasi, Giuseppe De Virgilio, Caterina Papazacharias, Apostolos Taurisano, Paolo Gelao, Barbara Fazio, Leonardo Ursini, Gianluca Sinibaldi, Lorenzo Andriola, Ileana Masellis, Rita Romano, Raffaella Rampino, Antonio Di Giorgio, Annabella Lo Bianco, Luciana Caforio, Grazia Piva, Francesco Popolizio, Teresa Bellantuono, Cesario Todarello, Orlando Kleinman, Joel E. Gadaleta, Gemma Weinberger, Daniel R. Bertolino, Alessandro TI Converging Evidence for the Association of Functional Genetic Variation in the Serotonin Receptor 2a Gene With Prefrontal Function and Olanzapine Treatment SO JAMA PSYCHIATRY LA English DT Article ID ATYPICAL ANTIPSYCHOTIC-DRUGS; WORKING-MEMORY PERFORMANCE; AMINO-ACID SUBSTITUTIONS; 5-HT2A RECEPTOR; ATTENTIONAL CONTROL; CLINICAL-RESPONSE; HIS452TYR POLYMORPHISM; PSYCHIATRIC-DISORDERS; COGNITIVE IMPAIRMENTS; VAL(158)MET GENOTYPE AB IMPORTANCE Serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with physiologic as well as behavioral effects. OBJECTIVE To use a hierarchical approach to determine the functional effects of this single-nucleotide polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with genetic risk for schizophrenia, and on treatment with olanzapine. DESIGN In silico predictions, in vitro, and case-control investigations. SETTING Academic and clinical facilities. PARTICIPANTS The postmortem study included 112 brains from healthy individuals; the in vivo investigation included a total sample of 371 healthy individuals and patients with schizophrenia. EXPOSURES Patients received olanzapine monotherapy for 8 weeks. MAIN OUTCOMES AND MEASURES In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine treatment in patients with schizophrenia. RESULTS Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro, inefficient prefrontal blood oxygen level-dependent functional magnetic resonance imaging response during working memory and attentional control processing, and impaired working memory and attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine treatment. CONCLUSIONS AND RELEVANCE Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment with olanzapine. C1 [Blasi, Giuseppe; Papazacharias, Apostolos; Taurisano, Paolo; Gelao, Barbara; Fazio, Leonardo; Ursini, Gianluca; Andriola, Ileana; Masellis, Rita; Romano, Raffaella; Rampino, Antonio; Lo Bianco, Luciana; Caforio, Grazia; Bertolino, Alessandro] Aldo Moro Univ, Grp Psychiat Neurosci, Dept Neurosci & Sense Organs, Bari, Italy. [De Virgilio, Caterina; Gadaleta, Gemma] Aldo Moro Univ, Dept Biochem & Mol Biol Ernesto Quagliariello, Bari, Italy. [Sinibaldi, Lorenzo; Di Giorgio, Annabella; Popolizio, Teresa] Ist Ricovero & Cura Carattere Sci Casa Sollievo, San Giovanni Rotondo, Italy. [Lo Bianco, Luciana; Bellantuono, Cesario] Polytech Univ Marche, United Hosp Ancona, Psychiat Unit, Dept Mental Hlth, Ancona, Italy. [Piva, Francesco] Polytech Univ Marche, Dept Biochem Biol & Genet, Ancona, Italy. [Todarello, Orlando] Aldo Moro Univ, Dept Neurosci & Sense Organs, Bari, Italy. [Kleinman, Joel E.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD USA. RP Bertolino, A (reprint author), Univ Bari Aldo Moro, Dipartimento Neurosci & Organi Senso, Piazza Giulio Cesare 9, I-70124 Bari, Italy. EM alessandro.bertolino@uniba.it RI Rampino, Antonio/Q-4465-2016; Di Giorgio, Annabella /D-7353-2017; OI Rampino, Antonio/0000-0002-9654-3266; Di Giorgio, Annabella /0000-0001-7876-3495; Papazacharias, Apostolos/0000-0001-5470-1601; PIVA, Francesco/0000-0003-1850-2482 FU Brain and Behavior Research Foundation FX This study was supported in part by a National Alliance for Research on Schizophrenia and Depression (now Brain and Behavior Research Foundation) Young Investigator Award to Dr Blasi. NR 71 TC 18 Z9 19 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-622X J9 JAMA PSYCHIAT JI JAMA Psychiatry PD SEP PY 2013 VL 70 IS 9 BP 921 EP 930 DI 10.1001/jamapsychiatry.2013.1378 PG 10 WC Psychiatry SC Psychiatry GA 228JN UT WOS:000325182200007 PM 23842608 ER PT J AU Seaquist, ER Miller, ME Fonseca, V Ismail-Beigi, F Launer, LJ Punthakee, Z Sood, A AF Seaquist, Elizabeth R. Miller, Michael E. Fonseca, Vivian Ismail-Beigi, Faramarz Launer, Lenore J. Punthakee, Zubin Sood, Ajay TI Effect of thiazolidinediones and insulin on cognitive outcomes in ACCORD-MIND SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Thiazolidinediones; Insulin; Diabetes; Cognition ID ROSIGLITAZONE; DISEASE; ASSOCIATION; IMPAIRMENT; MORTALITY; ADULTS; RISK AB Objective: To examine the relationship of cognitive performance to exposure to insulin (INS) and thiazolidinediones (TZD) in the ACCORD-MIND cohort. Methods: Participants (55-80 years) with type 2 diabetes (T2D), hemoglobin A1c (HbA1c) > 7.5% (> 58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive control targeting HbA1c to < 6.0% (42 mmol/mol) or a standard strategy targeting HbA1c to 7.0%-7.9% (53-63 mmol/mol). The Digit Symbol Substitution Test (DSST) was assessed at baseline and at 20 and 40 months. Exposure to INS was calculated as average daily dose/kg of body weight; exposure to rosiglitazone (ROS) was calculated as days of ROS prescription in the intervals preceding the 20- and 40-month DSSTs. Results: At baseline, INS use was associated with reduced DSST performance, but not after controlling for comorbidities and lab values. There was no relationship between use of a TZID and DSST performance on at baseline. ROS but not INS exposure was associated with greater decline in DSST performance over 40 months in subjects randomized to the intensive but not the standard group. Conclusions: Exposure to a TZD may increase cognitive decline in some patients with T2D. However, these results may be confounded by unexplained differences between participants. (C) 2013 Elsevier Inc. All rights reserved. C1 [Seaquist, Elizabeth R.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Miller, Michael E.] Wake Forest Univ, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Fonseca, Vivian] Tulane Univ, Dept Med, Endocrinol Sect, New Orleans, LA 70118 USA. [Ismail-Beigi, Faramarz; Sood, Ajay] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Ismail-Beigi, Faramarz; Sood, Ajay] Cleveland VA Med Ctr, Cleveland, OH USA. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Punthakee, Zubin] McMaster Univ, Dept Med, Hamilton, ON, Canada. RP Seaquist, ER (reprint author), Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA. EM seaqu001@umn.edu FU National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging, and the National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers FX This work was supported by Grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough. NR 17 TC 12 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD SEP-OCT PY 2013 VL 27 IS 5 BP 485 EP 491 DI 10.1016/j.jdiacomp.2013.03.005 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 229WX UT WOS:000325299700014 PM 23680059 ER PT J AU Hsu, C Abad, JD Morgan, RA AF Hsu, Cary Abad, John D. Morgan, Richard A. TI Characterization of human T lymphocytes engineered to express interleukin-15 and herpes simplex virus-thymidine kinase SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Human; T cells; Retroviral vector; Gene therapy; Cytokine; Cancer immunotherapy; Suicide gene ID CELL-TRANSFER THERAPY; METASTATIC MELANOMA; ADOPTIVE IMMUNOTHERAPY; SUICIDE-GENE; IL-15 GENE; CANCER; CYTOKINE; LEUKEMIA; DISEASE; BIOLOGY AB Introduction: Preclinical studies have demonstrated that tumor-reactive T cells expressing the interleukin (IL)-15 transgene had enhanced activity. Gene therapy strategies using IL-15 should include a safety mechanism in anticipation of possible adverse effects because IL-15 overexpression has been implicated in autoimmune disorders and may be involved in the pathogenesis of some leukemias. We developed a retroviral vector carrying both IL-15 and the herpes simplex virus-thymidine kinase (HSV-TK) suicide gene and characterized its application in the transduction of human T lymphocytes. Methods: A retroviral vector carrying IL-15 and HSV-TK genes was optimized for the transduction of human T lymphocytes. IL-15 production was measured by enzyme-linked immunosorbent assay. Thymidine incorporation and cell viability assays were used to assess the efficacy of the HSV-TK suicide gene. Genetically modified tumor-infiltrating lymphocytes (TILs) were assayed for survival after withdrawal from exogenous IL-2. The activity and specificity of retrovirally transduced TILs were assessed using tumor coculture assays. Results: Human T cells transduced with the IL-15 HSV-TK vector exhibited thymidine uptake in the absence of exogenous cytokine support and survived in culture for up to 80 d without IL-2. IL-15 HSV-TK-transduced T cells were efficiently killed by ganciclovir at concentrations as low as 0.1 mu M. TILs transduced with the IL-15 HSV-TK vector retained specific recognition of HLA-A2+, MART1+ melanomas, even after withdrawal of IL-2. Conclusions: Human T lymphocytes genetically modified with the IL-15 HSV-TK retroviral vector retained the ability to recognize tumor antigen while gaining the ability to secrete IL-15 and prolong their own survival. IL-15 HSV-TK-transduced T cells expressed HSV-TK and could be efficiently eliminated by ganciclovir. Published by Elsevier Inc. C1 [Hsu, Cary] Univ Calif Los Angeles, David Geffen Sch Med, Div Surg Oncol, Dept Gen Surg, Los Angeles, CA 90095 USA. [Abad, John D.] Indiana Univ Hlth Goshen Ctr Canc Care, Dept Surg, Div Surg Oncol, Goshen, IN USA. [Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hsu, C (reprint author), Univ Calif Los Angeles, Dept Gen Surg, Div Surg Oncol, David Geffen Sch Med, 1304 15th St,Suite 102, Santa Monica, CA 90404 USA. EM caryhsu@mednet.ucla.edu FU Intramural NIH HHS [Z99 CA999999] NR 26 TC 2 Z9 3 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD SEP PY 2013 VL 184 IS 1 BP 282 EP 289 DI 10.1016/j.jss.2013.03.054 PG 8 WC Surgery SC Surgery GA 207NX UT WOS:000323609400047 PM 23582229 ER PT J AU Ouaguia, L Morales, O Senechal, M Wychowski, C Carpentier, A Aoudjehane, L Calmus, Y de Launoit, Y Conti, F Delhem, N AF Ouaguia, L. Morales, O. Senechal, M. Wychowski, C. Carpentier, A. Aoudjehane, L. Calmus, Y. de Launoit, Y. Conti, F. Delhem, N. TI In vitro infection with HCV increases the suppressive phenotype and activity of the human regulatory T cell SO JOURNAL OF VIRAL HEPATITIS LA English DT Meeting Abstract CT Viral Hepatitis Congress CY SEP 26-28, 2013 CL Frankfurt, GERMANY C1 [Ouaguia, L.; Morales, O.; Senechal, M.; de Launoit, Y.; Delhem, N.] Inst Biol Lille, CNRS, UMR 8161, Lille, France. [Wychowski, C.] Ctr Infect & Immun Lille, CNRS, INSERM, U1019,UMR8204, Lille, France. [Carpentier, A.] NIH, Bethesda, MD 20892 USA. [Aoudjehane, L.; Calmus, Y.; Conti, F.] Univ Paris 06, Paris, France. [Aoudjehane, L.; Calmus, Y.; Conti, F.] CdR St Antoine, INSERM, UMR S 938, Paris, France. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD SEP PY 2013 VL 20 SU 3 SI SI BP 3 EP 3 PG 1 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 225XI UT WOS:000324998100006 ER PT J AU Yamaguchi, N Driscoll, CA Werdelin, L Abramov, AV Csorba, G Cuisin, J Fernholm, B Hiermeier, M Hills, D Hunter, L Itakura, H Johansson, US Kascheev, V Krohmann, K Martin, T Nowak-Kemp, M Pavlinov, IY Renoud, F Tomsett, L van der Mije, S Zholnerovskaya, E Groves, C Kitchener, AC Nijman, V Macdonald, DW AF Yamaguchi, Nobuyuki Driscoll, Carlos A. Werdelin, Lars Abramov, Alexei V. Csorba, Gabor Cuisin, Jacques Fernholm, Bo Hiermeier, Michael Hills, Daphne Hunter, Luke Itakura, Hiroyuki Johansson, Ulf S. Kascheev, Vitaliy Krohmann, Katrin Martin, Thomas Nowak-Kemp, Malgosia Pavlinov, Igor Ya. Renoud, Francis Tomsett, Louise van der Mije, Steven Zholnerovskaya, Elena Groves, Colin Kitchener, Andrew C. Nijman, Vincent Macdonald, David W. TI Locating specimens of extinct tiger (Panthera tigris) subspecies: Javan tiger (P. t. sondaica), Balinese tiger (P. t. balica), and Caspian tiger (P. t. virgata), including previously unpublished specimens SO MAMMAL STUDY LA English DT Article DE Central Asia; conservation; Indonesia; museum; Sunda Islands ID PHYLOGEOGRAPHY; CONSERVATION; POPULATIONS; PHYLOGENY; SIZE; ASIA; LEO AB Recent advances in multivariate statistics, and in ancient DNA techniques, have greatly increased understanding of tiger phylogeography. However, regardless of advances in analytical methodology, researchers will continue to need access to specimens for morphological measurements and sampling for genetic analysis. The tiger has become increasingly endangered, and out of the nine putative tiger subspecies, three (Javan, Balinese, and Caspian) have become extinct in the last 100 years, leaving the specimens kept in natural history collections as the only materials available for research. Frustratingly little information is widely available concerning the specimens of these extinct tiger subspecies. We conducted an extensive search for specimens of extinct tiger subspecies, and also developed a simple on-site method to assign unprovenanced and probable Indonesian specimens to either Javan/Balinese or Sumatran subspecies. We located a total of 88 Javan, 11 Balinese, and 46 Caspian tigers, including seven new Javan tigers, and three Balinese tigers that were not widely known previously. These specimens are critical for research in order to understand the intraspecific phylogeny and evolutionary history of the tiger. C1 [Yamaguchi, Nobuyuki; Driscoll, Carlos A.; Macdonald, David W.] Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Recanati Kaplan Ctr, Abingdon OX13 5QL, Oxon, England. [Driscoll, Carlos A.] NCI, Lab Genom Div, Frederick, MD 21702 USA. [Werdelin, Lars; Fernholm, Bo; Johansson, Ulf S.] Swedish Museum Nat Hist, SE-10405 Stockholm, Sweden. [Abramov, Alexei V.] Russian Acad Sci, Inst Zool, St Petersburg 199034, Russia. [Csorba, Gabor] Hungarian Nat Hist Museum, H-1088 Budapest, Hungary. [Cuisin, Jacques] Natl Museum Nat Hist, F-75005 Paris, France. [Hiermeier, Michael; Renoud, Francis] Bavarian State Collect Zool, D-81247 Munich, Germany. [Hills, Daphne; Tomsett, Louise] Nat Hist Museum, London SW7 5BD, England. [Hunter, Luke] Wildlife Conservat Soc, Great Cats Program, Bronx, NY 10460 USA. [Itakura, Hiroyuki] Cat Museum, Ito City, Shizuoka 4130235, Japan. [Kascheev, Vitaliy] Inst Zool, Alma Ata 480060, Kazakhstan. [Krohmann, Katrin; Martin, Thomas] Senckenberg Res Inst, D-60325 Frankfurt, Germany. [Krohmann, Katrin; Martin, Thomas] Nat Hist Museum, D-60325 Frankfurt, Germany. [Nowak-Kemp, Malgosia] Univ Oxford, Museum Nat Hist, Oxford OX1 3PW, England. [Pavlinov, Igor Ya.] Moscow MV Lomonosov State Univ, Zool Museum, Moscow 125009, Russia. [van der Mije, Steven] Netherlands Ctr Biodivers Naturalis, Natl Museum Nat Hist, NL-2300 RA Leiden, Netherlands. [Zholnerovskaya, Elena] Russian Acad Sci, Siberian Zool Museum, Novosibirsk 630091, Russia. [Groves, Colin] Australian Natl Univ, Sch Archaeol & Anthropol, Canberra, ACT 0200, Australia. [Kitchener, Andrew C.] Natl Museums Scotland, Edinburgh EH1 1JF, Midlothian, Scotland. [Kitchener, Andrew C.] Univ Edinburgh, Inst Geog, Sch Geosci, Edinburgh EH8 9XP, Midlothian, Scotland. [Nijman, Vincent] Univ Amsterdam, Zool Museum, NL-1092 AD Amsterdam, Netherlands. RP Yamaguchi, N (reprint author), Univ Qatar, Dept Biol & Environm Sci, POB 2713, Doha, Qatar. EM yamaguchi@qu.edu.qa RI Abramov, Alexei/A-9334-2011 OI Abramov, Alexei/0000-0001-9709-4469 FU Recanati-Kaplan Foundation FX We thank the European Union SYNTHESYS programme for allowing NY to visit the National Museum of Natural History, Paris, France, and the Museum of Natural History, Berlin, Germany, to examine skulls, and British Airways for transport between the UK and Kazakhstan, together with support of DWM by the Recanati-Kaplan Foundation. We also thank Robert Asher, Amankul Bekenov, Alex Borissenko, Peter Giere, Vitaliy Gromov, Olavi Gronwall, Roman Jashenko, Paula Jenkins, Sergey Kruskop, Natasha Lopatina, Doris Morike, Adri Rol, Richard Sabin, Chris Smeenk, Alexei Tikhonov, Irene Thomas, Peter van Bree, Hein van Grouw, Detlef Willborn for their kind support for locating specimens at their collections. NR 30 TC 2 Z9 3 U1 2 U2 51 PU MAMMALOGICAL SOC JAPAN PI KYOTO PA C/O NAKANISHI PRINTING CO, LTD, KAMIGYO-KU, KYOTO, 602-8048, JAPAN SN 1343-4152 EI 1348-6160 J9 MAMM STUDY JI Mamm. Study PD SEP PY 2013 VL 38 IS 3 BP 187 EP 198 PG 12 WC Zoology SC Zoology GA 228MX UT WOS:000325192000005 ER PT J AU Li, F Jiang, CT Krausz, KW Li, YF Albert, I Hao, HP Fabre, KM Mitchell, JB Patterson, AD Gonzalez, FJ AF Li, Fei Jiang, Changtao Krausz, Kristopher W. Li, Yunfei Albert, Istvan Hao, Haiping Fabre, Kristin M. Mitchell, James B. Patterson, Andrew D. Gonzalez, Frank J. TI Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity SO NATURE COMMUNICATIONS LA English DT Article ID BILE-ACID METABOLISM; GUT MICROBIOTA; INSULIN-RESISTANCE; GLUCOSE-HOMEOSTASIS; MICE; METABOLOMICS; CERAMIDE; METAGENOMICS; ACCUMULATION; CANCER AB The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-beta-muricholic acid (T-beta-MCA). T-beta-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (Fxr(Delta IE)) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr(Delta IE) mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs. C1 [Li, Fei; Jiang, Changtao; Krausz, Kristopher W.; Hao, Haiping; Patterson, Andrew D.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Li, Yunfei; Albert, Istvan] Penn State Univ, Bioinformat Consulting Ctr, University Pk, PA 16802 USA. [Fabre, Kristin M.; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov RI Li, Fei/F-6849-2013; Li, Yunfei/F-1546-2015; Patterson, Andrew/G-3852-2012; OI Patterson, Andrew/0000-0003-2073-0070; Hao, Haiping/0000-0003-2522-7546 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Pennsylvania Department of Health using Tobacco CURE Funds FX We thank Grace L. Guo (Rutgers University) for providing the PGL4-Shp-TK firefly luciferase construct and human FXR expression plasmid and Paul A. Dawson (Wake Forest University School of Medicine) for providing the human ASBT expression plasmid. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Sequencing was provided by the Penn State Genomics Core Facility, University Park, PA. This project was funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco CURE Funds. NR 45 TC 108 Z9 113 U1 14 U2 79 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD SEP PY 2013 VL 4 AR 2384 DI 10.1038/ncomms3384 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232ZB UT WOS:000325532400001 PM 24064762 ER PT J AU Carlson, CS Matise, TC North, KE Haiman, CA Fesinmeyer, MD Buyske, S Schumacher, FR Peters, U Franceschini, N Ritchie, MD Duggan, DJ Spencer, KL Dumitrescu, L Eaton, CB Thomas, F Young, A Carty, C Heiss, G Le Marchand, L Crawford, DC Hindorff, LA Kooperberg, CL AF Carlson, Christopher S. Matise, Tara C. North, Kari E. Haiman, Christopher A. Fesinmeyer, Megan D. Buyske, Steven Schumacher, Fredrick R. Peters, Ulrike Franceschini, Nora Ritchie, Marylyn D. Duggan, David J. Spencer, Kylee L. Dumitrescu, Logan Eaton, Charles B. Thomas, Fridtjof Young, Alicia Carty, Cara Heiss, Gerardo Le Marchand, Loic Crawford, Dana C. Hindorff, Lucia A. Kooperberg, Charles L. CA PAGE Consortium TI Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study SO PLOS BIOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; LINKAGE DISEQUILIBRIUM; LOCI; REPLICATION; MUTATIONS; VARIANTS; CHINESE; TRAITS; DESIGN AB The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging. C1 [Carlson, Christopher S.; Peters, Ulrike; Young, Alicia; Carty, Cara; Kooperberg, Charles L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [North, Kari E.; Franceschini, Nora; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.; Franceschini, Nora; Heiss, Gerardo] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Haiman, Christopher A.; Schumacher, Fredrick R.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Fesinmeyer, Megan D.] Seattle Childrens Res Inst, Ctr Child Hlth Behav & Dev, Seattle, WA USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Duggan, David J.] Translat Genom Res Inst, Phoenix, AZ USA. [Spencer, Kylee L.] Heidelberg Univ, Dept Biol & Environm Sci, Tiffin, OH USA. [Dumitrescu, Logan; Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Eaton, Charles B.] Brown Univ, Dept Family Med, Pawtucket, RI USA. [Thomas, Fridtjof] Univ Tennessee, Ctr Hlth Sci, Div Biostat & Epidemiol, Dept Prevent Med,Coll Med, Memphis, TN 38163 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. RP Carlson, CS (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM ccarlson@fhcrc.org RI Tiirikainen, Maarit/B-6954-2012; Nato, Alejandro/J-3880-2016; OI Buyske, Steven/0000-0001-8539-5416; Tiirikainen, Maarit/0000-0002-8124-3818; Nato, Alejandro/0000-0002-8745-9046; Bush, William/0000-0002-9729-6519 FU National Human Genome Research Institute (NHGRI) [U01HG004798-01, U01HG004802, U01HG004803]; NHLBI [N01-HV-48195, HHSN268201200036C, N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133]; Centers for Disease Control and Prevention; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; NIH; US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; National Institutes of Health, National Heart, Lung and Blood Institute [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205]; NIA [AG-023629, AG-15928, AG-20098, AG-027058]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; National Institutes of Mental Health; N.H.L.B.I [HL080295, U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] FX The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI). The data and materials included in this report result from a collaboration between the following studies: The "Epidemiologic Architecture for Genes Linked to Environment (EAGLE)'' is funded through the NHGRI PAGE program (U01HG004798-01). Genotyping services for select NHANES III SNPs presented here were also provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from NHLBI. The study participants derive from the National Health and Nutrition Examination Surveys (NHANES), and these studies are supported by the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative'' study is provided through the NHGRI PAGE program (U01HG004790). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program was provided through the NHGRI PAGE program (U01HG004803). The following studies contributed to this manuscript and are funded by the following agencies: The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022. The Coronary Artery Risk Development in Young Adults (CARDIA) study is supported by the following National Institutes of Health, National Heart, Lung and Blood Institute contracts: N01-HC-95095; N01-HC-48047; N01-HC-48048; N01-HC-48049; N01-HC-48050; N01-HC-45134; N01-HC-05187; and N01-HC-45205. The Cardiovascular Health Study (CHS) is supported by NHLBI contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI grant HL080295, with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also https://chs-nhlbi.org/. CHS GWAS DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Strong Heart Study (SHS) is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service.; Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 40 Z9 40 U1 2 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD SEP PY 2013 VL 11 IS 9 AR e1001661 DI 10.1371/journal.pbio.1001661 PG 11 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 224SU UT WOS:000324910500017 PM 24068893 ER PT J AU Candia, J Maunu, R Driscoll, M Biancotto, A Dagur, P McCoy, JP Sen, HN Wei, L Maritan, A Cao, K Nussenblatt, RB Banavar, JR Losert, W AF Candia, Julian Maunu, Ryan Driscoll, Meghan Biancotto, Angelique Dagur, Pradeep McCoy, J. Philip, Jr. Sen, H. Nida Wei, Lai Maritan, Amos Cao, Kan Nussenblatt, Robert B. Banavar, Jayanth R. Losert, Wolfgang TI From Cellular Characteristics to Disease Diagnosis: Uncovering Phenotypes with Supercells SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID FLOW-CYTOMETRY DATA; GILFORD PROGERIA SYNDROME; CD4(+) T-CELLS; SINGLE-CELL; HETEROGENEITY; EXPRESSION; IMMUNE AB Cell heterogeneity and the inherent complexity due to the interplay of multiple molecular processes within the cell pose difficult challenges for current single-cell biology. We introduce an approach that identifies a disease phenotype from multiparameter single-cell measurements, which is based on the concept of `` supercell statistics'', a single-cell-based averaging procedure followed by a machine learning classification scheme. We are able to assess the optimal tradeoff between the number of single cells averaged and the number of measurements needed to capture phenotypic differences between healthy and diseased patients, as well as between different diseases that are difficult to diagnose otherwise. We apply our approach to two kinds of single-cell datasets, addressing the diagnosis of a premature aging disorder using images of cell nuclei, as well as the phenotypes of two non-infectious uveitides (the ocular manifestations of Behc, et's disease and sarcoidosis) based on multicolor flow cytometry. In the former case, one nuclear shape measurement taken over a group of 30 cells is sufficient to classify samples as healthy or diseased, in agreement with usual laboratory practice. In the latter, our method is able to identify a minimal set of 5 markers that accurately predict Behc, et's disease and sarcoidosis. This is the first time that a quantitative phenotypic distinction between these two diseases has been achieved. To obtain this clear phenotypic signature, about one hundred CD8(+) T cells need to be measured. Although the molecular markers identified have been reported to be important players in autoimmune disorders, this is the first report pointing out that CD8(+) T cells can be used to distinguish two systemic inflammatory diseases. Beyond these specific cases, the approach proposed here is applicable to datasets generated by other kinds of state-of-the-art and forthcoming single-cell technologies, such as multidimensional mass cytometry, single-cell gene expression, and single-cell full genome sequencing techniques. C1 [Candia, Julian; Maunu, Ryan; Driscoll, Meghan; Banavar, Jayanth R.; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Candia, Julian] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Candia, Julian] Univ La Plata, IFLYSIB, La Plata, Buenos Aires, Argentina. [Candia, Julian] Univ La Plata, CONICET, La Plata, Buenos Aires, Argentina. [Biancotto, Angelique; McCoy, J. Philip, Jr.] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Biancotto, Angelique; Dagur, Pradeep; McCoy, J. Philip, Jr.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Sen, H. Nida; Wei, Lai; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Maritan, Amos] Univ Padua, Dipartimento Fis G Galilei, Consorzio Nazl Interuniv Sci Fis Mat, Padua, Italy. [Maritan, Amos] Ist Nazl Fis Nucl, Padua, Italy. [Cao, Kan] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. RP Candia, J (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM candia@umd.edu RI Wei, Lai/D-1088-2014; OI Candia, Julian/0000-0001-5793-8989 FU NIH [R00AG029761, R01GM085574, PHY1205965, 5T32CA154274-03]; CONICET (Argentina) FX KC was supported by NIH grant R00AG029761. WL and JC were partially supported by NIH grants R01GM085574 and PHY1205965. JC was partially supported by CONICET (Argentina) and NIH Project Number 5T32CA154274-03 (T32 Training Grant in Cancer Biology). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 12 Z9 12 U1 2 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD SEP PY 2013 VL 9 IS 9 AR e1003215 DI 10.1371/journal.pcbi.1003215 PG 10 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 227AZ UT WOS:000325080900016 PM 24039568 ER PT J AU Bacolla, A Temiz, NA Yi, M Ivanic, J Cer, RZ Donohue, DE Ball, EV Mudunuri, US Wang, GL Jain, A Volfovsky, N Luke, BT Stephens, RM Cooper, DN Collins, JR Vasquez, KM AF Bacolla, Albino Temiz, Nuri A. Yi, Ming Ivanic, Joseph Cer, Regina Z. Donohue, Duncan E. Ball, Edward V. Mudunuri, Uma S. Wang, Guliang Jain, Aklank Volfovsky, Natalia Luke, Brian T. Stephens, Robert M. Cooper, David N. Collins, Jack R. Vasquez, Karen M. TI Guanine Holes Are Prominent Targets for Mutation in Cancer and Inherited Disease SO PLOS GENETICS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ONE-ELECTRON OXIDATION; DEPENDENT DNA-DAMAGE; B-FORM DNA; LUNG-CANCER; DENSITY FUNCTIONALS; NONCODING SEQUENCES; SOMATIC MUTATION; BASE COMPOSITION; GGG TRIPLETS AB Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G.C bp in the context of all 64 5'-NGNN-3' motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines ( ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease. C1 [Bacolla, Albino; Wang, Guliang; Jain, Aklank; Vasquez, Karen M.] Univ Texas Austin, Dell Pediat Res Inst, Div Pharmacol & Toxicol, Austin, TX 78712 USA. [Bacolla, Albino; Temiz, Nuri A.; Yi, Ming; Ivanic, Joseph; Cer, Regina Z.; Donohue, Duncan E.; Mudunuri, Uma S.; Volfovsky, Natalia; Luke, Brian T.; Stephens, Robert M.; Collins, Jack R.] SAIC Frederic Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Ball, Edward V.; Cooper, David N.] Cardiff Univ, Sch Med, Inst Med Genet, Cardiff CF10 3AX, S Glam, Wales. RP Bacolla, A (reprint author), Univ Texas Austin, Dell Pediat Res Inst, Div Pharmacol & Toxicol, Austin, TX 78712 USA. EM karen.vasquez@austin.utexas.edu RI Bacolla, Albino/N-3877-2013; OI Bacolla, Albino/0000-0003-0206-8423; Cooper, David N./0000-0002-8943-8484 FU NIH [CA097175, CA093729]; NCI/NIH [HHSN261200800001E]; Frederick National Laboratory for Cancer Research; CBIIT/caBIG ISRCE; BIOBASE GmbH; Cardiff University FX This work was supported by grants from the NIH (CA097175 and CA093729) to KMV, NCI/NIH contract HHSN261200800001E to AB and the Frederick National Laboratory for Cancer Research, and CBIIT/caBIG ISRCE yellow task #09-260 to the Frederick National Laboratory for Cancer Research. DNC and EVB received financial support from BIOBASE GmbH through a license agreement (for HGMD) with Cardiff University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 103 TC 11 Z9 11 U1 1 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2013 VL 9 IS 9 AR e1003816 DI 10.1371/journal.pgen.1003816 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 226ZM UT WOS:000325076600071 PM 24086153 ER PT J AU Lada, AG Stepchenkova, EI Waisertreiger, ISR Noskov, VN Dhar, A Eudy, JD Boissy, RJ Hirano, M Rogozin, IB Pavlov, YI AF Lada, Artem G. Stepchenkova, Elena I. Waisertreiger, Irina S. R. Noskov, Vladimir N. Dhar, Alok Eudy, James D. Boissy, Robert J. Hirano, Masayuki Rogozin, Igor B. Pavlov, Youri I. TI Genome-Wide Mutation Avalanches Induced in Diploid Yeast Cells by a Base Analog or an APOBEC Deaminase SO PLOS GENETICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE GENOME; HUMAN CANCERS EXPRESS; DNA-REPLICATION; ESCHERICHIA-COLI; ADAPTIVE MUTATION; MUTAGENIC SPECIFICITY; CYTOSINE DEAMINATION; MISMATCH REPAIR; GENE; 6-N-HYDROXYLAMINOPURINE AB Genetic information should be accurately transmitted from cell to cell; conversely, the adaptation in evolution and disease is fueled by mutations. In the case of cancer development, multiple genetic changes happen in somatic diploid cells. Most classic studies of the molecular mechanisms of mutagenesis have been performed in haploids. We demonstrate that the parameters of the mutation process are different in diploid cell populations. The genomes of drug-resistant mutants induced in yeast diploids by base analog 6-hydroxylaminopurine (HAP) or AID/APOBEC cytosine deaminase PmCDA1 from lamprey carried a stunning load of thousands of unselected mutations. Haploid mutants contained almost an order of magnitude fewer mutations. To explain this, we propose that the distribution of induced mutation rates in the cell population is uneven. The mutants in diploids with coincidental mutations in the two copies of the reporter gene arise from a fraction of cells that are transiently hypersensitive to the mutagenic action of a given mutagen. The progeny of such cells were never recovered in haploids due to the lethality caused by the inactivation of single-copy essential genes in cells with too many induced mutations. In diploid cells, the progeny of hypersensitive cells survived, but their genomes were saturated by heterozygous mutations. The reason for the hypermutability of cells could be transient faults of the mutation prevention pathways, like sanitization of nucleotide pools for HAP or an elevated expression of the PmCDA1 gene or the temporary inability of the destruction of the deaminase. The hypothesis on spikes of mutability may explain the sudden acquisition of multiple mutational changes during evolution and carcinogenesis. C1 [Lada, Artem G.; Stepchenkova, Elena I.; Waisertreiger, Irina S. R.; Pavlov, Youri I.] Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Stepchenkova, Elena I.] Vavilov Inst Gen Genet, St Petersburg Branch, St Petersburg, Russia. [Stepchenkova, Elena I.; Pavlov, Youri I.] St Petersburg Univ, Dept Genet, St Petersburg, Russia. [Noskov, Vladimir N.] J Craig Venter Inst, Rockville, MD USA. [Dhar, Alok; Eudy, James D.] Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. [Dhar, Alok; Eudy, James D.] Univ Nebraska, Med Ctr, Munroe Meyer Inst, Omaha, NE USA. [Boissy, Robert J.] Univ Nebraska, Med Ctr, Dept Internal Med, Omaha, NE USA. [Hirano, Masayuki] Emory Univ, Emory Vaccine Ctr, Dept Pathol & Lab Med, Atlanta, GA USA. [Rogozin, Igor B.] Natl Ctr Biotechnol Informat, NIH, Natl Lib Med, Bethesda, MD USA. RP Lada, AG (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. EM ypavlov@unmc.edu RI Stepchenkova, Elena/F-9931-2014 OI Stepchenkova, Elena/0000-0002-5854-8701 FU UNMC Eppley Cancer Center; NCI [CA129925]; Smoking Disease Research Program DHHS grant [2013-21]; Russian Federal Government Research Program "Innovative Scientific Personnel"; Federal Grant-in-Aid Program "Human Capital for Science and Education in Innovative Russia" [8654]; Graduate Research Fellowship from the University of Nebraska Medical Center; NIH [R01AI072435, R01GM100151]; Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS; NCRR [1S10RR027754-01, 5P20RR016469, RR018788-08]; National Institute for General Medical Science (NIGMS) [8P20GM103427, GM103471-09]; [14.740.11.0916] FX The work was supported by UNMC Eppley Cancer Center seed grants and, in part, by NCI grant CA129925; Smoking Disease Research Program DHHS grant 2013-21; by the Russian Federal Government Research Program "Innovative Scientific Personnel"; State Contract 14.740.11.0916 to YIP; Federal Grant-in-Aid Program "Human Capital for Science and Education in Innovative Russia 2009-2013" to YIP; and the Federal Grant-in-Aid Program "Human Capital for Science and Education in Innovative Russia" (Governmental Contract No. 8654). AGL was supported by a Graduate Research Fellowship from the University of Nebraska Medical Center. MH was supported by NIH grants R01AI072435 and R01GM100151. IBR is supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS. The University of Nebraska DNA Sequencing Core receives partial support from the NCRR (1S10RR027754-01, 5P20RR016469, RR018788-08) and the National Institute for General Medical Science (NIGMS) (8P20GM103427, GM103471-09). This publication's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH, NCI or NIGMS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 20 Z9 20 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2013 VL 9 IS 9 AR e1003736 DI 10.1371/journal.pgen.1003736 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 226ZM UT WOS:000325076600012 PM 24039593 ER PT J AU O'Seaghdha, CM Wu, HS Yang, Q Kapur, K Guessous, I Zuber, AM Kottgen, A Stoudmann, C Teumer, A Kutalik, Z Mangino, M Dehghan, A Zhang, WH Eiriksdottir, G Li, G Tanaka, T Portas, L Lopez, LM Hayward, C Lohman, K Matsuda, K Padmanabhan, S Firsov, D Sorice, R Ulivi, S Brockhaus, AC Kleber, ME Mahajan, A Ernst, FD Gudnason, V Launer, LJ Mace, A Boerwinckle, E Arking, DE Tanikawa, C Nakamura, Y Brown, MJ Gaspoz, JM Theler, JM Siscovick, DS Psaty, BM Bergmann, S Vollenweider, P Vitart, V Wright, AF Zemunik, T Boban, M Kolcic, I Navarro, P Brown, EM Estrada, K Ding, JZ Harris, TB Bandinelli, S Hernandez, D Singleton, AB Girotto, G Ruggiero, D d'Adamo, AP Robino, A Meitinger, T Meisinger, C Davies, G Starr, JM Chambers, JC Boehm, BO Winkelmann, BR Huang, J Murgia, F Wild, SH Campbell, H Morris, AP Franco, OH Hofman, A Uitterlinden, AG Rivadeneira, F Volker, U Hannemann, A Biffar, R Hoffmann, W Shin, SY Lescuyer, P Henry, H Schurmann, C Munroe, PB Gasparini, P Pirastu, N Ciullo, M Gieger, C Marz, W Lind, L Spector, TD Smith, AV Rudan, I Wilson, JF Polasek, O Deary, IJ Pirastu, M Ferrucci, L Liu, YM Kestenbaum, B Kooner, JS Witteman, JCM Nauck, M Kao, WHL Wallaschofski, H Bonny, O Fox, CS Bochud, M AF O'Seaghdha, Conall M. Wu, Hongsheng Yang, Qiong Kapur, Karen Guessous, Idris Zuber, Annie Mercier Koettgen, Anna Stoudmann, Candice Teumer, Alexander Kutalik, Zoltan Mangino, Massimo Dehghan, Abbas Zhang, Weihua Eiriksdottir, Gudny Li, Guo Tanaka, Toshiko Portas, Laura Lopez, Lorna M. Hayward, Caroline Lohman, Kurt Matsuda, Koichi Padmanabhan, Sandosh Firsov, Dmitri Sorice, Rossella Ulivi, Sheila Brockhaus, A. Catharina Kleber, Marcus E. Mahajan, Anubha Ernst, Florian D. Gudnason, Vilmundur Launer, Lenore J. Mace, Aurelien Boerwinckle, Eric Arking, Dan E. Tanikawa, Chizu Nakamura, Yusuke Brown, Morris J. Gaspoz, Jean-Michel Theler, Jean-Marc Siscovick, David S. Psaty, Bruce M. Bergmann, Sven Vollenweider, Peter Vitart, Veronique Wright, Alan F. Zemunik, Tatijana Boban, Mladen Kolcic, Ivana Navarro, Pau Brown, Edward M. Estrada, Karol Ding, Jingzhong Harris, Tamara B. Bandinelli, Stefania Hernandez, Dena Singleton, Andrew B. Girotto, Giorgia Ruggiero, Daniela d'Adamo, Adamo Pio Robino, Antonietta Meitinger, Thomas Meisinger, Christa Davies, Gail Starr, John M. Chambers, John C. Boehm, Bernhard O. Winkelmann, Bernhard R. Huang, Jie Murgia, Federico Wild, Sarah H. Campbell, Harry Morris, Andrew P. Franco, Oscar H. Hofman, Albert Uitterlinden, Andre G. Rivadeneira, Fernando Voelker, Uwe Hannemann, Anke Biffar, Reiner Hoffmann, Wolfgang Shin, So-Youn Lescuyer, Pierre Henry, Hughes Schurmann, Claudia Munroe, Patricia B. Gasparini, Paolo Pirastu, Nicola Ciullo, Marina Gieger, Christian Maerz, Winfried Lind, Lars Spector, Tim D. Smith, Albert V. Rudan, Igor Wilson, James F. Polasek, Ozren Deary, Ian J. Pirastu, Mario Ferrucci, Luigi Liu, Yongmei Kestenbaum, Bryan Kooner, Jaspal S. Witteman, Jacqueline C. M. Nauck, Matthias Kao, W. H. Linda Wallaschofski, Henri Bonny, Olivier Fox, Caroline S. Bochud, Murielle CA SUNLIGHT Consortium GEFOS Consortium TI Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations SO PLOS GENETICS LA English DT Article ID IMPRINTED PHLDA2 GENE; VITAMIN-D METABOLISM; PARATHYROID-HORMONE; PHOSPHATE HOMEOSTASIS; PLACENTAL EXPRESSION; UROGENITAL SYSTEM; RENAL-FUNCTION; MAMMARY-GLAND; BIRTH-WEIGHT; PLASMA AB Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis. C1 [O'Seaghdha, Conall M.; Wu, Hongsheng; Yang, Qiong; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Seaghdha, Conall M.; Wu, Hongsheng; Yang, Qiong; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Boston, MA 02114 USA. [Wu, Hongsheng; Yang, Qiong] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Wu, Hongsheng] Univ Split, Sch Med, Dept Med Biol, Split, Croatia. [Kapur, Karen; Kutalik, Zoltan; Mace, Aurelien; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Guessous, Idris; Bochud, Murielle] Univ Lausanne Hosp, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland. [Guessous, Idris; Theler, Jean-Marc] Univ Hosp Geneva, Dept Community Med & Primary Care & Emergency Med, Div Primary Care Med, Unit Populat Epidemiol, Geneva, Switzerland. [Guessous, Idris] ASF, Geriatr Unit, Florence, Italy. [Zuber, Annie Mercier; Stoudmann, Candice; Firsov, Dmitri; Bonny, Olivier] Univ Lausanne, Dept Pharmacol & Toxicol, Lausanne, Switzerland. [Koettgen, Anna] Freiburg Univ Hosp, Div Renal, Freiburg, Germany. [Koettgen, Anna; Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Teumer, Alexander; Ernst, Florian D.; Voelker, Uwe; Schurmann, Claudia] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Kutalik, Zoltan; Mace, Aurelien; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Mangino, Massimo; Spector, Tim D.] Kings Coll London, London, England. [Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Zhang, Weihua; Chambers, John C.; Kooner, Jaspal S.] Ealing Gen Hosp, Catheter Lab, Southall, Middx, England. [Zhang, Weihua; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Eiriksdottir, Gudny; Gudnason, Vilmundur; Smith, Albert V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Li, Guo; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Tanaka, Toshiko] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Portas, Laura; Murgia, Federico; Pirastu, Mario] CNR Traversa La Crucca, Inst Populat Genet, Sassari, Italy. [Lopez, Lorna M.; Davies, Gail; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Hayward, Caroline; Vitart, Veronique; Wright, Alan F.; Navarro, Pau] Univ Edinburgh, MRC IGMM, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Lohman, Kurt] ClinPhenomics GmbH&Co KG, Cardiol Grp, Frankfurt, Germany. [Matsuda, Koichi; Tanikawa, Chizu; Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan. [Padmanabhan, Sandosh] Univ Glasgow, Div Cardiovasc & Med Sci, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Sorice, Rossella; Ruggiero, Daniela; Ciullo, Marina] CNR, Inst Genet & Biophys Adriano Buzzati Traverso, I-80125 Naples, Italy. [Ulivi, Sheila; Girotto, Giorgia; d'Adamo, Adamo Pio; Robino, Antonietta; Gasparini, Paolo; Pirastu, Nicola] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Brockhaus, A. Catharina; Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Brockhaus, A. Catharina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Kleber, Marcus E.] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany. [Mahajan, Anubha; Morris, Andrew P.] Wellcome Trust Ctr Human Genet, Oxford, England. [Gudnason, Vilmundur; Smith, Albert V.] Univ Iceland, Reykjavik, Iceland. [Launer, Lenore J.; Harris, Tamara B.; Ferrucci, Luigi] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Boerwinckle, Eric] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Brown, Morris J.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Gaspoz, Jean-Michel] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Vollenweider, Peter] Univ Lausanne Hosp, Dept Med, Lausanne, Switzerland. [Zemunik, Tatijana; Kolcic, Ivana; Polasek, Ozren] Univ Split, Fac Med, Split, Croatia. [Boban, Mladen] Univ Split, Fac Med, Dept Pharmacol, Split, Croatia. [Brown, Edward M.; Ding, Jingzhong] Univ Hosp Geneva, Div Lab Med, Geneva, Switzerland. [Estrada, Karol; Uitterlinden, Andre G.; Rivadeneira, Fernando] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Bandinelli, Stefania] Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England. [Hernandez, Dena; Singleton, Andrew B.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Meitinger, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Wentworth Inst Technol, Dept Comp Sci & Networking, Boston, MA USA. [Meisinger, Christa] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, London, England. [Boehm, Bernhard O.] Univ Ulm, Dept Internal Med 1, Med Ctr, D-89069 Ulm, Germany. [Boehm, Bernhard O.] Univ London Imperial Coll Sci Technol & Med, LKC Sch Med, Singapore, Singapore. [Boehm, Bernhard O.] Nanyang Technol Univ, Singapore 639798, Singapore. [Winkelmann, Bernhard R.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Huang, Jie] Univ Hosp Geneva, Dept Community Med & Primary Care & Emergency Med, Div Primary Care Med, Geneva, Switzerland. [Wild, Sarah H.; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Hannemann, Anke; Nauck, Matthias; Wallaschofski, Henri] Ernst Moritz Arndt Univ Greifswald, Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Biffar, Reiner] Univ Med Greifswald, Dept Prosthet Dent Gerostomatol & Dent Mat, Greifswald, Germany. [Hoffmann, Wolfgang] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Shin, So-Youn] Wellcome Trust Sanger Inst, Hinxton, England. [Lescuyer, Pierre] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Henry, Hughes] Univ Lausanne Hosp, Clin Chem Lab, Lausanne, Switzerland. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Maerz, Winfried] Synlab Ctr Lab Diagnost, Heidelberg, Germany. [Lind, Lars] Univ Uppsala Hosp, Inst Med Sci, Uppsala, Sweden. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Kestenbaum, Bryan] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, Fac Med, London, England. [Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London, England. [Kao, W. H. Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Bonny, Olivier] Univ Lausanne Hosp, Serv Nephrol, Lausanne, Switzerland. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP O'Seaghdha, CM (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov; Murielle.Bochud@chuv.ch RI Smith, Albert/K-5150-2015; ruggiero, daniela/K-5638-2016; Schurmann, Claudia/L-1204-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Padmanabhan, Sandosh/S-3963-2016; Boban, Mladen/E-2777-2017; Kolcic, Ivana/E-2713-2017; Colaus, PsyColaus/K-6607-2013; Gasparini, Paolo/B-6173-2014; d'Adamo, Adamo Pio/G-4064-2011; Meisinger, Christine/B-5358-2014; Singleton, Andrew/C-3010-2009; Yang, Qiong/G-5438-2014; Boehm, Bernhard/F-8750-2015; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Rudan, Igor/I-1467-2012 OI Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Pirastu, Nicola/0000-0002-5363-3886; Padmanabhan, Sandosh/0000-0003-3869-5808; Gieger, Christian/0000-0001-6986-9554; Meisinger, Christa/0000-0002-9026-6544; Girotto, Giorgia/0000-0003-4507-6589; Navarro, Pau/0000-0001-5576-8584; Smith, Albert/0000-0003-1942-5845; ruggiero, daniela/0000-0003-3898-7827; Schurmann, Claudia/0000-0003-4158-9192; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Kolcic, Ivana/0000-0001-7918-6052; Lescuyer, Pierre/0000-0001-6986-8738; d'Adamo, Adamo Pio/0000-0001-9367-4909; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Rudan, Igor/0000-0001-6993-6884 FU MIUR [5571/DSPAR/2002]; (FIRB) D. M. [718/Ric/2005]; [3100AO-116323/1,310000-112552]; [LSHG-CT-2006- 018947]; [108-1080315- 0302]; [N01-HC-25195]; [N02-HL-6-4278]; [N01AG62101]; [N01AG62103]; [N01AG62106]; [1R01AG032098-01A1]; [HHSN268200782096C]; [ICS110.1/RF97.71]; [263 MD 9164]; [263 MD 821336]; [N01-AG-1-2100]; [HHSN268201100005C]; [HHSN268201100006C]; [HHSN268201100007C]; [HHSN268201100008C]; [HHSN268201100009C]; [HHSN268201100010C]; [HHSN268201100011C]; [HSN268201100012C]; [01ZZ 0403]; [HEALTH-F2-2008-201865-GEFOS]; [HEALTH-F4-2007-201413]; [QLG2-CT-2002-01254]; [R01HL087641]; [R01HL59367]; [R01HL086694]; [U01HG004402]; [HHSN268200625226C]; [O3598/2-1]; [UL1RR025005]; [N01-HC-85239]; [N01-HC-85079]; [N01-HC-85080]; [N01-HC-85081]; [N01-HC-85082]; [N01-HC-85083]; [N01-HC-85084]; [N01-HC-85085]; [N01-HC-85086]; [N01-HC-35129]; [N01 HC-15103]; [N01 HC-55222]; [N01 - HC-75150]; [N01-HC-45133]; [HHSN268201200036C]; [HL080295]; [HL087652]; [HL105756]; [AG-023629]; [AG]; [SP/04/002. G0700704/84698]; [LSHG-CT-2006-018947]; [01ZZ9603]; [01ZZ0103]; [01ZZ0403]; [03IS2061A]; [03ZIK012]; [175.010.2005.011]; [911-03-012]; [014-93-015]; [RIDE2. 050-060-810]; [vici, 918-76-619]; [Vasoplus-037254]; [FIRB - RBIN064YAT]; [LSHM-CT-2004-503485]; [WT064890]; [-15928]; [AG-20098]; [AG-027058]; [UL1RR033176]; [UL1TR000124]; [DK063491]; [33CSCO- 122661]; [3200BO-111361/2]; [WT081682]; [G20234]; [091746/Z/10/Z]; [G9521010D]; [PG/02/128]; [SP/04/002]; [PP00P3-133648] FX All grant numbers for each human study and for the animal studies are listed in the Acknowledgement section of the Supplementary material. There is no specific funding for the GWAS meta-analysis itself. Grant numbers: N01-AG-1-2100. HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HSN268201100012C, R01HL087641, R01HL59367, R01HL086694, U01HG004402, HHSN268200625226C. KO3598/2-1. UL1RR025005. N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01 - HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756, AG-023629, AG-15928, AG-20098, AG-027058, UL1RR033176, UL1TR000124, DK063491. 33CSCO- 122661, 3200BO-111361/2, 3100AO-116323/1,310000-112552. LSHG-CT-2006- 018947. 108- 1080315-0302. LSHG-CT-2006-018947, 108-1080315- 0302. 108-1080315- 0302. N01-HC-25195. N02-HL-6-4278. N01AG62101, N01AG62103, N01AG62106. 1R01AG032098-01A1. HHSN268200782096C. ICS110.1/RF97.71. 263 MD 9164 and 263 MD 821336. SP/04/002. G0700704/84698. (MIUR) no. 5571/DSPAR/2002 and (FIRB) D. M. no. 718/Ric/2005. LSHG-CT-2006-018947. 01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03ZIK012. 175.010.2005.011, 911-03-012. 014-93-015; RIDE2. 050-060-810. vici, 918-76-619. Vasoplus-037254. FIRB - RBIN064YAT. LSHM-CT-2004-503485. WT064890, WT081682. 01ZZ9603, 01ZZ0103, and 01ZZ 0403. 03IS2061A. 03ZIK012. HEALTH-F2-2008-201865-GEFOS. HEALTH-F4-2007-201413. QLG2-CT-2002-01254. G20234. 091746/Z/10/Z. G9521010D. PG/02/128. SP/04/002. SP/04/002. PP00P3-133648. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 23 Z9 23 U1 1 U2 41 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2013 VL 9 IS 9 AR e1003796 DI 10.1371/journal.pgen.1003796 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 226ZM UT WOS:000325076600054 PM 24068962 ER PT J AU Phelan, JD Saba, I Zeng, H Kosan, C Messer, MS Olsson, HA Fraszczak, J Hildeman, DA Aronow, BJ Moroy, T Grimes, HL AF Phelan, James D. Saba, Ingrid Zeng, Hui Kosan, Christian Messer, Malynda S. Olsson, H. Andre Fraszczak, Jennifer Hildeman, David A. Aronow, Bruce J. Moeroey, Tarik Grimes, H. Leighton TI Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors SO PLOS GENETICS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ZINC-FINGER PROTEIN; HEMATOPOIETIC STEM-CELLS; NOTCH SIGNALING CONTROLS; T-LINEAGE SPECIFICATION; C-MYC; ACTIVATING MUTATIONS; ENRICHMENT ANALYSIS; TUMOR-SUPPRESSOR; REPRESSOR GFI1 AB Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T-cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1-activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1(-/-) mice. These defects correlate with an inability of Gfi1(-/-) progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity. C1 [Phelan, James D.; Messer, Malynda S.; Olsson, H. Andre; Hildeman, David A.; Grimes, H. Leighton] Cincinnati Childrens Hosp Med Ctr, Div Cellular & Mol Immunol, Cincinnati, OH 45229 USA. [Saba, Ingrid; Kosan, Christian; Fraszczak, Jennifer; Moeroey, Tarik] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Saba, Ingrid; Moeroey, Tarik] Inst Rech Clin Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ H2W 1R7, Canada. [Zeng, Hui] Capital Med Univ, Beijing Ditan Hosp, Inst Infect Dis, Beijing, Peoples R China. [Aronow, Bruce J.] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA. [Grimes, H. Leighton] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA. RP Phelan, JD (reprint author), NCI, Metab Branch, Bethesda, MD 20892 USA. EM Tarik.Moroy@ircm.qc.ca; Lee.Grimes@cchmc.org RI Hildeman, David/I-4884-2015; Kosan, Christian/C-1213-2017; OI Hildeman, David/0000-0002-0421-8483; Kosan, Christian/0000-0002-8387-3653; Grimes, H. Leighton/0000-0001-8162-6758 FU UC Cancer Therapeutics T32 training grant [T32-CA117846]; Canada Research Chair (Tier 1); CIHR [MOP - 84238, MOP - 111011]; CRS; CancerFree Kids; Leukemia and Lymphoma Society of America; NIH [CA105152, CA159845]; Alex's Lemonade Stand FX JDP was a Pelotonia Fellow (http://cancer.osu.edu/research/researcheducation/pelotoniafellowshippro gram/pages/index.aspx) in the Immunobiology Graduate Program at the University of Cincinnati College of Medicine, who was also supported by the UC Cancer Therapeutics T32 training grant (T32-CA117846). TM was supported by a Canada Research Chair (Tier 1) and grants from the CIHR (MOP - 84238, MOP - 111011, http://www.cihr-irsc.gc.ca/e/193.html) and the CRS (http://www.src-crs.ca/en-CA). HLG was supported by the CancerFree Kids (www.cancerfreekids.org/), Leukemia and Lymphoma Society of America (http://www.lls.org/), NIH (CA105152, CA159845, http://www.nih.gov) and Alex's Lemonade Stand (http://www.alexslemonade.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 12 Z9 12 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2013 VL 9 IS 9 AR e1003713 DI 10.1371/journal.pgen.1003713 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 226ZM UT WOS:000325076600004 PM 24068942 ER PT J AU Armstrong, AB Segars, JH AF Armstrong, Alicia Brooks Segars, James H. TI Correcting Reproductive Health Disparities in Women: An Opportunity to Improve the Health of Future Generations SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Editorial Material ID IN-VITRO FERTILIZATION; ASIAN ETHNICITY; DEVELOPMENTAL ORIGINS; BLACK-WOMEN; OUTCOMES; TECHNOLOGY; WHITE C1 [Armstrong, Alicia Brooks; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, CRC, Bldg 10,Room E1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU Intramural NIH HHS [ZIE HD008737-13] NR 14 TC 0 Z9 0 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD SEP PY 2013 VL 31 IS 5 BP 313 EP 315 DI 10.1055/s-0033-1348888 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 198DV UT WOS:000322903000002 PM 23934690 ER PT J AU Owen, CM Goldstein, EH Clayton, JA Segars, JH AF Owen, Carter M. Goldstein, Ellen H. Clayton, Janine A. Segars, James H. TI Racial and Ethnic Health Disparities in Reproductive Medicine: An Evidence-Based Overview SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE racial disparities; ancestry informative markers; admixture; infertility; transgenerational; epigenetic; developmental origins of adult disease ID ANCESTRY INFORMATIVE MARKERS; VITRO FERTILIZATION OUTCOMES; ADVERSE BIRTH OUTCOMES; INFANT-MORTALITY-RATES; AFRICAN-AMERICAN; BIOMEDICAL-RESEARCH; PERINATAL PERIODS; HUMAN-POPULATIONS; GENETIC-STRUCTURE; PRETERM BIRTH AB Racial and ethnic health disparities in reproductive medicine exist across the life span and are costly and burdensome to our healthcare system. Reduction and ultimate elimination of health disparities is a priority of the National Institutes of Health who requires reporting of race and ethnicity for all clinical research it supports. Given the increasing rates of admixture in our population, the definition and subsequent genetic significance of self-reported race and ethnicity used in health disparity research is not straightforward. Some groups have advocated using self-reported ancestry or carefully selected single-nucleotide polymorphisms, also known as ancestry informative markers, to sort individuals into populations. Despite the limitations in our current definitions of race and ethnicity in research, there are several clear examples of health inequalities in reproductive medicine extending from puberty and infertility to obstetric outcomes. We acknowledge that socioeconomic status, education, insurance status, and overall access to care likely contribute to the differences, but these factors do not fully explain the disparities. Epigenetics may provide the biologic link between these environmental factors and the transgenerational disparities that are observed. We propose an integrated view of health disparities across the life span and generations focusing on the metabolic aspects of fetal programming and the effects of environmental exposures. Interventions aimed at improving nutrition and minimizing adverse environmental exposures may act synergistically to reverse the effects of these epigenetic marks and improve the outcome of our future generations. C1 [Owen, Carter M.] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Goldstein, Ellen H.] Dartmouth Hitchcock Med Ctr, Dept Obstet & Gynecol, Lebanon, NH 03766 USA. [Clayton, Janine A.] NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. [Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, CRC, Bldg 10,Room E1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov OI Owen, Carter Monique/0000-0002-5012-2706 FU Intramural NIH HHS [ZIE HD008737-13] NR 76 TC 8 Z9 8 U1 0 U2 21 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD SEP PY 2013 VL 31 IS 5 BP 317 EP 324 DI 10.1055/s-0033-1348889 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 198DV UT WOS:000322903000003 PM 23934691 ER PT J AU Sauerbrun-Cutler, MT Segars, JH AF Sauerbrun-Cutler, May-Tal Segars, James H. TI Do In Utero Events Contribute to Current Health Disparities in Reproductive Medicine? SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE DOHaD; preterm labor; obesity; African Americans; preterm birth ID POLYCYSTIC-OVARY-SYNDROME; INTRAUTERINE GROWTH RESTRICTION; AFRICAN-AMERICAN WOMEN; PRETERM BIRTH; DEVELOPMENTAL ORIGINS; ADULT DISEASE; OMEGA-3-FATTY-ACID SUPPLEMENTATION; EPIGENETIC MODIFICATION; MATERNAL NUTRITION; PRENATAL EXPOSURE AB Health disparities exist in reproductive medicine as discussed in detail in the subsequent articles of this issue; however, in most cases, the exact cause of these differences is unknown. Some of these disparities can be linked to environmental exposures such as alcohol and other hazardous toxic exposures (polycarbonate, pesticides, nicotine) in adults. In addition, low socioeconomic status, behavioral risk factors, and lack of education have been linked to poor obstetric and reproductive outcomes in minority groups. Aside from these various environmental exposures later in life, there is evidence that adverse events in utero could contribute to poor reproductive outcome in specific minority groups. We will focus on the developmental origins of health and disease as a possible causal mechanism for health disparities in reproductive diseases, as this perspective may suggest tractable solutions of how to address and eliminate these health disparities. C1 [Sauerbrun-Cutler, May-Tal; Segars, James H.] St Lukes Roosevelt Hosp, Dept Obstet & Gynecol, New York, NY 10025 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,Room 1E3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU Intramural Research Division of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Division of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 68 TC 3 Z9 3 U1 1 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD SEP PY 2013 VL 31 IS 5 BP 325 EP 332 DI 10.1055/s-0033-1348890 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 198DV UT WOS:000322903000004 PM 23934692 ER PT J AU Ramnitz, MS Lodish, MB AF Ramnitz, Mary Scott Lodish, Maya B. TI Racial Disparities in Pubertal Development SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE puberty; menarche; Tanner stage; race ID SECONDARY SEXUAL CHARACTERISTICS; BODY-MASS INDEX; NUTRITION EXAMINATION SURVEY; HEALTH-EXAMINATION-SURVEY; OFFICE SETTINGS NETWORK; BLOOD-INSTITUTE GROWTH; US CHILDREN; PEDIATRIC RESEARCH; NATIONAL-HEALTH; BOGALUSA HEART AB The question of whether or not children, particularly girls, are entering puberty earlier than they did in the past has been a concern in both the medical community and the general population. A secular trend analysis of the current data on pubertal timing in boys and girls is limited by variations in the study design, the population assessed, and the methods used to determine pubertal development. These differences present a challenge when interpreting the available data, especially when comparing multiple studies. The influence of race on pubertal timing and development had not been assessed before the 1970s. The purpose of this article is to review the reported variations in pubertal timing among different racial/ethnic groups. Data suggest African American girls enter puberty earlier and reach menarche earlier than Caucasian and Hispanic girls. In addition, the trend toward earlier timing of puberty seems to be occurring faster in African American girls compared with Caucasian girls over the past 25 years. While the mechanism and understanding of the cause of racial disparities in pubertal development remain to be discerned, genetic and/or environmental factors may play a role and require further investigation. C1 [Ramnitz, Mary Scott; Lodish, Maya B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Ramnitz, MS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM ramnitzms@mail.nih.gov FU Intramural Research Division of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Division of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 30 TC 5 Z9 6 U1 5 U2 14 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD SEP PY 2013 VL 31 IS 5 BP 333 EP 339 DI 10.1055/s-0033-1348891 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 198DV UT WOS:000322903000005 PM 23934693 ER PT J AU Plowden, TC Novak, CM Spong, CY AF Plowden, Torie C. Novak, Christopher M. Spong, Catherine Y. TI Disparities in Obstetrical Outcomes in ART Pregnancies Compared with Natural Conceptions SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE assisted reproduction; spontaneous conception; ethnic disparities ID IN-VITRO-FERTILIZATION; ASSISTED REPRODUCTIVE TECHNOLOGY; INTRACYTOPLASMIC SPERM INJECTION; LOW-BIRTH-WEIGHT; PRETERM BIRTH; PERINATAL OUTCOMES; SINGLETON PREGNANCIES; ASIAN ETHNICITY; CEREBRAL-PALSY; INTRAUTERINE INSEMINATION AB Health disparities are observed in all fields of medicine and reproductive health is not immune to this phenomenon. The incidence of women using infertility treatments to conceive is increasing. Women undergoing assisted reproduction appear to be at increased risk of adverse outcomes, and minority women tend to be at even greater risk. This article examines several adverse obstetrical outcomes including preterm birth, congenital malformations, and preeclampsia among women receiving infertility treatments compared with those who conceive spontaneously. It will further examine societal costs associated with these procedures. C1 [Plowden, Torie C.] Bayne Jones Army Community Hosp, Dept Obstet & Gynecol, Ft Polk, LA 71459 USA. [Novak, Christopher M.] Ft Drum Obstet & Gynecol Clin, Watertown, NY USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Plowden, TC (reprint author), Bayne Jones Army Community Hosp, Dept Obstet & Gynecol, 1585 3rd St, Ft Polk, LA 71459 USA. EM tcomeaux@gmail.com NR 61 TC 0 Z9 0 U1 4 U2 13 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD SEP PY 2013 VL 31 IS 5 BP 340 EP 346 DI 10.1055/s-0033-1348892 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 198DV UT WOS:000322903000006 PM 23934694 ER PT J AU Catherino, WH Eltoukhi, HM Al-Hendy, A AF Catherino, William H. Eltoukhi, Heba M. Al-Hendy, Ayman TI Racial and Ethnic Differences in the Pathogenesis and Clinical Manifestations of Uterine Leiomyoma SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE uterine leiomyoma; African American; ethnicity; molecular; risk factor ID CATECHOL-O-METHYLTRANSFERASE; SMOOTH-MUSCLE-CELLS; AFRICAN-AMERICAN WOMEN; GROWTH-FACTOR-BETA; GONADOTROPIN-RELEASING-HORMONE; ACTIVATED-RECEPTOR-GAMMA; TRANS-RETINOIC ACID; MAJOR LIFE EVENTS; EKER RAT MODEL; VITAMIN-D AB Uterine leiomyomas are the most common benign gynecologic condition. The prevalence is three times more common among women of African ethnicity. Disparity in this disease is evidenced by earlier age of onset, greater severity of symptoms, and different response to treatment. Although the pathogenesis of disease development is not completely known, growing evidence focuses on investigating the molecular mechanisms in disease development and the influence of ethnicity. Variation in the expression levels or function of estrogen and progesterone receptors, polymorphism of genes involved in estrogen synthesis and/or metabolism (COMT, CYP17), retinoic acid nuclear receptors (retinoid acid receptor-, retinoid X receptor-), and aberrant expression of micro-RNAs (miRNAs) are some of the molecular mechanisms that may be involved. Nutritional factors, such as vitamin D deficiency, might also contribute to the higher incidence in dark skinned populations who are also commonly suffer from hypovitaminosis D. Culture and environmental difference might have a role in disease development. Further analysis and better understanding of these mechanisms will provide insight into the molecular basis of racial disparities in leiomyoma formation and will help to develop new innovations in leiomyoma treatment. C1 [Catherino, William H.; Eltoukhi, Heba M.] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Eltoukhi, Heba M.] Suez Canal Univ, Dept Obstet & Gynecol, Ismailia, Egypt. [Al-Hendy, Ayman] Meharry Med Coll, Ctr Womens Hlth Res, Dept Obstet & Gynecol, Nashville, TN 37208 USA. RP Al-Hendy, A (reprint author), Meharry Med Coll, Ctr Womens Hlth Res, Dept Obstet & Gynecol, 1005 Dr DB Todd Jr Blvd, Nashville, TN 37208 USA. EM Ahendy@MMC.edu FU NIH FX The authors acknowledge the support and assistance of Drs. DeCherney and Zahn. This research was supported, in part, by NIH grants to authors A.A. and W.C. NR 128 TC 17 Z9 19 U1 2 U2 11 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD SEP PY 2013 VL 31 IS 5 BP 370 EP 379 DI 10.1055/s-0033-1348896 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 198DV UT WOS:000322903000010 PM 23934698 ER PT J AU Mohiuddin, M Singh, A Corcoran, P Thomas, M Hoyt, R Lewis, B Clark, T Eckhaus, M Wolf, E Reimann, K Ayares, D Horvath, K AF Mohiuddin, Muhammad Singh, Avneesh Corcoran, Philip Thomas, Marvin Hoyt, Robert Lewis, Billeta Clark, Tannia Eckhaus, Michael Wolf, Eckhard Reimann, Keith Ayares, David Horvath, Keith TI Over 9 months graft survival of GTKO.hCD46tg.hTMtg pig heterotopic heart xenograft in Anti CD40 (2C10) treated baboon SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of 12th International-Xenotransplantation-Association and Organ Transplantation in ABO-incompatible and Hyperimmunized Recipients CY NOV 10-13, 2013 CL Osaka, JAPAN SP Int Xenotransplantat Assoc, Transplantat Soc, Int Xenotransplantat Assoc C1 [Mohiuddin, Muhammad; Singh, Avneesh; Corcoran, Philip; Horvath, Keith] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Thomas, Marvin; Lewis, Billeta; Eckhaus, Michael] NIH, DVR, ORS, Bethesda, MD 20892 USA. [Hoyt, Robert; Clark, Tannia] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Wolf, Eckhard] Univ Munich, Inst Mol Anim Breeding & Biotechnol, Munich, Germany. [Reimann, Keith] Univ Massachusetts, Boston, MA 02125 USA. [Ayares, David] Revivicor Inc, Blacksburgh, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2013 VL 20 IS 5 SI SI BP 329 EP 329 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 224YG UT WOS:000324928400046 ER PT J AU Singh, A Corcoran, P Thomas, M Hoyt, R Lewis, B Clark, T Eckhaus, M Reimann, K Ayares, D Horvath, K Mohiuddin, M AF Singh, Avneesh Corcoran, Philip Thomas, Marvin Hoyt, Robert Lewis, Billeta Clark, Tannia Eckhaus, Michael Reimann, Keith Ayares, David Horvath, Keith Mohiuddin, Muhammad TI Low and tapering dose of anti CD40 (2C10 or 3A8) for 8-week duration fails to extend GTKO.hCD46Tg pig to baboon cardiac xenograft survival beyond 5 months SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of 12th International-Xenotransplantation-Association and Organ Transplantation in ABO-incompatible and Hyperimmunized Recipients CY NOV 10-13, 2013 CL Osaka, JAPAN SP Int Xenotransplantat Assoc, Transplantat Soc, Int Xenotransplantat Assoc C1 [Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Thomas, Marvin; Lewis, Billeta; Eckhaus, Michael] NIH, DVR, ORS, Bethesda, MD 20892 USA. [Clark, Tannia] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Reimann, Keith] Univ Massachusetts, Boston, MA 02125 USA. [Ayares, David] Revivicor Inc, Blacksburgh, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2013 VL 20 IS 5 SI SI BP 342 EP 342 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 224YG UT WOS:000324928400084 ER PT J AU Singh, A Seavey, C Corcoran, P Lewis, B Thomas, M Hoyt, R Ayares, D Horvath, K Mohiuddin, M AF Singh, Avneesh Seavey, Caleb Corcoran, Philip Lewis, Billeta Thomas, Marvin Hoyt, Robert Ayares, David Horvath, Keith Mohiuddin, Muhammad TI Pig to baboon heterotopic cardiac xenotransplantation: Potential role of baboon CD4+CD25(Hi) FOxP3+T regulatory cells in long-term graft survival SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of 12th International-Xenotransplantation-Association and Organ Transplantation in ABO-incompatible and Hyperimmunized Recipients CY NOV 10-13, 2013 CL Osaka, JAPAN SP Int Xenotransplantat Assoc, Transplantat Soc, Int Xenotransplantat Assoc C1 [Singh, Avneesh; Seavey, Caleb; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DVR, ORS, Bethesda, MD 20892 USA. [Hoyt, Robert] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburgh, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2013 VL 20 IS 5 SI SI BP 343 EP 343 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 224YG UT WOS:000324928400085 ER PT J AU Mohiuddin, M AF Mohiuddin, Muhammad TI Ex vivo expanded Tregs suppress the baboon anti-pig T and B cell response SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of 12th International-Xenotransplantation-Association and Organ Transplantation in ABO-incompatible and Hyperimmunized Recipients CY NOV 10-13, 2013 CL Osaka, JAPAN SP Int Xenotransplantat Assoc, Transplantat Soc, Int Xenotransplantat Assoc C1 [Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2013 VL 20 IS 5 SI SI BP 349 EP 349 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 224YG UT WOS:000324928400104 ER PT J AU Clark, T Singh, A Corcoran, P Thomas, M Hoyt, R Lewis, B Horvath, K Mohiuddin, M AF Clark, Tannia Singh, Avneesh Corcoran, Philip Thomas, Marvin Hoyt, Robert Lewis, Billeta Horvath, Keith Mohiuddin, Muhammad TI Use of echocardiography to assess heterotopic cardiac xenograft function and clot reduction therapeutic intervention in a transgenic pig to baboon model SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of 12th International-Xenotransplantation-Association and Organ Transplantation in ABO-incompatible and Hyperimmunized Recipients CY NOV 10-13, 2013 CL Osaka, JAPAN SP Int Xenotransplantat Assoc, Transplantat Soc, Int Xenotransplantat Assoc C1 [Clark, Tannia; Hoyt, Robert; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Clark, Tannia; Singh, Avneesh; Corcoran, Philip; Thomas, Marvin; Hoyt, Robert; Lewis, Billeta; Horvath, Keith; Mohiuddin, Muhammad] Revivicor Inc, Blacksburgh, VA USA. [Singh, Avneesh; Corcoran, Philip] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Thomas, Marvin; Lewis, Billeta] NIH, DVR, ORS, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2013 VL 20 IS 5 SI SI BP 360 EP 360 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 224YG UT WOS:000324928400134 ER PT J AU Corcoran, P Singh, A Lewis, B Thomas, M Clark, T Hoyt, R Horvath, K Mohiuddin, M AF Corcoran, Philip Singh, Avneesh Lewis, Billeta Thomas, Marvin Clark, Tannia Hoyt, Robert Horvath, Keith Mohiuddin, Muhammad TI Telemetry, echocardiography and manual palpation of heterotopic cardiac xenograft together improves the measurement accuracy of graft contractility SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Congress of 12th International-Xenotransplantation-Association and Organ Transplantation in ABO-incompatible and Hyperimmunized Recipients CY NOV 10-13, 2013 CL Osaka, JAPAN SP Int Xenotransplantat Assoc, Transplantat Soc, Int Xenotransplantat Assoc C1 [Corcoran, Philip; Singh, Avneesh; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DVR, ORS, Bethesda, MD 20892 USA. NHLBI, LAMS, NIH, Bethesda, MD 20892 USA. [Clark, Tannia; Hoyt, Robert] Revivicor Inc, Blacksburgh, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2013 VL 20 IS 5 SI SI BP 378 EP 378 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 224YG UT WOS:000324928400187 ER PT J AU Ouimet, MC Pradhan, AK Simons-Morton, BG Divekar, G Mehranian, H Fisher, DL AF Ouimet, Marie Claude Pradhan, Anuj K. Simons-Morton, Bruce G. Divekar, Gautam Mehranian, Hasmik Fisher, Donald L. TI The effect of male teenage passengers on male teenage drivers: Findings from a driving simulator study SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Driving; Risky behavior; Social influence; Peers; Adolescence; Male ID SOCIAL FACILITATION; SENSATION-SEEKING; EYE-MOVEMENTS; ADOLESCENT SMOKING; PEER INFLUENCES; MERE PRESENCE; RISK-TAKING; SELF-ESTEEM; BEHAVIOR; DRINKING AB Studies have shown that teenage drivers are less attentive, more frequently exhibit risky driving behavior, and have a higher fatal crash risk in the presence of peers. The effects of direct peer pressure and conversation on young drivers have been examined. Little is known about the impact on driving performance of the presence of a non-interacting passenger and subtle modes of peer influence, such as perceived social norms. The goal of this study was to examine if teenagers would engage in more risky driving practices and be less attentive in the presence of a passenger (vs. driving alone) as well as with a risk-accepting (vs. risk-averse) passenger. A confederate portrayed the passenger's characteristics mainly by his non-verbal attitude. The relationship between driver characteristics and driving behavior in the presence of a passenger was also examined. Thirty-six male participants aged 16-17 years old were randomly assigned to drive with a risk-accepting or risk-averse passenger. Main outcomes included speed, headway, gap acceptance, eye glances at hazards, and horizontal eye movement. Driver characteristics such as tolerance of deviance, susceptibility to peer pressure, and self-esteem were measured. Compared to solo driving, the presence of a passenger was associated with significantly fewer eye glances at hazards and a trend for fewer horizontal eye movements. Contrary to the hypothesis, however, Passenger Presence was associated with waiting for a greater number of vehicles to pass before initiating a left turn. Results also showed, contrary to the hypothesis, that participants with the risk-accepting passenger maintained significantly longer headway with the lead vehicle and engaged in more eye glances at hazards than participants with the risk-averse passenger. Finally, when driving with the passenger, earlier initiation of a left turn in a steady stream of oncoming vehicles was significantly associated with higher tolerance of deviance and susceptibility to peer pressure, while fewer eye glances at hazards was linked to lower self-esteem. While the results of this study were mixed, they suggest that the presence of a teenage passenger can affect some aspects of teenage driver behavior even in the absence of overt pressure and distraction. Results are discussed in relation to theoretical concepts of social influence and social facilitation models. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Longueuil, PQ J4A 0A8, Canada. [Pradhan, Anuj K.; Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Divekar, Gautam; Mehranian, Hasmik; Fisher, Donald L.] Univ Massachusetts, Dept Mech & Ind Engn, Amherst, MA 01003 USA. RP Ouimet, MC (reprint author), Univ Sherbrooke, Fac Med & Hlth Sci, 150 Charles Lemoyne Pl Suite 200, Longueuil, PQ J4A 0A8, Canada. EM Marie.Claude.Ouimet@USherbrooke.ca OI Pradhan, Anuj/0000-0002-7612-4208; Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [ZIA HD001707-15]; PHS HHS [HHSN267200700281P] NR 57 TC 17 Z9 17 U1 1 U2 40 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD SEP PY 2013 VL 58 BP 132 EP 139 DI 10.1016/j.aap.2013.04.024 PG 8 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA 221KE UT WOS:000324657000018 PM 23727554 ER PT J AU Taylor, T Pradhan, AK Divekar, G Romoser, M Muttart, J Gomez, R Pollatsek, A Fisher, DL AF Taylor, T. Pradhan, A. K. Divekar, G. Romoser, M. Muttart, J. Gomez, R. Pollatsek, A. Fisher, D. L. TI The view from the road: The contribution of on-road glance-monitoring technologies to understanding driver behavior SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE On-road; Eye-tracking; Eye movements; Glance-monitoring; Hazard anticipation; Attention maintenance; Novice driver; Older driver; Distraction; Automobile crashes ID EXPERIENCED DRIVERS; EYE-MOVEMENTS; VISUAL-SEARCH; NOVICE DRIVERS; OLDER DRIVERS; CRASH RISK; ATTENTION; PATTERNS; VEHICLE; DISTRACTION AB Using glance-monitoring technologies for on-road studies is an excellent way to investigate driver behaviors in an ecologically valid setting. Recent advances in glance-monitoring technologies have made it possible to conduct on-road studies of drivers' glance behavior that heretofore were simply not possible. Yet it is not always easy to determine which glance-monitoring technology to use for a particular application. Here, we first identify the generic capabilities of the various glance-monitoring technologies. We then describe how particular glance-monitoring technologies have been used in the field to (a) identify the skill deficiencies of novice and older drivers, (b) evaluate the effectiveness of training programs that are designed to reduce deficits in these skills, and (c) address interface issues both inside (e.g., collision warning systems) and outside (e.g., yield markings) the vehicle. The limitations and advantages of on-road eye-tracking and the associated glance-monitoring technologies are identified throughout. A comparison, where possible, is made between the results of on-road eye-tracking studies of drivers' behaviors and the results of those studies conducted in the laboratory. Overall, the use of appropriate on-road glance-monitoring technologies has greatly enhanced our theoretical understanding of why drivers behave the way they do, and this knowledge has paved the way for significant improvements in road user safety. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Taylor, T.; Divekar, G.; Romoser, M.; Muttart, J.; Gomez, R.; Fisher, D. L.] Univ Massachusetts, Dept Mech & Ind Engn, Amherst, MA 01003 USA. [Pradhan, A. K.] NIH, Bethesda, MD 20892 USA. [Pollatsek, A.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. RP Taylor, T (reprint author), Univ Massachusetts, Dept Mech & Ind Engn, Amherst, MA 01003 USA. EM fisher@ecs.umass.edu; anujkp@gmail.com; gautamdivekar20000@gmail.com; mromoser@ecs.umass.edu; jmuttart@engin.umass.edu; ragomez@engin.umass.edu; pollatsek@psych.umass.edu; fisher@ecs.umass.edu OI Pradhan, Anuj/0000-0002-7612-4208 FU NICHD NIH HHS [R01HD057153-01] NR 76 TC 15 Z9 18 U1 2 U2 30 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD SEP PY 2013 VL 58 BP 175 EP 186 DI 10.1016/j.aap.2013.02.008 PG 12 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA 221KE UT WOS:000324657000023 PM 23548549 ER PT J AU Pletnev, VZ Pletneva, NV Lukyanov, KA Souslova, EA Fradkov, AF Chudakov, DM Chepurnykh, T Yampolsky, IV Wlodawer, A Dauter, Z Pletnev, S AF Pletnev, Vladimir Z. Pletneva, Nadya V. Lukyanov, Konstantin A. Souslova, Ekaterina A. Fradkov, Arkady F. Chudakov, Dmitry M. Chepurnykh, Tatyana Yampolsky, Ilia V. Wlodawer, Alexander Dauter, Zbigniew Pletnev, Sergei TI Structure of the red fluorescent protein from a lancelet (Branchiostoma lanceolatum): a novel GYG chromophore covalently bound to a nearby tyrosine SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID GFP-LIKE PROTEINS; STATE PROTON-TRANSFER; CIS PEPTIDE-BONDS; CRYSTAL-STRUCTURE; AMPHIOXUS GENOME; GREEN; EVOLUTION; VARIANTS; FAMILY; CORAL AB A key property of proteins of the green fluorescent protein (GFP) family is their ability to form a chromophore group by post-translational modifications of internal amino acids, e. g. Ser65-Tyr66-Gly67 in GFP from the jellyfish Aequorea victoria (Cnidaria). Numerous structural studies have demonstrated that the green GFP-like chromophore represents the 'core' structure, which can be extended in red-shifted proteins owing to modifications of the protein backbone at the first chromophore-forming position. Here, the three-dimensional structures of green laGFP (lambda(ex)/lambda(em) = 502/511 nm) and red laRFP (lambda(ex)/lambda(em) similar or equal to 521/592 nm), which are fluorescent proteins (FPs) from the lancelet Branchiostoma lanceolatum (Chordata), were determined together with the structure of a red variant laRFP-Delta S83 (deletion of Ser83) with improved folding. Lancelet FPs are evolutionarily distant and share only similar to 20% sequence identity with cnidarian FPs, which have been extensively characterized and widely used as genetically encoded probes. The structure of red-emitting laRFP revealed three exceptional features that have not been observed in wild-type fluorescent proteins from Cnidaria reported to date: (i) an unusual chromophore-forming sequence Gly58-Tyr59-Gly60, (ii) the presence of Gln211 at the position of the conserved catalytic Glu (Glu222 in Aequorea GFP), which proved to be crucial for chromophore formation, and (iii) the absence of modifications typical of known red chromophores and the presence of an extremely unusual covalent bond between the Tyr59 C-beta atom and the hydroxyl of the proximal Tyr62. The impact of this covalent bond on the red emission and the large Stokes shift (similar to 70 nm) of laRFP was verified by extensive structure-based site-directed mutagenesis. C1 [Pletnev, Vladimir Z.; Pletneva, Nadya V.; Lukyanov, Konstantin A.; Souslova, Ekaterina A.; Fradkov, Arkady F.; Chudakov, Dmitry M.; Chepurnykh, Tatyana; Yampolsky, Ilia V.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Dauter, Zbigniew; Pletnev, Sergei] NCI, Synchrotron Radiat Res Ctr, Macromol Crystallog Lab, Argonne, IL 60439 USA. [Pletnev, Sergei] SAIC Frederick, Basic Res Program, Argonne, IL 60439 USA. RP Pletnev, VZ (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. EM vzpletnev@gmail.com; pletnevs@mail.nih.gov RI Chudakov, Dmitriy/G-7741-2014; Pletneva, Nadya/F-7839-2014; Pletnev, Vladimir/Q-6151-2016; Yampolsky, Ilia/R-6798-2016 OI Chudakov, Dmitriy/0000-0003-0430-790X; Yampolsky, Ilia/0000-0003-2558-2476 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Russian Foundation for Basic Research [12-04-31615]; Ministry of Education and Science of the Russian Federation [14.512.11.0052] FX Diffraction experiments were carried out on beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT) located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This project has been supported in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH) contract No. HHSN261200800001E, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by a grant from the Russian Foundation for Basic Research 12-04-31615 and by the Ministry of Education and Science of the Russian Federation (project 14.512.11.0052). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 53 TC 4 Z9 4 U1 1 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD SEP PY 2013 VL 69 BP 1850 EP 1860 DI 10.1107/S0907444913015424 PN 9 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 223PG UT WOS:000324818000022 PM 23999308 ER PT J AU Swanson, CA Pearce, EN AF Swanson, Christine A. Pearce, Elizabeth N. TI Iodine Insufficiency: A Global Health Problem? SO ADVANCES IN NUTRITION LA English DT Editorial Material ID INFANTS; WOMEN AB As a result of collaborative efforts with international organizations and the salt industry, many developing and developed countries practice universal salt iodization (USI) or have mandatory salt fortification programs. As a consequence, the prevalence of iodine deficiency decreased dramatically. The United States and Canada are among the few developed countries that do not practice USI. Such an undertaking would require evidence of deficiency among vulnerable population groups, including pregnant women, newborns, and developing infants. Government agencies in the United States rely heavily on data from NHANES to assess the iodine status of the general population and pregnant women in particular. NHANES data suggest that pregnant women in the United States remain mildly deficient This is important, because the developing fetus is dependent on maternal iodine intake for normal brain development throughout pregnancy. Professional societies have recommended that pregnant and lactating women, or those considering pregnancy, consume a supplement providing 150 mu g iodine daily. The United States and Canada collaborate on the daily recommended intake and are also confronted with the challenge of identifying the studies needed to determine if USI is likely to be beneficial to vulnerable population groups without exposing them to harm. C1 [Swanson, Christine A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Pearce, Elizabeth N.] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. RP Swanson, CA (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. FU American Society for Nutrition FX This article is a summary of the symposium, "Iodine Insufficiency A Global Health Problem?," held April 21, 2013, at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2013 in Boston, MA. The symposium was sponsored by the American Society for Nutrition The organizer has indicated that related reviews of this symposium will be submitted for publication in upcoming issues of Advances in Nutrition. NR 6 TC 5 Z9 5 U1 2 U2 17 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2013 VL 4 IS 5 BP 533 EP 535 DI 10.3945/an.113.004192 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 217KH UT WOS:000324357900008 PM 24038248 ER PT J AU Gaine, PC Balentine, DA Erdman, JW Dwyer, JT Ellwood, KC Hu, FB Russell, RM AF Gaine, P. Courtney Balentine, Douglas A. Erdman, John W., Jr. Dwyer, Johanna T. Ellwood, Kathleen C. Hu, Frank B. Russell, Robert M. TI Are Dietary Bioactives Ready for Recommended Intakes? SO ADVANCES IN NUTRITION LA English DT Editorial Material AB Research has shown that numerous dietary bioactive components that are not considered essential may still be beneficial to health. The dietary reference intake (DRI) process has been applied to nonessential nutrients, such as fiber, yet the majority of bioactive components await a recommended intake. Despite a plethora of new research over the past several years on the health effects of bioactives, it is possible that the field may never reach a point where the current DRI framework is suitable for these food components. If bioactives are to move toward dietary guidance, they will likely require an alternative path to get there. C1 [Gaine, P. Courtney] Int Life Sci Inst, North Amer Branch, Washington, DC USA. [Balentine, Douglas A.] Unilever, Englewood Cliffs, NJ USA. [Erdman, John W., Jr.] Univ Illinois, Urbana, IL 61801 USA. [Dwyer, Johanna T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Ellwood, Kathleen C.] Coll Southern Maryland, La Plata, MD USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Russell, Robert M.] Tufts Univ, Boston, MA 02111 USA. [Russell, Robert M.] NIH, Bethesda, MD 20892 USA. RP Gaine, PC (reprint author), Int Life Sci Inst, North Amer Branch, Washington, DC USA. EM cgaine@ilsi.org OI Dwyer, Johanna/0000-0002-0783-1769 FU American Society for Nutrition; ASN Dietary Bioactives RIS; North American Branch of the International Life Sciences Institute's Committee on Flavonoids FX This article is a summary of the symposium "Are Dietary Bioactives Ready for Recommended Intakes?" held April 21, 2013, at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2013 in Boston, MA. The symposium was sponsored by the American Society for Nutrition, the ASN Dietary Bioactives RIS, and the North American Branch of the International Life Sciences Institute's Committee on Flavonoids This is a free access article, distributed under terms (http.//www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NR 0 TC 9 Z9 9 U1 0 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2013 VL 4 IS 5 BP 539 EP 541 DI 10.3945/an.113.004226 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 217KH UT WOS:000324357900010 PM 24038250 ER PT J AU Webb, D Leahy, MM Milner, JA Allison, DB Dodd, KW Gaine, PC Matthews, RAJ Schneeman, BO Tucker, KL Young, SS AF Webb, Densie Leahy, Margaret M. Milner, John A. Allison, David B. Dodd, Kevin W. Gaine, P. Courtney Matthews, Robert A. J. Schneeman, Barbara O. Tucker, Katherine L. Young, S. Stanley TI Strategies to Optimize the Impact of Nutritional Surveys and Epidemiological Studies SO ADVANCES IN NUTRITION LA English DT Editorial Material AB The development of nutrition and health guidelines and policies requires reliable scientific information. Unfortunately, theoretical considerations and empirical evidence indicate that a large percentage of science-based claims rely on studies that fail to replicate. The session "Strategies to Optimize the Impact of Nutrition Surveys and Epidemiological Studies" focused on the elements of design, interpretation, and communication of nutritional surveys and epidemiological studies to enhance and encourage the production of reliable, objective evidence for use in developing dietary guidance for the public. The speakers called for more transparency of research, raw data, consistent data-staging techniques, and improved data analysis. New approaches to collecting data are urgently needed to increase the credibility and utility of findings from nutrition epidemiological studies. Such studies are critical for furthering our knowledge and understanding of the effects of diet on health. C1 [Leahy, Margaret M.] Coca Cola Co, Atlanta, GA USA. [Milner, John A.] ARS, USDA, Beltsville, MD USA. [Allison, David B.] Univ Alabama Birmingham, Birmingham, AL USA. [Dodd, Kevin W.] NCI, Bethesda, MD 20892 USA. [Gaine, P. Courtney] Int Life Sci Inst, North Amer Branch, Washington, DC USA. [Matthews, Robert A. J.] Aston Univ, Birmingham B4 7ET, W Midlands, England. [Schneeman, Barbara O.] Univ Calif Davis, Davis, CA 95616 USA. [Tucker, Katherine L.] Northeastern Univ, Boston, MA 02115 USA. [Young, S. Stanley] Natl Inst Stat Sci, Res Triangle Pk, NC USA. EM dwebb1@austin.rr.com FU American Society for Nutrition; North American Branch of the International Life Sciences Institute's Committee on Carbohydrates; Frontiers Foundation; Federal Trade Commission FX This article is a summary of the symposium "Strategies to Optimize the Impact of Nutritional Surveys and Epidemiological Studies" held April 20, 2013 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2013 in Boston, MA. The symposium was sponsored by the American Society for Nutrition and the North American Branch of the International Life Sciences Institute's Committee on Carbohydrates. This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.; Author disclosures: M. M. Leahy is Vice-Chair of International Life Sciences Institute (ILSI) North America's Carbohydrates Committee. J. A. Milner is an ILSI Global, IFIC, and McCormick Science Institute Board Member. D B. Allison has received financial and other benefits from the Frontiers Foundation, Federal Trade Commission, and other government, nonprofit, and for-profit organizations. K. L Tucker is a scientific advisor to (ILSI North America and has received support from the Kraft Foods Group. S. S. Young is a member of the OmicSoft Scientific Advisory and the AJCN Editorial Boards. K. W. Dodd, P. C. Gaine, R. A. J. Matthews, and B. O. Schneeman, no conflicts of interest. NR 0 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2013 VL 4 IS 5 BP 545 EP 547 DI 10.3945/an.113.004259 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 217KH UT WOS:000324357900012 PM 24038252 ER PT J AU Cogswell, ME Elliott, P Wang, CY Rhodes, DG Pfeiffer, CM Loria, CM AF Cogswell, Mary E. Elliott, Paul Wang, Chia-Yih Rhodes, Donna G. Pfeiffer, Christine M. Loria, Catherine M. TI Assessing US Sodium Intake through Dietary Data and Urine Biomarkers SO ADVANCES IN NUTRITION LA English DT Editorial Material ID POTASSIUM EXCRETION; SPECIMEN; ADULTS AB Sodium intake is related to blood pressure, an established risk factor for heart disease and stroke. Reducing intake may save billions in United States health care dollars annually. Efforts targeting sodium reductions make accurate monitoring vital, yet limited information exists on the accuracy of the current data to assess sodium intake in the United States population. In this symposium, new findings were presented on the accuracy of estimating population 24-h urinary excretion of sodium from spot urine specimens or sodium intake from 24-h dietary recalls. Differences in accuracy by sex, BMI, and race were apparent as well as by timing of spot urine collections. Although some published equations appear promising for estimating group means, others are biased. Individual estimates of sodium intake were highly variable and adjustment for within-individual variation in intake is required for estimating population prevalence or percentiles. Estimates indicated United States sodium intake remains high. C1 [Cogswell, Mary E.; Pfeiffer, Christine M.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, London, England. [Wang, Chia-Yih] Ctr Dis Control & Prevent, Hyattsville, MD USA. [Rhodes, Donna G.] USDA, Beltsville, MD 20705 USA. [Loria, Catherine M.] NIH, Bethesda, MD 20892 USA. RP Cogswell, ME (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. EM mcogswell@cdc.gov FU ASN; U.S. Department of Health and Human Services; USDA; CDC [200-2010-43842]; National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College FX This article is a summary of the symposium "Assessing U.S. Sodium Intake Through Dietary Data and Urine Biomarkers" held April 24, 2013 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2013 in Boson, MA. The symposium was sponsored by the ASN and endorsed by ASN the Medical Nutrition Council.; Supported by the U.S. Department of Health and Human Services and USDA. Dr. Elliot's work supported by CDC contract no. 200-2010-43842. Dr. Elliott also acknowledges support from the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College. He is an NIHR Senior Investigator. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC nor those of the NHS, the NIHR or the Department of Health, UK. NR 5 TC 5 Z9 6 U1 0 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2013 VL 4 IS 5 BP 560 EP 562 DI 10.3945/an.113.004309 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 217KH UT WOS:000324357900017 PM 24038257 ER PT J AU Zachwieja, J Hentges, E Hill, JO Black, R Vassileva, M AF Zachwieja, Jeffrey Hentges, Eric Hill, James O. Black, Richard Vassileva, Maria TI Public-Private Partnerships: The Evolving Role of Industry Funding in Nutrition Research SO ADVANCES IN NUTRITION LA English DT Editorial Material AB The global burdens of morbidity and mortality associated with obesity-related chronic diseases are crippling public health and are predicted to exponentially increase over the next 3 decades. Meanwhile, the resources necessary to conduct research that may offer solutions to the obesity epidemic continue to decline and funding has become increasingly difficult to secure. Alternative models for funding nutrition and health research are necessary to make considerable and timely progress to improve public health. Key stakeholders include, but are not limited to, government agencies, foundations, private industry, and nongovernmental organizations. C1 [Zachwieja, Jeffrey] Dairy Res Inst, Rosemont, IL USA. [Hentges, Eric] Int Life Sci Inst North Amer, Washington, DC USA. [Hill, James O.] Univ Colorado, Anschutz Hlth & Wellness Ctr, Boulder, CO 80309 USA. [Black, Richard] PepsiCo Global Nutr, Purchase, NY USA. [Vassileva, Maria] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Zachwieja, J (reprint author), Dairy Res Inst, Rosemont, IL USA. FU ASN; Dairy Research Institute FX This article is a summary of the symposium, "Public-Private Partnerships: The Evolving Role of Industry Funding in Nutrition Research" held April 23, 2013 at the American Society for Nutrition Scientific Sessions and Annual Meeting held in conjunction with Experimental Biology 2013 in Boston, MA. The symposium was sponsored by the ASN and an educational grant from the Dairy Research Institute. NR 1 TC 1 Z9 1 U1 2 U2 16 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2013 VL 4 IS 5 BP 570 EP 572 DI 10.3945/an.113.004382 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 217KH UT WOS:000324357900021 PM 24038261 ER PT J AU Ohlhorst, SD Russell, R Bier, D Klurfeld, DM Li, ZP Mein, JR Milner, J Ross, AC Stover, P Konopka, E AF Ohlhorst, Sarah D. Russell, Robert Bier, Dennis Klurfeld, David M. Li, Zhaoping Mein, Jonathan R. Milner, John Ross, A. Catharine Stover, Patrick Konopka, Emily TI Nutrition research to affect food and a healthy lifespan SO ADVANCES IN NUTRITION LA English DT Article ID MEDITERRANEAN DIET; CHILDREN AB Proper nutrition offers one of the most effective and least costly ways to decrease the burden of many diseases and their associated risk factors, including obesity. Nutrition research holds the key to increasing our understanding of the causes of obesity and its related comorbidities and thus holds promise to markedly influence global health and economies. After outreach to 75 thought leaders, the American Society for Nutrition (ASN) convened a Working Group to identify the nutrition research needs whose advancement will have the greatest projected impact on the future health and well-being of global populations. ASN's Nutrition Research Needs focus on the following high priority areas: 1) variability in individual responses to diet and foods; 2) healthy growth, development, and reproduction; 3) health maintenance; 4) medical management; 5) nutrition-related behaviors; and 6) food supply/environment. ASN hopes the Nutrition Research Needs will prompt collaboration among scientists across all disciplines to advance this challenging research agenda given the high potential for translation and impact on public health. Furthermore, ASN hopes the findings from the Nutrition Research Needs will stimulate the development and adoption of new and innovative strategies that can be applied toward the prevention and treatment of nutrition-related diseases. The multidisciplinary nature of nutrition research requires stakeholders with differing areas of expertise to collaborate on multifaceted approaches to establish the evidence-based nutrition guidance and policies that will lead to better health for the, global population. In addition to the identified research needs, ASN also identified 5 tools that are critical to the advancement of the Nutrition Research Needs: 1) omics, 2) bioinformatics, 3) databases, 4) biomarkers, and 5) cost-effectiveness analysis. C1 [Ohlhorst, Sarah D.; Konopka, Emily] Amer Soc Nutr, Bethesda, MD 20814 USA. [Russell, Robert] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Russell, Robert] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Bier, Dennis] Baylor Coll Med, Childrens Nutr Res Ctr, USDA ARS, Dept Pediat, Houston, TX 77030 USA. [Klurfeld, David M.] USDA ARS, Human Nutr Program, Beltsville, MD USA. [Li, Zhaoping] Univ Calif Los Angeles, Ctr Human Nutr, Los Angeles, CA USA. [Li, Zhaoping] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Mein, Jonathan R.] Monsanto Vegetable Seed, Monsanto Ctr Food & Nutr Res, Kannapolis, NC USA. [Milner, John] NCI, NIH, Bethesda, MD 20892 USA. [Ross, A. Catharine] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Stover, Patrick] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Konopka, Emily] Nazareth Coll, Rochester, NY USA. RP Ohlhorst, SD (reprint author), Amer Soc Nutr, 9650 Rockville Pike, Bethesda, MD 20814 USA. EM sohlhorst@nutrition.org NR 12 TC 3 Z9 3 U1 0 U2 16 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2013 VL 4 IS 5 BP 579 EP 584 DI 10.3945/an.113004176 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 217KH UT WOS:000324357900025 PM 24038264 ER PT J AU Geda, YE Schneider, LS Gitlin, LN Miller, DS Smith, GS Bell, J Evans, J Lee, M Porsteinsson, A Lanctot, KL Rosenberg, PB Sultzer, DL Francis, PT Brodaty, H Padala, PP Onyike, CU Ortiz, LA Ancoli-Israel, S Bliwise, DL Martin, JL Vitiello, MV Yaffe, K Zee, PC Herrmann, N Sweet, RA Ballard, C Khin, NA Alfaro, C Murray, PS Schultz, S Lyketsos, CG AF Geda, Yonas E. Schneider, Lon S. Gitlin, Laura N. Miller, David S. Smith, Gwenn S. Bell, Joanne Evans, Jovier Lee, Michael Porsteinsson, Anton Lanctot, Krista L. Rosenberg, Paul B. Sultzer, David L. Francis, Paul T. Brodaty, Henry Padala, Prasad P. Onyike, Chiadikaobi U. Ortiz, Luis Agueera Ancoli-Israel, Sonia Bliwise, Donald L. Martin, Jennifer L. Vitiello, Michael V. Yaffe, Kristine Zee, Phyllis C. Herrmann, Nathan Sweet, Robert A. Ballard, Clive Khin, Ni A. Alfaro, Cara Murray, Patrick S. Schultz, Susan Lyketsos, Constantine G. CA Neuropsychiat Syndromes TI Neuropsychiatric symptoms in Alzheimer's disease: Past progress and anticipation of the future SO ALZHEIMERS & DEMENTIA LA English DT Article DE Neuropsychiatric symptoms; Behavioral and psychological symptoms of dementia; Agitation/aggression; Sleep disorders; Depression; Apathy; Psychosis; Delusions; Hallucinations; Dementia; Alzheimer's disease; Mild cognitive impairment; Mild behavioral impairment ID MILD COGNITIVE IMPAIRMENT; VASCULAR DEPRESSION HYPOTHESIS; PITTSBURGH COMPOUND-B; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; BEHAVIORAL SYMPTOMS; NATIONAL INSTITUTE; RANDOMIZED-TRIAL; RATING-SCALE; DOUBLE-BLIND AB Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis. (C) 2013 The Alzheimer's Association. All rights reserved. C1 [Geda, Yonas E.] Mayo Clin, Coll Med, Dept Psychiat, Scottsdale, AZ USA. [Geda, Yonas E.] Mayo Clin, Coll Med, Dept Neurol, Scottsdale, AZ USA. [Schneider, Lon S.] Univ So Calif, Los Angeles, CA USA. [Gitlin, Laura N.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Miller, David S.] Bracket, Wayne, PA USA. [Smith, Gwenn S.; Rosenberg, Paul B.; Onyike, Chiadikaobi U.; Lyketsos, Constantine G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Geriatr Psychiat & Neuropsychiat, Baltimore, MD 21218 USA. [Evans, Jovier] NIMH, Geriatr Res Branch, Geriatr Translat Neurosci & MultiModal Interv Pro, Geriatr Pharmacol Intervent, Bethesda, MD 20892 USA. [Lee, Michael] Univ Minnesota, Inst Translat Neurosci, Dept Neurosci, Minneapolis, MN USA. [Lee, Michael] Univ Minnesota, Inst Translat Neurosci, Ctr Neurodegenerat Dis, Minneapolis, MN USA. [Porsteinsson, Anton] Univ Rochester, Sch Med & Dent Rochester, Dept Psychiat, Rochester, NY USA. [Lanctot, Krista L.] Sunnybrook Res Inst, Brain Sci Program, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Dept Toxicol, Toronto, ON, Canada. [Sultzer, David L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Sultzer, David L.] VA Greater Angeles Healthcare Syst, Psychiat Serv, Los Angeles, CA USA. [Francis, Paul T.] Kings Coll London, Wolfson Ctr Age Related Dis, London, England. [Brodaty, Henry] Univ New S Wales, Dementia Collaborat Res Ctr, Sydney, NSW, Australia. [Padala, Prasad P.] Cent Arkansas Vet Healthcare Syst, Geriatr Res Educ & Clin Ctr, Little Rock, AR USA. [Padala, Prasad P.] Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. [Ortiz, Luis Agueera] C1BERSAM, Madrid, Spain. [Ortiz, Luis Agueera] Univ Hosp Doce Octubre, Madrid, Spain. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Bliwise, Donald L.] Emory Univ, Sch Med, Wesley Woods Hlth Ctr, Dept Neurol, Atlanta, GA USA. [Martin, Jennifer L.] Univ Calif Los Angeles, Educ & Clin Ctr, VA Greater Angeles Healthcare Geriatr Res, Los Angeles, CA USA. [Martin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Vitiello, Michael V.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Zee, Phyllis C.] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Sweet, Robert A.; Murray, Patrick S.] VA Pittsburgh Healthcare Syst, VISN 4 Mental Illness Res Educ & Clin Ctr MIRECC, Pittsburgh, PA USA. [Ballard, Clive] Kings Coll London, Wolfson Ctr Age Related Dis, Biomed Res Unit, Inst Psychiat & Alzheimers Soc, London WC2R 2LS, England. [Khin, Ni A.; Alfaro, Cara] US FDA, Ctr Drug Evaluat & Res, Off Drug Evaluat 1 OND, Div Psychiat Prod, Silver Spring, MD USA. [Schultz, Susan] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA USA. RP Lyketsos, CG (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Geriatr Psychiat & Neuropsychiat, Baltimore, MD 21218 USA. RI Lee, Michael/D-9491-2013; Francis, Paul/A-9199-2008; OI Lee, Michael/0000-0001-5865-9682; Murray, Patrick/0000-0002-6525-2888; Vitiello, Michael/0000-0002-9776-0473; Lanctot, Krista L./0000-0001-7024-6637 FU NIMH [K01-MH68351, R24-MH074779, R01-MH079814, RC1-MH090770-01]; NIA [U01-AG006786]; National Center for Research Resources [RR024150]; Robert Wood Johnson Foundation; European Union Regional Development Fund [FNUSA-ICRC: CZ.1.05/1.1.00/02.0123]; Baxter; Elan Pharmaceuticals; Johnson Johnson; Eli Lilly; Myriad; Novartis; Pfizer; Abbott Laboratories; AC Immune; Allergan; Allon; Alzheimer Drug Discovery Foundation; AstraZeneca; Bristol-Myers Squibb; Elan; Exonhit; Forest; GlaxoSmithKline; Ipsen Pharmaceuticals; Lundbeck; Medavante; Medivation; Merck; Merz; Roche; Sanofi-Aventis; Schering-Plough; Schwabe; Toyama; Transition Therapeutics; Alzheimer's Association [IIRG-07-28686]; Johns Hopkins Alzheimer's Disease Research Center [P50-AG005146]; NIMH, MA; Associated Jewish Federation of Baltimore; Weinberg Foundation; Eisai; Lilly; Ortho-McNeil; Bristol-Myers; National Football League; Functional Neuromodulation Inc. FX The authors thank Dr. Michelle M. Mielke for her helpful comments and feedback on early drafts of this manuscript. Dr. Geda was supported by NIMH grant K01-MH68351, NIA grant U01-AG006786 (the Mayo Clinic Study of Aging), National Center for Research Resources grant RR024150 (Mayo Clinic CTSA [Career Transition Award]), the Robert Wood Johnson Foundation (Harold Amos Scholar), and the European Union Regional Development Fund (Project FNUSA-ICRC: CZ.1.05/1.1.00/02.0123). Dr. Schneider reports being an editor on the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees systematic reviews of drugs for cognitive impairment and dementia. He received a grant from the Alzheimer's Association for a registry for dementia and cognitive impairment trials; he is also in receipt of grant or research support from Baxter, Elan Pharmaceuticals, Johnson & Johnson, Eli Lilly, Myriad, Novartis, and Pfizer. He has served as a consultant for or received consulting fees from Abbott Laboratories, AC Immune, Allergan, Allon, the Alzheimer Drug Discovery Foundation, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Exonhit, Forest, GlaxoSmithKline, Ipsen Pharmaceuticals, Johnson & Johnson, Lundbeck, Myriad, Medavante, Medivation, Merck, Merz, Novartis, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, Schwabe, Toyama, and Transition Therapeutics. Dr. Gitlin was supported by NIMH grants R24-MH074779, R01-MH079814, and RC1-MH090770-01 and Alzheimer's Association grant IIRG-07-28686 and served on the Phillips Life Line Falls Advisory Board. Dr. Miller is a full-time employee of Bracket. Dr. Lyketsos was supported by the Johns Hopkins Alzheimer's Disease Research Center (P50-AG005146). He has received grant support (research or CME) from NIMH, MA, the Associated Jewish Federation of Baltimore, the Weinberg Foundation, Forest, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, the National Football League, Elan, and Functional Neuromodulation Inc. He has served as consultant/advisor for AstraZeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, the NFL Players Association, the NFL Benefits Office, Avanir, and Zinfandel. He has also received honorarium or travel support from Pfizer, Forest, GlaxoSmithKline, and Health Monitor. NR 68 TC 75 Z9 76 U1 8 U2 43 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD SEP PY 2013 VL 9 IS 5 BP 602 EP 608 DI 10.1016/j.jalz.2012.12.001 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 222IN UT WOS:000324724500015 PM 23562430 ER PT J AU Whirledge, S Xu, XJ Cidlowski, JA AF Whirledge, Shannon Xu, Xiaojiang Cidlowski, John A. TI Global Gene Expression Analysis in Human Uterine Epithelial Cells Defines New Targets of Glucocorticoid and Estradiol Antagonism SO BIOLOGY OF REPRODUCTION LA English DT Article DE epithelial cells; ESR1; estrogen receptor; glucocorticoid receptor; microarray; NR3C1; uterus ID STIMULATING-HORMONE RECEPTOR; FEMALE REPRODUCTIVE-TRACT; FACTOR-BINDING PROFILES; OPEN-ACCESS DATABASE; TRANSCRIPTION FACTOR; EMBRYO IMPLANTATION; STROMAL CELLS; INFLAMMATORY RESPONSE; MICROARRAY ANALYSIS; MOUSE UTERUS AB In preparation for embryo implantation and pregnancy, the uterine epithelium undergoes a genomic and biological transition that mediates adhesion and invasion of the blastocyst. These events resemble an inflammatory response, and the immune system likely takes an active role in the establishment and maintenance of pregnancy. Although glucocorticoids are primary mediators of the immune system, the functional role of glucocorticoid signaling in the uterine epithelium is not well defined. To investigate the dynamic relationship between glucocorticoids and reproductive hormones, we performed whole-genome microarray analysis in a human uterine endometrial cancer cell line (ECC1 cells) treated with the synthetic glucocorticoid dexamethasone (Dex) alone or in combination with estradiol (E-2). Over 10 000 genes were significantly regulated in the presence of Dex and/or E-2. Surprisingly, unique targets of Dex and E-2 together represented the largest group of regulated genes. Ingenuity pathway analysis found both overlapping and independent regulated networks for each hormone. Several hundred genes were found to be coregulated by Dex and E-2, including several that were antagonistically regulated. The effects of glucocorticoids and E-2 are mediated primarily through the glucocorticoid receptor (NR3C1) and estrogen receptor (ESR1), respectively. In silico promoter analysis revealed that NR3C1 and ESR1 response elements are enriched in antagonistically regulated genes, and signaling through these receptors was required for antagonism. Glucocorticoid and E-2 antagonism of target genes may represent a critical junction between the immune system and female reproductive system. Moreover, identification and ontology analysis of glucocorticoid-regulated genes in a uterine epithelial-like cell line suggests that glucocorticoid signaling regulates important biological functions, including immune cell trafficking and embryonic development. C1 [Whirledge, Shannon; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Xu, Xiaojiang] NIEHS, Lab Integrat Bioinformat, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural Research Program of the NIH National Institute of Environmental Health Sciences FX Supported by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences. NR 75 TC 12 Z9 12 U1 0 U2 2 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD SEP PY 2013 VL 89 IS 3 AR 66 DI 10.1095/biolreprod.113.111054 PG 17 WC Reproductive Biology SC Reproductive Biology GA 226AS UT WOS:000325007200017 PM 23843231 ER PT J AU FitzGerald, LM Kumar, A Boyle, EA Zhang, YZ McIntosh, LM Kolb, S Stott-Miller, M Smith, T Karyadi, DM Ostrander, EA Hsu, L Shendure, J Stanford, JL AF FitzGerald, Liesel M. Kumar, Akash Boyle, Evan A. Zhang, Yuzheng McIntosh, Laura M. Kolb, Suzanne Stott-Miller, Marni Smith, Tiffany Karyadi, Danielle M. Ostrander, Elaine A. Hsu, Li Shendure, Jay Stanford, Janet L. TI Germline Missense Variants in the BTNL2 Gene Are Associated with Prostate Cancer Susceptibility SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID AUTISM SPECTRUM DISORDERS; BRCA2 GENE; MUTATIONS; HOXB13; RISK; LOCI; SEQUENCE; IDENTIFICATION; INFLAMMATION; SARCOIDOSIS AB Background: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified. Methods: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case-control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry. Results: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p. Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27-5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16-5.46; P = 0.019). Conclusions: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer. Impact: Results implicate BTNL2 as a novel prostate cancer susceptibility gene. (C) 2013 AACR. C1 [FitzGerald, Liesel M.; Zhang, Yuzheng; McIntosh, Laura M.; Kolb, Suzanne; Stott-Miller, Marni; Hsu, Li; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kumar, Akash; Boyle, Evan A.; Shendure, Jay] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Tiffany; Karyadi, Danielle M.; Ostrander, Elaine A.] NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,POB 19024,M4-B874, Seattle, WA 98109 USA. EM jstanfor@fhcrc.org OI Boyle, Evan/0000-0003-4494-9771; Shendure, Jay/0000-0002-1516-1865; Ostrander, Elaine/0000-0001-6075-9738 FU U.S. National Cancer Institute, NIH [RO1 CA080122, P50 CA097186]; Fred Hutchinson Cancer Research Center; Prostate Cancer Foundation; NIH [HHSN268200782096C]; NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926]; Achievement Award for College Scientists Fellowship; Lowell Milken Prostate Cancer Foundation Young Investigator Award; Intramural Program of the National Human Genome Research Institute; Prostate Cancer Foundation Creativity Award FX This work was supported by grants from the U.S. National Cancer Institute, NIH (grant numbers RO1 CA080122 and P50 CA097186 to J.L. Stanford); with additional support from the Fred Hutchinson Cancer Research Center; and the Prostate Cancer Foundation. Sequencing services were provided by the Center for Inherited Disease Research, which is funded through a contract from NIH to The Johns Hopkins University (contract no. HHSN268200782096C). Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (WHISP). The exome sequencing was conducted through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). A. Kumar is supported by an Achievement Award for College Scientists Fellowship; J. Shendure is supported by The Lowell Milken Prostate Cancer Foundation Young Investigator Award; E. A. Ostrander is supported by the Intramural Program of the National Human Genome Research Institute; J. L. Stanford is supported by a Prostate Cancer Foundation Creativity Award. NR 47 TC 12 Z9 12 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2013 VL 22 IS 9 BP 1520 EP 1528 DI 10.1158/1055-9965.EPI-13-0345 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 221QV UT WOS:000324674500005 PM 23833122 ER PT J AU Karami, S Andreotti, G Koutros, S Barry, KH Moore, LE Han, S Hoppin, JA Sandler, DP Lubin, JH Burdette, LA Yuenger, J Yeager, M Freeman, LEB Blair, A Alavanja, MCR AF Karami, Sara Andreotti, Gabriella Koutros, Stella Barry, Kathryn Hughes Moore, Lee E. Han, Summer Hoppin, Jane A. Sandler, Dale P. Lubin, Jay H. Burdette, Laurie A. Yuenger, Jeffrey Yeager, Meredith Freeman, Laura E. Beane Blair, Aaron Alavanja, Michael C. R. TI Pesticide Exposure and Inherited Variants in Vitamin D Pathway Genes in Relation to Prostate Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; NON-HODGKINS-LYMPHOMA; AGRICULTURAL HEALTH; SUN EXPOSURE; RISK-FACTORS; APPLICATORS; PREVENTION; RECEPTOR; POLYMORPHISMS; RADIATION AB Background: Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D's anticarcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants. Methods: We evaluated interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNP) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of Caucasian pesticide applicators within the Agricultural Health Study. We assessed P-interaction values using likelihood ratio tests from unconditional logistic regression and a false discovery rate (FDR) to account for multiple comparisons. Results: Five significant interactions (P < 0.01) displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB, and GC). The exposure-response pattern among participants with increasing parathion use with the homozygous CC genotype for GC rs7041 compared with unexposed participants was noteworthy [low vs. no exposure: OR, 2.58, 95% confidence interval (CI), 1.07-6.25; high vs. no exposure: OR, 3.09, 95% CI, 1.10-8.68; P-interaction = 3.8 x 10(-3)]. Conclusions: In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, an SNP previously linked to lower circulating vitamin D levels, modified pesticide associations with prostate cancer risk. Impact: Because our study is the first to examine this relationship, additional studies are needed to rule out chance findings. (C) 2013 AACR. C1 [Karami, Sara; Andreotti, Gabriella; Koutros, Stella; Barry, Kathryn Hughes; Moore, Lee E.; Han, Summer; Lubin, Jay H.; Freeman, Laura E. Beane; Blair, Aaron; Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Burdette, Laurie A.; Yuenger, Jeffrey; Yeager, Meredith] SAIC Frederick Inc, Natl Canc Inst Frederick, Core Genotyping Facil, Frederick, MD USA. [Hoppin, Jane A.; Sandler, Dale P.] NIH, Epidemiol Branch, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Karami, S (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,EPS 8121, Rockville, MD 20852 USA. EM karamis@mail.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NCI, Division of Cancer Epidemiology and Genetics [Z01CP010119]; National Institute of Environmental Health Sciences (NIEHS), NIH [Z01ES049030] FX This research was supported by the Intramural Research Program of the NCI, Division of Cancer Epidemiology and Genetics (Z01CP010119) and the National Institute of Environmental Health Sciences (NIEHS; Z01ES049030), NIH. NR 63 TC 7 Z9 8 U1 1 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2013 VL 22 IS 9 BP 1557 EP 1566 DI 10.1158/1055-9965.EPI-12-1454 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 221QV UT WOS:000324674500009 PM 23833127 ER PT J AU Andreotti, G Birmann, B De Roos, AJ Spinelli, J Cozen, W Camp, NJ Moysich, K Chiu, B Steplowski, E Krzystan, J Boffetta, P Benhaim-Luzon, V Brennan, P de Sanjose, S Costas, L Costantini, AS Miligi, L Cocco, P Becker, N Foretova, L Maynadie, M Nieters, A Staines, A Tricot, G Milliken, K Weisenburger, D Zheng, TZ Baris, D Purdue, MP AF Andreotti, Gabriella Birmann, Brenda De Roos, Anneclaire J. Spinelli, John Cozen, Wendy Camp, Nicola J. Moysich, Kirsten Chiu, Brian Steplowski, Emily Krzystan, Joseph Boffetta, Paolo Benhaim-Luzon, Veronique Brennan, Paul de Sanjose, Silvia Costas, Laura Costantini, Adele Seniori Miligi, Lucia Cocco, Pierluigi Becker, Nikolaus Foretova, Lenka Maynadie, Marc Nieters, Alexandra Staines, Anthony Tricot, Guido Milliken, Kevin Weisenburger, Dennis Zheng, Tongzhang Baris, Dalsu Purdue, Mark P. TI A Pooled Analysis of Alcohol Consumption and Risk of Multiple Myeloma in the International Multiple Myeloma Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NON-HODGKIN-LYMPHOMA; CONNECTICUT WOMEN; CIGARETTE-SMOKING; COHORT; DIET; NEOPLASMS; BEVERAGES; DRINKING; TOBACCO; CELLS AB Background: Recent findings suggest that alcohol consumption may reduce risk of multiple myeloma. Methods: To better understand this relationship, we conducted an analysis of six case-control studies participating in the International Multiple Myeloma Consortium (1,567 cases, 7,296 controls). Summary ORs and 95% confidence intervals (CI) relating different measures of alcohol consumption and multiple myeloma risk were computed by unconditional logistic regression with adjustment for age, race, and study center. Results: Cases were significantly less likely than controls to report ever drinking alcohol (men: OR = 0.72; 95% CI, 0.59-0.89; women: OR = 0.81; 95% CI, 0.68-0.95). The inverse association with multiple myeloma was stronger when comparing current to never drinkers (men: OR = 0.57; 95% CI, 0.45-0.72; women: OR = 0.55; 95% CI, 0.45-0.68), but null among former drinkers. We did not observe an exposure-response relationship with increasing alcohol frequency, duration, or cumulative lifetime consumption. Additional adjustment for body mass index, education, or smoking did not affect our results; and the patterns of association were similar for each type of alcohol beverage examined. Conclusions: Our study is, to our knowledge, the largest of its kind to date, and our findings suggest that alcohol consumption may be associated with reduced risk of multiple myeloma. Impact: Prospective studies, especially those conducted as pooled analyses with large sample sizes, are needed to confirm our findings and further explore whether alcohol consumption provides true biologic protection against this rare, highly fatal malignancy. (C) 2013 AACR. C1 [Andreotti, Gabriella; Baris, Dalsu; Purdue, Mark P.] NIH, DHHS, Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Steplowski, Emily; Krzystan, Joseph] Informat Management Serv Inc, Silver Spring, MD USA. [Birmann, Brenda] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Birmann, Brenda] Harvard Med Sch, Boston, MA USA. [De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Spinelli, John] Univ British Columbia, BC Canc Agcy, Vancouver, BC V5Z 1M9, Canada. [Spinelli, John] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Camp, Nicola J.] Univ Utah, Sch Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Moysich, Kirsten] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Boffetta, Paolo] Mt Sinai Sch Med, New York, NY USA. [Chiu, Brian] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Tricot, Guido] Univ Iowa, Dept Internal Med, Iowa City, IA USA. [Weisenburger, Dennis] Univ Nebraska, Med Ctr, Pathol & Microbiol Dept, Lincoln, NE USA. [Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Benhaim-Luzon, Veronique; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Maynadie, Marc] Univ Burgundy, Registry Hematol Malignanc Cote, EA4184, Dijon, France. [de Sanjose, Silvia; Costas, Laura] Univ Barcelona, IDIBELL, Catalan Inst Oncol, Unit Infect & Canc, Barcelona, Spain. [Costas, Laura] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Costantini, Adele Seniori; Miligi, Lucia] Ctr Study & Prevent Canc, Unit Occupat & Environm Epidemiol, Florence, Italy. [Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth, Occupat Hlth Sect, Cagliari, Italy. [Becker, Nikolaus] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Nieters, Alexandra] German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Germany. [Foretova, Lenka] Masaryk Mem Canc Inst, Dep Canc Epidemiol & Genet, Brno, Czech Republic. [Staines, Anthony] Publ Hlth Univ Coll, Dept Publ Hlth, Dublin, Ireland. RP Andreotti, G (reprint author), Natl Canc Inst, Med Ctr 6909, Dr Rm 6E622,MSC 9704, Bethesda, MD 20892 USA. EM andreotg@mail.nih.gov RI Spinelli, John/B-6210-2013; de Sanjose Llongueras, Silvia/H-6339-2014; Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Costas, Laura/0000-0003-2755-302X; Staines, Anthony/0000-0001-9161-1357 FU Leukemia and Lymphoma Society [6067-09]; NCI [CA152336, P30 CA42014, K07 CA115687, CA149445]; HCI Cancer Center; NCI SEER [HHSN261201000026C]; Utah State Department of Health; University of Utah; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; American Cancer Society [RSG-11-020-01-CNE] FX Funding for the Utah study was in part from the Leukemia and Lymphoma Society 6067-09 (N.J. Camp) and the NCI CA152336 (N.J. Camp). Data collection for the Utah resource was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the University of Utah Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 from the NCI. The UCR is funded by contract HHSN261201000026C from the NCI SEER program with additional support from the Utah State Department of Health and the University of Utah. The work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). The work conducted by B. Birmann was supported in part by grants from the NCI (K07 CA115687, CA149445) and the American Cancer Society (RSG-11-020-01-CNE). NR 28 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2013 VL 22 IS 9 BP 1620 EP 1627 DI 10.1158/1055-9965.EPI-13-0334 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 221QV UT WOS:000324674500015 PM 23964064 ER PT J AU Wernli, KJ Kitahara, CM Tamers, SL Al-Temimi, MH Braithwaite, D AF Wernli, Karen J. Kitahara, Cari M. Tamers, Sara L. Al-Temimi, Mohammed H. Braithwaite, Dejana TI Undertaking Cancer Research in International Settings: Report from the American Society for Preventive Oncology Special Interest Group on International Issues in Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEALTH RECORDS REGISTER; STRESSFUL LIFE EVENTS; COHORT PROFILE; ALCOHOL; HEIGHT AB The mission of the American Society for Preventive Oncology Special Interest Group in International Issues in Cancer is to serve as a worldwide cancer prevention resource. At the 2013 annual meeting, we presented three early career investigators who conducted research with international collaborators as part of postdoctoral studies. We present a synopsis of each of the scientific presentations. The investigators also highlight useful strategies to encourage a more successful international collaboration, including seeking out existing collaborations between colleagues and international researchers, maintaining awareness and sensitivity of cultural norms, establishing clear communication about investigator roles and expectations, and persevering in the face of potential challenges due to the nature of these collaborations. Incorporation of these key elements could prove useful for researchers interested in pursuing cross-country projects. (C) 2013 AACR. C1 [Wernli, Karen J.] Grp Hlth Res Inst, Seattle, WA USA. [Kitahara, Cari M.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Tamers, Sara L.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Tamers, Sara L.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Al-Temimi, Mohammed H.] Univ Utah, Dept Family & Prevent Med, Div Publ Hlth, Salt Lake City, UT USA. [Braithwaite, Dejana] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. RP Braithwaite, D (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Suite 5700, San Francisco, CA 94107 USA. EM DBraithwaite@epi.ucsf.edu RI Kitahara, Cari/R-8267-2016 FU Agency for Healthcare Research and Quality K12 Comparative Effectiveness Research Scholar Award [K12 HS019482]; Intramural Research Program of the National Cancer Institute (NCI), NIH; NIH/NCI Harvard Education Program in Cancer Prevention and Control [R25 CA057713]; NIH/NCI Reducing Social Disparities in Cancer Risk [K05 CA108663-05]; European Commission Public Health Programme, DG Sanco [2006 319]; American Cancer Society [121891-MRSG-12-007-01-CPHPS] FX K.J. Wernli was supported in part by Agency for Healthcare Research and Quality K12 Comparative Effectiveness Research Scholar Award (K12 HS019482). C. M. Kitahara was supported in part by the Intramural Research Program of the National Cancer Institute (NCI), NIH. S. L. Tamers was supported in part by the NIH/NCI Harvard Education Program in Cancer Prevention and Control (R25 CA057713; PI G. Sorensen), and the NIH/NCI Reducing Social Disparities in Cancer Risk (K05 CA108663-05 to GS). The work of M. H. Al-Temimi was part of the Women in Europe against Lung Cancer and Smoking (WELAS) project, which was supported by the European Commission Public Health Programme, DG Sanco (Grant # 2006 319). D. Braithwaite was supported in part by Grant # 121891-MRSG-12-007-01-CPHPS from the American Cancer Society. NR 20 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 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2013 VL 22 IS 9 BP 1638 EP 1641 DI 10.1158/1055-9965.EPI-13-0655 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 221QV UT WOS:000324674500019 PM 23845714 ER PT J AU Boudreaux, ED Miller, I Goldstein, AB Sullivan, AF Allen, MH Manton, AP Arias, SA Camargo, CA AF Boudreaux, Edwin D. Miller, Ivan Goldstein, Amy B. Sullivan, Ashley F. Allen, Michael H. Manton, Anne P. Arias, Sarah A. Camargo, Carlos A., Jr. TI The Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE): Method and design considerations SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Suicide; Research methods; Mental health; Emergency department ID SUICIDAL-BEHAVIOR; INTERVENTION RESEARCH; RISK; HEALTH; PREVALENCE; THOUGHTS; FIREARMS; SYSTEM AB Background: Due to the concentration of individuals at-risk for suicide, an emergency department visit represents an opportune time for suicide risk screening and intervention. Purpose: The Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) uses a quasi-experimental, interrupted time series design to evaluate whether (1) a practical approach to universally screening ED patients for suicide risk leads to improved detection of suicide risk and (2) a multi-component intervention delivered during and after the ED visit improves suicide-related outcomes. Methods: This paper summarizes the ED-SAFE's study design and methods within the context of considerations relevant to effectiveness research in suicide prevention and pertinent human participants concerns. 1440 suicidal individuals, from 8 general ED's nationally will be enrolled during three sequential phases of data collection (480 individuals/phase): (1) Treatment as Usual; (2) Universal Screening; and (3) Intervention. Data from the three phases will inform two separate evaluations: Screening Outcome (Phases 1 and 2) and Intervention (Phases 2 and 3). Individuals will be followed for 12 months. The primary study outcome is a composite reflecting completed suicide, attempted suicide, aborted or interrupted attempts, and implementation of rescue procedures during an outcome assessment. Conclusions: While 'classic' randomized control trials (RCT) are typically selected over quasi-experimental designs, ethical and methodological issues may make an RCT a poor fit for complex interventions in an applied setting, such as the ED. ED-SAFE represents an innovative approach to examining the complex public health issue of suicide prevention through a multi-phase, quasi-experimental design embedded in 'real world' clinical settings. (C) 2013 Elsevier Inc. All rights reserved. C1 [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Miller, Ivan] Butler Hosp, Providence, RI 02906 USA. [Goldstein, Amy B.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Goldstein, Amy B.] NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. [Sullivan, Ashley F.; Arias, Sarah A.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Allen, Michael H.] Univ Colorado, Depress Ctr, Aurora, CO USA. [Allen, Michael H.] VISN 19 MIRECC, Aurora, CO USA. [Manton, Anne P.] Cape Cod Hosp, Cape Psychiat Ctr, Cape Cod, MA USA. RP Boudreaux, ED (reprint author), Univ Massachusetts, Sch Med, LA 189,55 Lake Ave North, Worcester, MA 01655 USA. EM Edwin.Boudreaux@umassmed.edu RI Allen, Michael/A-8776-2011; OI Boudreaux, Edwin/0000-0002-3223-6371; Arias, Sarah/0000-0003-1832-8824 FU National Institute on Mental Health [U01MH088278] FX The project described was supported by Award Number U01MH088278 from the National Institute on Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. None of the authors have financial conflicts of interest to disclose. NR 26 TC 16 Z9 16 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD SEP PY 2013 VL 36 IS 1 BP 14 EP 24 DI 10.1016/j.cct.2013.05.008 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 225KH UT WOS:000324961300002 PM 23707435 ER PT J AU Eastmond, DA Vulimiri, SV French, JE Sonawane, B AF Eastmond, David A. Vulimiri, Suryanarayana V. French, John E. Sonawane, Babasaheb TI The use of genetically modified mice in cancer risk assessment: Challenges and limitations SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE Carcinogen; concordance; dose-response; hazard identification; mechanism; pathway-specificity; study duration; transgenic ID TRANSGENIC MOUSE MODELS; HA-RAS GENE; SHORT-TERM CARCINOGENICITY; CENTER-DOT-AC; WILD-TYPE P53; TG.AC MICE; IDENTIFYING CARCINOGENS; CHEMICAL CARCINOGENESIS; COLLABORATIVE CROSS; ALTERNATIVE MODELS AB The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53(+/-), Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program's conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals. C1 [Eastmond, David A.] Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. [Vulimiri, Suryanarayana V.; Sonawane, Babasaheb] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [French, John E.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Eastmond, DA (reprint author), Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. EM david.eastmond@ucr.edu OI Vulimiri, Suryanarayana/0000-0003-3734-0036 FU Intramural NIH HHS [Z99 ES999999] NR 140 TC 6 Z9 7 U1 0 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD SEP PY 2013 VL 43 IS 8 BP 611 EP 631 DI 10.3109/10408444.2013.822844 PG 21 WC Toxicology SC Toxicology GA 219EV UT WOS:000324489800001 PM 23985072 ER PT J AU Kennedy, AP Epstein, DH Phillips, KA Preston, KL AF Kennedy, Ashley P. Epstein, David H. Phillips, Karran A. Preston, Kenzie L. TI Sex differences in cocaine/heroin users: Drug-use triggers and craving in daily life SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Ecological momentary assessment; Sex differences; Craving; Cocaine; Heroin; Drug cues; Gender; Methadone treatment ID ECOLOGICAL MOMENTARY ASSESSMENT; SUBSTANCE-ABUSE TREATMENT; GENDER-DIFFERENCES; DEPENDENT WOMEN; MENSTRUAL-CYCLE; SMOKED COCAINE; HEROIN USERS; ADDICT CAREERS; ALCOHOL; MEN AB Background: Studies of sex differences have shown that men and women with drug-use disorders differ in course and outcome and in cue-induced activation of putative brain "control network" areas. We evaluated sex differences in daily functioning and subjective events related to drug use with ecological momentary assessment (EMA). Methods: EMA data were collected from cocaine- and heroin-using outpatients (72 men; 42 women) in methadone maintenance in 2-5 randomly prompted (RP) entries per day and in participant-initiated entries for heroin or cocaine use or craving, for up to 25 weeks. Urine drug screens were conducted three times weekly. Data were analyzed via repeated-measures logistic regression, using sex as a predictor of responses. Results: In RP reports, women and men reported significantly different patterns of drug-cue exposure, with women significantly more likely to report having seen cocaine or been tempted to use in the past hour. Women also had higher craving after past-hour exposure to drug cues. In reports of drug use, women, compared to men, were more likely to report that they had used more cocaine than they had meant to, tended to feel guilty more often after drug use, and to have used despite trying not to use. Conclusions: These findings provide real-time behavioral evidence that women respond differently than men to exposure to drug cues and to drug use, consistent with laboratory and brain-imaging findings. This information may be useful for development of sex-specific treatment strategies. Published by Elsevier Ireland Ltd. C1 [Kennedy, Ashley P.; Epstein, David H.; Phillips, Karran A.; Preston, Kenzie L.] NIDA, NIH, Treatment Sect,Clin Pharmacol & Therapeut Res Bra, Intramural Res Program,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, Clin Pharmacol & Therapeut Branch, Room 01B602,251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural Research Program of the NIH National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the NIH National Institute on Drug Abuse. NR 48 TC 16 Z9 16 U1 3 U2 26 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2013 VL 132 IS 1-2 BP 29 EP 37 DI 10.1016/j.drugalcdep.2012.12.025 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 216KE UT WOS:000324281400004 PM 23357742 ER PT J AU Wu, LT Swartz, MS Burchett, B Blazer, DG AF Wu, Li-Tzy Swartz, Marvin S. Burchett, Bruce Blazer, Dan G. CA NIDA AAPI Workgrp TI Tobacco use among Asian Americans, Native Hawaiians/Pacific Islanders, and mixed-race individuals: 2002-2010 SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Asian Americans; Mixed race; Pacific Islanders; Cigarette smoking; Tobacco use; National Survery on Drug Use and Health (NSDUH) ID UNITED-STATES; SMOKELESS TOBACCO; CIGARETTE-SMOKING; HEALTH; ADOLESCENTS; MORTALITY AB Background: Non-Hispanic Asian Americans, Native Hawaiians/Pacific Islanders (NHs/PIs), and mixed-race individuals are the fastest growing segments of the US population. We examined prevalences and correlates of tobacco use among these understudied groups. Prevalences among whites were included as a comparison. Methods: Data were drawn from the 2002-2010 National Surveys on Drug Use and Health. Respondents aged >= 12 years were assessed for current (past-month) use of cigarettes, cigars, smokeless tobacco (chewing tobacco, snuff), and pipe tobacco. Respondents' race/ethnicity, age, sex, household income, government assistance, urbanicity of residence, residential stability, self-rated health, alcohol use, and drug use were examined as correlates. Results: Between 2002 and 2010, there was a decline in the prevalence of cigarette smoking among whites (26.9% in 2002; 24.3% in 2010) and Asian Americans (18.0% in 2002; 11.1% in 2010). Prevalence of pipe tobacco use among mixed-race individuals increased from 0.2% in 2002 to 1.6% in 2010; there was little change in the prevalence of cigar and smokeless tobacco use in these racial/ethnic groups. Adjusted analyses showed that, compared with Asian Americans, mixed-race individuals had greater odds of using four tobacco products, and NHs/PIs had greater odds of using cigarettes, cigars, and smokeless tobacco. Regardless of race/ethnicity, male sex was a correlate of use of cigars, smokeless tobacco, and pipe tobacco; alcohol and drug use increased the odds of cigarette and cigar smoking. Conclusions: These new findings show prevalent tobacco use among NHs/PIs and mixed-race individuals, and highlight the importance of including these populations in future research and reporting. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Wu, Li-Tzy; Swartz, Marvin S.; Burchett, Bruce; Blazer, Dan G.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [NIDA AAPI Workgrp] Natl Inst Drug Abuse Asian Amer & Pacific Islande, Bethesda, MD 20892 USA. RP Wu, LT (reprint author), Duke Univ, Sch Med, Med Ctr, Dept Psychiat & Behav Sci, Box 3903, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU U.S. National Institute on Drug Abuse of the National Institutes of Health [HHSN271200900499P, R33DA027503, R01DA019623]; Duke University FX This work was made possible by research support from the U.S. National Institute on Drug Abuse of the National Institutes of Health (HHSN271200900499P, R33DA027503, and R01DA019623 to LT Wu) and by Duke University. The sponsoring agency had no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors. NR 44 TC 8 Z9 8 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2013 VL 132 IS 1-2 BP 87 EP 94 DI 10.1016/j.drugalcdep.2013.01.008 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 216KE UT WOS:000324281400012 PM 23394689 ER PT J AU Hill, KP Bennett, HE Griffin, ML Connery, HS Fitzmaurice, GM Subramaniam, G Woody, GE Weiss, RD AF Hill, Kevin P. Bennett, Heather E. Griffin, Margaret L. Connery, Hilary S. Fitzmaurice, Garrett M. Subramaniam, Geetha Woody, George E. Weiss, Roger D. TI Association of cannabis use with opioid outcomes among opioid-dependent youth SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cannabis use; Opioid dependence; Buprenorphine; Adolescent substance abuse ID METHADONE-MAINTENANCE; OPIATE-DEPENDENCE; MARIJUANA USE; TRIAL; ADOLESCENTS AB Objective: Cannabis use is common among opioid-dependent patients, but studies of its association with treatment outcome are mixed. In this secondary analysis, the association of cannabis use with opioid treatment outcome is assessed. Methods: In the main study, participants (n=152) aged 15-21 years were randomized to receive psychosocial treatments and either a 12-week course of buprenorphine-naloxone with a dose taper to zero in weeks 9-12, or a 2-week detoxification with buprenorphine-naloxone. Drug use was assessed by self-report and urine drug screen at baseline and during study weeks 1-12. The association between cannabis and opioid use at weeks 4, 8, and 12 was examined using logistic regression models. Results: Participants reported a median of 3.0 days (range = 0-30) cannabis use in the past month; half (50.3%; n=77) reported occasional use, one-third reported no use (33.1%; n = 50), and one-sixth reported daily cannabis use (16.6%; n = 25). Median lifetime cannabis use was 4.0 years (range = 0-11) and median age of initiation of use was 15.0 years (range 9-21). Neither past cannabis use (age of initiation and use in the month prior to baseline) nor concurrent use was associated with level of opioid use. Conclusions: Overall, cannabis use had no association with opioid use over 12 weeks in this sample of opioid-dependent youth. While cannabis use remains potentially harmful, it was not a predictor of poor opioid treatment outcome. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Hill, Kevin P.; Bennett, Heather E.; Griffin, Margaret L.; Connery, Hilary S.; Fitzmaurice, Garrett M.; Weiss, Roger D.] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02478 USA. [Hill, Kevin P.; Griffin, Margaret L.; Connery, Hilary S.; Fitzmaurice, Garrett M.; Weiss, Roger D.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Subramaniam, Geetha] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Woody, George E.] Univ Penn, Treatment Res Inst, Dept Psychiat, Philadelphia, PA 19106 USA. RP Hill, KP (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. EM khill@mclean.harvard.edu FU NIDA [K99/R00 DA029115, K24 DA022288]; NIDA CTN [U10 DA15831]; Adam Corneel Young Investigator Fellowship from McLean Hospital FX This study was supported by NIDA K99/R00 DA029115 (Kevin P. Hill, MD, MHS, PI), NIDA K24 DA022288 (Roger D. Weiss, MD, PI), NIDA CTN U10 DA15831 and the Adam Corneel Young Investigator Fellowship from McLean Hospital to Dr. Hill. The publications committee of the CTN gave final approval of the analysis and interpretation of the data and approved the manuscript. NR 23 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2013 VL 132 IS 1-2 BP 342 EP 345 DI 10.1016/j.drugalcdep.2013.02.030 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 216KE UT WOS:000324281400049 PM 23528523 ER PT J AU Compton, WM Dawson, DA Goldstein, RB Grant, BF AF Compton, Wilson M. Dawson, Deborah A. Goldstein, Rise B. Grant, Bridget F. TI Crosswalk between DSM-IV dependence and DSM-5 substance use disorders for opioids, cannabis, cocaine and alcohol SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE DSM-IV; DSM-5; Substance use disorder; Concordance; Kappa; Diagnosis ID NATIONAL EPIDEMIOLOGIC SURVEY; CONTROLLED-TRIAL; UNITED-STATES; COMORBIDITY; PREVALENCE; DISABILITY; DIAGNOSIS; THERAPY; ADULTS; ABUSE AB Background: Ascertaining agreement between DSM-IV and DSM-5 is important to determine the applicability of treatments for DSM-IV conditions to persons diagnosed according to the proposed DSM-5. Methods: Data from a nationally representative sample of US adults were used to compare concordance of past-year DSM-IV opioid, cannabis, cocaine and alcohol dependence with past-year DSM-5 disorders at thresholds of 3+, 4+, 5+ and 6+ positive DSM-5 criteria among past-year users of opioids (n = 264), cannabis (n = 1622), cocaine (n = 271) and alcohol (n = 23,013). Substance-specific 2 x 2 tables yielded overall concordance (kappa), sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV). Results: For DSM-IV alcohol, cocaine and opioid dependence, optimal concordance occurred when 4+ DSM-5 criteria were endorsed, corresponding to the threshold for moderate DSM-5 alcohol, cocaine and opioid use disorders. Maximal concordance of DSM-IV cannabis dependence and DSM-5 cannabis use disorder occurred when 6+ criteria were endorsed, corresponding to the threshold for severe DSM-5 cannabis use disorder. At these optimal thresholds, sensitivity, specificity, PPV and NPV generally exceeded 85% (>75% for cannabis). Conclusions: Overall, excellent correspondence of DSM-IV dependence with DSM-5 substance use disorders was documented in this general population sample of alcohol, cannabis, cocaine and opioid users. Applicability of treatments tested for DSM-IV dependence is supported by these results for those with a DSM-5 alcohol, cocaine or opioid use disorder of at least moderate severity or severe cannabis use disorder. Further research is needed to provide evidence for applicability of treatments for persons with milder substance use disorders. Published by Elsevier Ireland Ltd. C1 [Compton, Wilson M.] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. [Dawson, Deborah A.; Goldstein, Rise B.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD USA. [Dawson, Deborah A.] Kelly Govt Serv, Bethesda, MD USA. RP Compton, WM (reprint author), 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services; National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism FX The study on which this paper is based, the National Longitudinal Alcohol Epidemiologic Survey (NLAES), is sponsored by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services. This research was supported in part by the Intramural Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. All authors are Federal government employees, and none of the authors has any financial conflict of interest to report. NR 21 TC 27 Z9 28 U1 1 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 1 PY 2013 VL 132 IS 1-2 BP 387 EP 390 DI 10.1016/j.drugalcdep.2013.02.036 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 216KE UT WOS:000324281400057 PM 23642316 ER PT J AU Krijthe, BP Kunst, A Benjamin, EJ Lip, GYH Franco, OH Hofman, A Witteman, JCM Stricker, BH Heeringa, J AF Krijthe, Bouwe P. Kunst, Anton Benjamin, Emelia J. Lip, Gregory Y. H. Franco, Oscar H. Hofman, Albert Witteman, Jacqueline C. M. Stricker, Bruno H. Heeringa, Jan TI Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060 SO EUROPEAN HEART JOURNAL LA English DT Article DE Atrial fibrillation; Epidemiology ID HEART-FAILURE; GENERAL-POPULATION; STROKE PREVENTION; UNITED-STATES; RISK-FACTOR; PREVALENCE; ROTTERDAM; TRENDS; MORTALITY; FLUTTER AB Aims Since atrial fibrillation (AF) is associated with increased risks of cardiovascular and cerebrovascular complications, estimations on the number of individuals with AF are relevant to healthcare planning. We aimed to project the number of individuals with AF in the Netherlands and in the European Union from 2000 to 2060. Methods and results Age-and sex-specific AF prevalence estimates were obtained from the prospective community-based Rotterdam Study. Population projections for the Netherlands and the European Union were obtained from the European Union's statistics office. In the age stratum of 55-59 years, the prevalence of AF was 1.3% in men (95% CI: 0.4-3.6%) and 1.7% in women (95% CI: 0.7-4.0%). The prevalence of AF increased to 24.2% in men (95% CI: 18.5-30.7%), and 16.1% in women (95% CI: 13.1-19.4%), for those >85 years of age. This age-and sex-specific prevalence remained stable during the years of follow-up. Furthermore, we estimate that in the European Union, 8.8 million adults over 55 years had AF in 2010 (95% CI: 6.5-12.3 million). We project that this number will double by 2060 to 17.9 million (95% CI: 13.6-23.7 million) if the age-and sex-specific prevalence remains stable. Conclusion We estimate that from 2010 to 2060, the number of adults 55 years and over with AF in the European Union will more than double. As AF is associated with significant morbidities and mortality, this increasing number of individuals with AF may have major public health implications. C1 [Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Witteman, Jacqueline C. M.; Stricker, Bruno H.; Heeringa, Jan] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Kunst, Anton] Univ Amsterdam, Amsterdam Med Ctr, Dept Publ Hlth, Amsterdam, Netherlands. [Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med,Cardiol & Prevent Med Sect, Boston, MA 02118 USA. [Lip, Gregory Y. H.] Univ Birmingham, City Hosp, Ctr Cardiovasc Sci, Birmingham, W Midlands, England. [Stricker, Bruno H.] Inspectorate Hlth Care, The Hague, Netherlands. RP Stricker, BH (reprint author), Erasmus MC, Dept Epidemiol, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM b.stricker@erasmusmc.nl FU Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; [1R01HL092577]; [1R01 HL102214]; [1RC1HL101056] FX The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NWO); The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. E.J.B. was funded by 1R01HL092577, 1R01 HL102214, and 1RC1HL101056. NR 39 TC 87 Z9 90 U1 3 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD SEP PY 2013 VL 34 IS 35 BP 2746 EP 2751 DI 10.1093/eurheartj/eht280 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 228FW UT WOS:000325172300010 PM 23900699 ER PT J AU Wang, XF Wang, SB Ohkoshi, E Wang, LT Hamel, E Qian, K Morris-Natschke, SL Lee, KH Xie, L AF Wang, Xiao-Feng Wang, Sheng-Biao Ohkoshi, Emika Wang, Li-Ting Hamel, Ernest Qian, Keduo Morris-Natschke, Susan L. Lee, Kuo-Hsiung Xie, Lan TI N-Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines: A novel class of antitumor agents targeting the colchicine site on tubulin SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE N-Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines; Cytotoxicity; Tubulin polymerization inhibitors; Colchicine binding site ID VASCULAR DISRUPTING AGENTS; TUMOR-CELL LINES; CATALYZED AMINATION; ANTICANCER DRUGS; DIVERSE PANEL; BINDING; POLYMERIZATION; DERIVATIVES; INSIGHT; DESIGN AB Structural optimizations of the prior lead 1a led to the discovery of a series of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinoline derivatives as a novel class of tubulin polymerization inhibitors targeted at the colchicine binding site. The most active compound 6d showed extremely high cytotoxicity against a human tumor cell line panel (A549, KB, KBvin, and DU145) with GI(50) values ranging from 1.5 to 1.7 nM, significantly more potent than paclitaxel, especially against the drug-resistant KBvin cell line, in the same assays. Analogs 5f, 6b, 6c, and 6e were also quite potent, with a GI(50) range of 0.011-0.19 mu M. In further studies, active compounds 6b e and 5f significantly inhibited tubulin assembly, with IC50 values of 0.92 -1.0 mu M and strongly inhibited colchicine binding to tubulin, with inhibition rates of 75-99% (at 5 mu M), comparable with or more potent than combretastatin A-4 (IC50 0.96 mu M). Current studies included design, synthesis, and biological evaluations of 24 new compounds (series 3-6). Related SAR analysis, molecular modeling, and evaluation of essential drug-like properties, i.e. water solubility, log P, and in vitro metabolic stability, were also performed. (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Wang, Xiao-Feng; Wang, Sheng-Biao; Xie, Lan] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. [Ohkoshi, Emika; Wang, Li-Ting; Qian, Keduo; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung] Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. [Wang, Xiao-Feng] Urumqi Gen Hosp, Dept Pharm, Lanzhou Mil Region 830000, Urumqi, Peoples R China. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diagnosis,Frederick Natl Lab, Ft Detrick, MD 21702 USA. [Lee, Kuo-Hsiung; Xie, Lan] China Med Univ & Hosp, Chinese Med Res & Dev, Taichung, Taiwan. RP Xie, L (reprint author), Beijing Inst Pharmacol & Toxicol, 27 Tai Ping Rd, Beijing 100850, Peoples R China. EM lanxieshi@yahoo.com FU Natural Science Foundation of China (NSFC) [81120108022, 30930106]; NIH from the National Cancer Institute [CA17625-32]; Taiwan Department of Health, China Medical University Hospital Cancer Research Center of Excellence [DOH100-TD-C-111-005] FX This investigation was supported by Grants 81120108022 and 30930106 from the Natural Science Foundation of China (NSFC) awarded to Dr. Lan Xie and NIH Grant CA17625-32 from the National Cancer Institute awarded to Dr. K. H. Lee. This study was also supported in part by the Taiwan Department of Health, China Medical University Hospital Cancer Research Center of Excellence (DOH100-TD-C-111-005). NR 26 TC 16 Z9 17 U1 2 U2 34 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD SEP PY 2013 VL 67 BP 196 EP 207 DI 10.1016/j.ejmech.2013.06.041 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 227NY UT WOS:000325121800022 PM 23867604 ER PT J AU Lim, HJ Dersch, CM Rothman, RB Deschamps, JR Jacobson, AE Rice, KC AF Lim, Hwan Jung Dersch, Christina M. Rothman, Richard B. Deschamps, Jeffrey R. Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena. 48. C7-and C8-substituted 5-phenylmorphan opioids from diastereoselective alkylation SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE C7-and C8-substituted 5-phenylmorphans; Opioid receptor affinity; "One-pot" diastereoselective synthesis ID OXIDE-BRIDGED PHENYLMORPHANS; N-PHENETHYL ANALOGS; MU; AFFINITY; ANTAGONIST; SERIES AB The exploration of the effect of substituents at C7 and C8 of the 5-phenylmorphans on their affinity for opioid receptors was enabled by our recently introduced "one pot" diastereoselective synthesis that provided C7-oxo, hydroxy and alkyl substituents, C8-alkyl substituted 5-phenylmorphans, and compounds that had a new cyclohexane ring that includes the C7 and C8 carbon atoms of the 5-phenylmorphan. The affinity of the 5-phenylmorphans for opioid receptors is increased by a C8-methyl substituent, compared with its C7 analog. The affinity of the newly synthesized compounds is generally for the mu-opioid receptor, rather than the delta- or kappa-receptors. Addition of a new cyclohexane ring to the C7 and C8 positions on the cyclohexane ring of the 5-phenylmorphans enhances mu-receptor affinity, bringing the K-i to the subnanomolar level. Unexpectedly, the N-methyl substituted compounds generally had higher affinity than comparable N-phenethyl-substituted relatives. The configurations of two compounds were determined by single-crystal X-ray crystallographic analyses. Published by Elsevier Masson SAS. C1 [Lim, Hwan Jung; Jacobson, Arthur E.; Rice, Kenner C.] Natl Inst Drug Abuse, NIH, Dept Hlth & Human Serv, Drug Design & Synth Sect,Chem Biol Res Branch, Bethesda, MD 20892 USA. [Lim, Hwan Jung; Jacobson, Arthur E.; Rice, Kenner C.] Natl Inst Alcohol Abuse & Alcoholism, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dersch, Christina M.; Rothman, Richard B.] Natl Inst Drug Abuse, Addict Res Ctr, NIH, Dept Hlth & Human Serv,Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Struct Matter Lab, Naval Res Lab, Washington, DC 20375 USA. RP Rice, KC (reprint author), Natl Inst Drug Abuse, NIH, Dept Hlth & Human Serv, Drug Design & Synth Sect,Chem Biol Res Branch, 5625 Fishers Lane,Room 4N03, Bethesda, MD 20892 USA. EM kr21f@nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 FU NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism; NIH Intramural Research Program of the National Institute on Drug Abuse (NIDA); NIDA [Y1-DA1101]; Naval Research Laboratory (NRL) FX The work of the Drug Design and Synthesis Section, CBRB, NIDA, & NIAAA, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism. The Clinical Psychopharmacology Section, CBRB, NIDA, was supported by the NIH Intramural Research Program of the National Institute on Drug Abuse (NIDA). We also thank Dr. Klaus Gawrisch and Dr. Walter Teague (Laboratory of Membrane Biochemistry and Biophysics, NIAAA, for NMR spectral data). The authors also express their thanks to Noel Whittaker, Mass Spectrometry Facility, NIDDK, for mass spectral data. The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). NR 16 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD SEP PY 2013 VL 67 BP 335 EP 343 DI 10.1016/j.ejmech.2013.06.030 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 227NY UT WOS:000325121800035 PM 23880358 ER PT J AU Fejzo, MS Magtira, A Schoenberg, FP MacGibbon, K Mullin, P Romero, R Tabsh, K AF Fejzo, Marlena S. Magtira, Aromalyn Schoenberg, Frederic Paik MacGibbon, Kimber Mullin, Patrick Romero, Roberto Tabsh, Khalil TI Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum SO EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY LA English DT Article DE Hyperemesis gravidarum; Antihistamines; Fetal outcome; Nausea; Pregnancy ID PARENTERAL-NUTRITION; PREGNANCY; NAUSEA; COMPLICATIONS; COHORT; WOMEN AB Objective: The purpose of this study is to determine the frequency of adverse perinatal outcome in women with hyperemesis gravidarum and identify prognostic factors. Study design: This is a case-control study in which outcomes of first pregnancies were compared between 254 women with hyperemesis gravidarum treated with intravenous fluids and 308 controls. Prognostic factors were identified by comparing the clinical profile of patients with hyperemesis gravidarum with a normal and an adverse pregnancy outcome. Binary responses were analyzed using either a Chi-square or Fisher exact test and continuous responses were analyzed using a t-test. Results: Women with hyperemesis gravidarum have over a 4-fold increased risk of poor outcome including preterm birth and lower birth weight (p < 0.0001). Among maternal characteristics, only gestational hypertension had an influence on outcome (p < 0.0001). Treatment as an outpatient and/or by alternative medicine (acupuncture/acupressure/Bowen massage) was associated with a positive outcome (p < 0.0089). Poor outcomes were associated with early start of symptoms (p < 0.019), and treatment with methylprednisolone (p < 0.0217), promethazine (p < 0.0386), and other antihistamines [diphenhydramine (Benadryl), dimenhydrinate (Gravol), doxylamine (Unisom), hydroxyzine (Vistaril/Atarax), doxylamine and pyridoxine (Diclectin/Bendectin)] (p < 0.0151) independent of effectiveness. Among these medications, only the other antihistamines were prescribed independent of severity: they were effective in less than 20% of cases and were taken by almost 50% of patients with an adverse outcome. Conclusion: Poor outcomes are significantly greater in women with HG and are associated with gestational hypertension, early symptoms, and antihistamine use. Given these results, there is an urgent need to address the safety and effectiveness of medications containing antihistamines in women with severe nausea of pregnancy. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Fejzo, Marlena S.; Tabsh, Khalil] Univ Calif Los Angeles, Dept Obstet & Gynecol, Los Angeles, CA 90024 USA. [Magtira, Aromalyn; Schoenberg, Frederic Paik] Univ Calif Los Angeles, Dept Stat, Los Angeles, CA USA. [MacGibbon, Kimber] Hyperemesis Educ & Res Fdn, Leesburg, VA USA. [Mullin, Patrick] Univ So Calif, Keck Sch Med, Dept Maternal Fetal Med, Los Angeles, CA 90033 USA. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch,Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, Roberto] NICHD, NIH, DHHS, Perinatol Res Branch,Dept Hlth & Human Serv, Detroit, MI USA. RP Fejzo, MS (reprint author), 675 Charles E Young Dr, Los Angeles, CA 90095 USA. EM mfejzo@mednet.ucla.edu OI MacGibbon, Kimber/0000-0002-6534-3114 FU Intramural NIH HHS [ZIA HD002400-22] NR 21 TC 10 Z9 10 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-2115 J9 EUR J OBSTET GYN R B JI Eur. J. Obstet. Gynecol. Reprod. Biol. PD SEP PY 2013 VL 170 IS 1 BP 71 EP 76 DI 10.1016/j.ejogrb.2013.04.017 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 227OA UT WOS:000325122000014 PM 23751910 ER PT J AU Handjaras, G Ricciardi, E Szczepanik, J Pietrini, P Furey, ML AF Handjaras, Giacomo Ricciardi, Emiliano Szczepanik, Joanna Pietrini, Pietro Furey, Maura L. TI Cholinergic enhancement differentially modulates neural response to encoding during face identity and face location working memory tasks SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE Acetylcholinesterase inhibitors; cholinergic system; face perception; working memory; fMRI; visual cortex ID CEREBRAL-BLOOD-FLOW; CAT VISUAL-CORTEX; FUNCTIONAL-ORGANIZATION; ATTENTIONAL FUNCTIONS; SPATIAL INTEGRATION; SELECTIVE ATTENTION; EXTRASTRIATE CORTEX; ACETYLCHOLINE; COGNITION; SYSTEMS AB Potentiation of cholinergic transmission influences stimulus processing by enhancing signal detection through suppression and/or filtering out of irrelevant information (bottom-up modulation) and with top-down task-oriented executive mechanisms based on the recruitment of prefrontal and parietal attentional systems. The cholinergic system also plays a critical role in working memory (WM) processes and preferentially modulates WM encoding, likely through stimulus-processing mechanisms. Previous research reported increased brain responses in visual extrastriate cortical regions during cholinergic enhancement in the encoding phase of WM, independently addressing object and spatial encoding. The current study used functional magnetic resonance imaging to determine the effects of cholinergic enhancement on encoding of key visual processing features. Subjects participated in two scanning sessions, one during an intravenous (i.v.) infusion of saline and the other during an infusion of the acetylcholinesterase inhibitor physostigmine. In each scan session, subjects alternated between a face identity recognition and a spatial location WM. Enhanced cholinergic function increased neural activity in the ventral stream during encoding of face identity and in the dorsal stream during encoding of face location. Conversely, a reduction in brain response was found for scrambled sensorimotor control images. The cholinergic effects on neural activity in the ventral stream during encoding of face identity were stronger than those observed in the dorsal stream during encoding of face location, likely as a consequence of the role of acetylcholine in establishing the inherently relevant nature of face identity. Despite the limited sample-size, the results suggest the stimulus-dependent role of cholinergic system in signal detection, as they show that cholinergic potentiation enhances neural activity in regions associated with early perceptual processing in a selective manner depending on the attended stimulus feature. C1 [Handjaras, Giacomo; Ricciardi, Emiliano; Pietrini, Pietro] Univ Pisa, Lab Clin Biochem & Mol Biol, I-56126 Pisa, Italy. [Handjaras, Giacomo; Pietrini, Pietro] Pisa Univ Hosp, Clin Psychol Branch, I-56126 Pisa, Italy. [Szczepanik, Joanna; Furey, Maura L.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Ricciardi, E (reprint author), Univ Pisa, Lab Clin Biochem & Mol Biol, I-56126 Pisa, Italy. EM emiliano.ricciardi@bioclinica.unipi.it RI Ricciardi, Emiliano/E-6929-2011; OI Ricciardi, Emiliano/0000-0002-7178-9534; Handjaras, Giacomo/0000-0001-5677-8434 FU Intramural Research Program at the National Institute of Mental Health [00-M-0056] FX The authors thank James V. Haxby for input and support during early stages of this project, and Sabrina Danti and Anna Gaglianese for comments on an earlier version of the manuscript. The study was founded by the Intramural Research Program at the National Institute of Mental Health and approved by the Institutional Review Board (National Institutes of Health Protocol 00-M-0056). NR 47 TC 2 Z9 2 U1 0 U2 3 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD SEP PY 2013 VL 238 IS 9 BP 999 EP 1008 DI 10.1177/1535370213497326 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 220LA UT WOS:000324584000003 PM 23975732 ER PT J AU Nilsen, WJ Pavel, M AF Nilsen, Wendy J. Pavel, Misha TI Moving Behavioral Theories into the 21st Century SO IEEE PULSE LA English DT Article ID HEALTH; PEOPLE C1 [Nilsen, Wendy J.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Pavel, Misha] Natl Sci Fdn, Arlington, VA 22230 USA. RP Nilsen, WJ (reprint author), NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. EM nilsenwj@od.nih.gov NR 9 TC 6 Z9 6 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD SEP-OCT PY 2013 VL 4 IS 5 BP 25 EP 28 DI 10.1109/MPUL.2013.2271682 PG 4 WC Engineering, Biomedical SC Engineering GA 224KH UT WOS:000324883400008 PM 24056790 ER PT J AU Liew, SL Agashe, H Bhagat, N Paek, A Bulea, TC AF Liew, Sook-Lei Agashe, Harshavardhan Bhagat, Nikunj Paek, Andrew Bulea, Thomas C. TI A Clinical Roadmap for Brain-Neural Machine Interfaces SO IEEE PULSE LA English DT Article C1 [Liew, Sook-Lei] NINDS, NIH, Bethesda, MD 20892 USA. [Agashe, Harshavardhan; Bhagat, Nikunj; Paek, Andrew] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77004 USA. [Bulea, Thomas C.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Liew, SL (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM liews@mail.nih.gov FU National Institutes of Health (NIH) [NS082045]; NSF [IIS-1313620]; TIRR Memorial Hermann; University of Houston; Rice University; University Hospital of Tubingen, Germany; Instituto Tecnologico y de Estudios Superiores de Monterrey, Mexico FX We thank Dr. Jose Contreras-Vidal and Dr. Surjo Soekadar for their kind invitation to allow us to serve as scribes for the conference. This conference was funded by the National Institutes of Health (NIH) (Grant No. NS082045), NSF (Grant No. IIS-1313620), TIRR Memorial Hermann, the University of Houston, Rice University, and University Hospital of Tubingen, Germany. We also acknowledge the funding provided by the Instituto Tecnologico y de Estudios Superiores de Monterrey, Mexico, and industry sponsors. NR 3 TC 2 Z9 2 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD SEP-OCT PY 2013 VL 4 IS 5 BP 44 EP 48 DI 10.1109/MPUL.2013.2271686 PG 5 WC Engineering, Biomedical SC Engineering GA 224KH UT WOS:000324883400011 PM 24056793 ER PT J AU Klee, MM AF Klee, Maurice M. TI The Ebb and Flow of Patent Law SO IEEE PULSE LA English DT Editorial Material C1 [Klee, Maurice M.] Michigan State Univ, Coll Engn, E Lansing, MI 48824 USA. [Klee, Maurice M.] NIH, Bethesda, MD USA. EM mk@maurieklee.com NR 0 TC 0 Z9 0 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD SEP-OCT PY 2013 VL 4 IS 5 BP 52 EP + DI 10.1109/MPUL.2013.2271418 PG 2 WC Engineering, Biomedical SC Engineering GA 224KH UT WOS:000324883400013 PM 24180026 ER PT J AU Jawad, S Liu, BY Li, ZY Katamay, R Campos, M Wei, L Sen, HN Ling, D Estrada, FM Amaral, J Chan, CC Fariss, R Gordon, S Nussenblatt, RB AF Jawad, Shayma Liu, Baoying Li, Zhiyu Katamay, Robert Campos, Mercedes Wei, Lai Sen, H. Nida Ling, Diamond Estrada, Fernando Martinez Amaral, Juan Chan, Chi-Chao Fariss, Robert Gordon, Siamon Nussenblatt, Robert B. TI The Role of Macrophage Class A Scavenger Receptors in a Laser-Induced Murine Choroidal Neovascularization Model SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE AMD; CNV; macrophages; scavenger receptors ID RETINAL-PIGMENT EPITHELIUM; MONOCYTE CHEMOTACTIC PROTEIN-3; LOW-DENSITY-LIPOPROTEIN; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; DEPENDENT PHAGOCYTOSIS; INFLAMMATORY RESPONSE; COMPLEMENT ACTIVATION; HUMAN EOSINOPHILS; CHEMOKINE AB PURPOSE. Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. METHODS. Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A(-/-)), MARCO (MARCO(-/-)), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. RESULTS. Wild-type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1- and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice. CONCLUSIONS. The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD. C1 [Jawad, Shayma; Liu, Baoying; Li, Zhiyu; Katamay, Robert; Wei, Lai; Sen, H. Nida; Ling, Diamond; Chan, Chi-Chao; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Campos, Mercedes; Fariss, Robert] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [Estrada, Fernando Martinez; Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Amaral, Juan] NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Liu, BY (reprint author), Immunol Lab, Bldg 10,Room 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM liuba@nei.nih.gov; drbob@nei.nih.gov RI Wei, Lai/D-1088-2014 FU National Institutes of Health, National Eye Institute FX Supported by grants from the Intramural Research Program of National Institutes of Health, National Eye Institute. NR 92 TC 8 Z9 9 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2013 VL 54 IS 9 BP 5959 EP 5970 DI 10.1167/iovs.12-11380 PG 12 WC Ophthalmology SC Ophthalmology GA 228EV UT WOS:000325169500005 PM 23927892 ER PT J AU Domalpally, A Danis, RP Chew, EY Clemons, TE Reed, S SanGiovanni, JP Ferris, FL AF Domalpally, Amitha Danis, Ronald P. Chew, Emily Y. Clemons, Traci E. Reed, Susan SanGiovanni, John Paul Ferris, Frederick L., III CA Age-Related Eye Dis Study 2 Res Gr TI Evaluation of Optimized Digital Fundus Reflex Photographs for Lens Opacities in the Age-Related Eye Disease Study 2: AREDS2 Report 7 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE cataract; lens opacity; AREDS2 ID CATARACT GRADING SYSTEM; REPORT NO. 4; TRIAL AB PURPOSE. We described the system for grading lens opacities using stereoscopic digital fundus reflex photographs in the Age-Related Eye Disease Study 2 (AREDS2) and compared reproducibility with the AREDS lens grading system, which used retroillumination film images. METHODS. Stereoscopic fundus reflex photographs were acquired in a standardized fashion at baseline and annually. Images were enhanced and evaluated in the red channel at a central reading center. Percentage involvement of cortical and posterior subcapsular (PSC) lens opacities within the central 5 mm diameter zone of a modified AREDS lens grid was estimated. Reproducibility was assessed for contemporaneous variability (ongoing, monthly regrade on 5% of submissions, n = 777 eyes) and temporal drift (regrading a subset of baseline photographs annually, n = 88). RESULTS. In the contemporaneous exercise, the agreement for presence of cortical opacities was 93% (kappa = 0.86) and for PSC opacities it was 97% (kappa = 0.83). Intraclass correlation (ICC) for area of central zone involvement was 0.95 for cortical and 0.99 for PSC opacities. Historic data for contemporaneous regrading of film-based images in AREDS showed an ICC of 0.94 for cortical and 0.82 for PSC. The final annual temporal drift exercise had a reproducibility of 95% for cortical and PSC opacities. CONCLUSIONS. Digital grading using fundus reflex images with image enhancing tools has reproducibility comparable to film-based retroillumination images, and may be useful for centralized objective lens opacity assessment in clinical trials using widely available fundus cameras. Red reflex images limit evaluation to cortical and PSC opacities, and do not permit assessment of nuclear opacities. (ClinicalTrials.gov number, NCT00345176.) C1 [Domalpally, Amitha; Danis, Ronald P.; Reed, Susan] Fundus Photograph Reading Ctr, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Chew, Emily Y.; SanGiovanni, John Paul; Ferris, Frederick L., III] NEI, NIH, Bethesda, MD USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. RP Danis, RP (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, 8010 Excelsior Dr, Madison, WI 53717 USA. EM rpdanis@wisc.edu RI Domalpally, Amitha/B-2367-2015 FU NIH [U10-EY013018, HHS-N-260-2005-00007-C]; Administrative Data Base (ADB) [N01-EY-5-0007] FX Supported by NIH Grant U10-EY013018 (RD) and intramural program funds from NIH Contract No. HHS-N-260-2005-00007-C, and Administrative Data Base (ADB) Contract No. N01-EY-5-0007. NR 15 TC 2 Z9 3 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2013 VL 54 IS 9 BP 5989 EP 5994 DI 10.1167/iovs.13-12301 PG 6 WC Ophthalmology SC Ophthalmology GA 228EV UT WOS:000325169500009 PM 23887802 ER PT J AU Sullivan, LS Bowne, SJ Reeves, MJ Blain, D Goetz, K NDifor, V Vitez, S Wang, XJ Tumminia, SJ Daiger, SP AF Sullivan, Lori S. Bowne, Sara J. Reeves, Melissa J. Blain, Delphine Goetz, Kerry NDifor, Vida Vitez, Sally Wang, Xinjing Tumminia, Santa J. Daiger, Stephen P. TI Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE retinitis pigmentosa; eyeGENE; DNA sequencing; inherited retinal diseases; mutation prevalences ID DISEASE-CAUSING MUTATIONS; DEGENERATION SLOW GENE; RHODOPSIN GENE; POINT MUTATION; FAMILIES; PROTEIN; IDENTIFICATION; ADRP; RPGR; OPHTHALMOLOGY AB PURPOSE. To screen samples from patients with presumed autosomal dominant retinitis pigmentosa (adRP) for mutations in 12 disease genes as a contribution to the research and treatment goals of the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE). METHODS. DNA samples were obtained from eyeGENE. A total of 170 probands with an intake diagnosis of adRP were tested through enrollment in eyeGENE. The 10 most common genes causing adRP (IMPDH1, KLHL7, NR2E3, PRPF3/RP18, PRPF31/RP11, PRPF8/RP13, PRPH2/RDS, RHO, RP1, and TOPORS) were chosen for PCR-based dideoxy sequencing, along with the two X-linked RP genes, RPGR and RP2. RHO, PRPH2, PRPF31, RPGR, and RP2 were completely sequenced, while only mutation hotspots in the other genes were analyzed. RESULTS. Disease-causing mutations were identified in 52% of the probands. The frequencies of disease-causing mutations in the 12 genes were consistent with previous studies. CONCLUSIONS. The Laboratory for Molecular Diagnosis of Inherited Eye Disease at the University of Texas in Houston has thus far received DNA samples from 170 families with a diagnosis of adRP from the eyeGENE Network. Disease-causing mutations in autosomal genes were identified in 48% (81/170) of these families while mutations in X-linked genes accounted for an additional 4% (7/170). Of the 55 distinct mutations detected, 19 (33%) have not been previously reported. All diagnostic results were returned by eyeGENE to participating patients via their referring clinician. These genotyped samples along with their corresponding phenotypic information are also available to researchers who may request access to them for further study of these ophthalmic disorders. C1 [Sullivan, Lori S.; Bowne, Sara J.; Daiger, Stephen P.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Reeves, Melissa J.; Blain, Delphine; Goetz, Kerry; NDifor, Vida; Vitez, Sally; Wang, Xinjing] NEI, NIH, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Tumminia, Santa J.] NEI, NIH, Off Director, Bethesda, MD 20892 USA. RP Daiger, SP (reprint author), Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. EM stephen.p.daiger@uth.tmc.edu FU National Institutes of Health/National Eye Institute (NIH/NEI) [HHS-N-260-2007-00001-C]; National Ophthalmic Genotyping and Phenotyping Network of the NEI, or eyeGENE; NIH/NEI [EY007142]; Foundation Fighting Blindness; CLIA Certified Laboratory [45D0935007] FX Supported by the National Institutes of Health/National Eye Institute (NIH/NEI) under Contract No. HHS-N-260-2007-00001-C; by the National Ophthalmic Genotyping and Phenotyping Network of the NEI, or eyeGENE (a registered trademark of the National Institutes of Health) (Protocol 06-EI-0236); by NIH/NEI Grant EY007142; and by Center and Module grants from the Foundation Fighting Blindness. Stephen P. Daiger is Director of a CLIA Certified Laboratory (45D0935007) in the eyeGENE Network. NR 47 TC 20 Z9 20 U1 0 U2 9 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2013 VL 54 IS 9 BP 6255 EP 6261 DI 10.1167/iovs.13-12605 PG 7 WC Ophthalmology SC Ophthalmology GA 228EV UT WOS:000325169500041 PM 23950152 ER PT J AU Armstrong, J Mitnitski, A Launer, L White, L Rockwood, K AF Armstrong, J. Mitnitski, A. Launer, L. White, L. Rockwood, K. TI Frailty in Relation to Late-Life Cognition: Poisson Regression Models in Data from the Honolulu-Asian Aging Study SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Armstrong, J.; Mitnitski, A.; Rockwood, K.] Dalhousie Univ, Halifax, NS, Canada. [Launer, L.] NIA, Bethesda, MD 20892 USA. [White, L.] Univ Hawaii, Honolulu, HI 96822 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD SEP PY 2013 VL 182 SU 6 BP S237 EP S237 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 217CU UT WOS:000324335000086 ER PT J AU Arakelyan, A Fitzgerald, W Margolis, L Grivel, JC AF Arakelyan, Anush Fitzgerald, Wendy Margolis, Leonid Grivel, Jean-Charles TI Nanoparticle-based flow virometry for the analysis of individual virions SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL-MEMBRANE-PROTEINS; CUCUMBER MOSAIC-VIRUS; HOST HLA-DR; OPPORTUNISTIC INFECTION; HIV-1 INFECTION; IN-VIVO; CYTOMETRY; PARTICLES; ANTIBODY AB While flow cytometry has been used to analyze the antigenic composition of individual cells, the antigenic makeup of viral particles is still characterized predominantly in bulk. Here, we describe a technology, "flow virometry," that can be used for antigen detection on individual virions. The technology is based on binding magnetic nanoparticles to virions, staining the virions with monoclonal antibodies, separating the formed complexes with magnetic columns, and characterizing them with flow cytometers. We used this technology to study the distribution of two antigens (HLA-DR and LFA-1) that HIV-1 acquires from infected cells among individual HIV-1 virions. Flow virometry revealed that the antigenic makeup of virions from a single preparation is heterogeneous. This heterogeneity could not be detected with bulk analysis of viruses. Moreover, in two preparations of the same HIV-1 produced by different cells, the distribution of antigens among virions was different. In contrast, HIV-1 of two different HIV-1 genotypes replicating in the same cells became somewhat antigenically similar. This nanotechnology allows the study of virions in bodily fluids without virus propagation and in principle is not restricted to the analysis of HIV, but can be applied to the analysis of the individual surface antigenic makeup of any virus. C1 [Arakelyan, Anush; Fitzgerald, Wendy; Margolis, Leonid; Grivel, Jean-Charles] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Margolis, L (reprint author), NIH, 10 Ctr Dr,Bldg 10,Rm 9D58, Bethesda, MD 20892 USA. EM margolis@helix.nih.gov; grivelj@mail.nih.gov FU NCI, NIH [HHSN261200800001E]; intramural program of the Eunice Kennedy-Shriver National Institute of Child Health and Human Development FX The authors would like to thank John Mascola for providing VRC01, Tome Hope for providing GFP-expressing HIV-1, Mimi Gosh for providing samples of CVL, and Michael Lederman for providing plasma samples obtained from HIV-1-infected patients. These experiments used reagents provided by the AIDS and Cancer Virus Program, SAIC Frederick, Inc./National Cancer Institute (NCI), Frederick, supported with Federal funds from the NCI, NIH, under contract HHSN261200800001E. We are grateful to Elena Zaitseva for her excellent guidance in staining virions with lipophilic dyes and to Sonia Zicari for her generous help with dengue viruses. We are thankful to Jeremy Swan and Yumiko Shepherd for the preparation of Figure 1. This work was supported by the intramural program of the Eunice Kennedy-Shriver National Institute of Child Health and Human Development. NR 47 TC 14 Z9 15 U1 3 U2 21 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2013 VL 123 IS 9 BP 3716 EP 3727 DI 10.1172/JCI67042 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 220DQ UT WOS:000324562600017 PM 23925291 ER PT J AU Yang, JY Yoshihara, K Tanaka, K Hatae, M Masuzaki, H Itamochi, H Takano, M Ushijima, K Tanyi, JL Coukos, G Lu, YL Mills, GB Verhaak, RGW AF Yang, Ji-Yeon Yoshihara, Kosuke Tanaka, Kenichi Hatae, Masayuki Masuzaki, Hideaki Itamochi, Hiroaki Takano, Masashi Ushijima, Kimio Tanyi, Janos L. Coukos, George Lu, Yiling Mills, Gordon B. Verhaak, Roel G. W. CA Canc Genome Atlas TOGA Res Network TI Predicting time to ovarian carcinoma recurrence using protein markers SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ANDROGEN RECEPTOR EXPRESSION; PROPORTIONAL HAZARDS MODEL; GYNECOLOGIC-ONCOLOGY-GROUP; FALSE DISCOVERY RATE; FUNCTIONAL ANNOTATION; PROTEOMIC ANALYSIS; PROGNOSTIC-FACTORS; CANCER STATISTICS; SEROUS CARCINOMA; GENE-EXPRESSION AB Patients with ovarian cancer are at high risk of tumor recurrence. Prediction of therapy outcome may provide therapeutic avenues to improve patient outcomes. Using reverse-phase protein arrays, we generated ovarian carcinoma protein expression profiles on 412 cases from TCGA and constructed a PRotein-driven index of OVARian cancer (PROVAR). PROVAR significantly discriminated an independent cohort of 226 high-grade serous ovarian carcinomas into groups of high risk and low risk of tumor recurrence as well as short-term and long-term survivors. Comparison with gene expression-based outcome classification models showed a significantly improved capacity of the protein-based PROVAR to predict tumor progression. Identification of protein markers linked to disease recurrence may yield insights into tumor biology. When combined with features known to be associated with outcome, such as BRCA mutation, PROVAR may provide clinically useful predictions of time to tumor recurrence. C1 [Yang, Ji-Yeon; Yoshihara, Kosuke; Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77230 USA. [Yoshihara, Kosuke; Tanaka, Kenichi] Niigata Univ, Grad Sch Med & Dent Sci, Dept Obstet & Gynecol, Niigata, Japan. [Tanaka, Kenichi] Niigata Med Ctr Hosp, Niigata, Japan. [Hatae, Masayuki] Kagoshima City Hosp, Dept Obstet & Gynecol, Kagoshima, Japan. [Masuzaki, Hideaki] Nagasaki Univ, Sch Med, Dept Obstet & Gynecol, Nagasaki 852, Japan. [Itamochi, Hiroaki] Tottori Univ, Sch Med, Dept Obstet & Gynecol, Tottori 680, Japan. [Canc Genome Atlas TOGA Res Network] NCI, NIH, Bethesda, MD 20892 USA. [Takano, Masashi] Natl Def Med Coll, Dept Obstet & Gynecol, Tokorozawa, Saitama 359, Japan. [Ushijima, Kimio] Kurume Univ, Sch Med, Dept Obstet & Gynecol, Kurume, Fukuoka 830, Japan. [Tanyi, Janos L.; Coukos, George] Univ Penn, Div Gynecol Oncol, Philadelphia, PA 19104 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77230 USA. RP Verhaak, RGW (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, 1400 Pressler Dr,Unit 1410, Houston, TX 77230 USA. EM rverhaak@mdanderson.org OI Yoshihara, Kosuke/0000-0002-2254-3378 FU NCI [5 P50 CA083639-12, CA143883, P50 CA083639]; MD Anderson RPPA Core Facility; NIH [CA016672] FX The results published here are in whole or part based upon data generated by the TCGA pilot project established by the National Cancer Institute (NCI) and NHGRI. Information about TCGA and the investigators and institutions who constitute TCGA research network can be found at http://cancergenome.nih.gov/. This work is supported by NCI award no. 5 P50 CA083639-12 (to R.G.W. Verhaak), NCI grant no. CA143883 (MD Anderson Genome Data Analysis Center) and P50 CA083639 (to G.B. Mills), and MD Anderson RPPA Core Facility (supported by NIH grant CA016672). NR 50 TC 21 Z9 22 U1 0 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2013 VL 123 IS 9 BP 3740 EP 3750 DI 10.1172/JCI68509 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 220DQ UT WOS:000324562600019 PM 23945238 ER PT J AU Liu, WL Yan, M Sugui, JA Li, HZ Xu, CF Joo, J Kwon-Chung, KJ Coleman, WG Rodgers, GP AF Liu, Wenli Yan, Ming Sugui, Janyce A. Li, Hongzhen Xu, Chengfu Joo, Jungsoo Kwon-Chung, Kyung J. Coleman, William G. Rodgers, Griffin P. TI Olfm4 deletion enhances defense against Staphylococcus aureus in chronic granulomatous disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ASPERGILLUS-FUMIGATUS; INNATE IMMUNITY; RHIZOPUS-ORYZAE; MICE; NEUTROPHILS; ACTIVATION; INFECTION; PROTEASES; INVITRO; HYPHAE AB Chronic granulomatous disease (CGD) patients have recurrent life-threatening bacterial and fungal infections. Olfactomedin 4 (OLFM4) is a neutrophil granule protein that negatively regulates host defense against bacterial infection. The goal of this study was to evaluate the impact of Olfm4 deletion on host defense against Staphylococcus aureus and Aspergillus fumigatus in a murine X-linked gp91pbox-deficiency CGD model. We found that intracellular killing and in vivo clearance of S. aureus, as well as resistance to S. aureus sepsis, were significantly increased in gp91phox and Olfm4 double-deficient mice compared with CGD mice. The activities of cathepsin C and its downstream proteases (neutrophil elastase and cathepsin G) and serum levels of IL-1 beta, IL-6, IL-12p40, CXCL2, G-CSF, and GM-CSF in Olfm4-deficient as well as gp91phox and Olfm4 double-deficient mice were significantly higher than those in WT and CGD mice after challenge with S. aureus. We did not observe enhanced defense against A. fumigatus in Olfm4-deficient mice using a lung infection model. These results show that Olfm4 deletion can successfully enhance immune defense against S. aureus, but not A. fumigatus, in CGD mice. These data suggest that OLFM4 may be an important target in CGD patients for the augmentation of host defense against bacterial infection. C1 [Liu, Wenli; Li, Hongzhen; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Yan, Ming; Xu, Chengfu; Joo, Jungsoo; Coleman, William G.] NIDDK, Lab Biochem & Genet, Bethesda, MD 20892 USA. [Sugui, Janyce A.; Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wcoleman@helix.nih.gov; gr5n@nih.gov NR 23 TC 17 Z9 17 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2013 VL 123 IS 9 BP 3751 EP 3755 DI 10.1172/JCI68453 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 220DQ UT WOS:000324562600020 PM 23908114 ER PT J AU Goyama, S Schibler, J Cunningham, L Zhang, Y Rao, Y Nishimoto, N Nakagawa, M Olsson, A Wunderlich, M Link, KA Mizukawa, B Grimes, HL Kurokawa, M Liu, PP Huang, G Mulloy, JC AF Goyama, Susumu Schibler, Janet Cunningham, Lea Zhang, Yue Rao, Yalan Nishimoto, Nahoko Nakagawa, Masahiro Olsson, Andre Wunderlich, Mark Link, Kevin A. Mizukawa, Benjamin Grimes, H. Leighton Kurokawa, Mineo Liu, P. Paul Huang, Gang Mulloy, James C. TI Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID METHYLTRANSFERASE GENE EZH2; HEMATOPOIETIC STEM-CELLS; MYELODYSPLASTIC SYNDROME; ADULT HEMATOPOIESIS; MLL-AF9 LEUKEMIA; SOMATIC MUTATIONS; PROGENITOR CELLS; SELF-RENEWAL; DIFFERENTIATION; LEUKEMOGENESIS AB RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of Runx1/Cbfb inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins. C1 [Goyama, Susumu; Schibler, Janet; Zhang, Yue; Rao, Yalan; Wunderlich, Mark; Link, Kevin A.; Mizukawa, Benjamin; Grimes, H. Leighton; Huang, Gang; Mulloy, James C.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Cunningham, Lea; Liu, P. Paul] NIH, Natl Canc Inst, Ctr Canc Res, Oncogenesis & Dev Sect, Bethesda, MD 20892 USA. [Nishimoto, Nahoko; Nakagawa, Masahiro; Kurokawa, Mineo] Univ Tokyo, Grad Sch Med, Dept Hematol & Oncol, Tokyo, Japan. [Olsson, Andre; Grimes, H. Leighton] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. RP Mulloy, JC (reprint author), Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. EM james.mulloy@cchmc.org RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; Grimes, H. Leighton/0000-0001-8162-6758 FU Institutional Clinical and Translational Science Award; NIH/NCRR grant [1UL1RR026314-01]; Translational Trials Development and Support Laboratory award (USPHS) [MO1 RR 08084]; a Center of Excellence in Molecular Hematology P30 award [DK090971]; Cancer Free Kids Foundation for Cancer Research; Intramural Research Program of the National Human Genome Research Institute, NIH; JSPS Postdoctoral Fellowship FX We thank the Flow Cytometry Core, the Mouse Core, and the Microarray Core at Cincinnati Children's Hospital Medical Center for their help. This work was supported by an Institutional Clinical and Translational Science Award; an NIH/NCRR grant (1UL1RR026314-01); a Translational Trials Development and Support Laboratory award (USPHS, MO1 RR 08084); a Center of Excellence in Molecular Hematology P30 award (DK090971); a grant from the Cancer Free Kids Foundation for Cancer Research (to J.C. Mulloy and S. Goyama); a grant from the Intramural Research Program of the National Human Genome Research Institute, NIH (to P.P. Liu); and a JSPS Postdoctoral Fellowship for Research Abroad (to S. Goyama). J.C. Mulloy is a Leukemia and Lymphoma Society Scholar. The contents of the manuscript are solely the responsibility of the authors and donor necessarily represent the official views of the NIH. NR 53 TC 38 Z9 39 U1 0 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2013 VL 123 IS 9 BP 3876 EP 3888 DI 10.1172/JCI68557 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 220DQ UT WOS:000324562600032 PM 23979164 ER PT J AU Nayak, G Lee, SI Yousaf, R Edelmann, SE Trincot, C Van Itallie, CM Sinha, GP Rafeeq, M Jones, SM Belyantseva, IA Anderson, JM Forge, A Frolenkov, GI Riazuddinl, S AF Nayak, Gowri Lee, Sue I. Yousaf, Rizwan Edelmann, Stephanie E. Trincot, Claire Van Itallie, Christina M. Sinha, Ghanshyam P. Rafeeq, Maria Jones, Sherri M. Belyantseva, Inna A. Anderson, James M. Forge, Andrew Frolenkov, Gregory I. Riazuddinl, Saima TI Tricellulin deficiency affects tight junction architecture and cochlear hair cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID STRIA VASCULARIS; INNER-EAR; INTERCELLULAR-JUNCTIONS; EPITHELIAL-CELLS; BARRIER FUNCTION; EXPRESSION; HEARING; DEAFNESS; OCCLUDIN; ELECTROMOTILITY AB The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while the endocochlear potential and paracellular permeability of a biotin-based tracer in the stria vascularis were unaltered. Freeze-fracture electron microscopy revealed disruption of the strands of intramembrane particles connecting bicellular and tricellular junctions in the inner ear epithelia of tricellulin-deficient mice. These ultrastructural changes may selectively affect the paracellular permeability of ions or small molecules, resulting in a toxic microenvironment for cochlear hair cells. Consistent with this hypothesis, hair cell loss was rescued in tricellulin-deficient mice when generation of normal endolymph was inhibited by a concomitant deletion of the transcription factor, Pou3f4. Finally, comprehensive phenotypic screening showed a broader pathological phenotype in the mutant mice, which highlights the non-redundant roles played by tricellulin. C1 [Nayak, Gowri; Yousaf, Rizwan; Trincot, Claire; Riazuddinl, Saima] Cincinnati Childrens Hosp Res Fdn, Div Pediat Otolaryngol Head & Neck Surg, Mol Genet Lab, Cincinnati, OH 45229 USA. [Nayak, Gowri; Yousaf, Rizwan; Trincot, Claire; Riazuddinl, Saima] Univ Cincinnati, Coll Med, Dept Otolaryngol, Cincinnati, OH USA. [Lee, Sue I.; Belyantseva, Inna A.] NIDCD, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD USA. [Edelmann, Stephanie E.; Sinha, Ghanshyam P.; Frolenkov, Gregory I.] Univ Kentucky, Dept Physiol, Lexington, KY USA. [Van Itallie, Christina M.; Anderson, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Rafeeq, Maria] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Jones, Sherri M.] Univ Nebraska, Dept Special Educ & Commun Disorders, Omaha, NE 68182 USA. [Forge, Andrew] UCL, Ctr Auditory Res, London, England. RP Riazuddinl, S (reprint author), Cincinnati Childrens Hosp Res Fdn, Mol Genet Lab, 3333 Burnet Ave,MLC2018, Cincinnati, OH 45229 USA. EM Saima.Riazuddin@cchmc.org OI Frolenkov, Gregory/0000-0002-9810-5024 FU Deafness Research Foundation grant; Action on Hearing Loss grant; National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) [R01 DC011748, DC011803, R01 DC006443, R01 DC009434, DC000039-15]; International Center for Genetic Engineering and Biotechnology, Trieste, Italy [CRP/PAK08-01] FX We thank Thomas Friedman, Zubair Ahmed, Elodie Richard, and Arnaud Giese for critiques of our ideas and manuscript, Elizabeth Wilson for genotyping and maintaining our mouse colonies, and Manna Li and Kira Rehn for technical assistance. We also thank Penelope Friedman for her review of the Tric knockin mice biochemical and histology results. This work was supported by a Deafness Research Foundation grant, Action on Hearing Loss grant, and National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research grants (R01 DC011748 and DC011803 to S. Riazuddin; R01 DC006443 to S.M. Jones; R01 DC009434 to G.I. Frolenkov; the intramural funds from NIDCD DC000039-15) as well as the International Center for Genetic Engineering and Biotechnology, Trieste, Italy (project CRP/PAK08-01). NR 59 TC 29 Z9 29 U1 1 U2 14 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2013 VL 123 IS 9 BP 4036 EP 4049 DI 10.1172/JCI69031 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 220DQ UT WOS:000324562600044 PM 23979167 ER PT J AU Das, A Tanigawa, S Karner, CM Xin, M Lum, L Chen, C Olson, EN Perantoni, AO Carroll, TJ AF Das, Amrita Tanigawa, Shunsuke Karner, Courtney M. Xin, Mei Lum, Lawrence Chen, Chuo Olson, Eric N. Perantoni, Alan O. Carroll, Thomas J. TI Stromal-epithelial crosstalk regulates kidney progenitor cell differentiation SO NATURE CELL BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR PATHWAY; HIPPO PATHWAY; CARDIOMYOCYTE PROLIFERATION; RENAL DEVELOPMENT; HEART SIZE; GROWTH; CONSERVATION; FAT; MORPHOGENESIS; DISRUPTION AB Present models suggest that the fate of the kidney epithelial progenitors is solely regulated by signals from the adjacent ureteric bud. The bud provides signals that regulate the survival, renewal and differentiation of these cells. Recent data suggest that Wnt9b, a ureteric-bud-derived factor, is sufficient for both progenitor cell renewal and differentiation. How the same molecule induces two seemingly contradictory processes is unknown. Here, we show that signals from the stromal fibroblasts cooperate with Wnt9b to promote differentiation of the progenitors. The atypical cadherin Fat4 encodes at least part of this stromal signal. Our data support a model whereby proper kidney size and function is regulated by balancing opposing signals from the ureteric bud and stroma to promote renewal and differentiation of the nephron progenitors. C1 [Das, Amrita; Karner, Courtney M.; Carroll, Thomas J.] Univ Texas SW Med Ctr Dallas, Dept Internal Med Nephrol, Dallas, TX 75390 USA. [Das, Amrita; Karner, Courtney M.; Xin, Mei; Olson, Eric N.; Carroll, Thomas J.] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Tanigawa, Shunsuke; Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Lum, Lawrence] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Chen, Chuo] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. RP Carroll, TJ (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med Nephrol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Thomas.carroll@utsouthwestern.edu OI Chen, Chuo/0000-0002-3118-4901 FU Japanese Society for the Promotion of Science; NIH [R01DK080004, R01DK095057]; National Cancer Institute's Center for Cancer Research; George O'Brien Kidney Research Center at UTSW FX We thank Y. Yang (NIH, USA) for providing the Vangl2 mutant mice, M. Takeichi (RIKEN Center for Developmental Biology, Japan) for providing the Fat4 full-length and ECD plasmids, J. Cabera for artwork and O. Cleaver, Q. Li and D. Marciano for reading and commenting on the manuscript. This work was supported by a post-doctoral fellowship from the A.H.A. to A.D. and from the Japanese Society for the Promotion of Science to S.T., the NIH (R01DK080004 and R01DK095057 to T.C.) and National Cancer Institute's Center for Cancer Research (A.P.). This work was supported by the George O'Brien Kidney Research Center at UTSW. NR 33 TC 51 Z9 51 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD SEP PY 2013 VL 15 IS 9 BP 1035 EP + DI 10.1038/ncb2828 PG 22 WC Cell Biology SC Cell Biology GA 213IP UT WOS:000324050000004 PM 23974041 ER PT J AU Ezan, J Lasvaux, L Gezer, A Novakovic, A May-Simera, H Belotti, E Lhoumeau, AC Birnbaumer, L Beer-Hammer, S Borg, JP Le Bivic, A Nurnberg, B Sans, N Montcouquiol, M AF Ezan, Jerome Lasvaux, Lea Gezer, Aysegul Novakovic, Ana May-Simera, Helen Belotti, Edwige Lhoumeau, Anne-Catherine Birnbaumer, Lutz Beer-Hammer, Sandra Borg, Jean-Paul Le Bivic, Andre Nuernberg, Bernd Sans, Nathalie Montcouquiol, Mireille TI Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton SO NATURE CELL BIOLOGY LA English DT Article ID PLANAR CELL POLARITY; BARDET-BIEDL-SYNDROME; HETEROTRIMERIC G-PROTEINS; INNER-EAR; MICROTUBULE DYNAMICS; MAMMALIAN COCHLEA; PAR PROTEINS; POLARIZATION; EXPRESSION; CILIARY AB In ciliated mammalian cells, the precise migration of the primary cilium at the apical surface of the cells, also referred to as translational polarity, defines planar cell polarity (PCP) in very early stages. Recent research has revealed a co-dependence between planar polarization of some cell types and cilium positioning at the surface of cells. This important role of the primary cilium in mammalian cells is in contrast with its absence from Drosophila melanogaster PCP establishment. Here, we show that deletion of GTP-binding protein alpha-i subunit 3 (G alpha(i3)) and mammalian Partner of inscuteable (mPins) disrupts the migration of the kinocilium at the surface of cochlear hair cells and affects hair bundle orientation and shape. Inhibition of G-protein function in vitro leads to kinocilium migration defects, PCP phenotype and abnormal hair bundle morphology. We show that G alpha(i3)/mPins are expressed in an apical and distal asymmetrical domain, which is opposite and complementary to an aPKC/Par-3/Par-6b expression domain, and non-overlapping with the core PCP protein Vangl2. Thus G-protein-dependent signalling controls the migration of the cilium cell autonomously, whereas core PCP signalling controls long-range tissue PCP. C1 [Ezan, Jerome; Lasvaux, Lea; Gezer, Aysegul; Sans, Nathalie; Montcouquiol, Mireille] INSERM, Planar Polar & Plast Grp, Neuroctr Magendie, F-33077 Bordeaux, France. [Ezan, Jerome; Lasvaux, Lea; Gezer, Aysegul; Sans, Nathalie; Montcouquiol, Mireille] Univ Bordeaux, Neuroctr Magendie, F-33077 Bordeaux, France. [Novakovic, Ana; Beer-Hammer, Sandra; Nuernberg, Bernd] Univ Tubingen, Dept Pharmacol & Expt Therapy, Inst Expt & Clin Pharmacol & Toxicol, Eberhard Karls Univ Hosp & Clin, D-72074 Tubingen, Germany. [Novakovic, Ana; Beer-Hammer, Sandra; Nuernberg, Bernd] Univ Tubingen, Interfac Ctr Pharmacogen & Drug Res, D-72074 Tubingen, Germany. [May-Simera, Helen] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Belotti, Edwige; Lhoumeau, Anne-Catherine; Borg, Jean-Paul] CRCM, INSERM, U1068, F-13009 Marseille, France. [Belotti, Edwige; Lhoumeau, Anne-Catherine; Borg, Jean-Paul] CRCM, CNRS, UMR7258, F-13009 Marseille, France. [Belotti, Edwige; Lhoumeau, Anne-Catherine; Borg, Jean-Paul] Inst J Paoli I Calmettes, F-13009 Marseille, France. [Belotti, Edwige; Lhoumeau, Anne-Catherine; Borg, Jean-Paul] Aix Marseille Univ, F-13007 Marseille, France. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Durham, NC 27709 USA. [Le Bivic, Andre] CNRS, UMR 7288, IBDML, F-13288 Marseille 09, France. [Le Bivic, Andre] Aix Marseille Univ, IBDML, F-13288 Marseille, France. RP Montcouquiol, M (reprint author), INSERM, Planar Polar & Plast Grp, Neuroctr Magendie, F-33077 Bordeaux, France. EM mireille.montcouquiol@inserm.fr RI Beer-Hammer, Sandra/C-7442-2014; OI montcouquiol, mireille/0000-0001-8739-6519 FU INSEAM; Conseil Regional d'Aquitaine Neurocampus program; La Fondation pour la Recherche Medicale; European Commission Coordination Action ENINET [LSHM-CT-2005-19063]; Ligue Nationale Contre le Cancer; EUCAAD; Fondation ARC pour la Recherche sur le Cancer; Deutsche Forschungsgemeinschaft (DFG); Intramural Research Program of the NIH [Z01-ES-101643]; European FP7 program [HEALTH-F2-2008-200234]; ANR [BLAN07-2-186738]; [ANR-08-MNPS-040-01] FX We thank the animal and genotyping facilities' members of the Neurocentre for technical assistance, notably H. Doat and D. Gonzales. We also thank the entire team of the Bordeaux Imaging Center (BIC) for the constant technical assistance, notably P. Legros, S. Marais and C. Poujol. We thank P. Beales (UCL, UK) for the Mkks mutants. We thank L. Mays (Tubingen, Germany) for critical reading of the manuscript, and F. Schweisguth (Paris, France) and J. Raff (Oxford, UK) for thoughtful discussions. We apologize to all whose relevant work could not be cited. This research was supported by an INSEAM grant to M.M. and N.S., the Conseil Regional d'Aquitaine Neurocampus program, La Fondation pour la Recherche Medicale (M.M., N.S., J.E., A-C.L.), ANR-08-MNPS-040-01 (M.M.), the European Commission Coordination Action ENINET (LSHM-CT-2005-19063; N.S. and M.M.), Ligue Nationale Contre le Cancer (Label 2010, J-P.B.), EUCAAD (FP7 program, J-P.B.), Fondation ARC pour la Recherche sur le Cancer (B.N., E.B.), the Deutsche Forschungsgemeinschaft (DFG; B.N., S.B-H.), the Intramural Research Program of the NIH (Project Z01-ES-101643 to L.B.), the European FP7 program (HEALTH-F2-2008-200234, A.L.B.) and ANR (BLAN07-2-186738, A.L.B.). NR 39 TC 36 Z9 37 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD SEP PY 2013 VL 15 IS 9 BP 1107 EP + DI 10.1038/ncb2819 PG 17 WC Cell Biology SC Cell Biology GA 213IP UT WOS:000324050000011 PM 23934215 ER PT J AU Iyer, LM Zhang, DP Burroughs, AM Aravind, L AF Iyer, Lakshminarayan M. Zhang, Dapeng Burroughs, A. Maxwell Aravind, L. TI Computational identification of novel biochemical systems involved in oxidation, glycosylation and other complex modifications of bases in DNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSFER-RNA; ESCHERICHIA-COLI; COMPARATIVE GENOMICS; NATURAL-HISTORY; TET PROTEINS; ALPHA-PUTRESCINYLTHYMINE; STRUCTURE PREDICTION; CRYSTAL-STRUCTURE; MODIFYING ENZYME; BINDING DOMAINS AB Discovery of the TET/JBP family of dioxygenases that modify bases in DNA has sparked considerable interest in novel DNA base modifications and their biological roles. Using sensitive sequence and structure analyses combined with contextual information from comparative genomics, we computationally characterize over 12 novel biochemical systems for DNA modifications. We predict previously unidentified enzymes, such as the kinetoplastid J-base generating glycosyltransferase (and its homolog GREB1), the catalytic specificity of bacteriophage TET/JBP proteins and their role in complex DNA base modifications. We also predict the enzymes involved in synthesis of hypermodified bases such as alpha-glutamylthymine and alphaputrescinylthymine that have remained enigmatic for several decades. Moreover, the current analysis suggests that bacteriophages and certain nucleo-cytoplasmic large DNA viruses contain an unexpectedly diverse range of DNA modification systems, in addition to those using previously characterized enzymes such as Dam, Dcm, TET/JBP, pyrimidine hydroxymethylases, Mom and glycosyltransferases. These include enzymes generating modified bases such as deazaguanines related to queuine and archaeosine, pyrimidines comparable with lysidine, those derived using modified S-adenosyl methionine derivatives and those using TET/JBP-generated hydroxymethyl pyrimidines as biosynthetic starting points. We present evidence that some of these modification systems are also widely dispersed across prokaryotes and certain eukaryotes such as basidiomycetes, chlorophyte and stramenopile alga, where they could serve as novel epigenetic marks for regulation or discrimination of self from non-self DNA. Our study extends the role of the PUA-like fold domains in recognition of modified nucleic acids and predicts versions of the ASCH and EVE domains to be novel 'readers' of modified bases in DNA. These results open opportunities for the investigation of the biology of these systems and their use in biotechnology. C1 [Iyer, Lakshminarayan M.; Zhang, Dapeng; Burroughs, A. Maxwell; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU US Department of Health and Human Services (National Library of Medicine, National Institutes of Health (NIH)); NIH FX Intramural funds of the US Department of Health and Human Services (National Library of Medicine, National Institutes of Health (NIH)). Funding for open access charge: The intra-mural funds of the NIH. NR 118 TC 26 Z9 26 U1 1 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 16 BP 7635 EP 7655 DI 10.1093/nar/gkt573 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228GG UT WOS:000325173300014 PM 23814188 ER PT J AU Huang, SYN Murai, J Dalla Rosa, I Dexheimer, TS Naumova, A Gmeiner, WH Pommier, Y AF Huang, Shar-yin N. Murai, Junko Dalla Rosa, Ilaria Dexheimer, Thomas S. Naumova, Alena Gmeiner, William H. Pommier, Yves TI TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID STRAND BREAK REPAIR; I CLEAVAGE COMPLEXES; TOPOISOMERASE-I; PHOSPHODIESTERASE TDP1; SPINOCEREBELLAR ATAXIA; ARA-C; DIFFERENTIAL INCORPORATION; AXONAL NEUROPATHY; POLYMERASE; CELLS AB Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these drugs. Here, we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs-acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC)-we show that TDP1 is capable of removing the covalently linked corresponding CTNAs from DNA 3'-ends. We also show that Tdp1(-/-) cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing CTNA-induced DNA damage. As AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We find that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1(-/-) cells. Thus, TDP1 seems to be critical for repairing nuclear and mitochondrial DNA damage caused by CTNAs. C1 [Huang, Shar-yin N.; Murai, Junko; Dalla Rosa, Ilaria; Naumova, Alena; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Murai, Junko] Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. [Dexheimer, Thomas S.] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Gmeiner, William H.] Wake Forest Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Intramural Program of the National Cancer Institute, Center for Cancer Research [Z01 BC006150]; NIH-NCI [U01 CA102532] FX Intramural Program of the National Cancer Institute, Center for Cancer Research [Z01 BC006150]; NIH-NCI [U01 CA102532]. Funding for open access charge: Intramural Program of the National Cancer Institute, Center for Cancer Research [Z01 BC006150]. NR 55 TC 27 Z9 28 U1 0 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 16 BP 7793 EP 7803 DI 10.1093/nar/gkt483 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228GG UT WOS:000325173300026 PM 23775789 ER PT J AU Zhuang, R Rao, JN Zou, TT Liu, L Xiao, L Cao, S Hansraj, NZ Gorospe, M Wang, JY AF Zhuang, Ran Rao, Jaladanki N. Zou, Tongtong Liu, Lan Xiao, Lan Cao, Shan Hansraj, Natasha Z. Gorospe, Myriam Wang, Jian-Ying TI miR-195 competes with HuR to modulate stim1 mRNA stability and regulate cell migration SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BINDING PROTEIN HUR; INTESTINAL EPITHELIAL RESTITUTION; OPERATED CA2+ CHANNEL; DEPENDENT KINASE 4; PLASMA-MEMBRANE; SUPPRESSES TUMORIGENICITY; HEPATOCELLULAR-CARCINOMA; TRANSLATIONAL CONTROL; COMPETITIVE-BINDING; MUCOSAL RESTITUTION AB Stromal interaction molecule 1 (Stim1) functions as a sensor of Ca2+ within stores and plays an essential role in the activation of store-operated Ca2+ entry (SOCE). Although lowering Stim1 levels reduces store-operated Ca2+ entry and inhibits intestinal epithelial repair after wounding, the mechanisms that control Stim1 expression remain unknown. Here, we show that cellular Stim1 abundance is controlled posttranscriptionally via factors that associate with 3'-untranslated region (3'-UTR) of stim1 mRNA. MicroRNA-195 (miR-195) and the RNA-binding protein HuR competed for association with the stim1 3'-UTR and regulated stim1 mRNA decay in opposite directions. Interaction of miR-195 with the stim1 3'-UTR destabilized stim1 mRNA, whereas the stability of stim1 mRNA increased with HuR association. Interestingly, ectopic miR-195 overexpression enhanced stim1 mRNA association with argonautecontaining complexes and increased the colocalization of tagged stim1 RNA with processing bodies (P-bodies); the translocation of stim1 mRNA was abolished by HuR overexpression. Moreover, decreased levels of Stim1 by miR-195 overexpression inhibited cell migration over the denuded area after wounding but was rescued by increasing HuR levels. In sum, Stim1 expression is controlled by two factors competing for influence on stim1 mRNA stability: the mRNA-stabilizing protein HuR and the decay-promoting miR-195. C1 [Zhuang, Ran; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Xiao, Lan; Cao, Shan; Hansraj, Natasha Z.; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Zhuang, Ran; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Xiao, Lan; Cao, Shan; Hansraj, Natasha Z.; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, Genet Lab, IRP, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU US Department of Veterans Affairs; National Institutes of Health (NIH) [DK57819, DK61972, DK68491]; National Institute on Aging-Intramural Research Program, NIH; National Institute of Diabetes and Digestive and Kidney Diseases FX Merit Review Grants (to J-Y.W. and J.N.R.) from US Department of Veterans Affairs and from National Institutes of Health (NIH) [DK57819, DK61972, DK68491 to J-Y.W.]; National Institute on Aging-Intramural Research Program, NIH (to M.G.). Funding for open access charge: National Institute of Diabetes and Digestive and Kidney Diseases. NR 66 TC 30 Z9 30 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 16 BP 7905 EP 7919 DI 10.1093/nar/gkt565 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228GG UT WOS:000325173300035 PM 23804758 ER PT J AU Cho, DY Przytycka, TM AF Cho, Dong-Yeon Przytycka, Teresa M. TI Dissecting cancer heterogeneity with a probabilistic genotype-phenotype model SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CLINICALLY RELEVANT SUBTYPES; PATTERN DISCOVERY; GENE-EXPRESSION; GENOMIC DATA; GLIOBLASTOMA; NETWORKS; PATHWAYS; BREAST AB One of the obstacles hindering a better understanding of cancer is its heterogeneity. However, computational approaches to model cancer heterogeneity have lagged behind. To bridge this gap, we have developed a new probabilistic approach that models individual cancer cases as mixtures of subtypes. Our approach can be seen as a meta-model that summarizes the results of a large number of alternative models. It does not assume predefined subtypes nor does it assume that such subtypes have to be sharply defined. Instead given a measure of phenotypic similarity between patients and a list of potential explanatory features, such as mutations, copy number variation, microRNA levels, etc., it explains phenotypic similarities with the help of these features. We applied our approach to Glioblastoma Multiforme (GBM). The resulting model Prob_GBM, not only correctly inferred known relationships but also identified new properties underlining phenotypic similarities. The proposed probabilistic framework can be applied to model relations between similarity of gene expression and a broad spectrum of potential genetic causes. C1 [Cho, Dong-Yeon; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Przytycka, TM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 37 TC 6 Z9 6 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 17 BP 8011 EP 8020 DI 10.1093/nar/gkt577 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228HF UT WOS:000325175900010 PM 23821670 ER PT J AU Eun, B Sampley, ML Van Winkle, MT Good, AL Kachman, MM Pfeifer, K AF Eun, Bokkee Sampley, Megan L. Van Winkle, Matthew T. Good, Austin L. Kachman, Marika M. Pfeifer, Karl TI The Igf2/H19 muscle enhancer is an active transcriptional complex SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TISSUE-SPECIFIC ENHANCERS; NONCODING RNAS; HUMAN GENOME; GENE-TRANSCRIPTION; X-CHROMOSOME; HUMAN-CELLS; PROMOTERS; LOCUS; METHYLATIONS; COACTIVATOR AB In eukaryotic cells, gene expression is mediated by enhancer activation of RNA polymerase at distant promoters. Recently, distinctions between enhancers and promoters have been blurred by the discovery that enhancers are associated with RNA polymerase and are sites of RNA synthesis. Here, we present an analysis of the insulin-like growth factor 2/H19 muscle enhancer. This enhancer includes a short conserved core element that is organized into chromatin typical of mammalian enhancers, binds tissue-specific transcription factors and functions on its own in vitro to activate promoter transcription. However, in a chromosomal context, this element is not sufficient to activate distant promoters. Instead, enhancer function also requires transcription in cis of a long non-coding RNA, Nctc1. Thus, the insulin-like growth factor 2/H19 enhancer is an active transcriptional complex whose own transcription is essential to its function. C1 [Eun, Bokkee; Sampley, Megan L.; Van Winkle, Matthew T.; Good, Austin L.; Kachman, Marika M.; Pfeifer, Karl] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Eun, Bokkee] Korea Univ, Coll Med, Core Lab, Seoul 136701, South Korea. RP Pfeifer, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM pfeiferk@mail.nih.gov OI Pfeifer, Karl/0000-0002-0254-682X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Division of Intramural Research [1ZIAHD001804] FX Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Division of Intramural Research [1ZIAHD001804]. Funding for open access charge: Eunice Kennedy Shriver NICHD Division of Intramural Research [1ZIAHD001804]. NR 48 TC 9 Z9 10 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 17 BP 8126 EP 8134 DI 10.1093/nar/gkt597 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228HF UT WOS:000325175900019 PM 23842673 ER PT J AU Nagarajavel, V Iben, JR Howard, BH Maraia, RJ Clark, DJ AF Nagarajavel, V. Iben, James R. Howard, Bruce H. Maraia, Richard J. Clark, David J. TI Global 'bootprinting' reveals the elastic architecture of the yeast TFIIIB-TFIIIC transcription complex in vivo SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-III; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; READ ALIGNMENT; FISSION YEAST; GENES; NUCLEOSOME; GENOME; LOCALIZATION; CHROMATIN AB TFIIIB and TFIIIC are multi-subunit factors required for transcription by RNA polymerase III. We present a genome-wide high-resolution footprint map of TFIIIB-TFIIIC complexes in Saccharomyces cerevisiae, obtained by paired-end sequencing of micrococcal nuclease-resistant DNA. On tRNA genes, TFIIIB and TFIIIC form stable complexes with the same distinctive occupancy pattern but in mirror image, termed 'bootprints'. Global analysis reveals that the TFIIIB-TFIIIC transcription complex exhibits remarkable structural elasticity: tRNA genes vary significantly in length but remain protected by TFIIIC. Introns, when present, are markedly less protected. The RNA polymerase III transcription terminator is flexibly accommodated within the transcription complex and, unexpectedly, plays a major structural role by delimiting its 3'-boundary. The ETC sites, where TFIIIC binds without TFIIIB, exhibit different bootprints, suggesting that TFIIIC forms complexes involving other factors. We confirm six ETC sites and report a new site (ETC10). Surprisingly, TFIIIC, but not TFIIIB, interacts with some centromeric nucleosomes, suggesting that interactions between TFIIIC and the centromere may be important in the 3D organization of the nucleus. C1 [Nagarajavel, V.; Iben, James R.; Howard, Bruce H.; Maraia, Richard J.; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. EM maraiar@mail.nih.gov; clarkda@mail.nih.gov FU Intramural Research program of the NIH (NICHD); National Institutes of Health Intramural Program (NICHD) FX Intramural Research program of the NIH (NICHD). Funding for open access charge: National Institutes of Health Intramural Program (NICHD). NR 46 TC 21 Z9 21 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 17 BP 8135 EP 8143 DI 10.1093/nar/gkt611 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228HF UT WOS:000325175900020 PM 23856458 ER PT J AU Kazemian, M Pham, H Wolfe, SA Brodsky, MH Sinha, S AF Kazemian, Majid Pham, Hannah Wolfe, Scot A. Brodsky, Michael H. Sinha, Saurabh TI Widespread evidence of cooperative DNA binding by transcription factors in Drosophila development SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; GAGA FACTOR; COLLABORATIVE COMPETITION; INTERACTOME NETWORK; CHROMATIN-STRUCTURE; GENE-EXPRESSION; REGULATORY CODE; GLOBAL ANALYSIS; INTERACTION MAP; PARTNER CODE AB Regulation of eukaryotic gene transcription is often combinatorial in nature, with multiple transcription factors (TFs) regulating common target genes, often through direct or indirect mutual interactions. Many individual examples of cooperative binding by directly interacting TFs have been identified, but it remains unclear how pervasive this mechanism is during animal development. Cooperative TF binding should be manifest in genomic sequences as biased arrangements of TF-binding sites. Here, we explore the extent and diversity of such arrangements related to gene regulation during Drosophila embryogenesis. We used the DNA-binding specificities of 322 TFs along with chromatin accessibility information to identify enriched spacing and orientation patterns of TF-binding site pairs. We developed a new statistical approach for this task, specifically designed to accurately assess inter-site spacing biases while accounting for the phenomenon of homotypic site clustering commonly observed in developmental regulatory regions. We observed a large number of short-range distance preferences between TF-binding site pairs, including examples where the preference depends on the relative orientation of the binding sites. To test whether these binding site patterns reflect physical interactions between the corresponding TFs, we analyzed 27 TF pairs whose binding sites exhibited short distance preferences. In vitro protein-protein binding experiments revealed that > 65% of these TF pairs can directly interact with each other. For five pairs, we further demonstrate that they bind cooperatively to DNA if both sites are present with the preferred spacing. This study demonstrates how DNA-binding motifs can be used to produce a comprehensive map of sequence signatures for different mechanisms of combinatorial TF action. C1 [Kazemian, Majid; Sinha, Saurabh] Univ Illinois, Dept Comp Sci, Urbana, IL USA. [Kazemian, Majid] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD USA. [Kazemian, Majid] NHLBI, Ctr Immunol, NIH, Bethesda, MD USA. [Pham, Hannah; Wolfe, Scot A.; Brodsky, Michael H.] Univ Massachusetts, Program Gene Funct & Express, Sch Med, Amherst, MA 01003 USA. [Wolfe, Scot A.] Univ Massachusetts, Dept Biochem & Mol Pharmacol, Sch Med, Amherst, MA 01003 USA. [Brodsky, Michael H.] Univ Massachusetts, Dept Mol Med, Sch Med, Amherst, MA 01003 USA. [Sinha, Saurabh] Univ Illinois, Inst Genom Biol, Urbana, IL USA. RP Sinha, S (reprint author), Univ Illinois, Dept Comp Sci, Urbana, IL USA. EM Michael.brodsky@umassmed.edu; sinhas@illinois.edu OI Kazemian, Majid/0000-0001-7080-8820 FU National Institutes of Health (NIH) [GM085233]; National Science Foundation [DBI-0746303]; National Human Genome Research Institute of the NIH [R01 HG004744-01] FX Funding for open access charge: National Institutes of Health (NIH) [GM085233]; National Science Foundation [DBI-0746303 to S.S.]; National Human Genome Research Institute of the NIH [R01 HG004744-01 to M.H.B. and S.A.W.]. NR 78 TC 24 Z9 24 U1 0 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 17 BP 8237 EP 8252 DI 10.1093/nar/gkt598 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228HF UT WOS:000325175900027 PM 23847101 ER PT J AU Shuga, J Zeng, Y Novak, R Lan, Q Tang, XJ Rothman, N Vermeulen, R Li, LY Hubbard, A Zhang, LP Mathies, RA Smith, MT AF Shuga, Joe Zeng, Yong Novak, Richard Lan, Qing Tang, Xiaojiang Rothman, Nathaniel Vermeulen, Roel Li, Laiyu Hubbard, Alan Zhang, Luoping Mathies, Richard A. Smith, Martyn T. TI Single molecule quantitation and sequencing of rare translocations using microfluidic nested digital PCR SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MINIMAL RESIDUAL DISEASE; FOLLICULAR LYMPHOMA; HEALTHY-INDIVIDUALS; CHROMOSOMAL BREAKPOINT; CARRYING CELLS; DNA; T(14/18); MUTATIONS; EXPOSURE; LEUKEMIA AB Cancers are heterogeneous and genetically unstable. New methods are needed that provide the sensitivity and specificity to query single cells at the genetic loci that drive cancer progression, thereby enabling researchers to study the progression of individual tumors. Here, we report the development and application of a bead-based hemi-nested microfluidic droplet digital PCR (dPCR) technology to achieve 'quantitative' measurement and single-molecule sequencing of somatically acquired carcinogenic translocations at extremely low levels (<10(-6)) in healthy subjects. We use this technique in our healthy study population to determine the overall concentration of the t(14;18) translocation, which is strongly associated with follicular lymphoma. The nested dPCR approach improves the detection limit to 1 x 10(-7) or lower while maintaining the analysis efficiency and specificity. Further, the bead-based dPCR enabled us to isolate and quantify the relative amounts of the various clonal forms of t(14; 18) translocation in these subjects, and the single-molecule sensitivity and resolution of dPCR led to the discovery of new clonal forms of t(14; 18) that were otherwise masked by the conventional quantitative PCR measurements. In this manner, we created a quantitative map for this carcinogenic mutation in this healthy population and identified the positions on chromosomes 14 and 18 where the vast majority of these t(14; 18) events occur. C1 [Shuga, Joe; Hubbard, Alan; Zhang, Luoping; Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Zeng, Yong; Mathies, Richard A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Zeng, Yong] Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. [Novak, Richard; Mathies, Richard A.] Univ Calif Berkeley, UC San Francisco UC Berkeley Grad Program Bioengn, Berkeley, CA 94720 USA. [Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20852 USA. [Tang, Xiaojiang; Li, Laiyu] Guangdong Poison Control Ctr, Guangzhou 510300, Guangdong, Peoples R China. [Vermeulen, Roel] Univ Utrecht, Environm Epidemiol Div, Inst Risk Assessment Sci, NL-3508 Utrecht, Netherlands. RP Smith, MT (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. EM martynts@berkeley.edu FU Trans-National Institutes of Health Genes, Environment and Health Initiative, Biological Response Indicators of Environmental Systems Center Grant [U54 ES016115-01]; National Institute of Environmental Health Sciences Superfund Basic Research Program [P42 ES004705]; Canary Foundation; American Cancer Society [116373-PFTED-08-251-01-SIED]; University of Kansas; National Science Foundation Graduate Research Fellowship; National Institutes of Health [U54 ES016115-01] FX Trans-National Institutes of Health Genes, Environment and Health Initiative, Biological Response Indicators of Environmental Systems Center Grant [U54 ES016115-01 to M. T. S. and R. A. M.] and National Institute of Environmental Health Sciences Superfund Basic Research Program Grant [P42 ES004705 to M. T. S.]; Canary Foundation and ACS Postdoctoral Fellowship Award in Early Detection [116373-PFTED-08-251-01-SIED to J.S.] from the American Cancer Society; New faculty start-up funds from the University of Kansas (in part to Y.Z.). National Science Foundation Graduate Research Fellowship (to R.N.). Funding for open access charge: National Institutes of Health [U54 ES016115-01]. NR 42 TC 17 Z9 18 U1 2 U2 63 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2013 VL 41 IS 16 AR e159 DI 10.1093/nar/gkt613 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 228GG UT WOS:000325173300007 PM 23873959 ER PT J AU Blanch-Hartigan, D Ruben, MA AF Blanch-Hartigan, Danielle Ruben, Mollie A. TI Training clinicians to accurately perceive their patients: Current state and future directions SO PATIENT EDUCATION AND COUNSELING LA English DT Article; Proceedings Paper CT International Conference on Communication in Healthcare (ICCH) CY 2012 CL Univ St Andrews, Med Sch, St Andrews, SCOTLAND SP European Assoc Commun Healthcare HO Univ St Andrews, Med Sch DE Training; Person perception accuracy; Medical education; Emotion recognition; Patient-centered care ID IMPROVE PHYSICIANS DETECTION; MEDICAL-STUDENTS; NONVERBAL-COMMUNICATION; INTERPERSONAL SKILLS; EMOTION RECOGNITION; DETECTING DECEPTION; FACIAL EXPRESSIONS; SEQUENCE-ANALYSIS; SELF-ASSESSMENT; CANCER-PATIENTS AB Objective: To review the literature on training clinicians' person perception accuracy, or the ability to correctly judge patients' states and traits. To present the importance of training this skill, share evidence it is a trainable skill, and suggest evidence-based recommendations for implementing training. Methods: We conducted a literature review on person perception training studies developed for or implemented with clinicians. We also summarized measures to evaluate training efficacy, barriers to implementation, and future research directions. Results: Training studies exist to improve clinicians' ability to perceive patients' emotions, pain, distress, and depression. These varied in training approach, length of training, and study design. Ten of 13 studies showed training benefited person perception accuracy. Conclusions: The medical literature and previous meta-analysis on person perception training across contexts demonstrate that training person perception accuracy can be effective. Examples of effective trainings provide suggestions of best-practices for future efforts in this area. Practice implications: More evidence is needed to create and implement trainings which produce not only differences in accuracy but also in patient care and outcomes. Medical curriculum developers and researchers should collaborate to create effective person perception trainings for clinicians. Published by Elsevier Ireland Ltd. C1 [Blanch-Hartigan, Danielle] NCI, Div Canc Control & Populat Sci, Off Canc Survivorship, Bethesda, MD 20892 USA. [Ruben, Mollie A.] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. RP Blanch-Hartigan, D (reprint author), NCI, Off Canc Survivorship, 6116 Execut Blvd,Suite 404,MSC 8336, Rockville, MD 20892 USA. EM danielleblanch@gmail.com OI Ruben, Mollie/0000-0001-8918-8932 NR 67 TC 8 Z9 8 U1 3 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD SEP PY 2013 VL 92 IS 3 SI SI BP 328 EP 336 DI 10.1016/j.pec.2013.02.010 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 221KM UT WOS:000324657800008 PM 23490175 ER PT J AU Gallaher, AM Das, S Xiao, Z Andresson, T Kieffer-Kwon, P Happel, C Ziegelbauer, J AF Gallaher, Amelia M. Das, Sudipto Xiao, Zhen Andresson, Thorkell Kieffer-Kwon, Philippe Happel, Christine Ziegelbauer, Joseph TI Proteomic Screening of Human Targets of Viral microRNAs Reveals Functions Associated with Immune Evasion and Angiogenesis SO PLOS PATHOGENS LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; NF-KAPPA-B; INFLAMMATORY-CYTOKINE EXPRESSION; HUMAN GAMMA-HERPESVIRUSES; VIRUS-ENCODED MICRORNAS; HUMAN ENDOTHELIAL-CELLS; HEME OXYGENASE-1; GENE-TRANSFER; PROTEIN-SYNTHESIS; UBIQUITIN LIGASE AB Kaposi's sarcoma (KS) is caused by infection with Kaposi's sarcoma-associated herpesvirus (KSHV). The virus expresses unique microRNAs (miRNAs), but the targets and functions of these miRNAs are not completely understood. In order to identify human targets of viral miRNAs, we measured protein expression changes caused by multiple KSHV miRNAs using pulsed stable labeling with amino acids in cell culture (pSILAC) in primary endothelial cells. This led to the identification of multiple human genes that are repressed at the protein level, but not at the miRNA level. Further analysis also identified that KSHV miRNAs can modulate activity or expression of upstream regulatory factors, resulting in suppressed activation of a protein involved in leukocyte recruitment (ICAM1) following lysophosphatidic acid treatment, as well as up-regulation of a pro-angiogenic protein (HIF1 alpha), and up-regulation of a protein involved in stimulating angiogenesis (HMOX1). This study aids in our understanding of miRNA mechanisms of repression and miRNA contributions to viral pathogenesis. C1 [Gallaher, Amelia M.; Kieffer-Kwon, Philippe; Happel, Christine; Ziegelbauer, Joseph] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Das, Sudipto; Xiao, Zhen; Andresson, Thorkell] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Gallaher, AM (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM ziegelbauerjm@mail.nih.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Cancer Institute [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health and with federal funds from the National Cancer Institute under Contract HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 16 Z9 16 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2013 VL 9 IS 9 AR e1003584 DI 10.1371/journal.ppat.1003584 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 224WM UT WOS:000324922300014 PM 24039573 ER PT J AU Garver, LS Oliveira, GD Barillas-Mury, C AF Garver, Lindsey S. Oliveira, Giselle de Almeida Barillas-Mury, Carolina TI The JNK Pathway Is a Key Mediator of Anopheles gambiae Antiplasmodial Immunity SO PLOS PATHOGENS LA English DT Article ID NF-KAPPA-B; SMOOTH-MUSCLE-CELLS; PLASMODIUM-BERGHEI; SIGNALING PATHWAYS; MALARIA PARASITE; MIDGUT CELLS; DROSOPHILA; INFECTION; ACTIVATION; MOSQUITOS AB The innate immune system of Anopheles gambiae mosquitoes limits Plasmodium infection through multiple molecular mechanisms. For example, midgut invasion by the parasite triggers an epithelial nitration response that promotes activation of the complement-like system. We found that suppression of the JNK pathway, by silencing either Hep, JNK, Jun or Fos expression, greatly enhanced Plasmodium infection; while overactivating this cascade, by silencing the suppressor Puckered, had the opposite effect. The JNK pathway limits infection via two coordinated responses. It induces the expression of two enzymes (HPx2 and NOX5) that potentiate midgut epithelial nitration in response to Plasmodium infection and regulates expression of two key hemocyte-derived immune effectors (TEP1 and FBN9). Furthermore, the An. gambiae L3-5 strain that has been genetically selected to be refractory (R) to Plasmodium infection exhibits constitutive overexpression of genes from the JNK pathway, as well as midgut and hemocyte effector genes. Silencing experiments confirmed that this cascade mediates, to a large extent, the drastic parasite elimination phenotype characteristic of this mosquito strain. In sum, these studies revealed the JNK pathway as a key regulator of the ability of An. gambiae mosquitoes to limit Plasmodium infection and identified several effector genes mediating these responses. C1 [Garver, Lindsey S.; Oliveira, Giselle de Almeida; Barillas-Mury, Carolina] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, Rockville, MD USA. RP Garver, LS (reprint author), Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, Rockville, MD USA. EM cbarillas@niaid.nih.gov OI Oliveira, Giselle/0000-0002-5898-7843; Garver, Lindsey/0000-0003-2893-0130 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Malaria Infection Biology Research and Training Program, NIAID, NIH 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. LSG received funding from the Malaria Infection Biology Research and Training Program, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 32 Z9 33 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2013 VL 9 IS 9 AR e1003622 DI 10.1371/journal.ppat.1003622 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 224WM UT WOS:000324922300036 PM 24039583 ER PT J AU Huijben, S Bell, AS Sim, DG Tomasello, D Mideo, N Day, T Read, AF AF Huijben, Silvie Bell, Andrew S. Sim, Derek G. Tomasello, Danielle Mideo, Nicole Day, Troy Read, Andrew F. TI Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens SO PLOS PATHOGENS LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; MALARIA PARASITES; ANTIBIOTIC-RESISTANCE; BACTERIAL-MENINGITIS; COMPETITIVE RELEASE; PLASMODIUM-CHABAUDI; EVOLUTION; POPULATION; DYNAMICS; THERAPY AB Drug resistant pathogens are one of the key public health challenges of the 21 st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by.150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible. C1 [Huijben, Silvie; Bell, Andrew S.; Sim, Derek G.; Tomasello, Danielle; Mideo, Nicole; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Huijben, Silvie; Bell, Andrew S.; Sim, Derek G.; Tomasello, Danielle; Mideo, Nicole; Read, Andrew F.] Penn State Univ, Dept Entomol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Day, Troy] Queens Univ, Dept Math, Kingston, ON, Canada. [Day, Troy] Queens Univ, Dept Stat, Kingston, ON, Canada. [Day, Troy] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Huijben, S (reprint author), CRESIB Barcelona Ctr Int Hlth Res, Barcelona, Spain. EM silviehuijben@gmail.com; a.read@psu.edu FU National Institute of General Medical Sciences [R01GM089932] FX This work was supported by the National Institute of General Medical Sciences (R01GM089932). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 28 Z9 28 U1 1 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2013 VL 9 IS 9 AR e1003578 DI 10.1371/journal.ppat.1003578 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 224WM UT WOS:000324922300011 PM 24068922 ER PT J AU Omsland, A Hackstadt, T Heinzen, RA AF Omsland, Anders Hackstadt, Ted Heinzen, Robert A. TI Bringing Culture to the Uncultured: Coxiella burnetii and Lessons for Obligate Intracellular Bacterial Pathogens SO PLOS PATHOGENS LA English DT Article ID CHLAMYDIA-TRACHOMATIS; LEGIONELLA-PNEUMOPHILA; PROTEINS; TRANSPORT; DIFFERENTIATION; MACROPHAGES; INCLUSION; PROBES; CELLS C1 [Omsland, Anders; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. [Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Omsland, A (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. EM rheinzen@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was funded by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 6 Z9 6 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2013 VL 9 IS 9 AR e1003540 DI 10.1371/journal.ppat.1003540 PG 5 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 224WM UT WOS:000324922300005 PM 24039571 ER PT J AU Hikosaka, O Yamamoto, S Yasuda, M Kim, HF AF Hikosaka, Okihide Yamamoto, Shinya Yasuda, Masaharu Kim, Hyoung F. TI Why skill matters SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID SACCADIC EYE-MOVEMENTS; BASAL GANGLIA; MOTOR SKILL; SELECTIVE ATTENTION; VISUAL-ATTENTION; CAUDATE-NUCLEUS; PARIETAL CORTEX; HABIT FORMATION; RESPONSE BIAS; REWARD AB Maximizing rewards per unit time is ideal for success and survival in humans and animals. This goal can be approached by speeding up behavior aiming at rewards and this is done most efficiently by acquiring skills. Importantly, reward-directed skills consist of two components: finding a good object (i.e., object skill) and acting on the object (i.e., action skill), which occur sequentially. Recent studies suggest that object skill is based on high-capacity memory for object value associations. When a learned object is encountered the corresponding memory is quickly expressed as a valuebased gaze bias, leading to the automatic acquisition or avoidance of the object. Object skill thus plays a crucial role in increasing rewards per unit time. C1 [Hikosaka, Okihide; Yamamoto, Shinya; Yasuda, Masaharu; Kim, Hyoung F.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Yamamoto, Shinya] Natl Inst Adv Ind Sci & Technol, Human Technol Res Inst, Tsukuba, Ibaraki 3058568, Japan. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM oh@lsr.nei.nih.gov RI Yamamoto, Shinya/S-3134-2016 OI Yamamoto, Shinya/0000-0002-0505-8848 FU intramural research program at the National Eye Institute FX This work was supported by the intramural research program at the National Eye Institute. NR 108 TC 21 Z9 21 U1 7 U2 35 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD SEP PY 2013 VL 17 IS 9 BP 434 EP 441 DI 10.1016/j.tics.2013.07.001 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 223DJ UT WOS:000324784000004 PM 23911579 ER PT J AU Ferrari, PF Tramacere, A Simpson, EA Iriki, A AF Ferrari, Pier F. Tramacere, Antonella Simpson, Elizabeth A. Iriki, Atsushi TI Mirror neurons through the lens of epigenetics SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID GENE-EXPRESSION; PREMOTOR CORTEX; FACE PREFERENCE; MATERNAL-CARE; PARIETAL LOBE; SYSTEM; BRAIN; PLASTICITY; EVOLUTION; MOTOR AB The consensus view in mirror neuron research is that mirror neurons comprise a uniform, stable execution observation matching system. In this opinion article, we argue that, in light of recent evidence, this is at best an incomplete and oversimplified view of mirror neurons, where activity is actually variable and more plastic than previously theorized. We propose an epigenetic account for understanding developmental changes in sensorimotor systems, including variations in mirror neuron activity. Although associative and genetic accounts fail to consider the complexity of genetic and nongenetic interactions, we propose a new evolutionary developmental biology (evo-devo) perspective, which predicts that environmental differences early in development should produce variations in mirror neuron response patterns, tuning them to the social environment. C1 [Ferrari, Pier F.; Tramacere, Antonella; Simpson, Elizabeth A.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Simpson, Elizabeth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Poolesville, MD USA. [Tramacere, Antonella; Iriki, Atsushi] RIKEN Brain Sci Inst, Saitama, Japan. RP Ferrari, PF (reprint author), Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. EM pierfrancesco.ferrari@unipr.it OI Simpson, Elizabeth/0000-0003-2715-2533 FU Division of Intramural Research, NICHD [P01HD064653]; Worl-dleading Innovative R&D on Science and Technology FX This research was supported by the Division of Intramural Research, NICHD, NICHD P01HD064653, and by the Funding Program for Worl-dleading Innovative R&D on Science and Technology. We thank Valentina Sclafani and Sebo Uithol for their comments on an early version of this paper. NR 76 TC 24 Z9 24 U1 4 U2 31 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD SEP PY 2013 VL 17 IS 9 BP 450 EP 457 DI 10.1016/j.tics.2013.07.003 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 223DJ UT WOS:000324784000006 PM 23953747 ER PT J AU Strober, W AF Strober, Warren TI Impact of the gut microbiome on mucosal inflammation SO TRENDS IN IMMUNOLOGY LA English DT Review DE Gut microbiome; Mucosal regulatory T cells; Anti-inflammatory organisms; Proinflammatory (colitogenic organisms); Inflammatory Bowel Disease ID INVASIVE ESCHERICHIA-COLI; CROHNS-DISEASE; BOWEL-DISEASE; ULCERATIVE-COLITIS; ILEAL MUCOSA; INTESTINAL INFLAMMATION; RECEPTOR; MICE; COLONIZATION; MACROPHAGES AB In the past 10 years it has become increasingly apparent that the gut microbiome has profound effects on the immune system to which it is juxtaposed, the mucosal immune system. Here, I explore recent studies in which the effects of the microbiota expand or facilitate anti-inflammatory or regulatory immunological machinery or which favor development of proinflammatory immunological machinery in this system. I then focus on how these opposing processes play out in inflammatory bowel disease (IBD); a disease in which normal immune homeostasis is disturbed and inflammation takes hold. C1 NIAID, NIH, Bethesda, MD USA. RP Strober, W (reprint author), NIAID, NIH, Bethesda, MD USA. EM Wstrober@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000354-27] NR 47 TC 20 Z9 21 U1 3 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD SEP PY 2013 VL 34 IS 9 BP 423 EP 430 DI 10.1016/j.it.2013.07.001 PG 8 WC Immunology SC Immunology GA 225OG UT WOS:000324971600001 PM 23957963 ER PT J AU Kadmiel, M Cidlowski, JA AF Kadmiel, Mahita Cidlowski, John A. TI Glucocorticoid receptor signaling in health and disease SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review DE stress hormones; inflammation; nuclear receptor; glucocorticoid-response element ID CONGENITAL ADRENAL-HYPERPLASIA; OBSTRUCTIVE PULMONARY-DISEASE; INNATE IMMUNE-SYSTEM; GENE-EXPRESSION; CARDIOVASCULAR-SYSTEM; RESPONSE ELEMENTS; FUTURE-DIRECTIONS; LUNG MATURATION; BETA-ISOFORM; NR3C1 GENE AB Glucocorticoids are steroid hormones regulated in a circadian and stress-associated manner to maintain various metabolic and homeostatic functions that are necessary for life. Synthetic glucocorticoids are widely prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD), and inflammatory disorders of the eye. Research in the past few years has begun to unravel the profound complexity of glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies. Glucocorticoids signal through the glucocorticoid receptor (GR), a member of the superfamily of nuclear receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review, we provide an update on glucocorticoid receptor signaling and highlight the role of GR signaling in physiological and pathophysiological conditions in the major organ systems in the human body. C1 [Kadmiel, Mahita; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIEHS Intramural Research Program of the National Institutes of Health FX The authors thank all members of the Molecular Endocrinology Group for critical reading of this manuscript. They apologize to colleagues whose work they were unable to cite owing to space limitations. They thank these individuals for all their work that has significantly contributed to our current understanding of GR action. This work was supported by the NIEHS Intramural Research Program of the National Institutes of Health. NR 110 TC 109 Z9 112 U1 11 U2 79 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD SEP PY 2013 VL 34 IS 9 BP 518 EP 530 DI 10.1016/j.tips.2013.07.003 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 229DE UT WOS:000325241200006 PM 23953592 ER PT J AU Restaino, M Matthews, FE Minett, T Albanese, E Brayne, C Stephan, BCM AF Restaino, Marialuisa Matthews, Fiona E. Minett, Thais Albanese, Emiliano Brayne, Carol Stephan, Blossom Christa Maree TI Predicting risk of 2-year incident dementia using the CAMCOG total and subscale scores SO AGE AND AGEING LA English DT Article DE cognition; dementia risk prediction; Cambridge Cognitive Examination (CAMCOG); classification and regression tree (CART) analysis; predictive accuracy; older people ID MILD COGNITIVE IMPAIRMENT; CONCISE NEUROPSYCHOLOGICAL TEST; ELDERLY POPULATION-SAMPLE; PSYCHOMETRIC PROPERTIES; DIAGNOSIS; INSTRUMENT; PROFILE AB Objective: to identify cognitive changes associated with an increased risk of 2-year incident dementia using the Cambridge Cognitive Examination (CAMCOG). Design: longitudinal population representative sample aged 65+ years. Methods: individuals were from the Medical Research Council Cognitive Function and Ageing Study. Classification and Regression Tree analysis was used to detect the optimal cut-off value for the CAMCOG total, subscales and composite memory and non-memory scores, for predicting dementia. Sensitivity and specificity of each cut-off score were assessed. Results: from the 2,053 individuals without dementia at the first assessment, 137 developed dementia at the 2-year follow-up. The results indicate similar discriminative accuracy for incident dementia based on the CAMCOG total, memory subscale and composite scores. However, sensitivity and specificity of cut-off values were generally moderate. Scores on the non-memory subscales generally had high sensitivity but low specificity. Compared with the CAMCOG total score they had significantly lower discriminative accuracy. Conclusion: in a population setting, cut-off scores from the CAMCOG memory subscales predicted dementia with reasonable accuracy. Scores on the non-memory scales have lower accuracy and are not recommend for predicting high-risk cases unless all non-memory subdomain scores are combined. The added value of cognition when assessed using the CAMCOG to other risk factors (e.g. health and genetics) should be tested within a risk prediction framework. C1 [Restaino, Marialuisa] Univ Salerno, Dept Econ & Stat, Fisciano, SA, Italy. [Matthews, Fiona E.] Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England. [Minett, Thais; Brayne, Carol] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 0SR, England. [Albanese, Emiliano] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, WA USA. [Stephan, Blossom Christa Maree] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. RP Stephan, BCM (reprint author), Newcastle Univ, Inst Hlth & Soc, Baddiley Clark Bldg,Richardson Rd, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. EM blossom.stephan@ncl.ac.uk RI Restaino, Marialuisa/L-5665-2015; OI Restaino, Marialuisa/0000-0002-1150-8278; Stephan, Blossom/0000-0002-1235-360X; Matthews, Fiona/0000-0002-1728-2388 FU Medical Research Council [G9901400]; Department of Health; National Institute on Aging, National Institutes of Health FX MRC CFAS has been funded by the Medical Research Council (G9901400) and Department of Health. E. A. is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 19 TC 4 Z9 5 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD SEP PY 2013 VL 42 IS 5 BP 649 EP 653 DI 10.1093/ageing/aft082 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 204BX UT WOS:000323341000020 PM 23872637 ER PT J AU Kimmel, SE French, B Anderson, JL Gage, BF Johnson, JA Rosenberg, YD Geller, NL Kasner, SE Eby, CS Joo, J Caldwell, MD Goldhaber, SZ Hart, RG Cifelli, D Madigan, R Brensinger, CM Goldberg, S Califf, RM Ellenberg, JH AF Kimmel, Stephen E. French, Benjamin Anderson, Jeffrey L. Gage, Brian F. Johnson, Julie A. Rosenberg, Yves D. Geller, Nancy L. Kasner, Scott E. Eby, Charles S. Joo, Jungnam Caldwell, Michael D. Goldhaber, Samuel Z. Hart, Robert G. Cifelli, Denise Madigan, Rosemary Brensinger, Colleen M. Goldberg, Suzanne Califf, Robert M. Ellenberg, Jonas H. CA COAG Investigators TI Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial SO AMERICAN HEART JOURNAL LA English DT Article ID ORAL ANTICOAGULATION; ATRIAL-FIBRILLATION; AFRICAN-AMERICANS; COAG TRIAL; WARFARIN; INTENSITY; METAANALYSIS; POPULATION; ALGORITHMS; CAUCASIANS AB Background Current dosing practices for warfarin are empiric and result in the need for frequent dose changes as the international normalized ratio gets too high or too low. As a result, patients are put at increased risk for thromboembolism, bleeding, and premature discontinuation of anticoagulation therapy. Prior research has identified clinical and genetic factors that can alter warfarin dose requirements, but few randomized clinical trials have examined the utility of using clinical and genetic information to improve anticoagulation control or clinical outcomes among a large, diverse group of patients initiating warfarin. Methods The COAG trial is a multicenter, double-blind, randomized trial comparing 2 approaches to guiding warfarin therapy initiation: initiation of warfarin therapy based on algorithms using clinical information plus an individual's genotype using genes known to influence warfarin response ("genotype-guided dosing") versus only clinical information ("clinical-guided dosing") (www.clinicaltrials.gov Identifier: NCT00839657). Results The COAG trial design is described. The study hypothesis is that, among 1,022 enrolled patients, genotype-guided dosing relative to clinical-guided dosing during the initial dosing period will increase the percentage of time that patients spend in the therapeutic international normalized ratio range in the first 4 weeks of therapy. Conclusion The COAG will determine if genetic information provides added benefit above and beyond clinical information alone. C1 [Kimmel, Stephen E.; French, Benjamin; Kasner, Scott E.; Cifelli, Denise; Madigan, Rosemary; Brensinger, Colleen M.; Ellenberg, Jonas H.] Univ Penn Hlth Syst, Perelman Sch Med, Philadelphia, PA USA. [Anderson, Jeffrey L.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Gage, Brian F.; Eby, Charles S.] Washington Univ, Sch Med, St Louis, MO USA. [Johnson, Julie A.] Univ Florida, Gainesville, FL USA. [Rosenberg, Yves D.; Geller, Nancy L.; Joo, Jungnam; Goldberg, Suzanne] NHLBI, NIH, Bethesda, MD 20892 USA. [Caldwell, Michael D.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Goldhaber, Samuel Z.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hart, Robert G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Ellenberg, Jonas H.] Duke Univ, Med Ctr, Durham, NC USA. RP Kimmel, SE (reprint author), Univ Penn, Sch Med, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM stevek@mail.med.upenn.edu FU National Heart Lung and Blood Institute [HHSN268200800003C] FX This work was supported under contract HHSN268200800003C from the National Heart Lung and Blood Institute. NR 32 TC 8 Z9 10 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2013 VL 166 IS 3 BP 435 EP + DI 10.1016/j.ahj.2013.04.009 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 214UZ UT WOS:000324163600016 PM 24016491 ER PT J AU Mentz, RJ Bittner, V Schulte, PJ Fleg, JL Pina, IL Keteyian, SJ Moe, G Nigam, A Swank, AM Onwuanyi, AE Fitz-Gerald, M Kao, A Ellis, SJ Kraus, WE Whellan, DJ O'Connor, CM AF Mentz, Robert J. Bittner, Vera Schulte, Phillip J. Fleg, Jerome L. Pina, Ileana L. Keteyian, Steven J. Moe, Gordon Nigam, Anil Swank, Ann M. Onwuanyi, Anekwe E. Fitz-Gerald, Meredith Kao, Andrew Ellis, Stephen J. Kraus, William E. Whellan, David J. O'Connor, Christopher M. TI Race, exercise training, and outcomes in chronic heart failure: Findings from Heart Failure - A Controlled Trial Investigating Outcomes in Exercise TraiNing (HF-ACTION) SO AMERICAN HEART JOURNAL LA English DT Article ID QUALITY-OF-CARE; RANDOMIZED CONTROLLED-TRIAL; RACIAL-DIFFERENCES; AFRICAN-AMERICANS; MEDICARE BENEFICIARIES; STABLE OUTPATIENTS; PROGNOSTIC VALUE; RISK-FACTORS; MORTALITY; SCORE AB Background The strength of race as an independent predictor of long-term outcomes in a contemporary chronic heart failure (HF) population and its association with exercise training response have not been well established. We aimed to investigate the association between race and outcomes and to explore interactions with exercise training in patients with ambulatory HF. Methods We performed an analysis of HF-ACTION, which randomized 2331 patients with HF having an ejection fraction <= 35% to usual care with or without exercise training. We examined characteristics and outcomes (mortality/hospitalization, mortality, and cardiovascular mortality/HF hospitalization) by race using adjusted Cox models and explored an interaction with exercise training. Results There were 749 self-identified black patients (33%). Blacks were younger with significantly more hypertension and diabetes, less ischemic etiology, and lower socioeconomic status versus whites. Blacks had shorter 6-minute walk distance and lower peak VO2 at baseline. Over a median follow-up of 2.5 years, black race was associated with increased risk for all outcomes except mortality. After multivariable adjustment, black race was associated with increased mortality/hospitalization (hazard ratio [HR] 1.16, 95% CI 1.01-1.33) and cardiovascular mortality/HF hospitalization (HR 1.46, 95% CI 1.20-1.77). The hazard associated with black race was largely caused by increased HF hospitalization (HR 1.58, 95% CI 1.27-1.96), given similar cardiovascular mortality. There was no interaction between race and exercise training on outcomes (P > .5). Conclusions Black race in patients with chronic HF was associated with increased prevalence of modifiable risk factors, lower exercise performance, and increased HF hospitalization, but not increased mortality or a differential response to exercise training. C1 [Mentz, Robert J.; Kraus, William E.; O'Connor, Christopher M.] Duke Univ, Durham, NC USA. [Bittner, Vera; Fitz-Gerald, Meredith] Univ Alabama Birmingham, Birmingham, AL USA. [Schulte, Phillip J.; Ellis, Stephen J.] DCRI, Durham, NC USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Pina, Ileana L.] Montefiore Einstein Med Ctr, New York, NY USA. [Keteyian, Steven J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Moe, Gordon] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Nigam, Anil] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Nigam, Anil] Univ Montreal, Montreal, PQ, Canada. [Swank, Ann M.] Univ Louisville, Louisville, KY 40292 USA. [Onwuanyi, Anekwe E.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Kao, Andrew] St Lukes Midamer Heart Inst, Kansas City, MO USA. [Whellan, David J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. RP Mentz, RJ (reprint author), 2301 Erwin Rd, Durham, NC 27710 USA. EM robert.mentz@duke.edu OI Bittner, Vera/0000-0001-9456-850X; Kraus, William E/0000-0003-1930-9684 FU National Heart, Lung, and Blood Institute FX The HF-ACTION study was funded by the National Heart, Lung, and Blood Institute, but no extramural funding was used to support the current analysis. The authors are solely responsible for the design and conduct of this study, all analyses, the drafting and editing of the manuscript, and its final contents. NR 31 TC 13 Z9 13 U1 1 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2013 VL 166 IS 3 BP 488 EP + DI 10.1016/j.ahj.2013.06.002 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 214UZ UT WOS:000324163600023 PM 24016498 ER PT J AU Allison, MA Bluemke, DA McClelland, R Cushman, M Criqui, MH Polak, JF Lima, JA AF Allison, Matthew A. Bluemke, David A. McClelland, Robyn Cushman, Mary Criqui, Michael H. Polak, Joseph F. Lima, Joao A. TI Relation of Leptin to Left Ventricular Hypertrophy (from the Multi-Ethnic Study of Atherosclerosis) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIAC-HYPERTROPHY; MAGNETIC-RESONANCE; WEIGHT-LOSS; OBESITY; MICE; MASS; HEART; ASSOCIATION; RESISTANCE; IMPACT AB Increasing adiposity increases the risk for left ventricular (LV) hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data were obtained from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor-alpha, and resistin). One-thousand four hundred sixty four MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m(2), and 49% were women. With adjustment for age, gender, race, height, and weight, multivariate linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (beta: -4.66% predicted, p <0.01), LV volume (-5.87% predicted, p <0.01), stroke volume (-3.23 ml, p <0.01), and cardiac output (-120 ml/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (odds ratio 0.65, p <0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines, and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely nonsignificant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function. Published by Elsevier Inc. C1 [Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. [McClelland, Robyn] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Polak, Joseph F.] Tufts Med Ctr, Dept Radiol, Boston, MA USA. [Lima, Joao A.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Allison, MA (reprint author), Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. EM mallison@ucsd.edu OI Bluemke, David/0000-0002-8323-8086; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [R01-HL-088451, HC-95159, N01-HC-95165, N01-HC-95169] FX This research was supported by a grant R01-HL-088451 and contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. NR 26 TC 15 Z9 15 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 1 PY 2013 VL 112 IS 5 BP 726 EP 730 DI 10.1016/j.amjcard.2013.04.053 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 210ZZ UT WOS:000323875200019 PM 23711806 ER PT J AU Wyss, A Hashibe, M Chuang, SC Lee, YCA Zhang, ZF Yu, GP Winn, DM Wei, QY Talamini, R Szeszenia-Dabrowska, N Sturgis, EM Smith, E Shangina, O Schwartz, SM Schantz, S Rudnai, P Purdue, MP Eluf-Neto, J Muscat, J Morgenstern, H Michaluart, P Menezes, A Matos, E Mates, IN Lissowska, J Levi, F Lazarus, P La Vecchia, C Koifman, S Herrero, R Hayes, RB Franceschi, S Wunsch, V Fernandez, L Fabianova, E Daudt, AW Dal Maso, L Curado, MP Chen, C Castellsague, X de Carvalho, MB Cadoni, G Boccia, S Brennan, P Boffetta, P Olshan, AF AF Wyss, Annah Hashibe, Mia Chuang, Shu-Chun Lee, Yuan-Chin Amy Zhang, Zuo-Feng Yu, Guo-Pei Winn, Deborah M. Wei, Qingyi Talamini, Renato Szeszenia-Dabrowska, Neonila Sturgis, Erich M. Smith, Elaine Shangina, Oxana Schwartz, Stephen M. Schantz, Stimson Rudnai, Peter Purdue, Mark P. Eluf-Neto, Jose Muscat, Joshua Morgenstern, Hal Michaluart, Pedro, Jr. Menezes, Ana Matos, Elena Mates, Ioan Nicolae Lissowska, Jolanta Levi, Fabio Lazarus, Philip La Vecchia, Carlo Koifman, Sergio Herrero, Rolando Hayes, Richard B. Franceschi, Silvia Wuensch-Filho, Victor Fernandez, Leticia Fabianova, Eleonora Daudt, Alexander W. Dal Maso, Luigino Curado, Maria Paula Chen, Chu Castellsague, Xavier de Carvalho, Marcos Brasilino Cadoni, Gabriella Boccia, Stefania Brennan, Paul Boffetta, Paolo Olshan, Andrew F. TI Cigarette, Cigar, and Pipe Smoking and the Risk of Head and Neck Cancers: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE head and neck neoplasms; smoking ID UPPER AERODIGESTIVE TRACT; UNITED-STATES VETERANS; UPPER DIGESTIVE-TRACT; ORAL-CAVITY; ALCOHOL-CONSUMPTION; PHARYNGEAL CANCER; TOBACCO SMOKING; DRINKING; MEN; ASSOCIATION AB Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (P-trend <= 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers. C1 [Wyss, Annah; Olshan, Andrew F.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Hashibe, Mia; Lee, Yuan-Chin Amy] Univ Utah, Sch Med, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. [Chuang, Shu-Chun] Natl Hlth Res Inst, Inst Populat Hlth Sci, Miaoli, Taiwan. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Yu, Guo-Pei] New York Med Coll, Dept Otolaryngol, New York, NY USA. [Yu, Guo-Pei] Peking Univ, Med Informat Ctr, Beijing 100871, Peoples R China. [Winn, Deborah M.] NIH, NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Wei, Qingyi; Sturgis, Erich M.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Talamini, Renato; Dal Maso, Luigino] Natl Canc Inst Aviano, Epidemiol & Biostat Unit, Aviano, Italy. [Szeszenia-Dabrowska, Neonila] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Sturgis, Erich M.] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Div Surg, Houston, TX 77030 USA. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Shangina, Oxana] NN Blokhin Canc Res Ctr, Inst Carcinogenesis, Dept Epidemiol & Prevent, Moscow, Russia. [Schwartz, Stephen M.; Chen, Chu] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Schwartz, Stephen M.; Chen, Chu] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Schantz, Stimson] New York Eye & Ear Infirm, Dept Otolaryngol, Biostat & Epidemiol Serv, New York, NY 10003 USA. [Rudnai, Peter] Natl Inst Environm Hlth, Dept Environm Epidemiol, Budapest, Hungary. [Purdue, Mark P.] NIH, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NCI, Bethesda, MD 20892 USA. [Eluf-Neto, Jose] Univ Sao Paulo, Fac Med, Dept Prevent Med, Sao Paulo, Brazil. [Muscat, Joshua] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Michaluart, Pedro, Jr.] Univ Sao Paulo, Fac Med, Head & Neck Serv, Sao Paulo, Brazil. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Matos, Elena] Univ Buenos Aires, Angel H Roffo Inst Oncol, Buenos Aires, DF, Argentina. [Mates, Ioan Nicolae] Carol Davila Univ Med & Pharm, Bucharest, Romania. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Levi, Fabio] Vaudois Univ, Ctr Hosp, Canc Epidemiol Unit, Lausanne, Switzerland. [Levi, Fabio] Vaudois Univ, Ctr Hosp, Vaud Canc Registry, Lausanne, Switzerland. [Levi, Fabio] Univ Lausanne, Lausanne, Switzerland. [Lazarus, Philip] Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, Spokane, WA USA. [La Vecchia, Carlo] Univ Milan, Mario Negri Inst Pharmacol Res, Dept Epidemiol, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Koifman, Sergio] Fundacao Oswaldo Cruz, Natl Sch Publ Hlth, Dept Epidemiol, Rio De Janeiro, Brazil. [Herrero, Rolando] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, Dept Populat Hlth, New York, NY USA. [Franceschi, Silvia] Int Agcy Res Canc, Infect & Canc Epidemiol Grp, F-69372 Lyon, France. [Wuensch-Filho, Victor] Univ Sao Paulo, Fac Publ Hlth, Dept Epidemiol, Sao Paulo, Brazil. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Fabianova, Eleonora] Reg Author Publ Hlth Banska Bystrica, Banska Bystrica, Slovakia. [Daudt, Alexander W.] Clin Hosp Porto Alegre, Porto Alegre, RS, Brazil. [Curado, Maria Paula; Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Castellsague, Xavier] Catalan Inst Oncol, Lhospitalet De Llobregat, Spain. [de Carvalho, Marcos Brasilino] Heliopolis Hosp, Mol Biol Lab, Sao Paulo, Brazil. [Cadoni, Gabriella] Univ Cattolica Sacro Cuore, A Gemelli Hosp, Dept Head & Neck Surg Otorhinolaryngol, I-00168 Rome, Italy. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Inst Hyg, I-00168 Rome, Italy. [Boccia, Stefania] Inst Res Hospitalizat & Hlth Care, Rome, Italy. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, F-69372 Lyon, France. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. RP Olshan, AF (reprint author), Gillings Sch Global Publ Hlth, Dept Epidemiol, CB 7435,2101B McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. EM andy_olshan@unc.edu RI Chuang, Shu-Chun/N-3358-2013; Menezes, Ana/G-7266-2012; Castellsague Pique, Xavier/N-5795-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Eluf-Neto, Jose/B-2522-2009; Purdue, Mark/C-9228-2016; Curado, Maria Paula/M-6200-2013; Mates, Ioan Nicolae/E-9255-2017 OI Lissowska, Jolanta/0000-0003-2695-5799; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X; Ioan Nicoale, Mates/0000-0001-7210-0615; Schwartz, Stephen/0000-0001-7499-8502; Castellsague Pique, Xavier/0000-0002-0802-3595; Eluf-Neto, Jose/0000-0001-7504-2115; Purdue, Mark/0000-0003-1177-3108; Curado, Maria Paula/0000-0001-8172-2483; FU Union for International Cancer Control International Cancer Technology Transfer Fellowship; National Cancer Institute [T32-CA09330, R03 CA113157]; National Institute of Environmental Health Sciences [T32ES007018] FX This work was supported by a Union for International Cancer Control International Cancer Technology Transfer Fellowship, by the National Cancer Institute (grants T32-CA09330 and R03 CA113157), and by the National Institute of Environmental Health Sciences (grant T32ES007018). NR 34 TC 27 Z9 28 U1 1 U2 36 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 SEP 1 PY 2013 VL 178 IS 5 BP 679 EP 690 DI 10.1093/aje/kwt029 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211YX UT WOS:000323949800003 PM 23817919 ER PT J AU Olson, SH Hsu, M Satagopan, JM Maisonneuve, P Silverman, DT Lucenteforte, E Anderson, KE Borgida, A Bracci, PM Bueno-de-Mesquita, HB Cotterchio, M Dai, Q Duell, EJ Fontham, EH Gallinger, S Holly, EA Ji, BT Kurtz, RC La Vecchia, C Lowenfels, AB Luckett, B Ludwig, E Petersen, GM Polesel, J Seminara, D Strayer, L Talamini, R AF Olson, Sara H. Hsu, Meier Satagopan, Jaya M. Maisonneuve, Patrick Silverman, Debra T. Lucenteforte, Ersilia Anderson, Kristin E. Borgida, Ayelet Bracci, Paige M. Bueno-de-Mesquita, H. Bas Cotterchio, Michelle Dai, Qi Duell, Eric J. Fontham, Elizabeth H. Gallinger, Steven Holly, Elizabeth A. Ji, Bu-Tian Kurtz, Robert C. La Vecchia, Carlo Lowenfels, Albert B. Luckett, Brian Ludwig, Emmy Petersen, Gloria M. Polesel, Jerry Seminara, Daniela Strayer, Lori Talamini, Renato CA Pancreatic Canc Case-Control Conso TI Allergies and Risk of Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Case-Control Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE allergic rhinitis; case-control studies; hypersensitivity; pancreatic neoplasms ID NUTRITION EXAMINATION SURVEY; MEDICAL CONDITIONS; NATIONAL-HEALTH; LIFE-STYLE; HISTORY; POPULATION; ATOPY; ASTHMA; GLIOMA; ANTIHISTAMINE AB In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (P-heterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age. C1 [Olson, Sara H.; Hsu, Meier; Satagopan, Jaya M.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Maisonneuve, Patrick] European Inst Oncol, Div Epidemiol & Biostat, Milan, Italy. [Silverman, Debra T.; Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lucenteforte, Ersilia; La Vecchia, Carlo] Mario Negri Inst Pharmacol Res, Dept Epidemiol, Milan, Italy. [Lucenteforte, Ersilia] Univ Florence, Dept Preclin & Clin Pharmacol, Florence, Italy. [Polesel, Jerry; Talamini, Renato] Ctr Riferimento Oncol, I-33081 Aviano, PN, Italy. [Bracci, Paige M.; Fontham, Elizabeth H.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Fontham, Elizabeth H.] Louisiana State Univ, Hlth Sci Ctr, Dept Publ Hlth & Prevent Med, New Orleans, LA USA. [Luckett, Brian] Tulane Univ, Sch Publ Hlth & Trop Med, Prevent Res Ctr, New Orleans, LA USA. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Borgida, Ayelet] Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Toronto, ON M5G 1X5, Canada. [Dai, Qi] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37212 USA. [Duell, Eric J.] Catalan Inst Oncol, Unit Nutr Environm & Canc, Barcelona, Spain. [Anderson, Kristin E.; Strayer, Lori] Univ Minnesota, Div Epidemiol & Community Hlth, Masonic Canc Ctr, Minneapolis, MN USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Kurtz, Robert C.; Ludwig, Emmy] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Lowenfels, Albert B.] New York Med Coll, Dept Surg, Valhalla, NY 10595 USA. [Petersen, Gloria M.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Petersen, Gloria M.] Mayo Clin, Coll Med, Dept Gastroenterol, Rochester, MN USA. [Petersen, Gloria M.] Mayo Clin, Coll Med, Dept Med Genet, Rochester, MN USA. RP Olson, SH (reprint author), Dept Epidemiol & Biostat, 307 East 63rd St,3rd Floor, New York, NY 10065 USA. EM olsons@mskcc.org RI Gallinger, Steven/E-4575-2013; OI La Vecchia, Carlo/0000-0003-1441-897X; Lucenteforte, Ersilia/0000-0001-5608-5902; Maisonneuve, Patrick/0000-0002-5309-4704; Duell, Eric J/0000-0001-5256-0163; Satagopan, Jaya/0000-0001-7102-5633; Polesel, Jerry/0000-0001-9381-1520 FU National Cancer Institute, National Institutes of Health [CA141570, CA137420, CA58697, CA97075, CA74783, CA098889, CA59706, CA108370, CA109767, CA89726, CA121846]; Italian Association for Cancer Research (AIRC) [10068]; Ministry of Welfare, Health, and Culture [808]; Polish Cancer Program [PR-6]; Cancer Research Society; Fondation Hotel-Dieu de Montreal; Fonds de la Recherche en Sante du Quebec-Sante; National Cancer Institute of Canada; Louisiana Board of Regents Millennium Trust Health Excellence Fund [HEF (20002005]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [N01-CP-51090, N01-CP-51089, N01-CP-51092, N01-CP-05225, N01-CP31022, N01-CP-05227]; Rombauer Pancreatic Cancer Research Fund; California Department of Public Health; National Cancer Institute's Surveillance, Epidemiology, and End Results Program [N01-PC-35136]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U55/CCR921930-02]; Prevention, Control, and Population Research Goldstein Award; Society of the MSKCC; Geoffrey Beene Cancer Research Fund; Christopher D. Smithers Foundation, Inc.; Spanish Ministry of Health [ISCIII RETICC RD06/0020] FX This pooled analysis was supported by grants CA141570 (to S. H. O.) and CA137420 (to J. M. S.) from the National Cancer Institute, National Institutes of Health. The Milan and Italy studies were supported by the Italian Association for Cancer Research (AIRC, Project 10068). The Minnesota study was supported by grant CA58697 from the National Cancer Institute, National Institutes of Health. The SEARCH study in Utrecht, the Netherlands, was supported by grant 808 from the Ministry of Welfare, Health, and Culture (formerly Ministry of Health and Environmental Hygiene) of the Netherlands. The SEARCH study in Opole, Poland, was funded by Polish Cancer Program PR-6. The SEARCH study in Montreal, Canada, was supported by the Cancer Research Society, the Fondation Hotel-Dieu de Montreal, and the Fonds de la Recherche en Sante du Quebec-Sante. The SEARCH study in Toronto was supported by the National Cancer Institute of Canada. The Louisiana State University study was supported by the Louisiana Board of Regents Millennium Trust Health Excellence Fund (Project 5: HEF (20002005, Genetics Studies in the Acadian Population)). The Ontario Pancreas Cancer Study was supported by grants CA97075 (as part of the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium) and CA74783 from the National Cancer Institute, National Institutes of Health; the Lustgarten Foundation for Pancreatic Cancer Research; and PancreaticCancerCanada. TheNationalCancerInstitute study was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (N01-CP-51090, N01-CP-51089, N01-CP-51092, N01-CP-05225, N01-CP31022, N01-CP-05227). The University of California, San Francisco, study was supported in part by grants CA098889, CA59706, CA108370, CA109767, CA89726, andCA121846 from the National Cancer Institute, National Institutes of Health, and by the Rombauer Pancreatic Cancer Research Fund. The collection of cancer incidence data for the University of California, San Francisco, study was supported by the California Department of Public Health as part of the statewide cancer reporting program; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract N01-PC-35136 awarded to the Northern California Cancer Center; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement U55/CCR921930-02 awarded to the Public Health Institute. The Pancreatic Cancer Family Registry at the MSKCC was supported by the Prevention, Control, and Population Research Goldstein Award, the Society of the MSKCC, and the Geoffrey Beene Cancer Research Fund. Financial support for A. B. L. is from the Christopher D. Smithers Foundation, Inc. E. J. D. is supported by the Spanish Ministry of Health (ISCIII RETICC RD06/0020). NR 38 TC 15 Z9 15 U1 0 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 1 PY 2013 VL 178 IS 5 BP 691 EP 700 DI 10.1093/aje/kwt052 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211YX UT WOS:000323949800004 PM 23820785 ER PT J AU Mannisto, T Mendola, P Reddy, U Laughon, SK AF Maennistoe, Tuija Mendola, Pauline Reddy, Uma Laughon, S. Katherine TI Neonatal Outcomes and Birth Weight in Pregnancies Complicated by Maternal Thyroid Disease SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE anemia; neonatal; birth weight; intensive care; neonatal; pregnancy; respiratory distress syndrome; newborn; thyroid diseases ID POPULATION-BASED COHORT; SUBCLINICAL HYPOTHYROIDISM; GESTATIONAL-AGE; DYSFUNCTION; FETAL; HYPOTHYROXINEMIA; HYPERTHYROIDISM; EPIDEMIOLOGY; POSTPARTUM; CONCEPTION AB Maternal hypothyroidism has previously been shown to increase risk for neonatal intensive care treatment, but otherwise the association between thyroid diseases and neonatal morbidity is understudied. The Consortium on Safe Labor, a retrospective cohort (2002-2008), included 223,512 singleton deliveries of which 0.2% had hyperthyroidism, 1.4% primary and 0.1% iatrogenic hypothyroidism, and 1.3% other/unspecified thyroid disease. Logistic regression with generalized estimating equations estimated adjusted odds ratios of adverse outcomes. Intensive care treatment was more common for neonates of women with thyroid disease. Hyperthyroidism and primary hypothyroidism were associated with sepsis, respiratory distress syndrome, transient tachypnea, and apnea. Iatrogenic hypothyroidism was associated with sepsis and neonatal anemia. Hyperthyroidism was also associated with rare outcomes (prevalence, <1%) including cardiomyopathy, retinopathy of prematurity, and neonatal thyroid diseases. Hyperthyroid non-Hispanic black women had higher odds of term infants that weighed <2,500 g, and hypothyroid non-Hispanic white women had higher odds of large-for-gestational-age infants. These analyses were stratified by race/ethnicity due to interaction. Associations were similar in analyses restricted to term infants. In conclusion, thyroid diseases were associated with increased neonatal morbidity. Although we lacked data on treatment during pregnancy, these nationwide data suggest a need for better thyroid disease management to reduce neonatal morbidity. C1 [Maennistoe, Tuija; Mendola, Pauline; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Reddy, Uma] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Rockville, MD 20852 USA. RP Mannisto, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,7B05, Rockville, MD 20852 USA. EM mannistoti@mail.nih.gov OI Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX This work was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development.; The data included in this paper were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through contract HHSN267200603425C. The institutions involved in the Consortium include the following, in alphabetical order: Baystate Medical Center, Springfield, Massachusetts; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, California; Christiana Care Health System, Newark, Delaware; George-town University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, Indiana; Intermountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, New York; MetroHealth Medical Center, Cleveland, Ohio; Summa Health System, Akron City Hospital, Akron, Ohio; The EMMES Corporation, Rockville, Maryland (Data Coordinating Center); University of Illinois at Chicago, Chicago, Illinois; University of Miami, Miami, Florida; and University of Texas Health Science Center at Houston, Houston, Texas. NR 35 TC 14 Z9 16 U1 1 U2 18 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 SEP 1 PY 2013 VL 178 IS 5 BP 731 EP 740 DI 10.1093/aje/kwt031 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211YX UT WOS:000323949800009 PM 23666815 ER PT J AU Rodriguez, AC Solomon, D Herrero, R Hildesheim, A Gonzalez, P Wacholder, S Porras, C Jimenez, S Schiffman, M AF Cecilia Rodriguez, Ana Solomon, Diane Herrero, Rolando Hildesheim, Allan Gonzalez, Paula Wacholder, Sholom Porras, Carolina Jimenez, Silvia Schiffman, Mark CA CVT Grp TI Impact of Human Papillomavirus Vaccination on Cervical Cytology Screening, Colposcopy, and Treatment SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cervical cancer; HPV; HPV vaccination; human papillomavirus; screening ID HPV-16/18 AS04-ADJUVANTED VACCINE; BLIND PATRICIA TRIAL; OF-STUDY ANALYSIS; YOUNG-WOMEN; COSTA-RICA; GUANACASTE; INFECTION; EFFICACY; SYSTEM AB The impact of human papillomavirus (HPV) vaccination on cervical screening, colposcopy, and treatment is incompletely understood. In 2004-2005, investigators in the Costa Rica Vaccine Trial randomized 7,466 women aged 1825 years, 1: 1, to receive HPV vaccination or hepatitis A vaccination. The worst-ever cytology diagnosis and the 4-year cumulative proportions of colposcopy referral and treatment by vaccination arm were compared for 2 cohorts. The total vaccinated cohort included 6,844 women who provided cervical samples. The naive cohort included 2,284 women with no evidence of previous HPV exposure. In the total vaccinated cohort, HPV-vaccinated women had a significant (P = 0.01) reduction in cytological abnormalities: 12.4% for high-grade lesions and 5.9% for minor lesions. Colposcopy referral was reduced by 7.9% (P = 0.03) and treatment by 11.3% (P = 0.24). Greater relative reductions in abnormal cytology (P < 0.001) were observed for HPV-vaccinated women in the naive cohort: 49.2% for high-grade lesions and 18.1% for minor lesions. Colposcopy referral and treatment were reduced by 21.3% (P = 0.01) and 45.6% (P = 0.08), respectively, in the naive cohort. The overall impact on health services will be modest in the first years after vaccine introduction among young adult women, even in regions with high coverage. C1 [Cecilia Rodriguez, Ana; Herrero, Rolando; Gonzalez, Paula; Porras, Carolina; Jimenez, Silvia] INCIENSA Fdn, Guanacaste Epidemiol Project, San Jose, Costa Rica. [Solomon, Diane; Hildesheim, Allan; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Herrero, Rolando; Gonzalez, Paula] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. RP Rodriguez, AC (reprint author), INCIENSA Fdn, Guanacaste Epidemiol Project, Torre La Sabana, San Jose, Costa Rica. EM acrodriguez@racsa.co.cr RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI [N01-CP-11005]; Office of Research on Women's Health, US National Institutes of Health FX The Costa Rica Vaccine Trial was part of a longstanding collaboration between investigators in Costa Rica and the US National Cancer Institute (NCI), was sponsored and funded by the NCI (contract N01-CP-11005) with support from the Office of Research on Women's Health, US National Institutes of Health, and was conducted in agreement with the Ministry of Health of Costa Rica. Vaccine for the trial was provided by GlaxoSmithKline Biologicals (Rixensart, Belgium) under a Clinical Trials Agreement with the NCI. GlaxoSmithKline Biologicals also provided support for aspects of the trial associated with the regulatory submission needs of the company. NR 14 TC 18 Z9 18 U1 0 U2 10 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 SEP 1 PY 2013 VL 178 IS 5 BP 752 EP 760 DI 10.1093/aje/kwt047 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211YX UT WOS:000323949800011 PM 23843026 ER PT J AU Park, SL Cheng, I Pendergrass, SA Kucharska-Newton, AM Lim, U Ambite, JL Caberto, CP Monroe, KR Schumacher, F Hindorff, LA Oetjens, MT Wilson, S Goodloe, RJ Love, SA Henderson, BE Kolonel, LN Haiman, CA Crawford, DC North, KE Heiss, G Ritchie, MD Wilkens, LR Le Marchand, L AF Park, Sungshim Lani Cheng, Iona Pendergrass, Sarah A. Kucharska-Newton, Anna M. Lim, Unhee Ambite, Jose Luis Caberto, Christian P. Monroe, Kristine R. Schumacher, Fredrick Hindorff, Lucia A. Oetjens, Matthew T. Wilson, Sarah Goodloe, Robert J. Love, Shelly-Ann Henderson, Brian E. Kolonel, Laurence N. Haiman, Christopher A. Crawford, Dana C. North, Kari E. Heiss, Gerardo Ritchie, Marylyn D. Wilkens, Lynne R. Le Marchand, Loic TI Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE energy intake; fat mass and obesity-associated (FTO) gene; obesity; percent calories from fat; race/ethnicity ID BODY-MASS INDEX; DIETARY-INTAKE; FOOD-INTAKE; EPIDEMIOLOGY PAGE; GENE-EXPRESSION; LOCI; BMI; EXPENDITURE; TRAITS; HEALTH AB Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993-2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987-1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991-1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (beta(meta) = 0.2244 (standard error, 0.0548); P = 4 x10(-5)) and inversely associated with percentage of calories derived from carbohydrate (beta(meta) = -0.2796 (standard error, 0.0709); P = 8 x 10(-5)). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m(2),95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake. C1 [Park, Sungshim Lani; Lim, Unhee; Caberto, Christian P.; Kolonel, Laurence N.; Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Pendergrass, Sarah A.; Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Kucharska-Newton, Anna M.; Love, Shelly-Ann; North, Kari E.; Heiss, Gerardo] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Monroe, Kristine R.; Schumacher, Fredrick; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Oetjens, Matthew T.; Wilson, Sarah; Goodloe, Robert J.; Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. RP Park, SL (reprint author), Univ Hawaii, Ctr Canc, Program Epidemiol, 701 Ilalo St,5th Floor, Honolulu, HI 96813 USA. EM lpark@cc.hawaii.edu FU National Human Genome Research Institute (NHGRI); Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) Consortium [U01HG004803]; Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study [U01HG004798]; Multiethnic Cohort (MEC) Study [U01HG004802]; Women's Health Initiative [U01HG004790]; PAGE Coordinating Center [U01HG004801, U01HG 004801]; NHGRI PAGE Study [U01HG004803, U01HG004798, U01HG004802]; Centers for Disease Control and Prevention; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN26820 1100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN26820 1100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; NHGRI [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C]; [UL1RR025005] FX The Population Architecture using Genomics and Epidemiology (PAGE) Study is funded by the National Human Genome Research Institute (NHGRI), supported by grants U01HG004803 (Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) Consortium), U01HG004798 (Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study), U01HG004802 (Multiethnic Cohort (MEC) Study), U01HG004790 (Women's Health Initiative), and U01HG004801 (PAGE Coordinating Center), and their respective NHGRI American Recovery and Reinvestment Act (ARRA) supplements. The data and materials included in this report resulted from a collaboration between the following studies: The EAGLE Study is funded through the NHGRI PAGE Study (grant U01HG004798-01 and its NHGRI ARRA supplement). The study participants were derived from the Third National Health and Nutrition Examination Survey, which is supported by the Centers for Disease Control and Prevention. The MEC characterization of epidemiologic architecture is funded through the NHGRI PAGE Study (grant U01HG004802 and its NHGRI ARRA supplement). The MEC Study is funded by the National Cancer Institute (grants R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). Funding for CALiCo was provided through the NHGRI PAGE Study (grant U01HG004803). The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN26820 1100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN26820 1100011C, and HHSN268201100012C; National Heart, Lung, and Blood Institute grants R01HL087641, R01HL59367, and R01HL086694; NHGRI contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. The infrastructure of the ARIC Study was partly supported by grant UL1RR025005, a component of the NIH and the NIH Roadmap for Medical Research. Assistance with phenotype harmonization, single-nucleotide polymorphism selection and annotation, data-cleaning, data management, integration, and dissemination, and general study coordination was provided by the PAGE Coordinating Center (grant U01HG 004801). The National Institute of Mental Health also contributes support for the Coordinating Center. NR 58 TC 21 Z9 22 U1 1 U2 16 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 SEP 1 PY 2013 VL 178 IS 5 BP 780 EP 790 DI 10.1093/aje/kwt028 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211YX UT WOS:000323949800014 PM 23820787 ER PT J AU Mondul, AM Giovannucci, E Platz, EA AF Mondul, Alison M. Giovannucci, Edward Platz, Elizabeth A. TI A Prospective Study of Statin Drug Use and Lower Urinary Tract Symptoms in Older Men SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort; lower urinary tract symptoms; risk; statin drug ID BENIGN PROSTATIC HYPERPLASIA; RISK; ENLARGEMENT; ASSOCIATION; CANCER; INDEX AB Dyslipidemia and chronic inflammation may play a role in the cause of lower urinary tract symptoms (LUTS) in older men. Use of statin drugs, which are prescribed to lower cholesterol and appear to reduce inflammation, may decrease the incidence or progression of LUTS. The associations of statin drug use with LUTS incidence and progression were prospectively evaluated in the Health Professionals Follow-up Study from 1992 to 2008. Hazard ratios and 95% confidence intervals of incident LUTS (from no or a low International Prostate Symptom Score (IPSS) of 0-7 to a moderate or worse IPSS of >= 15; n = 5,790 cases in 24,715 men) and of LUTS progression (from modest IPSS of 8-14 to severe IPSS of >= 20; n = 2,238 cases in 8,709 men) were calculated comparing current statin use with nonuse. The hazard ratios of LUTS incidence and progression comparing current use to nonuse were greater than 1. However, when comparisons were restricted to participants who used drugs to treat hypertension (a surrogate for uptake of medical care), statin use was not associated with LUTS incidence (hazard ratio = 1.02, 95% confidence interval: 0.94, 1.12) or progression (hazard ratio = 0.98, 95% confidence interval: 0.85, 1.13). Thus, statin use is unlikely to beneficially influence the development or course of LUTS. The present study highlights a methodological issue (confounding) that must be addressed in observational studies on the use of common drugs for indications other than the primary use. C1 [Mondul, Alison M.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. [Giovannucci, Edward] Brigham & Womens Hosp, Boston, MA 02115 USA. [Platz, Elizabeth A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Brady Urol Res Inst, Baltimore, MD USA. RP Mondul, AM (reprint author), 9609 Med Ctr Dr,Room 6E328, Rockville, MD 20850 USA. EM mondulam@mail.nih.gov OI Mondul, Alison/0000-0002-8843-1416 FU Urologic Diseases in America Project [N01 DK70003]; Public Health Service from the National Institutes of Health, Department of Health and Human Services [R01 DK45779, P01 CA55075, P50 DK82998] FX This study was supported by The Urologic Diseases in America Project (grant N01 DK70003) and by Public Health Service grants R01 DK45779 (Harvard), P01 CA55075 (Harvard), and P50 DK82998 (Hopkins) from the National Institutes of Health, Department of Health and Human Services. NR 15 TC 7 Z9 7 U1 0 U2 3 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 SEP 1 PY 2013 VL 178 IS 5 BP 797 EP 803 DI 10.1093/aje/kwt055 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211YX UT WOS:000323949800016 PM 23847173 ER PT J AU Ferreccio, C Smith, AH Duran, V Barlaro, T Benitez, H Valdes, R Aguirre, JJ Moore, LE Acevedo, J Vasquez, MI Perez, L Yuan, Y Liaw, J Cantor, KP Steinmaus, C AF Ferreccio, Catterina Smith, Allan H. Duran, Viviana Barlaro, Teresa Benitez, Hugo Valdes, Rodrigo Jose Aguirre, Juan Moore, Lee E. Acevedo, Johanna Isabel Vasquez, Maria Perez, Liliana Yuan, Yan Liaw, Jane Cantor, Kenneth P. Steinmaus, Craig TI Case-Control Study of Arsenic in Drinking Water and Kidney Cancer in Uniquely Exposed Northern Chile SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arsenic; case-control; Chile; drinking water; kidney cancer ID CIGARETTE-SMOKING; LUNG-CANCER; MORTALITY; TOXICITY; BLADDER AB Millions of people worldwide are exposed to arsenic in drinking water. The International Agency for Research on Cancer has concluded that ingested arsenic causes lung, bladder, and skin cancer. However, a similar conclusion was not made for kidney cancer because of a lack of research with individual data on exposure and dose-response. With its unusual geology, high exposures, and good information on past arsenic water concentrations, northern Chile is one of the best places in the world to investigate the carcinogenicity of arsenic. We performed a case-control study in 2007-2010 of 122 kidney cancer cases and 640 population-based controls with individual data on exposure and potential confounders. Cases included 76 renal cell, 24 transitional cell renal pelvis and ureter, and 22 other kidney cancers. For renal pelvis and ureter cancers, the adjusted odds ratios by average arsenic intakes of <400, 400-1,000, and >1,000 mu g/day (median water concentrations of 60, 300, and 860 mu g/L) were 1.00, 5.71 (95% confidence interval: 1.65, 19.82), and 11.09 (95% confidence interval: 3.60, 34.16) (P-trend < 0.001), respectively. Odds ratios were not elevated for renal cell cancer. With these new findings, including evidence of dose-response, we believe there is now sufficient evidence in humans that drinking-water arsenic causes renal pelvis and ureter cancer. C1 [Ferreccio, Catterina; Acevedo, Johanna; Perez, Liliana] Pontificia Univ Catolica Chile, Dept Salud Publ, Santiago, Chile. [Smith, Allan H.; Yuan, Yan; Liaw, Jane; Steinmaus, Craig] Univ Calif Berkeley, Sch Publ Hlth, Arsen Res Grp, Berkeley, CA 94720 USA. [Duran, Viviana; Barlaro, Teresa] Hosp Reg Iquique, Unidad Anat Patol, Iquique, Chile. [Benitez, Hugo] Hosp Reg Antofagasta, Unidad Anat Patol, Antofagasta, Chile. [Valdes, Rodrigo] Histonor Ltda, Labs Anat Patol, Antofagasta, Chile. [Jose Aguirre, Juan] Citonet Ltda, Labs Anat Patol, Antofagasta, Chile. [Moore, Lee E.; Cantor, Kenneth P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Isabel Vasquez, Maria] Univ Tarapaca, Arica, Chile. [Steinmaus, Craig] Calif Environm Protect Agcy, Off Environm Hlth Hazard Assessment, Oakland, CA USA. RP Steinmaus, C (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 50 Univ Hall,MC7360, Berkeley, CA 94720 USA. EM craigs@berkeley.edu FU US National Institute of Environmental Health Sciences [R01 ES014032-01, P42 ES04705] FX This work was supported by grants R01 ES014032-01 and P42 ES04705 from the US National Institute of Environmental Health Sciences. NR 21 TC 21 Z9 25 U1 0 U2 35 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 SEP 1 PY 2013 VL 178 IS 5 BP 813 EP 818 DI 10.1093/aje/kwt059 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211YX UT WOS:000323949800018 PM 23764934 ER PT J AU Freeman, LEB Blair, A Lubin, JH Stewart, PA Hayes, RB Hoover, RN Hauptmann, M AF Freeman, Laura E. Beane Blair, Aaron Lubin, Jay H. Stewart, Patricia A. Hayes, Richard B. Hoover, Robert N. Hauptmann, Michael TI Mortality from solid tumors among workers in formaldehyde industries: An update of the NCI cohort SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE formaldehyde; cancer; epidemiology ID NATIONAL-CANCER-INSTITUTE; OCCUPATIONAL RISK-FACTORS; SQUAMOUS-CELL CARCINOMA; JOB-EXPOSURE MATRIX; NASOPHARYNGEAL CANCER; LUNG-CANCER; CHEMICAL WORKERS; SINONASAL CANCER; UNITED-STATES; NASAL CAVITY AB Background Formaldehyde, a widely used chemical, is considered a human carcinogen. Methods We extended follow-up of the largest industrial cohort of workers in formaldehyde industries (n=25,619) by 10 years through 2004. Standardized mortality ratios (SMRs) and rate ratios (RRs) were calculated for deaths from solid tumors using quantitative formaldehyde exposure estimates. Results During 998,239 person-years, 13,951 deaths occurred. With one additional death, previously observed excesses for nasopharyngeal cancer (n=10) persisted for peak, average intensity and cumulative exposure; RRs in the highest exposure categories were 7.66 (95% CI: 0.94, 62.34), P-trend=0.005, 11.54 (95% CI: 1.38, 96.81), P-trend=0.09, and 2.94 (95% CI: 0.65, 13.28), P-trend=0.06, respectively. For all cancer, solid tumors and lung cancer, SMRs among exposed workers were elevated, but internal analyses revealed no positive associations with formaldehyde exposure. Conclusions Consistent with previous analyses of this cohort, this update continues to suggest a link between formaldehyde exposure and nasopharyngeal cancer. Am. J. Ind. Med. 56:1015-1026, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Freeman, Laura E. Beane; Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Lubin, Jay H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Hayes, Richard B.] NYU Med Ctr, Dept Environm Med, Div Epidemiol, New York, NY 10016 USA. [Hoover, Robert N.] Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD USA. [Hauptmann, Michael] Netherlands Canc Inst, Dept Epidemiol & Biostat, Amsterdam, Netherlands. RP Freeman, LEB (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. EM freemala@mail.nih.gov OI Hayes, Richard/0000-0002-0918-661X FU Intramural Research Program of the National Cancer Institute FX Contract grant sponsor: Intramural Research Program of the National Cancer Institute. NR 61 TC 4 Z9 4 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD SEP PY 2013 VL 56 IS 9 BP 1015 EP 1026 DI 10.1002/ajim.22214 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200XX UT WOS:000323106000004 ER PT J AU Beck, L Bomback, AS Choi, MJ Holzman, LB Langford, C Mariani, LH Somers, MJ Trachtman, H Waldman, M AF Beck, Laurence Bomback, Andrew S. Choi, Michael J. Holzman, Larry B. Langford, Carol Mariani, Laura H. Somers, Michael J. Trachtman, Howard Waldman, Meryl TI KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Glomerulonephritis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; IDIOPATHIC MEMBRANOUS NEPHROPATHY; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; DENSE DEPOSIT DISEASE; ACUTE-RENAL-FAILURE; RESISTANT NEPHROTIC SYNDROME; MINIMAL-CHANGE DISEASE; ANTIBODY-ASSOCIATED VASCULITIS; ANCA-ASSOCIATED VASCULITIS AB Glomerulonephritis (GN) is an important cause of morbidity and mortality in patients of all ages throughout the world. Because these disorders are relatively rare, it is difficult to perform randomized clinical trials to define optimal treatment for many of the specific glomerulopathies. In the absence of high-grade evidence to guide the care of glomerular diseases, in June 2012, KDIGO (Kidney Disease: Improving Global Outcomes) published an international clinical guideline for GN. The Work Group report represents an important review of the literature in this area and offers valid and useful guidelines for the most common situations that arise in the management of patients with glomerular disease. This commentary, developed by a panel of clinical experts convened by the National Kidney Foundation, attempts to put the GN guideline into the context of the US health care system. Overall, we support the vast majority of the recommendations and highlight select areas in which epidemiological factors and medical practice patterns in this country justify modifications and adjustments in order to achieve favorable outcomes. There remain large gaps in our knowledge of the best approaches to treat glomerular disease and we strongly endorse an expanded clinical research effort to improve the health and long-term outcomes of children and adults with GN. (C) 2013 by the National Kidney Foundation, Inc. C1 [Beck, Laurence] Boston Univ Sch Med, Boston, MA USA. [Bomback, Andrew S.] Columbia Univ Med Ctr, New York, NY USA. [Choi, Michael J.] Johns Hopkins Univ Sch Med, Baltimore, MD USA. [Holzman, Larry B.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Langford, Carol] Cleveland Clin, Cleveland, OH 44106 USA. [Mariani, Laura H.] Univ Michigan Sch Med, Ann Arbor, MI USA. [Somers, Michael J.] Boston Childrens Hosp, Boston, MA USA. [Trachtman, Howard] New York Univ Langone Med Ctr, New York, NY USA. [Waldman, Meryl] NIDDK, NIH, Bethesda, MD USA. RP Choi, MJ (reprint author), Johns Hopkins Univ, Div Nephrol, Dept Med, 1830 E Monument St,Ste 416, Baltimore, MD 21287 USA. EM mchoi3@jhmi.edu OI Beck, Laurence/0000-0003-1482-4089; Trachtman, Howard/0000-0001-7447-9489 NR 206 TC 32 Z9 35 U1 2 U2 16 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD SEP PY 2013 VL 62 IS 3 BP 403 EP 441 DI 10.1053/j.ajkd.2013.06.002 PG 39 WC Urology & Nephrology SC Urology & Nephrology GA 212ZZ UT WOS:000324023700002 PM 23871408 ER PT J AU Kasiske, BL Anderson-Haag, T Ibrahim, HN Pesavento, TE Weir, MR Nogueira, JM Cosio, FG Kraus, ES Rabb, HH Kalil, RS Posselt, AA Kimmel, PL Steffes, MW AF Kasiske, Bertram L. Anderson-Haag, Teresa Ibrahim, Hassan N. Pesavento, Todd E. Weir, Matthew R. Nogueira, Joseph M. Cosio, Fernando G. Kraus, Edward S. Rabb, Hamid H. Kalil, Roberto S. Posselt, Andrew A. Kimmel, Paul L. Steffes, Michael W. TI A Prospective Controlled Study of Kidney Donors: Baseline and 6-Month Follow-up SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; unilateral nephrectomy; glomerular filtration rate; patient safety; mineral and bone disorders ID GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; SINGLE-CENTER EXPERIENCE; LONG-TERM CONSEQUENCES; SERUM URIC-ACID; INSULIN-RESISTANCE; UNILATERAL NEPHRECTOMY; MINERAL METABOLISM; CYSTATIN C; CARDIOVASCULAR-DISEASE AB Background: Most previous studies of living kidney donors have been retrospective and have lacked suitable healthy controls. Needed are prospective controlled studies to better understand the effects of a mild reduction in kidney function from kidney donation in otherwise healthy individuals. Study Design: Prospective, controlled, observational cohort study. Setting & Participants: Consecutive patients approved for donation at 8 transplant centers in the United States were asked to participate. For every donor enrolled, an equally healthy control with 2 kidneys who theoretically would have been suitable to donate a kidney also was enrolled. Predictor: Kidney donation. Measurements: At baseline predonation and at 6 months after donation, medical history, vital signs, measured (iohexol) glomerular filtration rate, and other measurements were collected. There were 201 donors and 198 controls who completed both baseline and 6-month visits and form the basis of this report. Results: Compared with controls, donors had 28% lower glomerular filtration rates at 6 months (94.6 +/- 15.1 [SD] vs 67.6 +/- 10.1 mL/min/1.73 m(2); P < 0.001), associated with 23% greater parathyroid hormone (42.8 +/- 15.6 vs 52.7 +/- 20.9 pg/mL; P < 0.001), 5.4% lower serum phosphate (3.5 +/- 0.5 vs 3.3 +/- 0.5 mg/dL; P < 0.001), 3.7% lower hemoglobin (13.6 +/- 1.4 vs 13.1 +/- 1.2 g/dL; P < 0.001), 8.2% greater uric acid (4.9 +/- 1.2 vs 5.3 +/- 1.1 mg/dL; P < 0.001), 24% greater homocysteine (1.2 +/- 0.3 vs 1.5 +/- 0.4 mg/L; P < 0.001), and 1.5% lower high-density lipoprotein cholesterol (54.9 +/- 16.4 vs 54.1 +/- 13.9 mg/dL; P = 0.03) levels. There were no differences in albumin-creatinine ratios (5.0 [IQR, 4.0-6.6] vs 5.0 [IQR, 3.3-5.4] mg/g; P = 0.5), office blood pressures, or glucose homeostasis. Limitations: Short duration of follow-up and possible bias resulting from an inability to screen controls with kidney and vascular imaging performed in donors. Conclusions: Kidney donors have some, but not all, abnormalities typically associated with mild chronic kidney disease 6 months after donation. Additional follow-up is warranted. (C) 2013 by the National Kidney Foundation, Inc. C1 [Kasiske, Bertram L.; Anderson-Haag, Teresa] Hennepin Cty Med Ctr, Dept Med, Minneapolis, MN 55415 USA. [Ibrahim, Hassan N.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Pesavento, Todd E.] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. [Weir, Matthew R.; Nogueira, Joseph M.] Univ Maryland Sch Med, Dept Med, Baltimore, MD USA. [Cosio, Fernando G.] Mayo Clin, Dept Med, Rochester, MN USA. [Kraus, Edward S.; Rabb, Hamid H.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Kalil, Roberto S.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Posselt, Andrew A.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Steffes, Michael W.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. RP Kasiske, BL (reprint author), Hennepin Cty Med Ctr, Dept Med, 701 Pk Ave, Minneapolis, MN 55415 USA. EM kasis001@umn.edu FU National Institutes of Health [U01 DK066013]; Minneapolis Medical Research Foundation, Minneapolis, MN FX This study was funded by the National Institutes of Health under cooperative agreement U01 DK066013, Paul L. Kimmel, MD, Project Officer. It was also supported by funds from the Minneapolis Medical Research Foundation, Minneapolis, MN. NR 70 TC 24 Z9 25 U1 0 U2 20 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD SEP PY 2013 VL 62 IS 3 BP 577 EP 586 DI 10.1053/j.ajkd.2013.01.027 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 212ZZ UT WOS:000324023700019 PM 23523239 ER PT J AU St Peter, WL Weinhandl, ED Flessner, MF AF St Peter, Wendy L. Weinhandl, Eric D. Flessner, Michael F. TI In Reply to 'Primary Objective of Study of Sitagliptin in Patients With ESRD on Dialysis' SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Letter C1 [St Peter, Wendy L.] Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. [St Peter, Wendy L.; Weinhandl, Eric D.] Minneapolis Med Res Fdn Inc, Minneapolis, MN USA. [Flessner, Michael F.] NIH, Bethesda, MD 20892 USA. RP St Peter, WL (reprint author), Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. OI St Peter, Wendy/0000-0002-2201-3019 NR 4 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD SEP PY 2013 VL 62 IS 3 BP 642 EP 643 DI 10.1053/j.ajkd.2013.06.009 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 212ZZ UT WOS:000324023700028 PM 23972059 ER PT J AU Baxter, SL Pistilli, M Pujari, SS Liesegang, TL Suhler, EB Thorne, JE Foster, CS Jabs, DA Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Kempen, JH AF Baxter, Sally L. Pistilli, Maxwell Pujari, Siddharth S. Liesegang, Teresa L. Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Kempen, John H. TI Risk of Choroidal Neovascularization among the Uveitides SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID PUNCTATE INNER CHOROIDOPATHY; INTRAVITREAL BEVACIZUMAB; MULTIFOCAL CHOROIDITIS; REGRESSION-ANALYSIS; DISEASES; VEGF; COMPLICATIONS; NOMENCLATURE; PANUVEITIS; SECONDARY AB PURPOSE: To evaluate the risk, risk factors, and visual impact of choroidal neovascularization (CNV) in uveitis cases. DESIGN: Retrospective cohort study. METHODS: Standardized medical record review at 5 tertiary centers. RESULTS: Among 15 137 uveitic eyes (8868 patients), CNV was rare in the cases of anterior or intermediate uveitis. Among the 4041 eyes (2307 patients) with posterior uveitis or panuveitis, 81(2.0%) had CNV at presentation. Risk factors included posterior uveitis in general and specific uveitis syndromes affecting the outer retina retinal pigment epithelium choroid interface. Among the 2364 eyes (1357 patients) with posterior uveitis or panuveitis and free of CNV at the time of cohort entry, the cumulative 2-year incidence of CNV was 2.7% (95% confidence interval [CI], 1.8% to 3.5%). Risk factors for incident CNV included currently active inflammation (adjusted hazard ratio [aHR], 2.13; 95% CI, 1.26 to 3.60), preretinal neovascularization (aHR, 3.19; 95% CI, 1.30 to 7.80), and prior diagnosis of CNV in the contralateral eye (aHR, 5.79; 95% CI, 2.77 to 12.09). Among specific syndromes, the incidence was greater in Vogt-Koyanagi-Harada syndrome (aHR, 3.37; 95% CI, 1.52 to 7.46) and punctate inner choroiditis (aHR, 8.67; 95% CI, 2.83 to 26.54). Incident CNV was associated with a 2-line loss of visual acuity (+0.19 logarithm of the minimal angle of resolution units; 95% CI, 0.079 to 0.29) from the preceding visit. CONCLUSIONS: CNV is an uncommon complication Of uveitis associated with visual impairment that occurs more commonly in forms affecting the outer retina retinal pigment epithelium choroid interface, during periods of inflammatory activity, in association with preretinal neovascularization, and in second eyes of patients with unilateral CNV. Because CNV is treatable, a systematic approach to early detection in high-risk patients may be appropriate. ((C) 2013 by Elsevier Inc. All rights reserved.) C1 [Baxter, Sally L.; Kempen, John H.] Univ Penn, Perelman Sch Med, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Pistilli, Maxwell; Kempen, John H.] Univ Penn, Perelman Sch Med, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Pujari, Siddharth S.; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Pujari, Siddharth S.] Vasan Eye Care Hosp, Belgaum, Karnataka, India. [Liesegang, Teresa L.; Suhler, Eric B.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Suhler, Eric B.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Levy-Clarke, Grace A.] Johnson & Johnson, New Brunswick, NJ USA. [Rosenbaum, James T.] Legacy Hlth Syst, Devers Eye Inst, Portland, OR USA. [Kempen, John H.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Pistilli, Maxwell/0000-0002-4266-4150 FU Research to Prevent Blindness, Inc, New York, New York; Paul and Evanina Mackall Foundation; National Eye Institute; Department of Veterans' Affairs FX ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and the following were reported. Jennifer E. Thome serves a consultant for Allergan and XOMA. C. Stephen Foster serves as a lecturer for Alcon, Inspire, Ista, and Centocor; as a Consultant for Sirion; as a consultant and lecturer for Allergan and Bausch & Lomb; and as an equity owner for EyeGate. Douglas A. Jabs serves a consultant for Abbott Laboratories, Alcon Laboratories, Allergan Pharmaceutical Corporation, Corcept Therapeutics, Genentech, Genzyme Corporation, GlaxoSmith Kline, and Roche Pharmaceuticals and is a member of the Data and Safety Monitoring Board for Applied Genetic Technologies Corporation and Novartis Pharmaceutical Corporation. Grace A. Levy-Clarke is employed by Johnson & Johnson Vision Care. James T. Rosenbaum serves or has served as a consultant for Abbott Laboratories, Amgen, Allergan, Genentech, Novartis, and UCB and has been involved in clinical trials for Abbott Laboratories, Genentech, Lux Biosciences, and Eyegate Pharma. John H. Kempen serves or has served as a consultant for Alcon, Allergan, Can-Fite, Clearside, Lux Biosciences, Sanofi-Pasteur, and Xoma. Supported primarily by Grant EY014943 from the National Eye Institute, National Institutes of Health, Bethesda, Maryland (J.H.K.). Additional support was provided by Research to Prevent Blindness, Inc, New York, New York, and the Paul and Evanina Mackall Foundation. Dr Kempen was a Research to Prevent Blindness James S Adams Special Scholar Award recipient, Dr Thome was a Research to Prevent Blindness Harrington Special Scholar Award recipient, and Drs Jabs and Rosenbaum were Research to Prevent Blindness Senior Scientific Investigator Award recipients during the course of the study. Dr Levy-Clarke was previously supported by and Dr Nussenblatt continues to be supported by intramural funds from the National Eye Institute. Dr Suhler receives support from the Department of Veterans' Affairs. None of the sponsors had any role in the design and conduct of the report; collection, management, analysis, and interpretation of the data; or in the preparation, review, and approval of this manuscript. Involved in Design and conduct of study (S.L.B., M.P., J.H.K.); Collection, management, analysis, and interpretation of data (all authors); Preparation of manuscript (S.L.B., M.P., J.H.K.); and review and approval of manuscript (all authors). NR 28 TC 16 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD SEP PY 2013 VL 156 IS 3 BP 468 EP 477 DI 10.1016/j.ajo.2013.04.040 PG 10 WC Ophthalmology SC Ophthalmology GA 214RM UT WOS:000324153500009 PM 23795984 ER PT J AU Toy, BC Krishnadev, N Indaram, M Cunningham, D Cukras, CA Chew, EY Wong, WT AF Toy, Brian C. Krishnadev, Nupura Indaram, Maanasa Cunningham, Denise Cukras, Catherine A. Chew, Emily Y. Wong, Wai T. TI Drusen Regression is Associated With Local Changes in Fundus Autofluorescence in Intermediate Age-Related Macular Degeneration SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; SCANNING LASER OPHTHALMOSCOPE; GEOGRAPHIC ATROPHY; SOFT DRUSEN; BRUCHS MEMBRANE; PIGMENT; PHOTOCOAGULATION; MACULOPATHY; PATHOGENESIS; MACROPHAGES AB PURPOSE: To investigate the association of spontaneous drusen regression in intermediate age-related macular degeneration (AMD) with Changes on fundus photography and fundus autofluorescence (FAF) imaging. DESIGN: Prospective observational case series. METHODS: Fundus images from 58 eyes (in 58 patients) with intermediate AMD and large drusen were assessed over 2 years for areas of drusen regression that exceeded the area of circle Cl (diameter 125 mu m; Age-Related Eye Disease Study grading protocol). Manual segmentation and computer-based image analysis were used to detect and delineate areas of drusen regression. Delineated regions were graded as to their appearance on fundus photographs and FAF images, and changes in FAF signal were graded manually and quantitated using automated image analysis. RESULTS: Drusen regression was detected in approximately half of study eyes using manual (48%) and computer-assisted (50%) techniques. At year-2, the clinical appearance of areas of drusen regression on fundus photography was mostly unremarkable, with a majority of eyes (71%) demonstrating no detectable clinical abnormalities, and the remainder (29%) showing minor pigmentary changes. However, drusen regression areas were associated with local changes in FAF that were significantly more prominent than changes on fundus photography. A majority of eyes (64%-66%) demonstrated a predominant decrease in overall FAF signal, while 14%-21% of eyes demonstrated a predominant increase in overall FAF signal. CONCLUSIONS: FAF imaging demonstrated that drusen regression in intermediate AMD was often accompanied by changes in local autofluorescence signal. Drusen regression may be associated with concurrent structural and physiologic changes in the outer retina. (Published by Elsevier Inc.) C1 [Toy, Brian C.; Indaram, Maanasa; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Krishnadev, Nupura; Cukras, Catherine A.; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Cunningham, Denise] NEI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bldg 6,Room 215, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU Clinical Research Training Program; National Institutes of Health (Bethesda, Maryland, USA); Pfizer Inc (New York, New York, USA); National Eye Institute Intramural Research Program (Bethesda, Maryland, USA) FX ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial disclosures: B.T. was supported by the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health (Bethesda, Maryland, USA) and Pfizer Inc (New York, New York, USA; via a grant to the Foundation for the National Institutes of Health [Bethesda, Maryland, USA] from Pfizer). The sponsor or funding organization had no role in the design or conduct of this research. This research was funded by the National Eye Institute Intramural Research Program (Bethesda, Maryland, USA). Contributions of authors: design of study (B.T., N.K., E.C., W.W.); conduct of study (N.K., D.C., C.C., E.Y., W.W.); analysis and interpretation of data (B.T., N.K., M.I., W.W.); writing of manuscript (B.T., N.K., M.I., D.C., C.C., E.Y., W.W.); and final approval of version to be published (B.T., N.K., M.I., D.C., C.C., E.Y., W.W.). NR 56 TC 9 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD SEP PY 2013 VL 156 IS 3 BP 532 EP 542 DI 10.1016/j.ajo.2013.04.031 PG 11 WC Ophthalmology SC Ophthalmology GA 214RM UT WOS:000324153500015 PM 23830564 ER PT J AU Martinez-Anton, A Sokolowska, M Kern, S Davis, AS Alsaaty, S Taubenberger, JK Sun, JF Cai, RM Danner, RL Eberlein, M Logun, C Shelhamer, JH AF Martinez-Anton, Asuncion Sokolowska, Milena Kern, Steven Davis, A. Sally Alsaaty, Sara Taubenberger, Jeffery K. Sun, Junfeng Cai, Rongman Danner, Robert L. Eberlein, Michael Logun, Carolea Shelhamer, James H. TI Changes in microRNA and mRNA Expression with Differentiation of Human Bronchial Epithelial Cells SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE airways epithelium; differentiation; microarrays; mucin 1; cell division cycle homolog A ID TRANSMEMBRANE CONDUCTANCE REGULATOR; AIR-LIQUID INTERFACE; CYSTIC-FIBROSIS; MUCOCILIARY DIFFERENTIATION; MIR-17-92 CLUSTER; MUCIN 1; PROLIFERATION; TARGETS; CDC25A; PATHOGENESIS AB We studied the changes in expression of microRNAs (miRNAs or miRs) and mRNA in normal human bronchial epithelial cells as they differentiate from an undifferentiated monolayer to a differentiated pseudostratified epithelium after 28 days of air-liquid interface (ALI) culture. After 28 days in ALI, the epithelial cells differentially expressed basal, ciliated, and goblet cell markers. Using Affymetrix microarrays, 20 human miRNAs were found to be up-regulated, whereas 35 miRNAs were found to be down-regulated in differentiated cells compared with undifferentiated cells. An analysis of changes in global mRNA expression revealed that 1,201 probe sets demonstrated an 8-fold change (FC) or greater at Day 28 of ALI culture. Of these, 816 were up-regulated and 385 were down-regulated. With differentiation, miR-449a increased (FC, 38.15), and was related to changes in mRNA for cell division cycle 25 homolog A (FC, 0.11). MiR-455 decreased (FC, 0.12) and was related to changes in mRNA for the epithelial cell marker, mucin 1 (FC, 136). Transfection with anti-miR-449 or miR-455-3p resulted in changes in target protein expression (cell division cycle 25 homolog A and mucin 1, respectively), whereas transfection with reporter genes with 3'-untranslated regions of these targets confirmed control of expression through that structure. Therefore, changes in specific miRNAs during human airway epithelial cell differentiation control gene and protein expression important for differentiation. C1 [Martinez-Anton, Asuncion; Sokolowska, Milena; Kern, Steven; Alsaaty, Sara; Sun, Junfeng; Cai, Rongman; Danner, Robert L.; Eberlein, Michael; Logun, Carolea; Shelhamer, James H.] NIAID, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Davis, A. Sally; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Shelhamer, JH (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM jshelhamer@cc.nih.gov RI Cai, Rongman/C-5998-2015; Martinez Anton, Asuncion/A-5806-2017; OI Cai, Rongman/0000-0003-2404-4852; Martinez Anton, Asuncion/0000-0001-9758-5911; Davis, Anne/0000-0001-5711-3936 FU National Institutes of Health intramural research program FX This work was supported by the National Institutes of Health intramural research program. NR 45 TC 16 Z9 16 U1 1 U2 10 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD SEP PY 2013 VL 49 IS 3 BP 384 EP 395 DI 10.1165/rcmb.2012-0368OC PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 215FQ UT WOS:000324195400006 PM 23590309 ER PT J AU Zhou, J Enewold, L Zahm, SH Jatoi, I Shriver, C Anderson, WF Jeffery, DD Andaya, A Potter, JF McGlynn, KA Zhu, KM AF Zhou, Jing Enewold, Lindsey Zahm, Shelia H. Jatoi, Ismail Shriver, Craig Anderson, William F. Jeffery, Diana D. Andaya, Abegail Potter, John F. McGlynn, Katherine A. Zhu, Kangmin TI Breast conserving surgery versus mastectomy: the influence of comorbidities on choice of surgical operation in the Department of Defense health care system SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Breast cancer; Breast conserving surgery; Comorbidity; Department of Defense health system; Mastectomy; Military ID 20-YEAR FOLLOW-UP; CANCER PATIENTS; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; OLDER WOMEN; POSTOPERATIVE RADIOTHERAPY; RADIATION-THERAPY; LOCAL RECURRENCE; SURVIVAL; CARCINOMA AB BACKGROUND: Studies on the effect of comorbidities on breast cancer operation have been limited and inconsistent. This study investigated whether pre-existing comorbidities influenced breast cancer surgical operation in an equal access health care system. METHODS: This study was based on linked Department of Defense cancer registry and medical claims data. The study subjects were patients diagnosed with stage I to III breast cancer during 2001 to 2007. Logistic regression was used to determine if comorbidity was associated with operation type and time between diagnosis and operation. RESULTS: Breast cancer patients with comorbidities were more likely to receive mastectomy (odds ratio [OR] = 1.27; 95% confidence interval [CI], 1.14 to 1.42) than breast conserving surgery plus radiation. Patients with comorbidities were also more likely to delay having operation than those without comorbidities (OR = 1.27; 95% CI, 1.14 to 1.41). CONCLUSIONS: In an equal access health care system, comorbidity was associated with having a mastectomy and with a delay in undergoing operation. (C) 2013 Elsevier Inc. All rights reserved. C1 [Zhou, Jing; Shriver, Craig; Andaya, Abegail; Potter, John F.; Zhu, Kangmin] Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Bethesda, MD USA. [Enewold, Lindsey; Zahm, Shelia H.; Anderson, William F.; McGlynn, Katherine A.] NCI, NIH, Bethesda, MD 20892 USA. [Jatoi, Ismail] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Shriver, Craig] Walter Reed Natl Mil Med Ctr, Gen Surg Serv, Bethesda, MD USA. [Shriver, Craig; Potter, John F.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Jeffery, Diana D.] Tricare Management Act, Falls Church, VA USA. RP Zhu, KM (reprint author), Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Div Mil Epidemiol & Populat Sci, 11300 Rockville Pike,Suite 1215, Rockville, MD 20852 USA. EM kangmin.zhu@usuhs.edu RI Zahm, Shelia/B-5025-2015 FU John P. Murtha Cancer Center; Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences; Henry M. Jackson Foundation for the Advancement of Military Medicine; National Cancer Institute FX This project was supported by John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine and by the intramural research program of the National Cancer Institute. The original data linkage was supported by the former United States Military Cancer Institute (USMCI) and Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute. The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Army, Department of Defense, National Cancer Institute, or the U. S. Government. Nothing in the presentation implies any federal/DOD/DON endorsement. NR 41 TC 5 Z9 5 U1 0 U2 7 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD SEP PY 2013 VL 206 IS 3 BP 393 EP 399 DI 10.1016/j.amjsurg.2013.01.034 PG 7 WC Surgery SC Surgery GA 213YK UT WOS:000324096400017 PM 23866763 ER PT J AU Fung, KW Kayaalp, M Callaghan, F McDonald, CJ AF Fung, Kin Wah Kayaalp, Mehmet Callaghan, Fiona McDonald, Clement J. TI Comparison of Electronic Pharmacy Prescription Records With Manually Collected Medication Histories in an Emergency Department SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID ADVERSE DRUG EVENTS; ADMISSION; DISCREPANCIES; VISITS AB Study objective: Medication history is an essential part of patient assessment in emergency care. Patient-reported medication history can be incomplete. We study whether an electronic pharmacy-sourced prescription record can supplement the patient-reported history. Methods: In a community hospital, we compared the patient-reported history obtained by triage nurses to a proprietary electronic pharmacy record in all emergency department (ED) patients during 3 months. Results: Of 9,426 triaged patients, 5,001 (53%) had at least 1 (mean 7.7) prescription medication in the full-year electronic pharmacy record. Counting only recent prescription medications (supply lasting to at least 7 days before the ED visit), 3,688 patients (39%) had at least 1 (mean 4.0) recent medication. After adjustment for possible false-positive results, recent electronic prescription medication record enriched the patient-reported history by 28% (adding 1.1 drugs per patient). However, only 60% of patients with any active prescription medications from either source had any recent prescription medications in their electronic pharmacy record. Conclusion: The electronic pharmacy prescription record augments the manually collected history. C1 [Fung, Kin Wah; Kayaalp, Mehmet; Callaghan, Fiona; McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20892 USA. RP McDonald, CJ (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM clemmcdonald@mail.nih.gov FU National Naval Medical Center; Intramural Research Program of the National Institutes of Health, National Library of Medicine FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. This work was funded in part by the National Naval Medical Center in support of the Bethesda Hospitals' Emergency Preparedness Partnership and was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 21 TC 2 Z9 3 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2013 VL 62 IS 3 BP 205 EP 211 DI 10.1016/j.annemergmed.2013.04.014 PG 7 WC Emergency Medicine SC Emergency Medicine GA 218QS UT WOS:000324448100004 PM 23688770 ER PT J AU Elagawany, M Schmitt, M Ghiaty, A El-Etrawy, AS Ibrahim, MA Bihel, F Sbardelotto, AB Pessoa, C Nguyen, TL Hamel, E Bourguignon, JJ AF Elagawany, Mohamed Schmitt, Martine Ghiaty, Adel El-Etrawy, A. Sh. Ibrahim, Mohamed A. Bihel, Frederic Sbardelotto, Aline Borba Pessoa, Claudia Tam Luong Nguyen Hamel, Ernest Bourguignon, Jean Jacques TI Synthesis and Antiproliferative Effects of 5,6-Disubstituted Pyridazin-3(2H)-ones Designed as Conformationally Constrained Combretastatin A-4 Analogues SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Pyridazine; Combretastatin A-4; Cytotoxicity; Suzuki-Miyaura cross coupling; Anticancer agent and Tubulin activity ID CYTOTOXIC EVALUATION; TUBULIN; POTENT; AGENTS; POLYMERIZATION; DERIVATIVES; INHIBITORS AB Novel 5,6-disubstituted pyridazin-3(2H)-one derivatives were designed and synthesized as combretastatin A-4 analogues. Our objective was to overcome the spontaneous cis to trans isomerization of the compound. We therefore replaced the cis-double bond with a pyridazine ring. The antiproliferative activity of the novel analogues was evaluated against four human cancer cell lines (HL-60, MDA-MB-435, SF-295 and HCT-8). We found that the analogues had little activity either against selected cell lines or against purified tubulin. Molecular modeling studies may account for their inactivity. C1 [Elagawany, Mohamed; Schmitt, Martine; Ibrahim, Mohamed A.; Bihel, Frederic; Bourguignon, Jean Jacques] Univ Strasbourg, Fac Pharm, Lab Innovat Therapeut, UMR 7200, F-67401 Illkirch Graffenstaden, France. [Elagawany, Mohamed; El-Etrawy, A. Sh.; Ibrahim, Mohamed A.] Misr Univ Sci & Technol, Organ Chem Dept, Coll Pharm, Giza, Egypt. [Ghiaty, Adel] Al Azhar Univ, Organ Chem Dept, Fac Pharm, Cairo 11884, Egypt. [Sbardelotto, Aline Borba; Pessoa, Claudia] Univ Fed Ceara, Dept Fisiol & Farmacol, BR-60430270 Fortaleza, Ceara, Brazil. [Tam Luong Nguyen] NIAID, Biodef Drug Dev Sect, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Elagawany, M (reprint author), Univ Strasbourg, Fac Pharm, Lab Innovat Therapeut, UMR 7200, 74 Route Rhin,BP 60024, F-67401 Illkirch Graffenstaden, France. EM alfath_tours@yahoo.com; mschmitt@unistra.fr RI Schmitt, Martine/B-5878-2016; BIHEL, Frederic/B-2895-2008 OI Schmitt, Martine/0000-0002-8723-9502; BIHEL, Frederic/0000-0002-4122-0929 FU Intramural NIH HHS [Z99 CA999999] NR 18 TC 1 Z9 1 U1 1 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD SEP PY 2013 VL 13 IS 7 BP 1133 EP 1140 PG 8 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 215ZG UT WOS:000324249500018 PM 23574386 ER PT J AU Marfeo, EE Haley, SM Jette, AM Eisen, SV Ni, PS Bogusz, K Meterko, M McDonough, CM Chan, L Brandt, DE Rasch, EK AF Marfeo, Elizabeth E. Haley, Stephen M. Jette, Alan M. Eisen, Susan V. Ni, Pengsheng Bogusz, Kara Meterko, Mark McDonough, Christine M. Chan, Leighton Brandt, Diane E. Rasch, Elizabeth K. TI Conceptual Foundation for Measures of Physical Function and Behavioral Health Function for Social Security Work Disability Evaluation SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Concept formation; Disability evaluation; Disabled persons; Mental health; Rehabilitation; Work disability ID MENTAL-DISORDERS; INTERNATIONAL CLASSIFICATION; PERSONALITY; ICF; PERFORMANCE; PERSPECTIVE; PREDICTORS; MODEL; REHABILITATION; PARTICIPATION AB Physical and mental impairments represent the 2 largest health condition categories for which workers receive Social Security disability benefits. Comprehensive assessment of physical and mental impairments should include aspects beyond medical conditions such as a person's underlying capabilities as well as activity demands relevant to the context of work. The objective of this article is to describe the initial conceptual stages of developing new measurement instruments of behavioral health and physical functioning relevant for Social Security work disability evaluation purposes. To outline a clear conceptualization of the constructs to be measured, 2 content models were developed using structured and informal qualitative approaches. We performed a structured literature review focusing on work disability and incorporating aspects of the International Classification of Functioning, Disability and Health as a unifying taxonomy for framework development. Expert interviews provided advice and consultation to enhance face validity of the resulting content models. The content model for work-related behavioral health function identifies 5 major domains: (1) behavior control, (2) basic interactions, (3) temperament and personality, (4) adaptability, and (5) workplace behaviors. The content model describing physical functioning includes 3 domains: (1) changing and maintaining body position, (2) whole-body mobility, and (3) carrying, moving, and handling objects. These content models informed subsequent measurement properties including item development and measurement scale construction, and provided conceptual coherence guiding future empirical inquiry. The proposed measurement approaches show promise to comprehensively and systematically assess physical and behavioral health functioning relevant to work. (C) 2013 by the American Congress of Rehabilitation Medicine C1 [Marfeo, Elizabeth E.; Haley, Stephen M.; Jette, Alan M.; Ni, Pengsheng; Bogusz, Kara; McDonough, Christine M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Eisen, Susan V.] Edith Nourse Rogers Mem Vet Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Eisen, Susan V.; Meterko, Mark] Boston Univ, Sch Publ Hlth, Hlth Policy & Management Dept, Boston, MA 02118 USA. [McDonough, Christine M.] Geisel Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Chan, Leighton; Brandt, Diane E.; Rasch, Elizabeth K.] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Marfeo, EE (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA. EM emarfeo@bu.edu FU Social Security Administration and National Institutes of Health (SSA-NIH) Interagency Agreements (NIH) [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I]; NIH FX Supported by Social Security Administration and National Institutes of Health (SSA-NIH) Interagency Agreements (NIH contract nos. HHSN269200900004C, HHSN269201000011C, HHSN269201100009I) and by the NIH intramural research program. NR 62 TC 10 Z9 10 U1 3 U2 21 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2013 VL 94 IS 9 BP 1645 EP 1652 DI 10.1016/j.apmr.2013.03.015 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 214QZ UT WOS:000324151900001 PM 23548543 ER PT J AU McDonough, CM Jette, AM Ni, PS Bogusz, K Marfeo, EE Brandt, DE Chan, L Meterko, M Haley, SM Rasch, EK AF McDonough, Christine M. Jette, Alan M. Ni, Pengsheng Bogusz, Kara Marfeo, Elizabeth E. Brandt, Diane E. Chan, Leighton Meterko, Mark Haley, Stephen M. Rasch, Elizabeth K. TI Development of a Self-Report Physical Function Instrument for Disability Assessment: Item Pool Construction and Factor Analysis SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT Meeting of the International-Association-of-Bodily-Impairment CY SEP 12, 2012 CL Montreal, CANADA SP Int Assoc Bodily Impairment DE Disability evaluation; Disabled persons; Factor analysis, statistical; Insurance; Questionnaires; Rehabilitation ID INFORMATION-SYSTEM PROMIS; FIT INDEXES; OUTCOMES MEASUREMENT; CRITERIA; MODELS; BANKS AB Objectives: To build a comprehensive item pool representing work-relevant physical functioning and to test the factor structure of the item pool. These developmental steps represent initial outcomes of a broader project to develop instruments for the assessment of function within the context of Social Security Administration (SSA) disability programs. Design: Comprehensive literature review; gap analysis; item generation with expert panel input; stakeholder interviews; cognitive interviews; cross-sectional survey administration; and exploratory and confirmatory factor analyses to assess item pool structure. Setting: In-person and semistructured interviews and Internet and telephone surveys. Participants: Sample of SSA claimants (n=1017) and a normative sample of adults from the U.S. general population (n=999). Interventions: Not applicable. Main Outcome Measure: Model fit statistics. Results: The final item pool consisted of 139 items. Within the claimant sample, 58.7% were white; 31.8% were black; 46.6% were women; and the mean age was 49.7 years. Initial factor analyses revealed a 4-factor solution, which included more items and allowed separate characterization of: (1) changing and maintaining body position, (2) whole body mobility, (3) upper body function, and (4) upper extremity fine motor. The final 4-factor model included 91 items. Confirmatory factor analyses for the 4-factor models for the claimant and the normative samples demonstrated very good fit. Fit statistics for claimant and normative samples, respectively, were: Comparative Fit Index=.93 and .98; Tucker-Lewis Index =.92 and .98; and root mean square error approximation=.05 and .04. Conclusions: The factor structure of the physical function item pool closely resembled the hypothesized content model. The 4 scales relevant to work activities offer promise for providing reliable information about claimant physical functioning relevant to work disability. (C) 2013 by the American Congress of Rehabilitation Medicine C1 [McDonough, Christine M.; Jette, Alan M.; Ni, Pengsheng; Bogusz, Kara; Marfeo, Elizabeth E.; Meterko, Mark] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Dept Hlth Policy & Management, Boston, MA 02118 USA. [McDonough, Christine M.] Geiset Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Brandt, Diane E.; Chan, Leighton; Rasch, Elizabeth K.] NIH, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. RP McDonough, CM (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St T5W, Boston, MA 02118 USA. EM cmm@bu.edu OI Jette, Alan/0000-0002-2117-9973; Ni, Pengsheng/0000-0003-1774-2185; McDonough, Christine/0000-0002-4493-8610; Marfeo, Elizabeth/0000-0003-3848-6918 FU CLC NIH HHS [HHSN269200900004C, HHSN269200900004I, HHSN269201000011C, HHSN269201100009I]; Intramural NIH HHS [ZIA CL060065-06]; NIAMS NIH HHS [P60 AR062799]; PHS HHS [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I] NR 37 TC 10 Z9 12 U1 2 U2 24 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2013 VL 94 IS 9 BP 1653 EP 1660 DI 10.1016/j.apmr.2013.03.011 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 214QZ UT WOS:000324151900002 PM 23542402 ER PT J AU Ni, PS McDonough, CM Jette, AM Bogusz, K Marfeo, EE Rasch, EK Brandt, DE Meterko, M Haley, SM Chan, L AF Ni, Pengsheng McDonough, Christine M. Jette, Alan M. Bogusz, Kara Marfeo, Elizabeth E. Rasch, Elizabeth K. Brandt, Diane E. Meterko, Mark Haley, Stephen M. Chan, Leighton TI Development of a Computer-Adaptive Physical Function Instrument for Social Security Administration Disability Determination SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT Meeting of the International-Association-of-Bodily-Impairment CY SEP 12, 2012 CL Montreal, CANADA SP Int Assoc Bodily Impairment DE Disability evaluation; Disabled persons; Health Status Indicators; Insurance; Psychometrics; Questionnaires; Rehabilitation; Statistical model ID ITEM RESPONSE THEORY; INFORMATION-SYSTEM PROMIS; FIT INDEX; OUTCOMES; EFFICIENCY; BANK; REHABILITATION; PERFORMANCE; MODELS; S-X-2 AB Objectives: To develop and test an instrument to assess physical function for Social Security Administration (SSA) disability programs, the SSA-Physical Function (SSA-PF) instrument. Item response theory (IRT) analyses were used to (1) create a calibrated item bank for each of the factors identified in prior factor analyses, (2) assess the fit of the items within each scale, (3) develop separate computer-adaptive testing (CAT) instruments for each scale, and (4) conduct initial psychometric testing. Design: Cross-sectional data collection; IRT analyses; CAT simulation. Setting: Telephone and Internet survey. Participants: Two samples: SSA claimants (n=1017) and adults from the U.S. general population (n=999). Interventions: None. Main Outcome Measures: Model fit statistics, correlation, and reliability coefficients. Results: IRT analyses resulted in 5 unidimensional SSA-PF scales: Changing & Maintaining Body Position, Whole Body Mobility, Upper Body Function, Upper Extremity Fine Motor, and Wheelchair Mobility for a total of 102 items. High CAT accuracy was demonstrated by strong correlations between simulated CAT scores and those from the full item banks. On comparing the simulated CATs with the full item banks, very little loss of reliability or precision was noted, except at the lower and upper ranges of each scale. No difference in response patterns by age or sex was noted. The distributions of claimant scores were shifted to the lower end of each scale compared with those of a sample of U.S. adults. Conclusions: The SSA-PF instrument contributes important new methodology for measuring the physical function of adults applying to the SSA disability programs. Initial evaluation revealed that the SSA-PF instrument achieved considerable breadth of coverage in each content domain and demonstrated noteworthy psychometric properties. (C) 2013 by the American Congress of Rehabilitation Medicine C1 [Ni, Pengsheng; McDonough, Christine M.; Jette, Alan M.; Bogusz, Kara; Marfeo, Elizabeth E.; Meterko, Mark] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Hlth & Disabil Res Inst, Boston, MA USA. [McDonough, Christine M.] Geisel Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Rasch, Elizabeth K.; Brandt, Diane E.; Chan, Leighton] NIH, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. RP Ni, PS (reprint author), Hlth & Disabil Res Inst, 715 Albany St T5W, Boston, MA 02118 USA. EM psni@bu.edu OI Jette, Alan/0000-0002-2117-9973; Ni, Pengsheng/0000-0003-1774-2185; Marfeo, Elizabeth/0000-0003-3848-6918; McDonough, Christine/0000-0002-4493-8610 FU CLC NIH HHS [HHSN269200900004C, HHSN269200900004I, HHSN269201000011C, HHSN269201100009I]; Intramural NIH HHS [ZIA CL060065-06]; NIAMS NIH HHS [P60 AR062799]; PHS HHS [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I] NR 33 TC 10 Z9 10 U1 0 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2013 VL 94 IS 9 BP 1661 EP 1669 DI 10.1016/j.apmr.2013.03.021 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 214QZ UT WOS:000324151900003 PM 23578594 ER PT J AU Marfeo, EE Ni, PS Haley, SM Jette, AM Bogusz, K Meterko, M McDonough, CM Chan, L Brandt, DE Rasch, EK AF Marfeo, Elizabeth E. Ni, Pengsheng Haley, Stephen M. Jette, Alan M. Bogusz, Kara Meterko, Mark McDonough, Christine M. Chan, Leighton Brandt, Diane E. Rasch, Elizabeth K. TI Development of an Instrument to Measure Behavioral Health Function for Work Disability: Item Pool Construction and Factor Analysis SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Disability evaluation; Mental health; Outcome assessment (health care); Psychometrics; Rehabilitation ID QUALITY-OF-LIFE; INFORMATION-SYSTEM PROMIS; PSYCHIATRIC DISABILITIES; MENTAL-HEALTH; INDIVIDUALS; NEUROLOGY; PEOPLE; MODEL; BANKS; ICF AB Objectives: To develop a broad set of claimant-reported items to assess behavioral health functioning relevant to the Social Security disability determination processes, and to evaluate the underlying structure of behavioral health functioning for use in development of a new functional assessment instrument. Design: Cross-sectional. Setting: Community. Participants: Item pools of behavioral health functioning were developed, refined, and field tested in a sample of persons applying for Social Security disability benefits (N=1015) who reported difficulties working because of mental or both mental and physical conditions. Interventions: None. Main Outcome Measure: Social Security Administration Behavioral Health (SSA-BH) measurement instrument. Results: Confirmatory factor analysis (CFA) specified that a 4-factor model (self-efficacy, mood and emotions, behavioral control, social interactions) had the optimal fit with the data and was also consistent with our hypothesized conceptual framework for characterizing behavioral health functioning. When the items within each of the 4 scales were tested in CFA, the fit statistics indicated adequate support for characterizing behavioral health as a unidimensional construct along these 4 distinct scales of function. Conclusions: This work represents a significant advance both conceptually and psychometrically in assessment methodologies for work-related behavioral health. The measurement of behavioral health functioning relevant to the context of work requires the assessment of multiple dimensions of behavioral health functioning. Specifically, we identified a 4-factor model solution that represented key domains of work-related behavioral health functioning. These results guided the development and scale formation of a new SSA-BH instrument. (C) 2013 by the American Congress of Rehabilitation Medicine C1 [Marfeo, Elizabeth E.; Ni, Pengsheng; Haley, Stephen M.; Jette, Alan M.; Bogusz, Kara; Meterko, Mark; McDonough, Christine M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Chan, Leighton; Brandt, Diane E.; Rasch, Elizabeth K.] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [McDonough, Christine M.] Geisel Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. RP Marfeo, EE (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA. EM emarfeo@bu.edu OI Marfeo, Elizabeth/0000-0003-3848-6918 FU SSA-NIH [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I]; NIH FX Supported by SSA-NIH Interagency Agreements (NIH contract nos. HHSN269200900004C, HHSN269201000011C, HHSN269201100009I) and by the NIH intramural research program. NR 36 TC 8 Z9 8 U1 2 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2013 VL 94 IS 9 BP 1670 EP 1678 DI 10.1016/j.apmr.2013.03.013 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 214QZ UT WOS:000324151900004 PM 23548542 ER PT J AU Marfeo, EE Ni, PS Haley, SM Bogusz, K Meterko, M McDonough, CM Chan, L Rasch, EK Brandt, DE Jette, AM AF Marfeo, Elizabeth E. Ni, Pengsheng Haley, Stephen M. Bogusz, Kara Meterko, Mark McDonough, Christine M. Chan, Leighton Rasch, Elizabeth K. Brandt, Diane E. Jette, Alan M. TI Scale Refinement and Initial Evaluation of a Behavioral Health Function Measurement Tool for Work Disability Evaluation SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Disability evaluation; Outcome assessment (health care); Rehabilitation; United States Social Security Administration ID ITEM RESPONSE THEORY; FIT INDEX; PERFORMANCE; RELIABILITY; MODELS; S-X-2; PAC AB Objective: To use item response theory (IRT) data simulations to construct and perform initial psychometric testing of a newly developed instrument, the Social Security Administration Behavioral Health Function (SSA-BH) instrument, that aims to assess behavioral health functioning relevant to the context of work. Design: Cross-sectional survey followed by IRT calibration data simulations. Setting: Community. Participants: Sample of individuals applying for Social Security Administration disability benefits: claimants (n=1015) and a normative comparative sample of U.S. adults (n=1000). Interventions: None. Main Outcome Measure: SSA-BH measurement instrument. Results: IRT analyses supported the unidimensionality of 4 SSA-BH scales: mood and emotions (35 items), self-efficacy (23 items), social interactions (6 items), and behavioral control (15 items). All SSA-BH scales demonstrated strong psychometric properties including reliability, accuracy, and breadth of coverage. High correlations of the simulated 5- or 10-item computer adaptive tests with the full item bank indicated robust ability of the computer adaptive testing approach to comprehensively characterize behavioral health function along 4 distinct dimensions. Conclusions: Initial testing and evaluation of the SSA-BH instrument demonstrated good accuracy, reliability, and content coverage along all 4 scales. Behavioral function profiles of Social Security Administration claimants were generated and compared with age- and sex-matched norms along 4 scales: mood and emotions, behavioral control, social interactions, and self-efficacy. Using the computer adaptive test-based approach offers the ability to collect standardized, comprehensive functional information about claimants in an efficient way, which may prove useful in the context of the Social Security Administration's work disability programs. (C) 2013 by the American Congress of Rehabilitation Medicine C1 [Marfeo, Elizabeth E.; Ni, Pengsheng; Haley, Stephen M.; Bogusz, Kara; Meterko, Mark; McDonough, Christine M.; Jette, Alan M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [McDonough, Christine M.] Geisel Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Chan, Leighton; Rasch, Elizabeth K.; Brandt, Diane E.] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Marfeo, EE (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA. EM emarfeo@bu.edu OI Jette, Alan/0000-0002-2117-9973; Ni, Pengsheng/0000-0003-1774-2185; McDonough, Christine/0000-0002-4493-8610; Marfeo, Elizabeth/0000-0003-3848-6918 FU Social Security Administration and the National Institutes of Health Interagency Agreements (National Institutes of Health) [HHSN269200900004C, HHSN269201000 011C, HHSN269201100009I]; National Institutes of Health FX Supported by Social Security Administration and the National Institutes of Health Interagency Agreements (National Institutes of Health contract nos. HHSN269200900004C, HHSN269201000 011C, and HHSN269201100009I); and the National Institutes of Health Intramural Research Program. NR 33 TC 8 Z9 8 U1 2 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2013 VL 94 IS 9 BP 1679 EP 1686 DI 10.1016/j.apmr.2013.03.012 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 214QZ UT WOS:000324151900005 PM 23542404 ER PT J AU McIver, ZA Yin, F Hughes, T Battiwalla, M Ito, S Koklanaris, E Haggerty, J Barrett, AJ AF McIver, Z. A. Yin, F. Hughes, T. Battiwalla, M. Ito, S. Koklanaris, E. Haggerty, J. Barrett, A. John TI Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival SO BONE MARROW TRANSPLANTATION LA English DT Article DE second SCT; leukemia; relapse; T-depleted; survival ID ACUTE LYMPHOBLASTIC-LEUKEMIA; OUTCOMES; AML; MALIGNANCIES; MDS AB Patients with leukemia relapsing after allogeneic hematopoietic SCT have a dismal prognosis. A second SCT offers a further opportunity for cure, but has a high rate of treatment failure. To determine the utility of this option, we analyzed 59 consecutive patients relapsing after a myeloablative HLA-matched sibling T cell-depleted (TCD) SCT. Twenty-five patients (13 relapsing within 6 months and 12 relapsing between 6 and 170 months after the first SCT) received a T-replete second SCT. Thirty-eight patients relapsing early had a shorter survival than the 21 patients relapsing later (median 96 vs 298 days, P = 0.0002). In patients relapsing early, the second SCT did not improve OS compared with patients receiving non-SCT treatments (median survival 109 vs 80 days, P = 0.41). In patients relapsing late, despite an early trend in favor of second SCT, survival was comparable for patients receiving a second SCT compared with non retransplanted patients (median survival 363.5 vs 162 days, P = 0.49). Disappointingly, our results do not demonstrate an important survival benefit for a second T-replete allogeneic SCT to treat relapse following a TCD SCT. C1 [McIver, Z. A.; Yin, F.; Hughes, T.; Battiwalla, M.; Ito, S.; Koklanaris, E.; Haggerty, J.; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP McIver, ZA (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Blg 10-CRC Rm 3-5320, Bethesda, MD 20892 USA. EM zmciver@tulane.edu; fang.yin@nih.gov FU National Heart, Lung, and Blood Institute FX The study was sponsored by the National Heart, Lung, and Blood Institute, and registered as ClinicalTrials.gov-registered trials NCT00001623, NCT00001873, NCT00353860, NCT00066300, NCT00079391, NCT00398346 and NCT00467961. NR 20 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD SEP PY 2013 VL 48 IS 9 BP 1192 EP 1197 DI 10.1038/bmt.2013.39 PG 6 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 214VX UT WOS:000324166300008 PM 23524640 ER PT J AU Alavanja, MCR Ross, MK Bonner, MR AF Alavanja, Michael C. R. Ross, Matthew K. Bonner, Matthew R. TI Reply to Increased cancer burden among pesticide applicators and others due to pesticide exposure SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Letter C1 [Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, North Bethesda, MD USA. [Ross, Matthew K.] Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Ctr Environm Hlth Sci, Mississippi State, MS 39762 USA. [Bonner, Matthew R.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Alavanja, MCR (reprint author), NCI, Div Canc Epidemiol & Genet, North Bethesda, MD USA. FU Intramural NIH HHS [ZIA CP010119-17] NR 5 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD SEP PY 2013 VL 63 IS 5 BP 366 EP 367 DI 10.3322/caac.21193 PG 2 WC Oncology SC Oncology GA 213BT UT WOS:000324029100007 PM 23722636 ER PT J AU Stamatakis, L Siddiqui, MM Nix, JW Logan, J Rais-Bahrami, S Walton-Diaz, A Hoang, AN Vourganti, S Truong, H Shuch, B Parnes, HL Turkbey, B Choyke, PL Wood, BJ Simon, RM Pinto, PA AF Stamatakis, Lambros Siddiqui, M. Minhaj Nix, Jeffrey W. Logan, Jennifer Rais-Bahrami, Soroush Walton-Diaz, Annerleim Hoang, Anthony N. Vourganti, Srinivas Hong Truong Shuch, Brian Parnes, Howard L. Turkbey, Baris Choyke, Peter L. Wood, Bradford J. Simon, Richard M. Pinto, Peter A. TI Accuracy of multiparametric magnetic resonance imaging in confirming eligibility for active surveillance for men with prostate cancer SO CANCER LA English DT Article DE prostate neoplasms; active surveillance; magnetic resonance imaging; early detection of cancer ID TUMOR VOLUME; BIOPSY; MANAGEMENT; FUSION; MRI; PREDICTION; EXPERIENCE; UPDATE; TRUS AB BACKGROUND Active surveillance (AS) is an attempt to avoid overtreatment of clinically insignificant prostate cancer (PCa); however, patient selection remains controversial. Multiparametric prostate magnetic resonance imaging (MP-MRI) may help better select AS candidates. METHODS We reviewed a cohort of men who underwent MP-MRI with MRI/Ultrasound fusion-guided prostate biopsy and selected potential AS patients at entry using Johns Hopkins criteria. MP-MRI findings were assessed, including number of lesions, dominant lesion diameter, total lesion volume, prostate volume, and lesion density (calculated as total lesion volume/prostate volume). Lesions were assigned a suspicion score for cancer by MRI. AS criteria were reapplied based on the confirmatory biopsy, and accuracy of MP-MRI in predicting AS candidacy was assessed. Logistic regression modeling and chi-square statistics were used to assess associations between MP-MRI interpretation and biopsy results. RESULTS Eighty-five patients qualified for AS with a mean age of 60.2 years and mean prostate-specific antigen level of 4.8 ng/mL. Of these, 25 patients (29%) were reclassified as not meeting AS criteria based on confirmatory biopsy. Number of lesions, lesion density, and highest MRI lesion suspicion were significantly associated with confirmatory biopsy AS reclassification. These MRI-based factors were combined to create a nomogram that generates a probability for confirmed AS candidacy. CONCLUSION As clinicians counsel patients with PCa, MP-MRI may contribute to the decision-making process when considering AS. Three MRI-based factors (number of lesions, lesion suspicion, and lesion density) were associated with confirmatory biopsy outcome and reclassification. A nomogram using these factors has promising predictive accuracy for which future validation is necessary. Cancer 2013;119:3359-66. Published 2013. This article is a U.S. Government work and is in the public domain in the USA C1 [Stamatakis, Lambros; Siddiqui, M. Minhaj; Nix, Jeffrey W.; Logan, Jennifer; Rais-Bahrami, Soroush; Walton-Diaz, Annerleim; Hoang, Anthony N.; Vourganti, Srinivas; Hong Truong; Shuch, Brian; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Parnes, Howard L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Simon, Richard M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10 CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Siddiqui, Mohummad/0000-0002-4484-6820; Rais-Bahrami, Soroush/0000-0001-9466-9925 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 29 TC 90 Z9 90 U1 1 U2 5 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 SEP PY 2013 VL 119 IS 18 BP 3359 EP 3366 DI 10.1002/cncr.28216 PG 8 WC Oncology SC Oncology GA 211EN UT WOS:000323887900017 PM 23821585 ER PT J AU Dowling, EC Chawla, N Forsythe, LP de Moor, J McNeel, T Rozjabek, HM Ekwueme, DU Yabroff, KR AF Dowling, Emily C. Chawla, Neetu Forsythe, Laura P. de Moor, Janet McNeel, Timothy Rozjabek, Heather M. Ekwueme, Donatus U. Yabroff, K. Robin TI Lost productivity and burden of illness in cancer survivors with and without other chronic conditions SO CANCER LA English DT Article DE MEPS; quality of life; cancer survivors; chronic conditions; comorbidities ID MENTAL-HEALTH STATUS; QUALITY-OF-LIFE; CARE; LIMITATIONS; RECORDS; AGE AB BACKGROUND Cancer survivors may experience long-term and late effects from treatment that adversely affect health and limit functioning. Few studies examine lost productivity and disease burden in cancer survivors compared with individuals who have other chronic conditions or by cancer type. METHODS We identified 4960 cancer survivors and 64,431 other individuals from the 2008-2010 Medical Expenditure Panel Survey and compared multiple measures of disease burden, including health status and lost productivity, between conditions and by cancer site for cancer survivors. All analyses controlled for the effects of age, sex, race/ethnicity, and number of comorbid conditions. RESULTS Overall, in adjusted analyses in multiple models, cancer survivors with another chronic disease (heart disease or diabetes) experienced higher levels of burden compared with individuals with a history of cancer only, chronic disease only, and neither cancer, heart disease, nor diabetes across multiple measures (P<.05). Among cancer survivors, individuals with short survival cancers and multiple cancers consistently had the highest levels of burden across multiple measures (P<.0001). CONCLUSIONS Cancer survivors who have another chronic disease experience more limitations and higher levels of burden across multiple measures. Limitations are particularly severe in cancer survivors with short survival cancer and multiple cancers. Cancer 2013;119:3393-401. (c) 2013 American Cancer Society. C1 [Dowling, Emily C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Chawla, Neetu; Forsythe, Laura P.; de Moor, Janet; Rozjabek, Heather M.; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [McNeel, Timothy] Informat Management Serv Inc, Rockville, MD USA. [Ekwueme, Donatus U.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Dowling, EC (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM edowling@mgh-ita.org OI Yabroff, K. Robin/0000-0003-0644-5572 NR 27 TC 14 Z9 14 U1 2 U2 7 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 SEP PY 2013 VL 119 IS 18 BP 3393 EP 3401 DI 10.1002/cncr.28214 PG 9 WC Oncology SC Oncology GA 211EN UT WOS:000323887900021 PM 23794146 ER PT J AU Witherspoon, M Chen, QY Kopelovich, L Gross, SS Lipkin, SM AF Witherspoon, Mavee Chen, Qiuying Kopelovich, Levy Gross, Steven S. Lipkin, Steven M. TI Unbiased Metabolite Profiling Indicates That a Diminished Thymidine Pool Is the Underlying Mechanism of Colon Cancer Chemoprevention by Alpha-Difluoromethylornithine SO CANCER DISCOVERY LA English DT Article ID DEOXYRIBONUCLEOSIDE TRIPHOSPHATE POOLS; S-ADENOSYLMETHIONINE DECARBOXYLASE; METHYLENETETRAHYDROFOLATE REDUCTASE; POLYAMINE METABOLISM; CELLS; INHIBITION; PREVENTION; MOUSE; TRIAL; CARCINOGENESIS AB The ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) is a highly effective chemopreventive agent for colorectal cancer thought to act via polyamine depletion. However, in DFMO-treated patients, mucosal polyamine levels do not directly correlate with colorectal cancer risk. Untargeted metabolite profiling was used to broadly survey DFMO actions on colon cancer cell metabolism. We found that DFMO treatment of Apc(Min) intestinal tumors and human colorectal cancer cells is associated with reduced levels of folate-dependent metabolites, including S-adenosylmethionine (SAM), thymidine pools, and related pathway intermediates. We hypothesized that unrestrained SAM consumption/regeneration constitutes a futile DFMO-triggered cascade that can steal tetrahydrofolate from thymidylate synthase and thereby diminish thymidine pools. In accord with this hypothesis, DFMO treatment altered the folate cofactor balance and thymidine supplementation prevented DFMO-elicited cytostasis without restoring polyamine levels. These findings suggest that thymidine metabolite pool insufficiency is a fundamental mechanism of DFMO cytostatic activity. SIGNIFICANCE: A previously unappreciated metabolic linkage between polyamine and thymidine biosynthesis is revealed, based on the competing requirement of these pathways for a limited pool of tetrahydrofolate cofactor. This study identifies the first shared mechanism for colorectal cancer chemoprevention and chemotherapy, suggesting a common metabolic target for both premalignant and malignant colon cells. (C) 2013 AACR. C1 [Witherspoon, Mavee; Lipkin, Steven M.] Weill Cornell Med Coll, Dept Med Genet Med & Cell Biol, New York, NY 10021 USA. [Chen, Qiuying; Gross, Steven S.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA. [Kopelovich, Levy] NCI, Div Chemoprevent, Frederick, MD 21701 USA. RP Lipkin, SM (reprint author), Weill Cornell Med Coll, Room 718 HSS,101 City Dr, New York, NY 10021 USA. EM ssgross@med.cornell.edu; stl2012@med.cornell.edu FU NCI [NO1-CN 43302]; NHLBI [R37 HL87062] FX This research was supported by NCI NO1-CN 43302 (to S. M. Lipkin), NHLBI grant R37 HL87062 (to S. S. Gross), and gifts from the Agilent Foundation and Matthew Bell. NR 41 TC 16 Z9 16 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD SEP PY 2013 VL 3 IS 9 BP 1072 EP 1081 DI 10.1158/2159-8290.CD-12-0305 PG 10 WC Oncology SC Oncology GA 215YH UT WOS:000324246600026 PM 23771434 ER PT J AU Subbaramaiah, K Sue, E Bhardwaj, P Du, BH Hudis, CA Giri, D Kopelovich, L Zhou, XK Dannenberg, AJ AF Subbaramaiah, Kotha Sue, Erika Bhardwaj, Priya Du, Baoheng Hudis, Clifford A. Giri, Dilip Kopelovich, Levy Zhou, Xi Kathy Dannenberg, Andrew J. TI Dietary Polyphenols Suppress Elevated Levels of Proinflammatory Mediators and Aromatase in the Mammary Gland of Obese Mice SO CANCER PREVENTION RESEARCH LA English DT Article ID NF-KAPPA-B; INDUCED INSULIN-RESISTANCE; BODY-MASS INDEX; BREAST-CANCER; POSTMENOPAUSAL WOMEN; PROSTATE-CANCER; ANDROGEN RECEPTOR; KINASE-ACTIVITY; ADIPOSE-TISSUE; EXPRESSION AB In postmenopausal women, obesity is a risk factor for the development of hormone receptor-positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity-inflammation-aromatase axis. This obesity-induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose tissue. CLS occur in association with NF-kappa B activation, elevated levels of proinflammatory mediators, and increased aromatase expression. Saturated fatty acids released from adipocytes have been linked to obesity-related white adipose tissue inflammation. Here we found that stearic acid, a prototypic saturated fatty acid, stimulated Akt-dependent activation of NF-kappa B resulting in increased levels of proinflammatory mediators [TNF-alpha, interleukin (IL)-1 beta, COX-2] in macrophages leading, in turn, to the induction of aromatase. Several polyphenols (resveratrol, curcumin, epigallocatechin gallate) blocked these inductive effects of stearic acid. Zyflamend, a widely used polyherbal preparation that contains numerous polyphenols, possessed similar suppressive effects. In a mouse model of obesity, treatment with Zyflamend suppressed levels of phospho-Akt, NF-kappa B binding activity, proinflammatory mediators, and aromatase in the mammary gland. Collectively, these results suggest that targeting the activation of NF-kappa B is a promising approach for reducing levels of proinflammatory mediators and aromatase in inflamed mouse mammary tissue. Further investigation in obese women is warranted. Cancer Prev Res; 6(9); 886-97. (C) 2013 AACR. C1 [Subbaramaiah, Kotha; Sue, Erika; Bhardwaj, Priya; Du, Baoheng; Hudis, Clifford A.; Dannenberg, Andrew J.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Zhou, Xi Kathy] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY 10065 USA. [Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Giri, Dilip] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Dannenberg, AJ (reprint author), Weill Cornell Med Coll, Dept Med, 525 East 68th St,Room F-206, New York, NY 10065 USA. EM ksubba@med.cornell.edu; ajdannen@med.cornell.edu FU NCI [1R01CA154481, N01-CN-43302]; NIH [UL1-RR024996]; Breast Cancer Research Foundation; New Chapter, Inc.; Botwinick-Wolfensohn Foundation FX This work was supported by NCI 1R01CA154481, NCI N01-CN-43302, NIH UL1-RR024996, the Breast Cancer Research Foundation, New Chapter, Inc., and the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick). NR 49 TC 9 Z9 9 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2013 VL 6 IS 9 BP 886 EP 897 DI 10.1158/1940-6207.CAPR-13-0140 PG 12 WC Oncology SC Oncology GA 214XH UT WOS:000324171000002 PM 23880231 ER PT J AU Zhang, G He, PJ Gaedcke, J Ghadimi, BM Ried, T Yfantis, HG Lee, DH Hanna, N Alexander, HR Hussain, SP AF Zhang, Geng He, Peijun Gaedcke, Jochen Ghadimi, B. Michael Ried, Thomas Yfantis, Harris G. Lee, Dong H. Hanna, Nader Alexander, H. Richard Hussain, S. Perwez TI FOXL1, a Novel Candidate Tumor Suppressor, Inhibits Tumor Aggressiveness and Predicts Outcome in Human Pancreatic Cancer SO CANCER RESEARCH LA English DT Article ID APOPTOSIS-INDUCING LIGAND; FORKHEAD TRANSCRIPTION FACTOR; MULTIPLE-MYELOMA PATIENTS; GENE-EXPRESSION PROFILES; INTRAEPITHELIAL-NEOPLASIA; DUCTAL ADENOCARCINOMA; DECOY RECEPTORS; CELL-SURVIVAL; FAS LIGAND; TRAIL AB The forkhead box L1 (FOXL1) transcription factor regulates epithelial proliferation and development of gastrointestinal tract and has been implicated in gastrointestinal tumorigenesis in mouse models. However, the role of FOXL1 in pancreatic cancer development and progression remains to be elucidated. Here, we report that higher expression of FOXL1 is significantly associated with better clinical outcome in human pancreatic ductal adenocarcinoma (PDAC). A lower FOXL1 expression is correlated with metastasis and advanced pathologic stage of pancreatic cancer. Mechanistic analyses showed that overexpression of FOXL1 induces apoptosis and inhibits proliferation and invasion in pancreatic cancer cells, whereas silencing of FOXL1 by siRNA inhibits apoptosis and enhances tumor cell growth and invasion. Furthermore, FOXL1 overexpression significantly suppressed the growth of tumor xenografts in nude mice. FOXL1 promoted apoptosis partly through the induction of TNF-related apoptosis-inducing ligand (TRAIL) in pancreatic cancer cells. In addition, FOXL1 suppressed the transcription of zinc finger E-box-binding homeobox 1 (ZEB1), an activator of epithelial-mesenchymal transition, and the negative regulation of ZEB1 contributed to the inhibitory effect of FOXL1 on tumor cell invasion. Taken together, our findings suggest that FOXL1 expression is a candidate predictor of clinical outcome in patients with resected PDAC and it plays an inhibitory role in pancreatic tumor progression. Cancer Res; 73(17); 5416-25. (C) 2013 AACR. C1 [Zhang, Geng; He, Peijun; Hussain, S. Perwez] NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Gaedcke, Jochen; Ghadimi, B. Michael] Univ Med, Dept Gen & Visceral Surg, Gottingen, Germany. [Yfantis, Harris G.; Lee, Dong H.] Univ Maryland, Sch Med, Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Dept Surg, Div Surg Oncol, Baltimore, MD 21201 USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Hussain, SP (reprint author), NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37,Room 3044B, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU National Cancer Institute, Center for Cancer Research, NIH FX This work is supported by Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 47 TC 9 Z9 11 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 SEP 1 PY 2013 VL 73 IS 17 BP 5416 EP 5425 DI 10.1158/0008-5472.CAN-13-0362 PG 10 WC Oncology SC Oncology GA 214ER UT WOS:000324114400013 PM 23801748 ER PT J AU Saud, SM Young, MR Jones-Hall, YL Ileva, L Evbuomwan, MO Wise, J Colburn, NH Kim, YS Bobe, G AF Saud, Shakir M. Young, Matthew R. Jones-Hall, Yava L. Ileva, Lilia Evbuomwan, Moses O. Wise, Jennifer Colburn, Nancy H. Kim, Young S. Bobe, Gerd TI Chemopreventive Activity of Plant Flavonoid Isorhamnetin in Colorectal Cancer Is Mediated by Oncogenic Src and beta-Catenin SO CANCER RESEARCH LA English DT Article ID PROTEIN-TYROSINE KINASE; COLON-CANCER; FAMILY KINASES; ULCERATIVE-COLITIS; C-SRC; EXPRESSION; CSK; INFLAMMATION; PREVENTION; CELLS AB Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. MRI, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than the control diet. Isorhamnetin inhibited AOM/DSS-induced oncogenic c-Src activation and beta-catenin nuclear translocation, while promoting the expression of C-terminal Src kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and beta-catenin nuclear translocation by inducing expression of csk, as verified by RNA interference knockdown of csk. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear beta-catenin, activities that are dependent on CSK expression. Cancer Res; 73(17); 5473-84. (C) 2013 AACR. C1 [Saud, Shakir M.; Kim, Young S.] NCI, Nutr Sci Res Grp, Canc Prevent Div, Rockville, MD USA. [Saud, Shakir M.; Young, Matthew R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Ileva, Lilia] SAIC Frederick, Small Anim Imaging Program, Frederick, MD USA. [Wise, Jennifer] SAIC Frederick, Lab Anim Sci, Frederick, MD USA. [Evbuomwan, Moses O.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Jones-Hall, Yava L.] Purdue Univ, Coll Vet Med, Comparat Pathobiol Dept, W Lafayette, IN 47907 USA. [Bobe, Gerd] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA. [Bobe, Gerd] Oregon State Univ, Dept Anim & Rangeland Sci, Corvallis, OR 97331 USA. RP Young, MR (reprint author), NCI, Bldg 576 Rm 100D, Frederick, MD 21702 USA. EM youngma@mail.nih.gov FU Office of Complementary and Alternative Medicine, Office of Dietary Supplements; Division of Cancer Prevention; Intramural Research Program, National Cancer Institute, NIH, Department of Health and Human Services (DHHS), Bethesda, MD FX This study was funded by the Office of Complementary and Alternative Medicine, Office of Dietary Supplements, the Division of Cancer Prevention and the Intramural Research Program, National Cancer Institute, NIH, Department of Health and Human Services (DHHS), Bethesda, MD. NR 40 TC 26 Z9 27 U1 1 U2 16 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 SEP 1 PY 2013 VL 73 IS 17 BP 5473 EP 5484 DI 10.1158/0008-5472.CAN-13-0525 PG 12 WC Oncology SC Oncology GA 214ER UT WOS:000324114400018 PM 23824743 ER PT J AU Aggarwal, M Banerjee, T Sommers, JA Iannascoli, C Pichierri, P Shoemaker, RH Brosh, RM AF Aggarwal, Monika Banerjee, Taraswi Sommers, Joshua A. Iannascoli, Chiara Pichierri, Pietro Shoemaker, Robert H. Brosh, Robert M., Jr. TI Werner Syndrome Helicase Has a Critical Role in DNA Damage Responses in the Absence of a Functional Fanconi Anemia Pathway SO CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; CROSS-LINK REPAIR; HOMOLOGOUS RECOMBINATION; GENOMIC STABILITY; SYNDROME PROTEIN; BLOOMS-SYNDROME; WRN; INHIBITION; DEFICIENT; ARREST AB Werner syndrome is genetically linked to mutations in WRN that encodes a DNA helicase-nuclease believed to operate at stalled replication forks. Using a newly identified small-molecule inhibitor of WRN helicase (NSC 617145), we investigated the role of WRN in the interstrand cross-link (ICL) response in cells derived from patients with Fanconi anemia, a hereditary disorder characterized by bone marrow failure and cancer. In FA-D2(-/-) cells, NSC 617145 acted synergistically with very low concentrations of mitomycin C to inhibit proliferation in a WRN-dependent manner and induce double-strand breaks (DSB) and chromosomal abnormalities. Under these conditions, ataxia-telangiectasia mutated activation and accumulation of DNA-dependent protein kinase, catalytic subunit pS2056 foci suggested an increased number of DSBs processed by nonhomologous end-joining (NHEJ). Rad51 foci were also elevated in FA-D2(-/-) cells exposed to NSC 617145 and mitomycin C, suggesting that WRN helicase inhibition interferes with later steps of homologous recombination at ICL-induced DSBs. Thus, when the Fanconi anemia pathway is defective, WRN helicase inhibition perturbs the normal ICL response, leading to NHEJ activation. Potential implication for treatment of Fanconi anemia-deficient tumors by their sensitization to DNA cross-linking agents is discussed. Cancer Res; 73(17); 5497-507. (C) 2013 AACR. C1 [Aggarwal, Monika; Banerjee, Taraswi; Sommers, Joshua A.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21701 USA. [Iannascoli, Chiara; Pichierri, Pietro] Ist Super Sanita, Sect Expt & Computat Carcinogenesis, I-00161 Rome, Italy. RP Brosh, RM (reprint author), NIA, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH, National Institute on Aging; National Cancer Institute; Fanconi Anemia Research Fund FX This work was supported by Intramural Research Program of NIH, National Institute on Aging, and National Cancer Institute, and Fanconi Anemia Research Fund (R.M. Brosh, Jr.). NR 36 TC 14 Z9 14 U1 1 U2 11 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 SEP 1 PY 2013 VL 73 IS 17 BP 5497 EP 5507 DI 10.1158/0008-5472.CAN-12-2975 PG 11 WC Oncology SC Oncology GA 214ER UT WOS:000324114400020 PM 23867477 ER PT J AU Wan, BB Yin, JH Horvath, K Sarkar, J Chen, Y Wu, J Wan, K Lu, J Gu, PL Yu, EY Lue, NF Chang, S Liu, Y Lei, M AF Wan, Bingbing Yin, Jinhu Horvath, Kent Sarkar, Jaya Chen, Yong Wu, Jian Wan, Ke Lu, Jian Gu, Peili Yu, Eun Young Lue, Neal F. Chang, Sandy Liu, Yie Lei, Ming TI SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres SO CELL REPORTS LA English DT Article ID HOLLIDAY JUNCTION RESOLVASE; DNA-REPAIR; MAMMALIAN TELOMERES; TRF1; LENGTH; MECHANISM; PROTEINS; CIRCLES; CELLS; LOOP AB SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4(TBM)) in complex with the TRFH domain of TRF2 (TRF2(TRFH)) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance. C1 [Wan, Bingbing; Chen, Yong; Wu, Jian; Lei, Ming] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China. [Wan, Bingbing; Chen, Yong; Wu, Jian; Lei, Ming] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai 200031, Peoples R China. [Wan, Bingbing; Wan, Ke; Lei, Ming] Univ Michigan, Sch Med, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. [Wan, Bingbing; Wan, Ke; Lei, Ming] Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Yin, Jinhu; Horvath, Kent; Sarkar, Jaya; Lu, Jian; Liu, Yie] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21044 USA. [Horvath, Kent] Univ Med & Dent New Jersey, New Jersey Med Sch, Grad Sch Biomed Sci, Newark, NJ 07103 USA. [Gu, Peili; Chang, Sandy] Yale Univ, Sch Med, Dept Lab Med & Pathol, New Haven, CT 06520 USA. [Yu, Eun Young; Lue, Neal F.] Cornell Univ, Weill Med Coll, WR Hearst Microbiol Res Ctr, Dept Microbiol & Immunol, New York, NY 10065 USA. RP Liu, Y (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Dr, Baltimore, MD 21044 USA. EM liuyie@mail.nih.gov; leim@sibcb.ac.cn FU Ministry of Science and Technology of China [2013CB910400]; NIA, National Institutes of Health, USA FX We thank Dr. J. Wade Harper for the templates of SLX4 and its interacting nucleases and Bob Wersto, Tonya Wolf, Honwei Liu, Chorong Song, and Cuong Nguyen for technical support. M. L. is a Howard Hughes Medical Institute Early Career Scientist. This work was supported by grants from the Ministry of Science and Technology of China (2013CB910400) and the Intramural Research Program of the NIA, National Institutes of Health, USA. NR 24 TC 39 Z9 39 U1 1 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD SEP PY 2013 VL 4 IS 5 BP 861 EP 869 DI 10.1016/j.celrep.2013.08.017 PG 9 WC Cell Biology SC Cell Biology GA 216LZ UT WOS:000324286300002 PM 24012755 ER PT J AU Wu, JJ Liu, J Chen, EB Wang, JJ Cao, L Narayan, N Fergusson, MM Rovira, II Allen, M Springer, DA Lago, CU Zhang, SL DuBois, W Ward, T deCabo, R Gavrilova, O Mock, B Finkel, T AF Wu, J. Julie Liu, Jie Chen, Edmund B. Wang, Jennifer J. Cao, Liu Narayan, Nisha Fergusson, Marie M. Rovira, Ilsa I. Allen, Michele Springer, Danielle A. Lago, Cory U. Zhang, Shuling DuBois, Wendy Ward, Theresa deCabo, Rafael Gavrilova, Oksana Mock, Beverly Finkel, Toren TI Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression SO CELL REPORTS LA English DT Article ID HETEROGENEOUS MICE; OLDER ADULTS; STEM-CELLS; RAPAMYCIN; GROWTH; TOR; DROSOPHILA; PATHWAY; DISEASE; KINASE AB We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTOR(Delta/Delta)) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTOR(Delta/Delta) mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTOR(Delta/Delta) mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTOR(Delta/Delta) mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion. C1 [Wu, J. Julie; Liu, Jie; Chen, Edmund B.; Wang, Jennifer J.; Narayan, Nisha; Fergusson, Marie M.; Rovira, Ilsa I.; Lago, Cory U.; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Allen, Michele; Springer, Danielle A.] NHLBI, Murine Phenotyping Core, NIH, Bethesda, MD 20892 USA. [Zhang, Shuling; DuBois, Wendy; Mock, Beverly] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core, NIH, Bethesda, MD 20892 USA. [Cao, Liu] China Med Univ, Key Lab Med Cell Biol, Shenyang 110001, Peoples R China. [Ward, Theresa; deCabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov RI Mock, Beverly/B-3110-2015; de Cabo, Rafael/J-5230-2016; OI Mock, Beverly/0000-0003-2479-4549; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIH FX We are grateful to Kumiko Torisu for helpful advice; Zu-Xi Yu for help with tissue sectioning; Lauren Brinster for animal pathology advice; William Jou and Tatyana Chanturiya for help with the metabolic testing; and David Allison, Timothy Mark Beasley, and John Dawson for statistical assistance. This work was supported by the NIH Intramural Research Program. NR 31 TC 74 Z9 77 U1 1 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD SEP PY 2013 VL 4 IS 5 BP 913 EP 920 DI 10.1016/j.celrep.2013.07.030 PG 8 WC Cell Biology SC Cell Biology GA 216LZ UT WOS:000324286300008 PM 23994476 ER PT J AU Quax, TEF Wolf, YI Koehorst, JJ Wurtzel, O van der Oost, R Ran, WQ Blombach, F Makarova, KS Brouns, SJJ Forster, AC Wagner, EGH Sorek, R Koonin, EV van der Oost, J AF Quax, Tessa E. F. Wolf, Yuri I. Koehorst, Jasper J. Wurtzel, Omri van der Oost, Richard Ran, Wenqi Blombach, Fabian Makarova, Kira S. Brouns, Stan J. J. Forster, Anthony C. Wagner, E. Gerhart H. Sorek, Rotem Koonin, Eugene V. van der Oost, John TI Differential Translation Tunes Uneven Production of Operon-Encoded Proteins SO CELL REPORTS LA English DT Article ID ESCHERICHIA-COLI; GENE-EXPRESSION; MESSENGER-RNAS; CODON BIAS; TRANSCRIPTION; SEQUENCE; RIBOSOME; BACTERIA; GENOME; ARCHITECTURE AB Clustering of functionally related genes in operons allows for coregulated gene expression in prokaryotes. This is advantageous when equal amounts of gene products are required. Production of protein complexes with an uneven stoichiometry, however, requires tuning mechanisms to generate subunits in appropriate relative quantities. Using comparative genomic analysis, we show that differential translation is a key determinant of modulated expression of genes clustered in operons and that codon bias generally is the best in silico indicator of unequal protein production. Variable ribosome density profiles of polycistronic transcripts correlate strongly with differential translation patterns. In addition, we provide experimental evidence that de novo initiation of translation can occur at intercistronic sites, allowing for differential translation of any gene irrespective of its position on a polycistronic messenger. Thus, modulation of translation efficiency appears to be a universal mode of control in bacteria and archaea that allows for differential production of operon-encoded proteins. C1 [Quax, Tessa E. F.; Koehorst, Jasper J.; van der Oost, Richard; Blombach, Fabian; Brouns, Stan J. J.; van der Oost, John] Wageningen Univ, Microbiol Lab, NL-6703 HB Wageningen, Netherlands. [Wolf, Yuri I.; Ran, Wenqi; Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Wurtzel, Omri; Sorek, Rotem] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Forster, Anthony C.; Wagner, E. Gerhart H.] Uppsala Univ, Dept Cell & Mol Biol, S-75124 Uppsala, Sweden. RP Quax, TEF (reprint author), Wageningen Univ, Microbiol Lab, Dreijenpl 10, NL-6703 HB Wageningen, Netherlands. EM tessa.quax@wur.nl; john.vanderoost@wur.nl OI Koehorst, Jasper Jan/0000-0001-8172-8981; Blombach, Fabian/0000-0001-5337-8662 FU Netherlands Organization for Scientific Research (NWO) via an ALW TOP grant [854.10.003]; ALW Vidi grant [864.11.005]; Ministere de l'Enseignement Superieur et de la Recherche de France; U.S. Department of Health and Human Services intramural program (National Library of Medicine, NIH); Azrieli PhD fellowship; ERC-StG grant [260432]; Israeli Science Foundation [ISF-1303/12]; Swedish Research Council; Uppsala RNA Research Centre FX We thank Jonathan Weissman and Gene-Wei Li (UCSF) for providing ribosome profiling data and stimulating discussions. This project was funded by the Netherlands Organization for Scientific Research (NWO) via an ALW TOP grant (854.10.003) to J.v.d.O. and an ALW Vidi grant (864.11.005) to S.J.J.B. T. E. F. Q. was supported by a fellowship from the Ministere de l'Enseignement Superieur et de la Recherche de France. Y.I.W., W. R., K. S. M., and E. V. K. were supported by the U.S. Department of Health and Human Services intramural program (National Library of Medicine, NIH). O.W. was supported by an Azrieli PhD fellowship, and R. S. was supported by an ERC-StG grant (260432) and the Israeli Science Foundation (grant ISF-1303/12). A. C. F. and E. G. H. W. were supported by grants from the Swedish Research Council, including the Uppsala RNA Research Centre. NR 45 TC 21 Z9 21 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD SEP PY 2013 VL 4 IS 5 BP 938 EP 944 DI 10.1016/j.celrep.2013.07.049 PG 7 WC Cell Biology SC Cell Biology GA 216LZ UT WOS:000324286300011 PM 24012761 ER PT J AU Chandramohan, V Bao, XH Keir, ST Pegram, CN Szafranski, SE Piao, H Wikstrand, CJ McLendon, RE Kuan, CT Pastan, IH Bigner, DD AF Chandramohan, Vidyalakshmi Bao, Xuhui Keir, Stephen T. Pegram, Charles N. Szafranski, Scott E. Piao, Hailan Wikstrand, Carol J. McLendon, Roger E. Kuan, Chien-Tsun Pastan, Ira H. Bigner, Darell D. TI Construction of an Immunotoxin, D2C7-(scdsFv)-PE38KDEL, Targeting EGFRwt and EGFRvIII for Brain Tumor Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-RECEPTOR; PHASE-II TRIAL; HUMAN GLIOBLASTOMA-MULTIFORME; INTEGRATED GENOMIC ANALYSIS; SINGLE-CHAIN IMMUNOTOXIN; MALIGNANT GLIOMA; MONOCLONAL-ANTIBODIES; XENOGRAFTS; EXPRESSION; CELLS AB Purpose: The EGF receptor gene (EGFR) is most frequently amplified and overexpressed, along with its deletion mutant, EGFRvIII, in glioblastoma. We tested the preclinical efficacy of the recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, which is reactive with a 55-amino acid (AA) region present in the extracellular domain of both EGFRwt (583-637 AAs) and EGFRvIII (292-346 AAs) proteins. Experimental Design: The binding affinity and specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII were measured by surface-plasmon resonance and flow cytometry. In vitro cytotoxicity of D2C7-(scdsFv)-PE38KDEL was measured by inhibition of protein synthesis in human EGFRwt-transfected NR6 (NR6W), human EGFRvIII-transfected NR6 (NR6M), EGFRwt-overexpressing A431-epidermoid-carcinoma, and glioblastoma xenograft cells (43, D08-0493MG, D2159MG, and D270MG). In vivo antitumor efficacy of D2C7-(scdsFv)-PE38KDEL was evaluated using 43, NR6M, and D270MG orthotopic tumor models. Results: The KD of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII was 1.6 x 10(-9) mol/L and 1.3 x 10(-9) mol/L, respectively. Flow cytometry with NR6W and NR6M cells confirmed the specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII. The D2C7-(scdsFv)-PE38KDEL IC50 was 0.18 to 2.5 ng/mL on cells expressing EGFRwt (NR6W, A431, 43, and D08-0493MG). The D2C7-(scdsFv)-PE38KDEL IC50 was approximately 0.25 ng/mL on EGFRvIII-expressing cells (NR6M) and on EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells (D2159MG and D270MG). Significantly, in intracranial tumor models of 43, NR6M, and D270MG, treatment with D2C7-(scdsFv)-PE38KDEL by convection-enhanced delivery prolonged survival by 310% (P = 0.006), 28% (P = 0.002), and 166% (P = 0.001), respectively. Conclusions: In preclinical studies, the D2C7-(scdsFv)-PE38KDEL immunotoxin exhibited significant potential for treating brain tumors expressing EGFRwt, EGFRvIII, or both. (C)2013 AACR. C1 [Chandramohan, Vidyalakshmi; Bao, Xuhui; Keir, Stephen T.; Pegram, Charles N.; Szafranski, Scott E.; Piao, Hailan; McLendon, Roger E.; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA. [Chandramohan, Vidyalakshmi; Bao, Xuhui; Keir, Stephen T.; Pegram, Charles N.; Szafranski, Scott E.; Piao, Hailan; McLendon, Roger E.; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Pastan, Ira H.] NCI, NIH, Ctr Canc Res, Mol Biol Lab, Bethesda, MD 20892 USA. [Bao, Xuhui] Fudan Univ, Huashan Hosp, Dept Neurol, Shanghai 200433, Peoples R China. [Wikstrand, Carol J.] Saba Univ, Sch Med, Saba, Dutch Caribbean, Netherlands. RP Bigner, DD (reprint author), Duke Univ, Med Ctr, Dept Pathol, Box 3156,177 MSRB 1,Res Dr, Durham, NC 27710 USA. EM darell.bigner@duke.edu FU NIH [P50 NS020023-29, P01 CA154291-01, R37 CA011898-42, P30 CA014236-39]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The study was funded in part by the following NIH grants: P50 NS020023-29 (to D. D. Bigner), P01 CA154291-01 (to D. D. Bigner), R37 CA011898-42 (NCI Merit Award to D. D. Bigner), and P30 CA014236-39 (to M. B. Kastan). This research was supported in part by grants from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to I. H. Pastan). NR 49 TC 19 Z9 20 U1 0 U2 5 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 SEP 1 PY 2013 VL 19 IS 17 BP 4717 EP 4727 DI 10.1158/1078-0432.CCR-12-3891 PG 11 WC Oncology SC Oncology GA 213ZE UT WOS:000324098400020 PM 23857604 ER PT J AU Figg, WD Chau, CH Madan, RA Gulley, JL Gao, R Sissung, TM Spencer, S Beatson, M Aragon-Ching, J Steinberg, SM Dahut, WL AF Figg, William D. Chau, Cindy H. Madan, Ravi A. Gulley, James L. Gao, Rui Sissung, Tristan M. Spencer, Shawn Beatson, Melony Aragon-Ching, Jeanny Steinberg, Seth M. Dahut, William L. TI Phase II Study of Satraplatin and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer: A Pharmacogenetic Assessment of Outcome and Toxicity SO CLINICAL GENITOURINARY CANCER LA English DT Article DE ERCC1; Genotyping; Prostate cancer; Satraplatin; XRCC1 ID CELL LUNG-CANCER; PLATINUM-BASED CHEMOTHERAPY; NUCLEOTIDE EXCISION-REPAIR; ADVANCED COLORECTAL-CANCER; COMPLEMENTATION GROUP-1 POLYMORPHISM; MITOXANTRONE PLUS PREDNISONE; ERCC1 CODON-118 POLYMORPHISM; EPITHELIAL OVARIAN-CANCER; ADVANCED NSCLC PATIENTS; COMBINATION CHEMOTHERAPY AB Genetic polymorphisms in DNA repair enzymes (excision repair cross-complementing group 1 [ERCC1] and x-ray cross-complementing group 1 [XRCC1]) may predict treatment outcome and response to platinum-based treatment. Twenty-four patients were enrolled in this single-arm study to assess the association between ERCC1 and XRCC1 gene variants and treatment outcomes with satraplatin in patients with docetaxel-refractory metastatic castration-resistant prostate cancer. Background: We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. Patients and Methods: Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity. Results: After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P = .18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those carrying GA or AA alleles (2.7 months; 2P = .02). Similarly, those carrying GG alleles did not reach median OS, whereas those carrying GA or AA alleles had a median OS of 9.6 months (2P = .12, adjusted). Multivariable analysis by using Cox proportional hazards modeling demonstrated that only XRCC1 was associated with PFS. Conclusions: To our knowledge, this is the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin. Published by Elsevier Inc. C1 [Figg, William D.; Chau, Cindy H.; Madan, Ravi A.; Gulley, James L.; Gao, Rui; Sissung, Tristan M.; Beatson, Melony; Dahut, William L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Spencer, Shawn] Natl Canc Inst Frederick, Clin Pharmacol Program, SAIC Frederick Inc, Bethesda, MD USA. [Aragon-Ching, Jeanny] George Washington Univ, Med Ctr, Dept Med, Div Hematol & Oncol, Washington, DC 20037 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Mendez, Pedro /J-8955-2016; Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016; OI Mendez, Pedro /0000-0001-6713-7907; Gulley, James/0000-0002-6569-2912; Aragon-Ching, Jeanny/0000-0002-6714-141X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We thank the nursing staff of National Cancer Institute and the fellows of the Medical Oncology Branch at National Cancer Institute for their care of our patients; Eileen Curreri for data management assistance. Most importantly, we appreciate the patients with cancer who enroll in investigational trials to advance the knowledge of this disease. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E (Shawn Spencer). This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. This is a US Government work. There are no restrictions on its use. The views expressed within this article do not necessarily reflect those of the US Government. NR 59 TC 10 Z9 10 U1 0 U2 9 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD SEP PY 2013 VL 11 IS 3 BP 229 EP 237 DI 10.1016/j.clgc.2013.04.007 PG 9 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 215ZX UT WOS:000324251400003 PM 23684781 ER PT J AU Rojan, A Funches, R Regan, MM Gulley, JL Bubley, GJ AF Rojan, Adam Funches, Renee Regan, Meredith M. Gulley, James L. Bubley, Glenn J. TI Dramatic and Prolonged PSA Response After Retreatment With a PSA Vaccine SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Immunologic response; PROSTVAC-VF; Revaccination ID RESISTANT PROSTATE-CANCER; TRIAL; IMMUNOTHERAPY C1 [Rojan, Adam; Bubley, Glenn J.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Funches, Renee] Midatlantic Permanente Med Grp, Dept Hematol Oncol, Washington, DC USA. [Regan, Meredith M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Gulley, James L.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bubley, GJ (reprint author), Beth Israel Deaconess Med Ctr, CLS 449,330 Brookline Ave, Boston, MA 02215 USA. EM gbubley@bidmc.harvard.edu RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 11 TC 2 Z9 2 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD SEP PY 2013 VL 11 IS 3 BP 362 EP 364 DI 10.1016/j.clgc.2013.01.003 PG 3 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 215ZX UT WOS:000324251400024 PM 23791437 ER PT J AU Bagci, U Jaster-Miller, K Olivier, KN Yao, JH Mollura, DJ AF Bagci, Ulas Jaster-Miller, Kirsten Olivier, Kenneth N. Yao, Jianhua Mollura, Daniel J. TI Synergistic combination of clinical and imaging features predicts abnormal imaging patterns of pulmonary infections SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE Infectious diseases; Parainfluenza; Pneumonias; NTM; Biomarker; Texture analysis; Lung CT; Feature extraction; AmRMR ID BOOSTED DECISION TREES; FEATURE-SELECTION; MUTUAL INFORMATION; DATA SETS; DIAGNOSIS; TEXTURE; CANCER; REGRESSION AB We designed and tested a novel hybrid statistical model that accepts radiologic image features and clinical variables, and integrates this information in order to automatically predict abnormalities in chest computed-tomography (CT) scans and identify potentially important infectious disease biomarkers. In 200 patients, 160 with various pulmonary infections and 40 healthy controls, we extracted 34 clinical variables from laboratory tests and 25 textural features from CT images. From the CT scans, pleural effusion (PE), linear opacity (or thickening) (LT), tree-in-bud (TIB), pulmonary nodules, ground glass opacity (GGO), and consolidation abnormality patterns were analyzed and predicted through clinical, textural (imaging), or combined attributes. The presence and severity of each abnormality pattern was validated by visual analysis of the CT scans. The proposed biomarker identification system included two important steps: (i) a coarse identification of an abnormal imaging pattern by adaptively selected features (AmRMR), and (ii) a fine selection of the most important features from the previous step, and assigning them as biomarkers, depending on the prediction accuracy. Selected biomarkers were used to classify normal and abnormal patterns by using a boosted decision tree (BDT) classifier. For all abnormal imaging patterns, an average prediction accuracy of 76.15% was obtained. Experimental results demonstrated that our proposed biomarker identification approach is promising and may advance the data processing in clinical pulmonary infection research and diagnostic techniques. Published by Elsevier Ltd. C1 [Bagci, Ulas; Jaster-Miller, Kirsten; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Yao, Jianhua] NIH, Clin Image Proc Serv, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Bagci, U (reprint author), NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM ulas.bagci@nih.gov OI Bagci, Ulas/0000-0001-7379-6829 FU Center for Infectious Disease Imaging (CIDI); Intramural Program of the National Institutes of Allergy and Infectious Diseases (NIAID); Intramural Research Program of the National Institutes of Biomedical Imaging and Bioengineering (NIBIB) at the National Institutes of Health (NIH) FX We thank Albert Wu and Omer Aras for visual scoring, and T. Palmore for useful information on clinical variables. This research is supported by the Center for Infectious Disease Imaging (CIDI), the Intramural Program of the National Institutes of Allergy and Infectious Diseases (NIAID), and the Intramural Research Program of the National Institutes of Biomedical Imaging and Bioengineering (NIBIB) at the National Institutes of Health (NIH). We thank Brent Foster for useful discussions on the revised paper, and Kristine Evers for editing of this paper. NR 30 TC 2 Z9 2 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD SEP 1 PY 2013 VL 43 IS 9 BP 1241 EP 1251 DI 10.1016/j.compbiomed.2013.06.008 PG 11 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA 214RY UT WOS:000324154700017 PM 23930819 ER PT J AU Alinger, JB Ireland, R Bosio, CM AF Alinger, J. B. Ireland, R. Bosio, C. M. TI Bacterial driven inhibition of IL-12p40 in primary human cells via modulation of IRF1 and IRF8 independent of GPCR signaling and IL-10 SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Alinger, J. B.; Ireland, R.; Bosio, C. M.] NIAID, Immun Pulm Pathogens Sect, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RI Bosio, Catharine/D-7456-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 243 EP 244 DI 10.1016/j.cyto.2013.06.007 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700016 ER PT J AU Bekisz, J Eichberg, D Dolan, M Zhao, TM Zoon, KC AF Bekisz, Joseph Eichberg, Daniel Dolan, Michael Zhao, Tongmao Zoon, Kathryn C. TI Characterization of human interferon-alpha subtypes and mutants SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Bekisz, Joseph; Eichberg, Daniel; Zhao, Tongmao; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. [Dolan, Michael] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 247 EP 247 DI 10.1016/j.cyto.2013.06.021 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700030 ER PT J AU Bergamaschi, C Chen, S Valentin, A Kulkarni, V Bear, J Rosati, M Alicea, C Beach, RK Sowder, R Chertova, E Felber, BK Pavlakis, GN AF Bergamaschi, Cristina Chen, Stephanie Valentin, Antonio Kulkarni, Viraj Bear, Jenifer Rosati, Margherita Alicea, Candido Beach, Rachel Kelly Sowder, Raymond Chertova, Elena Felber, Barbara K. Pavlakis, George N. TI Heterodimeric IL-15 regulates the balance of effector and regulatory cells, favoring anti-tumor responses SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Bergamaschi, Cristina; Valentin, Antonio; Rosati, Margherita; Beach, Rachel Kelly; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, CCR, Frederick, MD 21701 USA. [Chen, Stephanie; Kulkarni, Viraj; Bear, Jenifer; Alicea, Candido; Beach, Rachel Kelly; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, CCR, Frederick, MD 21701 USA. [Sowder, Raymond; Chertova, Elena] SAIC Frederick Inc, Retroviral Prot Chem Core, AIDS & Canc Virus Program, FNLCR, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 247 EP 248 DI 10.1016/j.cyto.2013.06.023 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700032 ER PT J AU Chen, KQ Liu, MY Liu, Y Wang, CY Yoshimura, T Gong, WH Le, YY Tessarollo, L Wang, JM AF Chen, Keqiang Liu, Mingyong Liu, Ying Wang, Chunyan Yoshimura, Teizo Gong, Wanghua Le, Yingying Tessarollo, Lino Wang, Ji Ming TI Signal relay by CCR2 and formylpeptide receptor-2 (Fpr2) in the recruitment of monocyte-derived dendritic cells in allergic airway inflammation SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Chen, Keqiang; Liu, Mingyong; Liu, Ying; Wang, Chunyan; Yoshimura, Teizo; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Gong, Wanghua] SAIC Frederick, Frederick, MD 21702 USA. [Le, Yingying] Chinese Acad Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 253 EP 253 DI 10.1016/j.cyto.2013.06.045 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700054 ER PT J AU Chong, WP Chen, J Silver, PB Horai, R Mattapallil, MJ Zhou, R Caspi, RR AF Chong, Wai Po Chen, Jun Silver, Phyllis B. Horai, Reiko Mattapallil, Mary J. Zhou, Ru Caspi, Rachel R. TI Reciprocal interaction between NK and DC regulates the autopathogenic Th17 response by controlling the innate IFN-gamma/IL-27 axis SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Chong, Wai Po; Chen, Jun; Silver, Phyllis B.; Horai, Reiko; Mattapallil, Mary J.; Zhou, Ru; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 254 EP 254 DI 10.1016/j.cyto.2013.06.049 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700058 ER PT J AU Dai, L Lidie, KB Chen, Q Adelsberger, JW Zheng, X Huang, DW Yang, J Lempicki, RA Rehman, T Dewar, RL Wang, YM Hornung, RL Canizales, KA Lockett, SJ Lane, HC Imamichi, T AF Dai, Lue Lidie, Kristy B. Chen, Qian Adelsberger, Joseph W. Zheng, Xin Huang, DaWei Yang, Jun Lempicki, Richard A. Rehman, Tauseef Dewar, Robin L. Wang, Yanmei Hornung, Ronald L. Canizales, Kelsey A. Lockett, Stephen J. Lane, H. Clifford Imamichi, Tomozumi TI IL-27 inhibits HIV-1 infection in human macrophages by down-regulating host factor SPTBN1 during monocyte to macrophage differentiation SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Dai, Lue; Lidie, Kristy B.; Chen, Qian; Adelsberger, Joseph W.; Zheng, Xin; Huang, DaWei; Yang, Jun; Lempicki, Richard A.; Rehman, Tauseef; Dewar, Robin L.; Wang, Yanmei; Hornung, Ronald L.; Canizales, Kelsey A.; Imamichi, Tomozumi] Sci Applicat Int Corp Frederick Inc, Appl & Dev Directorate, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Lockett, Stephen J.] Sci Applicat Int Corp Frederick Inc, Adv Technol Program Directorate, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X NR 0 TC 0 Z9 0 U1 0 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 257 EP 257 DI 10.1016/j.cyto.2013.06.061 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700070 ER PT J AU Datta, S AF Datta, Sandip TI IL-20 receptor signaling inhibits cutaneous IL-1 beta and IL-17A production to promote methicillin-resistant staphylococcus aureus infection SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Datta, Sandip] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 257 EP 257 DI 10.1016/j.cyto.2013.06.064 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700073 ER PT J AU Du, N Kwon, HJ Li, P Oh, J Liao, W Leonard, WJ AF Du, Ning Kwon, Hyok-Joon Li, Peng Oh, Jangsuk Liao, Wei Leonard, Warren J. TI EGR2 is critical for peripheral Naive T cell differentiation and the T-cell mediated response to influenza SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 260 EP 260 DI 10.1016/j.cyto.2013.06.075 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700084 ER PT J AU Durum, SK Li, WQ Zenatti, P Ribeiro, D Zuurbier, L Silva, MC Paganin, M Tritapoe, J Hixon, JA Silveira, AB Cardoso, BA Sarmento, LM Correia, N Toribio, ML Kobarg, J Horstmann, M Pieters, R Brandalise, SR Ferrando, AA Meijerink, JP Yunes, JA Barata, JT AF Durum, Scott K. Li, W. Q. Zenatti, P. Ribeiro, D. Zuurbier, L. Silva, M. C. Paganin, M. Tritapoe, J. Hixon, J. A. Silveira, A. B. Cardoso, B. A. Sarmento, L. M. Correia, N. Toribio, M. L. Kobarg, J. Horstmann, M. Pieters, R. Brandalise, S. R. Ferrando, A. A. Meijerink, J. P. Yunes, J. A. Barata, J. T. TI IL-7R: Mutations in T-ALL and polymorphisms in autoimmunity SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Durum, Scott K.; Li, W. Q.; Tritapoe, J.; Hixon, J. A.] NCI, Bethesda, MD 20892 USA. [Ribeiro, D.; Silva, M. C.; Cardoso, B. A.; Sarmento, L. M.; Correia, N.; Barata, J. T.] Univ Lisbon, P-1699 Lisbon, Portugal. [Paganin, M.; Ferrando, A. A.] Columbia Univ, New York, NY 10027 USA. [Toribio, M. L.] Univ Autonoma Madrid, E-28049 Madrid, Spain. [Horstmann, M.] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Brandalise, S. R.; Yunes, J. A.] Univ Estadual Campinas, BR-13081970 Campinas, SP, Brazil. NR 0 TC 0 Z9 0 U1 1 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 260 EP 261 DI 10.1016/j.cyto.2013.06.077 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700086 ER PT J AU Green, DS Bekisz, J Dolan, M Zoon, KC AF Green, Daniel S. Bekisz, Joseph Dolan, Michael Zoon, Kathryn C. TI Characterization of the interferon alpha inducible protein LY6E SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Green, Daniel S.; Bekisz, Joseph; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. [Dolan, Michael] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 267 EP 267 DI 10.1016/j.cyto.2013.06.104 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700113 ER PT J AU Griffin, AJ Crane, DD Wehrly, TD Bosio, CM AF Griffin, Amanda J. Crane, Debbie D. Wehrly, Tara D. Bosio, Catharine M. TI Virulent Francisella tularensis do not induce arginase as a mechanism of virulence SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Griffin, Amanda J.; Crane, Debbie D.; Wehrly, Tara D.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RI Bosio, Catharine/D-7456-2015 NR 0 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 267 EP 267 DI 10.1016/j.cyto.2013.06.106 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700115 ER PT J AU Ha, HL Wang, HS Pisitkun, P Kim, JC Morasso, M Udey, M Siebenlist, U AF Ha, Hve-Lin Wang, Hongshan Pisitkun, Prapaporn Kim, Jin-Chul Morasso, Maria Udey, Mark Siebenlist, Ulrich TI Critical cell-type specific functions of the Il-17 receptor signaling adaptor CIKS/ACT1 in imiquimod-induced psoriasis SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Ha, Hve-Lin; Wang, Hongshan; Pisitkun, Prapaporn; Siebenlist, Ulrich] NIAID, Immune Activat Sect, Lab Mol Immunol, Bethesda, MD 20892 USA. [Udey, Mark] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 268 EP 269 DI 10.1016/j.cyto.2013.06.112 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700121 ER PT J AU Hanson, ML Hixon, JA Li, WQ Felber, BK Anver, MR Stewart, CA Shen, W McLean, M Rottiers, P Steidler, L Durum, SK AF Hanson, Miranda L. Hixon, Julie A. Li, Wenqing Felber, Barbara K. Anver, Miriam R. Stewart, Charles A. Shen, Wei McLean, Mairi Rottiers, Pieter Steidler, Lothar Durum, Scott K. TI Lactococcus lactis expressing IL-27: A potential therapeutic for inflammatory bowel disease SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Hanson, Miranda L.; Hixon, Julie A.; Li, Wenqing; Stewart, Charles A.; Shen, Wei; McLean, Mairi; Durum, Scott K.] NCI, Canc Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Anver, Miriam R.] NCI, Lab Anim Serv Program, Sci Applicat Int Corp, Ctr Canc Res, Frederick, MD 21701 USA. [Rottiers, Pieter; Steidler, Lothar] ActoGenix NV, Zwijnaarde, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 269 EP 269 DI 10.1016/j.cyto.2013.06.115 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700124 ER PT J AU Harper, MS Barrett, BS Smith, DS Heilman, KJ Li, SX Dittmer, U Hasenkrug, KJ Santiago, ML AF Harper, Michael S. Barrett, Bradley S. Smith, Diana S. Heilman, Karl J. Li, Sam X. Dittmer, Ulf Hasenkrug, Kim J. Santiago, Mario L. TI Interferon-alpha therapy enhances the anti-friend virus B cell response through Apobec3 SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Harper, Michael S.; Barrett, Bradley S.; Smith, Diana S.; Heilman, Karl J.; Li, Sam X.; Santiago, Mario L.] Univ Colorado Denver, Div Infect Dis, Aurora, CO USA. [Dittmer, Ulf] Univ Duisburg Essen, Duisburg, Germany. [Hasenkrug, Kim J.] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 270 EP 270 DI 10.1016/j.cyto.2013.06.117 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700126 ER PT J AU Hodge, DL Berthet, C Coppola, V Shirota, H Reynolds, D Sanford, M Lin, FC Klinman, DM Young, HA AF Hodge, Deborah L. Berthet, Cyril Coppola, Vincenzo Shirota, Hidekazu Reynolds, Della Sanford, Michael Lin, Fanching Klinman, Dennis M. Young, Howard A. TI Loss of IFN-gamma 3 ' untranslated region AU-rich element affects B220+cell populations in novel murine lupus model SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Hodge, Deborah L.; Shirota, Hidekazu; Reynolds, Della; Sanford, Michael; Lin, Fanching; Klinman, Dennis M.; Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Berthet, Cyril] Oncodesign, Dijon, France. [Coppola, Vincenzo] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RI Coppola, Vincenzo/E-2917-2011 OI Coppola, Vincenzo/0000-0001-6163-1779 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 271 EP 271 DI 10.1016/j.cyto.2013.06.123 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700132 ER PT J AU Jin, TC Jiang, JS Smith, P Xiao, TS AF Jin, Tengchuan Jiang, Jiansheng Smith, Patrick Xiao, Tsan Sam TI Sensing of DNA by innate immune receptors SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Jin, Tengchuan; Jiang, Jiansheng; Smith, Patrick; Xiao, Tsan Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RI Xiao, Tsan/I-7616-2013; Xiao, Tsan/A-8590-2010 OI Xiao, Tsan/0000-0001-9688-475X; NR 0 TC 0 Z9 0 U1 0 U2 14 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 274 EP 274 DI 10.1016/j.cyto.2013.06.135 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700144 ER PT J AU Johnson, CL Green, DS Bekisz, J Zoon, KC AF Johnson, Chase L. Green, Daniel S. Bekisz, Joseph Zoon, Kathryn C. TI In vitro eradication of serous ovarian cancer with IFN-alpha 2 alpha and IFN-gamma in combination with monocytes SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Johnson, Chase L.; Green, Daniel S.; Bekisz, Joseph; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 274 EP 274 DI 10.1016/j.cyto.2013.06.136 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700145 ER PT J AU Kurotaki, D Osato, N Nishiyama, A Yamamoto, M Ban, T Sato, H Nakabayashi, J Umehara, M Nakazawa, M Miyake, N Matsumoto, N Ozato, K Tamura, T AF Kurotaki, Daisuke Osato, Naoki Nishiyama, Akira Yamamoto, Michio Ban, Tatsuma Sato, Hideaki Nakabayashi, Jun Umehara, Marina Nakazawa, Masatoshi Miyake, Noriko Matsumoto, Naomichi Ozato, Keiko Tamura, Tomohiko TI The IRF8-KLF4 transcription factor cascade is essential for the development of monocytes SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Kurotaki, Daisuke; Osato, Naoki; Nishiyama, Akira; Yamamoto, Michio; Ban, Tatsuma; Sato, Hideaki; Nakabayashi, Jun; Umehara, Marina; Tamura, Tomohiko] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa 232, Japan. [Nakazawa, Masatoshi] Yokohama City Univ, Grad Sch Med, Dept Expt Anim Sci, Yokohama, Kanagawa 232, Japan. [Miyake, Noriko; Matsumoto, Naomichi] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Kanagawa 232, Japan. [Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 279 EP 279 DI 10.1016/j.cyto.2013.06.157 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700166 ER PT J AU Le Saout, C Hasley, RB Imamichi, H Tcheung, L Luckey, M Park, H Hu, ZH Sneller, M Lane, HC Catalfamo, M AF Le Saout, Cecile Hasley, Rebecca B. Imamichi, Hiromi Tcheung, Lueng Luckey, Megan Park, Hyun Hu, Zonghui Sneller, Michael Lane, H. Clifford Catalfamo, Marta TI Lymphopenia modulates levels of signal transducer and activator of transcription-1 expression leading to enhanced CD4 T cell responsiveness to type-I IFN SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Le Saout, Cecile; Hasley, Rebecca B.; Imamichi, Hiromi; Tcheung, Lueng; Sneller, Michael; Lane, H. Clifford; Catalfamo, Marta] NIAID, CMRS Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Luckey, Megan; Park, Hyun] NCI, Expt Immunol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Hu, Zonghui] NIAID, Biostat Res Branch, DCR, NIH, Bethesda, MD 20892 USA. RI Davis, Megan/F-5339-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 280 EP 280 DI 10.1016/j.cyto.2013.06.161 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700170 ER PT J AU Lin, B Fraser, IDC AF Lin, Bin Fraser, Iain D. C. TI Investigating the mechanism of TLR signaling crosstalk in mouse macrophages SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Lin, Bin; Fraser, Iain D. C.] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 282 EP 282 DI 10.1016/j.cyto.2013.06.170 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700179 ER PT J AU Lin, FC Saleh, B Hodge, DL Boelte, K Chan, T Keller, JP Young, HA AF Lin, Fanching Saleh, Bahara Hodge, Deborah L. Boelte, Kimberly Chan, Tim Keller, Jonathon P. Young, Howard A. TI IFN-gamma causes aplastic anemia by altering HSC composition and interrupting lineage differentiation SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Lin, Fanching; Saleh, Bahara; Hodge, Deborah L.; Boelte, Kimberly; Chan, Tim; Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA. [Keller, Jonathon P.] NCI, Hematopoiesis & Stem Cell Biol Sect, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 282 EP 282 DI 10.1016/j.cyto.2013.06.171 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700180 ER PT J AU Meylan, F Hawley, E Barron, L Barlow, J Tan, CY Penumetcha, P Richard, A Chen, X Paul, WE Wynn, TA Gery, I McKenzie, A Siegel, RM AF Meylan, Francoise Hawley, Eric Barron, Luke Barlow, Jillian Tan, Cuyian Penumetcha, Pallavi Richard, Arianne Chen, Xi Paul, William E. Wynn, Thomas A. Gery, Igal McKenzie, Andrew Siegel, Richard M. TI The TNF family member TL1A: A key player in type 2 immunity in both adaptive and innate lymphocytes SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Barron, Luke; Barlow, Jillian; Chen, Xi; Paul, William E.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, LPD, Bethesda, MD 20892 USA. [Barlow, Jillian; Tan, Cuyian; Chen, Xi; Paul, William E.; Gery, Igal] NEI, Expt Immunol Sect, NIH, Bethesda, MD 20892 USA. [Barlow, Jillian; Chen, Xi; Paul, William E.; McKenzie, Andrew] Univ Cambridge, Mol Biol Lab, Cambridge, England. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 285 EP 285 DI 10.1016/j.cyto.2013.06.183 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700192 ER PT J AU Morrow, AN Zoon, KC AF Morrow, A. N. Zoon, K. C. TI Ribavirin enhances and prolongs IFN signaling and ISG expression in virally-infected human lung epithelial cells SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Morrow, A. N.; Zoon, K. C.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 285 EP 285 DI 10.1016/j.cyto.2013.06.184 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700193 ER PT J AU Muchmore, B Tang, W Porter-Gill, P Kohaar, I Liu, LY Brand, N Park, H Dickensheets, H Sheikh, F Rehermann, B Donnelly, RP O'Brien, TR Prokunina-Olsson, L AF Muchmore, Brian Tang, Wei Porter-Gill, Patricia Kohaar, Indu Liu, Luyang Brand, Nathan Park, Heiyoung Dickensheets, Harold Sheikh, Faruk Rehermann, Barbara Donnelly, Raymond P. O'Brien, Thomas R. Prokunina-Olsson, Ludmila TI Identification and characterization of interferon-lambda 4 (IFN-lambda 4), a novel class-2 cytokine which impairs clearance of hepatitis C virus SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Muchmore, Brian; Tang, Wei; Porter-Gill, Patricia; Kohaar, Indu; Liu, Luyang; Brand, Nathan; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Park, Heiyoung; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, Bethesda, MD USA. [Dickensheets, Harold; Sheikh, Faruk; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 286 EP 286 DI 10.1016/j.cyto.2013.06.185 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700194 ER PT J AU Olejnik, J Marzi, A Feldmann, H Muhlberger, E AF Olejnik, Judith Marzi, Andrea Feldmann, Heinz Muehlberger, Elke TI Differences in cytokine responses during infection with high and low pathogenic Ebola viruses SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Olejnik, Judith; Muehlberger, Elke] Boston Univ, Dept Microbiol, Boston, MA 02215 USA. [Olejnik, Judith; Muehlberger, Elke] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 1 U2 16 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 287 EP 288 DI 10.1016/j.cyto.2013.06.192 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700201 ER PT J AU Ozato, K Yoshimi, R Yoshida, Y Gupta, M Yoshii, H Munasinghe, J Maximova, O Xiong, HB Wang, HS Morse, HC AF Ozato, Keiko Yoshimi, Ryusuke Yoshida, Yuko Gupta, Monica Yoshii, Hiroaki Munasinghe, Jeeva Maximova, Olga Xiong, Huabao Wang, Hongsheng Morse, Herbert C. TI IRF8 regulates autophagy and activates microglia to exacerbate neuroinflammation SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Ozato, Keiko; Yoshimi, Ryusuke; Yoshida, Yuko; Gupta, Monica; Yoshii, Hiroaki] NICHD, Program Genom Differentiat, NIH, Bethesda, MD USA. [Munasinghe, Jeeva] NINDS, Lab Mol Imaging, NIH, Bethesda, MD 20892 USA. [Maximova, Olga] NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Xiong, Huabao] Mt Sinai Sch Med, Inst Immunol, New York, NY USA. [Wang, Hongsheng; Morse, Herbert C.] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 288 EP 289 DI 10.1016/j.cyto.2013.06.197 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700206 ER PT J AU Rasmussen, AL Falzarano, D de Wit, E Feldmann, F Okumura, A Scott, DP Brining, D Bushmaker, T Martellaro, C Benecke, AG Munster, VJ Feldmann, H Katze, MG AF Rasmussen, Angela L. Falzarano, Darryl de Wit, Emmie Feldmann, Friederike Okumura, Atsushi Scott, Dana P. Brining, Douglas Bushmaker, Trent Martellaro, Cynthia Benecke, Arndt G. Munster, Vincent J. Feldmann, Heinz Katze, Michael G. TI Transcriptional signatures of pathogenesis and successful type I interferon and ribavirin therapy in a rhesus macaque model of MERS-CoV infection SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Rasmussen, Angela L.; Okumura, Atsushi; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Falzarano, Darryl; de Wit, Emmie; Martellaro, Cynthia; Feldmann, Heinz] Dis Modeling & Transmiss, Hamilton, MT USA. [Feldmann, Friederike] NIAID, Off Operat Management, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Scott, Dana P.; Brining, Douglas] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Bushmaker, Trent; Munster, Vincent J.] NIAID, Virus Ecol Units, Virol Lab, Div Intramural Res,NIH,Rocky Mt Labs, Hamilton, MT USA. [Benecke, Arndt G.] Univ Paris 06, Ctr Natl Rech Sci, UMR7224, Paris, France. RI Okumura, Atsushi/E-8012-2015 OI Okumura, Atsushi/0000-0002-7779-3059 NR 0 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 291 EP 292 DI 10.1016/j.cyto.2013.06.209 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700218 ER PT J AU Ren, M Li, P Zheng, M Peltz, G Leonard, WJ AF Ren, Min Li, Peng Zheng, Ming Peltz, Gary Leonard, Warren J. TI Towards the identification novel regulators for Th1 differentiation by computational genetics SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Ren, Min; Li, Peng; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Zheng, Ming; Peltz, Gary] Stanford Univ, Dept Anesthesia, Sch Med, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 292 EP 292 DI 10.1016/j.cyto.2013.06.212 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700221 ER PT J AU Roychoudhuri, R Hirahara, K Mousavi, K Clever, D Bonelli, M Sciume, G Zare, H Vahedi, G Klebanoff, C Sartorelli, V Kanno, Y Gattinoni, L Nakamura, A Muto, A O'Shea, J Restifo, N AF Roychoudhuri, R. Hirahara, K. Mousavi, K. Clever, D. Bonelli, M. Sciume, G. Zare, H. Vahedi, G. Klebanoff, C. Sartorelli, V. Kanno, Y. Gattinoni, L. Nakamura, A. Muto, A. O'Shea, J. Restifo, N. TI BACH2 represses effector differentiation and cytokine expression to stabilize T-reg-mediated immune homeostasis SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Roychoudhuri, R.; Clever, D.; Klebanoff, C.; Gattinoni, L.; Restifo, N.] NCI, NIH, Bethesda, MD 20892 USA. [Hirahara, K.; Mousavi, K.; Bonelli, M.; Sciume, G.; Zare, H.; Vahedi, G.; Sartorelli, V.; Kanno, Y.; O'Shea, J.] NIAMSD, Bethesda, MD 20892 USA. [Nakamura, A.; Muto, A.] Tohoku Univ, Sendai, Miyagi 980, Japan. RI Hirahara, Kiyoshi/E-2460-2017 OI Hirahara, Kiyoshi/0000-0002-9128-9449 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 294 EP 294 DI 10.1016/j.cyto.2013.06.220 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700229 ER PT J AU Salerno, F Engels, S Zhao, WQ Hodge, D Young, HA Medema, JP Wolkers, MC AF Salerno, Fiamma Engels, Sander Zhao, Wanqi Hodge, Deborah Young, Howard A. Medema, Jan Paul Wolkers, Monika C. TI Post-transcriptional regulation of interferon gamma in memory CD8(+) T cells SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Salerno, Fiamma; Engels, Sander; Zhao, Wanqi; Wolkers, Monika C.] Sanquin Res, Dept Hematopoiesis, Amsterdam, Netherlands. [Hodge, Deborah; Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA. [Medema, Jan Paul] Univ Amsterdam, Acad Med Ctr, Ctr Expt Mol Med, Lab Expt Oncol & Radiobiol LEXOR, NL-1105 AZ Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 295 EP 295 DI 10.1016/j.cyto.2013.06.224 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700233 ER PT J AU Sandler, NG Zhu, RT Estes, JD Boritz, E Rao, S Lifson, JD Levin, D Schreiber, G Langer, JA Douek, DC AF Sandler, Netanya G. Zhu, Richard T. Estes, Jacob D. Boritz, Eli Rao, Srinivas Lifson, Jeffrey D. Levin, Doron Schreiber, Gideon Langer, Jerome A. Douek, Daniel C. TI A novel type I interferon antagonist has in vivo efficacy in a model of SIV infection in rhesus macaques SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Sandler, Netanya G.; Zhu, Richard T.; Boritz, Eli; Rao, Srinivas; Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Estes, Jacob D.; Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Levin, Doron; Schreiber, Gideon] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Langer, Jerome A.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 296 EP 296 DI 10.1016/j.cyto.2013.06.226 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700235 ER PT J AU Sasaki, H Kurotak, D Sato, H Morse, HC Ozato, K Tamura, T AF Sasaki, Haruka Kurotak, Daisuke Sato, Hideaki Morse, Herbert C. Ozato, Keiko Tamura, Tomohiko TI The transcription factor IRF8 is required for the development of basophils SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Sasaki, Haruka; Kurotak, Daisuke; Sato, Hideaki; Tamura, Tomohiko] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa 232, Japan. [Morse, Herbert C.] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Ozato, Keiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 296 EP 296 DI 10.1016/j.cyto.2013.06.229 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700238 ER PT J AU Schmeisser, H Fey, SB Horowitz, J Fischer, ER Balinsky, CA Miyake, K Bekisz, J Snow, AL Zoon, KC AF Schmeisser, Hana Fey, Samuel B. Horowitz, Julie Fischer, Elizabeth R. Balinsky, Corey A. Miyake, Kotaro Bekisz, Joseph Snow, Andrew L. Zoon, Kathryn C. TI MTOR-signaling pathway plays a role in induction of autophagy by type I interferons SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Schmeisser, Hana; Fey, Samuel B.; Horowitz, Julie; Balinsky, Corey A.; Miyake, Kotaro; Bekisz, Joseph; Zoon, Kathryn C.] NIAID, NIH, Cytokine Biol Sect, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.] NIAID, NIH, Rocky Mt Labs, Res Technol Sect, Hamilton, MT USA. [Snow, Andrew L.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 297 EP 297 DI 10.1016/j.cyto.2013.06.231 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700240 ER PT J AU Silverman, RH Zhang, R Jha, BK Ogden, KM Dong, BH Elliott, R Zhao, L Patton, JT Weiss, SR AF Silverman, Robert H. Zhang, Rong Jha, Babal K. Ogden, Kristen M. Dong, Beihua Elliott, Ruth Zhao, Ling Patton, John T. Weiss, Susan R. TI Homologous 2 ',5 '-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Silverman, Robert H.; Jha, Babal K.; Dong, Beihua] Cleveland Clin, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44106 USA. [Zhang, Rong; Elliott, Ruth; Zhao, Ling; Weiss, Susan R.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ogden, Kristen M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 300 EP 301 DI 10.1016/j.cyto.2013.06.247 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700256 ER PT J AU Wan, ECK Oh, J Li, P West, EE Wong, EA Andraski, AB Spolski, R Yu, ZX He, JP Kelsall, BL Leonard, WJ AF Wan, Edwin Chi-Keung Oh, Jangsuk Li, Peng West, Erin E. Wong, Elizabeth A. Andraski, Allison B. Spolski, Rosanne Yu, Zu-Xi He, Jianping Kelsall, Brian L. Leonard, Warren J. TI The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Wan, Edwin Chi-Keung; Oh, Jangsuk; Li, Peng; West, Erin E.; Wong, Elizabeth A.; Andraski, Allison B.; Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bethesda, MD 20892 USA. [He, Jianping; Kelsall, Brian L.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 307 EP 307 DI 10.1016/j.cyto.2013.06.273 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700282 ER PT J AU Wang, HY Ma, CA Zhao, YG Fan, XY Zhou, Q Edmonds, P Uzel, G Oliveria, JB Orange, J Jain, A AF Wang, Hong-Ying Ma, Chi A. Zhao, Yongge Fan, Xiying Zhou, Qing Edmonds, Pamela Uzel, Gulbu Oliveria, Joao Bosco Orange, Jordan Jain, Ashish TI Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Wang, Hong-Ying; Ma, Chi A.; Zhao, Yongge; Fan, Xiying; Edmonds, Pamela; Jain, Ashish] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Uzel, Gulbu] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Oliveria, Joao Bosco] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Orange, Jordan] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 308 EP 308 DI 10.1016/j.cyto.2013.06.276 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700285 ER PT J AU Whibley, N Mamo, AJ Traggiai, E Kolbinger, F Vogel, B Kammuller, M Siebenlist, U Gaffen, SL AF Whibley, Natasha Mamo, Anna J. Traggiai, Elisabetta Kolbinger, Frank Vogel, Beate Kammueller, Michael Siebenlist, Ulrich Gaffen, Sarah L. TI Experimental analysis of acute murine oral candidiasis after in vivo Anti-IL-17A/IL-17F treatment and in knockout mice SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Whibley, Natasha; Mamo, Anna J.; Gaffen, Sarah L.] Univ Pittsburgh, Div Rheumatol & Clin Immunol, Pittsburgh, PA 15260 USA. [Traggiai, Elisabetta; Kolbinger, Frank; Vogel, Beate; Kammueller, Michael] Novartis Inst Biomed Res, Basel, Switzerland. [Siebenlist, Ulrich] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 309 EP 309 DI 10.1016/j.cyto.2013.06.282 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700291 ER PT J AU Zaritsky, LA Zoon, KC AF Zaritsky, Luna A. Zoon, Kathryn C. TI The differential regulation of the interferon alpha subtypes in response to viral infection SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Zaritsky, Luna A.; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 313 EP 313 DI 10.1016/j.cyto.2013.06.298 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700307 ER PT J AU Blumberg, S Lloyd-Smith, JO AF Blumberg, S. Lloyd-Smith, J. O. TI Comparing methods for estimating R-0 from the size distribution of subcritical transmission chains SO EPIDEMICS LA English DT Article DE Stuttering chain; Basic reproductive number; Transmission heterogeneity; Imperfect observation; Measles ID INFECTIOUS-DISEASES; BRANCHING-PROCESSES; MEASLES ELIMINATION; UNITED-STATES; SURVEILLANCE; VACCINATION; EMERGENCE; OUTBREAKS; POLIOMYELITIS; IMMUNIZATION AB Many diseases exhibit subcritical transmission (i.e. 0 < R-0 < 1) so that infections occur as self-limited 'stuttering chains'. Given an ensemble of stuttering chains, information about the number of cases in each chain can be used to infer R-0, which is of crucial importance for monitoring the risk that a disease will emerge to establish endemic circulation. However, the challenge of imperfect case detection has led authors to adopt a variety of work-around measures when inferring R-0, such as discarding data on isolated cases or aggregating intermediate-sized chains together. Each of these methods has the potential to introduce bias, but a quantitative comparison of these approaches has not been reported. By adapting a model based on a negative binomial offspring distribution that permits a variable degree of transmission heterogeneity, we present a unified analysis of existing R-0 estimation methods. Simulation studies show that the degree of transmission heterogeneity, when improperly modeled, can significantly impact the bias of R-0 estimation methods designed for imperfect observation. These studies also highlight the importance of isolated cases in assessing whether an estimation technique is consistent with observed data. Analysis of data from measles outbreaks shows that likelihood scores are highest for models that allow a flexible degree of transmission heterogeneity. Aggregating intermediate sized chains often has similar performance to analyzing a complete chain size distribution. However, truncating isolated cases is beneficial only when surveillance systems clearly favor full observation of large chains but not small chains. Meanwhile, if data on the type and proportion of cases that are unobserved were known, we demonstrate that maximum likelihood inference of R-0 could be adjusted accordingly. This motivates the need for future empirical and theoretical work to quantify observation error and incorporate relevant mechanisms into stuttering chain models used to estimate transmission parameters. (C) 2013 Elsevier B.V. All rights reserved. C1 [Blumberg, S.; Lloyd-Smith, J. O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Blumberg, S.; Lloyd-Smith, J. O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Blumberg, S.] Univ Calif San Francisco, Francis I Proctor Fdn, San Francisco, CA 94143 USA. RP Blumberg, S (reprint author), Univ Calif San Francisco, Francis I Proctor Fdn, 95 Kirkham St, San Francisco, CA 94143 USA. EM blumberg.seth@gmail.com; jlloydsmith@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Science Foundation [EF-0928690, PHY05-51164]; National Institute of Health MIDAS program (Modeling Infectious Disease Agent Study) [NIH NIGMS 1-U01-GM087728]; De Logi Chair in Biological Sciences FX Feedback provided by anonymous reviewers lead to substantial improvements of this manuscript. Financial support was provided by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, National Institutes of Health, and by the National Science Foundation under grants EF-0928690 and PHY05-51164. SB is also grateful to the National Institute of Health MIDAS program (Modeling Infectious Disease Agent Study, grant number NIH NIGMS 1-U01-GM087728). JLS is also grateful for the support of the De Logi Chair in Biological Sciences. NR 33 TC 11 Z9 11 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD SEP PY 2013 VL 5 IS 3 BP 131 EP 145 DI 10.1016/j.epidem.2013.05.002 PG 15 WC Infectious Diseases SC Infectious Diseases GA 213ZX UT WOS:000324100600002 PM 24021520 ER PT J AU Silbergleit, R Lowenstein, D Durkalski, V Conwit, R AF Silbergleit, Robert Lowenstein, Daniel Durkalski, Valerie Conwit, Robin CA NETT Investigators TI Lessons from the RAMPART study-and which is the best route of administration of benzodiazepines in status epilepticus SO EPILEPSIA LA English DT Article DE Midazolam; Lorazepam; Comparative efficacy; Emergency medical services; Intramuscular ID DIAZEPAM; MIDAZOLAM; TRIALS AB Early treatment of prolonged seizures with benzodiazepines given intravenously by paramedics in the prehospital setting had been shown to be associated with improved outcomes, but the comparative efficacy and safety of an intramuscular (IM) route, which is faster and consistently achievable, was previously unknown. RAMPART (the Rapid Anticonvulsant Medication Prior to Arrival Trial) was a double-blind randomized clinical trial to determine if the efficacy of intramuscular (IM) midazolam is noninferior by a margin of 10% to that of intravenous (IV) lorazepam in patients treated by paramedics for status epilepticus (SE). In children and adults with >5min of convulsions and who are still seizing at paramedic arrival, midazolam administered by IM autoinjector was noninferior to IV lorazepam on the primary efficacy outcome with comparable safety. Patients treated with IM midazolam were more likely to have stopped seizing at emergency department (ED) arrival, without emergency medical services (EMS) rescue therapy, and were less likely to require any hospitalization or admission to an intensive care unit. Lessons from the RAMPART study's findings and potential implications on clinical practice, on the potential role of other routes of administration, on the effect of timing of interventions, and on future clinical trials are discussed. C1 [Silbergleit, Robert] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48105 USA. [Lowenstein, Daniel] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Durkalski, Valerie] Med Univ S Carolina, Dept Publ Hlth Sci, Coll Med, Charleston, SC 29425 USA. [Conwit, Robin] NINDS, NIH, Bethesda, MD 20892 USA. RP Silbergleit, R (reprint author), Univ Michigan, Dept Emergency Med, 24 Frank Lloyd wright Dr, Ann Arbor, MI 48105 USA. EM Robert.silbergleit@umich.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [5U01NS056975-04]; Office of the Director, National Institutes of Health (OD); BARDA; NIH CounterACT program FX This work is supported by award 5U01NS056975-04 from the National Institute of Neurological Disorders and Stroke (NINDS), the Office of the Director, National Institutes of Health (OD), BARDA, and the NIH CounterACT program. This trial is registered with Clinical Trials.gov (NCT00809146). NR 7 TC 12 Z9 12 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD SEP PY 2013 VL 54 SU 6 SI SI BP 74 EP 77 DI 10.1111/epi.12284 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 210JA UT WOS:000323826600022 PM 24001080 ER PT J AU Horvath, KA AF Horvath, Keith A. TI Welcome (bienvenida, bienvenue, willkommen, pryzwitanie, accoglienza, welkom) to the new EACTS cardiac surgery database SO EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY LA English DT Editorial Material DE Database; European cardiac surgery; Outcomes C1 [Horvath, Keith A.] NIH, NHLBI Cardiothorac Surg Res Program, Bethesda, MD 20892 USA. RP Horvath, KA (reprint author), 10 Ctr Dr,MSC 1550,10-B1D47, Bethesda, MD 20892 USA. EM khorvath@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1010-7940 J9 EUR J CARDIO-THORAC JI Eur. J. Cardio-Thorac. Surg. PD SEP PY 2013 VL 44 IS 3 BP E181 EP E181 DI 10.1093/ejcts/ezt323 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 204FL UT WOS:000323350400004 PM 23786915 ER PT J AU Shaffer, BC Modric, M Stetler-Stevenson, M Arthur, DC Steinberg, SM Liewehr, DJ Fowler, DH Gale, RP Bishop, MR Pavletic, SZ AF Shaffer, Brian C. Modric, Marko Stetler-Stevenson, Maryalice Arthur, Diane C. Steinberg, Seth M. Liewehr, David J. Fowler, Daniel H. Gale, Robert P. Bishop, Michael R. Pavletic, Steven Z. TI Rapid complete donor lymphoid chimerism and graft-versus-leukemia effect are important in early control of chronic lymphocytic leukemia SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; MINIMAL RESIDUAL DISEASE; ALLOGENEIC TRANSPLANTATION; PROGRESSION-FREE; CLL3X TRIAL; ENGRAFTMENT; MALIGNANCIES; SURVIVAL; CHEMOTHERAPY AB Eradication of minimal residual disease (MRD) after allotransplantation in persons with chronic lymphocytic leukemia (CLL) is associated with lower rates of relapse. Rapid engraftment of donor lymphocyte elements can contribute to MRD control, but it remains unclear whether this strategy will benefit patients. In this study, we report the incidence of MRD eradication and graft-versus-host disease (GvHD) in persons with rapid versus later donor T lymphocyte engraftment after lymphodepleting chemotherapy and reduced intensity conditioning (RIC) allotransplantation. Twenty-seven subjects received lymphodepleting chemotherapy to facilitate donor engraftment followed by fludarabine and cyclophosphamide RIC and a blood cell allograft. MRD was monitored by multicolor flow cytometry after transplantation. Complete donor T lymphoid chimerism (TLC) and myeloid chimerism (MC) were achieved in 25 subjects at a median of 28 days (range, 14-60 days) and 21 days (range, 14-180 days), respectively. Achieving complete donor TLC by day 14 versus day 28 or later correlated with occurrence of grade 2 or higher acute GvHD (90% [95% confidence interval {CI}, 78-100%] versus 35% [95% CI, 16-54%]; p = 0.014) and better control of MRD in the bone marrow at day 100, median 0% (range, 0-0.1%) versus 8.5% (range, 0-92%; p = 0.016). Among 11 persons with early donor TLC, none had progressive disease, and seven died of treatment -related mortality (TRM). In persons with later development of TLC, 8 of 16 had progressive disease and 2 died of TRM. Time to donor myeloid chimerism had no effect on outcomes. Rapid establishment of donor TLC resulted in more complete eradication of early MRD, but greater incidence of acute GvHD and TRM in persons with CLL undergoing RIC allotransplantation. Published by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells. C1 [Shaffer, Brian C.; Fowler, Daniel H.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Modric, Marko; Stetler-Stevenson, Maryalice; Arthur, Diane C.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.; Liewehr, David J.] NCI, Biostat & Data Management Sect, Off Clin Director, NIH, Rockville, MD USA. [Gale, Robert P.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Expt Med, Haematol Sect, London, England. [Bishop, Michael R.] Univ Chicago, Div Hematol & Oncol, Chicago, IL 60637 USA. RP Shaffer, BC (reprint author), Expt Transplantat & Immunol Branch, 10 Ctr Dr,Bldg 10 CRC,Room 3-3248, Bethesda, MD 20892 USA. EM shafferbc@mail.nih.gov FU Center for Cancer Research, the Intramural Program of the National Cancer Institute, National Institutes of Health; National Institutes of Health Research Biomedical Research Centre FX This work was supported by the Center for Cancer Research, the Intramural Program of the National Cancer Institute, National Institutes of Health. R.P.G. acknowledges support from the National Institutes of Health Research Biomedical Research Centre funding scheme. NR 35 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2013 VL 41 IS 9 BP 772 EP 778 DI 10.1016/j.exphem.2013.04.015 PG 7 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 217KU UT WOS:000324359200003 PM 23689118 ER PT J AU Uchida, N Hsieh, MM Washington, KN Tisdale, JF AF Uchida, Naoya Hsieh, Matthew M. Washington, Kareem N. Tisdale, John F. TI Efficient transduction of human hematopoietic repopulating cells with a chimeric HIV1-based vector including SIV capsid SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; GENE-THERAPY; LENTIVIRAL VECTOR; STEM-CELLS; RESTRICTION FACTORS; TRIM5-ALPHA; PROTEASOME; ACTIVATION; HIV-1; INHIBITION AB Innate immune factors, such as TRIM5 alpha and cyclophilin A (CypA), act as a major restriction factor of retroviral infection among species. When HIV1 infects human cells, HIV1 capsid binds to human CypA to escape from human TRIM5 alpha restriction. However, in rhesus cells, the mismatch between HIV1 capsid and rhesus CypA is recognized by rhesus TRIM5 alpha to reduce HIV1 infectivity through proteasomal degradation. To circumvent this block, we previously developed a chimeric HIV1 vector (HIV) that substituted HIV1 capsid with SIV capsid, and it significantly increased transduction efficiency for nonhuman primate cells. In this study, we evaluated whether the chi HIV vector efficiently transduces human cells, and the transduction efficiency might increase by a CypA inhibitor (cyclosporine) and a proteasome inhibitor (MG132). The chi HIV vector could transduce human CD34(+) cells, as efficiently as the HIV1 vector, in vitro and in xenograft mice, even in the mismatch between SIV capsid and human CypA. Cyclosporine decreased transduction efficiency with the HIV1 vector, whereas it slightly increased transduction efficiency with the chi HIV vector in human CD34(+) cells. MG132 increased transduction efficiency with both chi HIV and HIV1 vectors in the same manner. However, MG132 was toxic to human CD34(+) cells at high concentrations, and both drugs had a small range of effective dosage. These findings demonstrate that both chi HIV and HIV1 vectors have similar transduction efficiency for human hematopoietic repopulating cells, suggesting that the chi HIV vector escapes from TRIM5 alpha restriction, which is independent of human CypA. Published by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells. C1 [Uchida, Naoya; Hsieh, Matthew M.; Washington, Kareem N.; Tisdale, John F.] NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD USA. [Washington, Kareem N.] Howard Univ, Coll Med, Howard Univ Hosp, Dept Pediat & Child Hlth,Div Genet & Human Genet, Washington, DC USA. RP Tisdale, JF (reprint author), Mol & Clin Hematol Branch, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU National Heart, Lung, and Blood Institute; National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health FX We thank Hayato Unno for help with this study. This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health. NR 33 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2013 VL 41 IS 9 BP 779 EP 788 DI 10.1016/j.exphem.2013.04.014 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 217KU UT WOS:000324359200004 PM 23665451 ER PT J AU Kubinak, JL Ruff, JS Cornwall, DH Middlebrook, EA Hasenkrug, KJ Potts, WK AF Kubinak, J. L. Ruff, J. S. Cornwall, D. H. Middlebrook, E. A. Hasenkrug, K. J. Potts, W. K. TI Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence SO GENES AND IMMUNITY LA English DT Article DE MHC; experimental evolution; serial passage; host-pathogen ID CYTOTOXIC T-LYMPHOCYTES; EMERGING INFECTIOUS-DISEASES; CAPTIVE BREEDING PROGRAMS; GENETIC DIVERSITY; MHC POLYMORPHISM; ESCAPE MUTATIONS; LABORATORY MOUSE; VIRUS-INFECTION; HUMAN HEALTH; SELECTION AB Using an experimental evolution approach, we recently demonstrated that the mouse-specific pathogen Friend virus (FV) complex adapted to specific major histocompatibility complex (MHC) genotypes, which resulted in fitness tradeoffs when viruses were exposed to hosts possessing novel MHC polymorphisms. Here we report the analysis of patterns of pathogen adaptation and virulence evolution from viruses adapting to one of three hosts that differ across the entire genome (A/WySn, DBA/2J and BALB/c). We found that serial passage of FV complex through these mouse genotypes resulted in significant increases in pathogen fitness (156-fold) and virulence (11-fold). Adaptive responses by post-passage viruses also resulted in host-genotype-specific patterns of adaptation. To evaluate the relative importance of MHC versus non-MHC polymorphisms as factors influencing pathogen adaptation and virulence, we compared the magnitude of fitness tradeoffs incurred by post-passage viruses when infecting hosts possessing either novel MHC polymorphisms alone or hosts possessing novel MHC and non-MHC polymorphisms. MHC polymorphisms alone accounted for 71% and 83% of the total observed reductions in viral fitness and virulence in unfamiliar host genotypes, respectively. Strikingly, these data suggest that genetic polymorphisms within the MHC, a gene region representing only similar to 0.1% of the genome, are major host factors influencing pathogen adaptation and virulence evolution. C1 [Kubinak, J. L.; Ruff, J. S.; Cornwall, D. H.; Middlebrook, E. A.; Potts, W. K.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Kubinak, J. L.] Univ Utah, Dept Pathol, Salt Lake City, UT 84112 USA. [Hasenkrug, K. J.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Kubinak, JL (reprint author), Univ Utah, Dept Biol, 257 South 1400 East, Salt Lake City, UT 84112 USA. EM jason.kubinak@path.utah.edu OI Cornwall, Douglas/0000-0002-8536-3139; Potts, Wayne/0000-0003-4137-0326 FU National Science Foundation [DEB 0918969, DEB 0910052, DGE 08-41233] FX This work was supported by National Science Foundation Grant DEB 0918969 (to WKP and Dr Fred Adler); National Science Foundation Doctoral Dissertation Improvement Grant DEB 0910052 (to JLK and WKP); and National Science Foundation Educational Outreach Grant DGE 08-41233 (to JLK and JSR). We thank Dr Sandra Ruscetti for her useful insights regarding FV complex as well as her generous provision of reagents throughout these experiments. We also thank Linda Morrison for her help in the design and optimization of assays. Finally, we thank two anonymous reviewers for their constructive comments during manuscript preparation. NR 42 TC 5 Z9 5 U1 0 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD SEP PY 2013 VL 14 IS 6 BP 365 EP 372 DI 10.1038/gene.2013.27 PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 213ZR UT WOS:000324099900003 PM 23698707 ER PT J AU Yu, ZS Ren, MD Wang, ZX Zhang, B Rong, YKS Jiao, RJ Gao, GJ AF Yu, Zhongsheng Ren, Mengda Wang, Zhanxiang Zhang, Bo Rong, Yikang S. Jiao, Renjie Gao, Guanjun TI Highly Efficient Genome Modifications Mediated by CRISPR/Cas9 in Drosophila SO GENETICS LA English DT Article ID GUIDED CAS9 NUCLEASE; GENE; MELANOGASTER; TALEN AB We report that Cas9/gRNA mediates efficient genetic modifications in Drosophila. Through targeting seven loci, we achieved a germline efficiency of up to 100%. Genes in both heterochromatin and euchromatin can be modified efficiently. Thus the Cas9/gRNA system is an attractive tool for rapid disruption of essentially any gene in Drosophila. C1 [Yu, Zhongsheng; Jiao, Renjie] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China. [Ren, Mengda; Gao, Guanjun] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. [Wang, Zhanxiang; Zhang, Bo] Peking Univ, Coll Life Sci, Minist Educ, Key Lab Cell Proliferat & Differentiat, Beijing 100871, Peoples R China. [Yu, Zhongsheng] Univ Chinese Acad Sci, Beijing 100080, Peoples R China. [Rong, Yikang S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Jiao, RJ (reprint author), Chinese Acad Sci, Inst Biophys, Datun Rd 15, Beijing 100101, Peoples R China. EM rjiao@sun5.ibp.ac.cn; gaogu@mail.tsinghua.edu.cn RI Yu, Zhongsheng/C-8764-2015; Wang, Zhanxiang/K-4162-2016 OI Yu, Zhongsheng/0000-0001-6348-5293; Wang, Zhanxiang/0000-0003-4066-1498 FU National Natural Science Foundation of China, NSFC [31171278, 31271542]; 973 program [2009CB918702, 2012CB825504]; NSFC [31071087, 31271573]; National Cancer Institute FX We thank Dr. Jingwei Xiong for providing the plasmid of pMD19-T gRNA scaffold vector, Wei Wei and Wenyuan Li for technical assistance in DNA sequencing and constructing the pSP6-2sNLS-spcas9 plasmid, and Dr. Hui Wang for providing the bacterium strain of S. pyogenes that contains the Cas9 gene. This work was supported by the grants from the National Natural Science Foundation of China, NSFC (31171278, 31271542). R.J. is supported by the grants from the 973 program (2009CB918702 and 2012CB825504) and the NSFC (31071087 and 31271573). Research in Y.S.R.'s laboratory is supported by the intramural program of National Cancer Institute. NR 14 TC 122 Z9 137 U1 8 U2 114 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 1943-2631 J9 GENETICS JI Genetics PD SEP PY 2013 VL 195 IS 1 BP 289 EP + DI 10.1534/genetics.113.153825 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 214YC UT WOS:000324174200024 PM 23833182 ER PT J AU Fu, R Wassif, CA Yanjanin, NM Watkins-Chow, DE Baxter, LL Incao, A Liscum, L Sidhu, R Firnkes, S Graham, M Ory, DS Porter, FD Pavan, WJ AF Fu, Rao Wassif, Christopher A. Yanjanin, Nicole M. Watkins-Chow, Dawn E. Baxter, Laura L. Incao, Art Liscum, Laura Sidhu, Rohini Firnkes, Sally Graham, Mark Ory, Daniel S. Porter, Forbes D. Pavan, William J. TI Efficacy of N-acetylcysteine in phenotypic suppression of mouse models of NiemannPick disease, type C1 SO HUMAN MOLECULAR GENETICS LA English DT Article ID LIPID STORAGE DISORDER; PICK-DISEASE; OXIDATIVE STRESS; CHOLESTEROL HOMEOSTASIS; NEURONAL CHOLESTEROL; LYSOSOMAL CALCIUM; MURINE MODEL; EVERY ORGAN; BALB/C MICE; NPC1 AB NiemannPick disease, type C1 (NPC1), which arises from a mutation in the NPC1 gene, is characterized by abnormal cellular storage and transport of cholesterol and other lipids that leads to hepatic disease and progressive neurological impairment. Oxidative stress has been hypothesized to contribute to the NPC1 disease pathological cascade. To determine whether treatments reducing oxidative stress could alleviate NPC1 disease phenotypes, the in vivo effects of the antioxidant N-acetylcysteine (NAC) on two mouse models for NPC1 disease were studied. NAC was able to partially suppress phenotypes in both antisense-induced (NPC1ASO) and germline (Npc1/) knockout genetic mouse models, confirming the presence of an oxidative stress-related mechanism in progression of NPC1 phenotypes and suggesting NAC as a potential molecule for treatment. Gene expression analyses of NAC-treated NPC1ASO mice suggested NAC affects pathways distinct from those initially altered by Npc1 knockdown, data consistent with NAC achieving partial disease phenotype suppression. In a therapeutic trial of short-term NAC administration to NPC1 patients, no significant effects on oxidative stress in these patients were identified other than moderate improvement of the fraction of reduced CoQ10, suggesting limited efficacy of NAC monotherapy. However, the mouse model data suggest that the distinct antioxidant effects of NAC could provide potential treatment of NPC1 disease, possibly in concert with other therapeutic molecules at earlier stages of disease progression. These data also validated the NPC1ASO mouse as an efficient model for candidate NPC1 drug screening, and demonstrated similarities in hepatic phenotypes and genome-wide transcript expression patterns between the NPC1ASO and Npc1/ models. C1 [Fu, Rao; Wassif, Christopher A.; Yanjanin, Nicole M.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Watkins-Chow, Dawn E.; Baxter, Laura L.; Incao, Art; Pavan, William J.] NHGRI, Dept Hlth & Human Serv, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Liscum, Laura] Tufts Univ, Dept Physiol, Sch Med, Boston, MA 02111 USA. [Sidhu, Rohini; Firnkes, Sally; Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. [Graham, Mark] Isis Pharmaceut Inc, Cardiovasc Grp, Dept Antisense Drug Discovery, Carlsbad, CA 92008 USA. RP Pavan, WJ (reprint author), NHGRI, Dept Hlth & Human Serv, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov RI Sidhu, Rohini/G-3547-2012; OI Wassif, Christopher/0000-0002-2524-1420; Watkins-Chow, Dawn/0000-0002-4355-0868 FU National Human Genome Research Institute, National Institutes of Health; Dana's Angels Research Trust; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Ara Parseghian Medical Research Foundation; Office of Rare Diseases; National Institutes of Health Clinical Center FX This work was supported by the intramural research program of the National Human Genome Research Institute, National Institutes of Health (W.J.P., A. I., D. E. W-C., L. L. B.); Dana's Angels Research Trust (D.S.O, R. S., S. F.); the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F. D. P, C. A. W., N.M.Y.); the Ara Parseghian Medical Research Foundation (D.O., F. D. P., N.M.Y.); and a Bench to Bedside award from the Office of Rare Diseases and the National Institutes of Health Clinical Center. NR 63 TC 10 Z9 10 U1 0 U2 4 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 SEP 1 PY 2013 VL 22 IS 17 BP 3508 EP 3523 DI 10.1093/hmg/ddt206 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 198KK UT WOS:000322921400010 PM 23666527 ER PT J AU Graff, M Ngwa, JS Workalemahu, T Homuth, G Schipf, S Teumer, A Volzke, H Wallaschofski, H Abecasis, GR Edward, L Francesco, C Sanna, S Scheet, P Schlessinger, D Sidore, C Xiao, XJ Wang, ZM Chanock, SJ Jacobs, KB Hayes, RB Hu, F Van Dam, RM Crout, RJ Marazita, ML Shaffer, JR Atwood, LD Fox, CS Heard-Costa, NL White, C Choh, AC Czerwinski, SA Demerath, EW Dyer, TD Towne, B Amin, N Oostra, BA Van Duijn, CM Zillikens, MC Esko, T Nelis, M Nikopensius, T Metspalu, A Strachan, DP Monda, K Qi, L North, KE Cupples, LA Gordon-Larsen, P Berndt, SI AF Graff, Mariaelisa Ngwa, Julius S. Workalemahu, Tsegaselassie Homuth, Georg Schipf, Sabine Teumer, Alexander Voelzke, Henry Wallaschofski, Henri Abecasis, Goncalo R. Edward, Lakatta Francesco, Cucca Sanna, Serena Scheet, Paul Schlessinger, David Sidore, Carlo Xiao, Xiangjun Wang, Zhaoming Chanock, Stephen J. Jacobs, Kevin B. Hayes, Richard B. Hu, Frank Van Dam, Rob M. Crout, Richard J. Marazita, Mary L. Shaffer, John R. Atwood, Larry D. Fox, Caroline S. Heard-Costa, Nancy L. White, Charles Choh, Audrey C. Czerwinski, Stefan A. Demerath, Ellen W. Dyer, Thomas D. Towne, Bradford Amin, Najaf Oostra, Ben A. Van Duijn, Cornelia M. Zillikens, M. Carola Esko, Tonu Nelis, Mari Nikopensius, Tit Metspalu, Andres Strachan, David P. Monda, Keri Qi, Lu North, Kari E. Cupples, L. Adrienne Gordon-Larsen, Penny Berndt, Sonja I. CA GIANT Consortium TI Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course SO HUMAN MOLECULAR GENETICS LA English DT Article ID BODY-MASS INDEX; CHILDHOOD OBESITY; COMMON VARIANTS; EARLY-ONSET; FAT MASS; ASSOCIATION; RISK; FTO; WEIGHT; SH2B1 AB Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P 5.0 10(8)) near FTO (P 3.72 10(23)), TMEM18 (P 3.24 10(17)), MC4R (P 4.41 10(17)), TNNI3K (P 4.32 10(11)), SEC16B (P 6.24 10(9)), GNPDA2 (P 1.11 10(8)) and POMC (P 4.94 10(8)) as well as a potential secondary signal at the POMC locus (rs2118404, P 2.4 10(5) after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 1890) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages. C1 [Graff, Mariaelisa; Monda, Keri; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Graff, Mariaelisa; Gordon-Larsen, Penny] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Ngwa, Julius S.; White, Charles; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Workalemahu, Tsegaselassie; Hu, Frank; Van Dam, Rob M.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Homuth, Georg; Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Schipf, Sabine; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Abecasis, Goncalo R.; Sidore, Carlo] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Edward, Lakatta; Schlessinger, David; Sidore, Carlo] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Francesco, Cucca; Sanna, Serena] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Scheet, Paul; Xiao, Xiangjun] Univ Texas MD Anderson, Dept Epidemiol, Houston, TX USA. [GIANT Consortium] GIANT, Bethesda, MD USA. [Wang, Zhaoming; Chanock, Stephen J.; Jacobs, Kevin B.; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Jacobs, Kevin B.] NCI Frederick, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21702 USA. [Hayes, Richard B.] NYU Med Ctr, New York, NY 10016 USA. [Hu, Frank] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hu, Frank] Harvard Univ, Sch Med, Boston, MA USA. [Van Dam, Rob M.] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Van Dam, Rob M.] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore. [Crout, Richard J.] W Virginia Univ, Dept Periodont, Morgantown, WV 26506 USA. [Marazita, Mary L.] Univ Pittsburgh, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA USA. [Shaffer, John R.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Atwood, Larry D.; Fox, Caroline S.; Heard-Costa, Nancy L.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Ngwa, Julius S.; Atwood, Larry D.; Heard-Costa, Nancy L.; Cupples, L. Adrienne] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Choh, Audrey C.; Czerwinski, Stefan A.; Towne, Bradford] Wright State Univ, Sch Med, Dayton, OH USA. [Demerath, Ellen W.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Dyer, Thomas D.] Texas Biomed Res Inst, Dept Genet, Houston, TX USA. [Amin, Najaf; Oostra, Ben A.; Van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Zillikens, M. Carola] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Esko, Tonu; Nelis, Mari; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu; Nikopensius, Tit; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Esko, Tonu; Nelis, Mari; Metspalu, Andres] Estonian Bioctr, Tartu, Estonia. [Nelis, Mari] Univ Geneva, Sch Med, Dept Med Genet & Dev, CH-1211 Geneva, Switzerland. [Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [Monda, Keri] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Gordon-Larsen, Penny] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. RP Graff, M (reprint author), Univ N Carolina, Dept Epidemiol, Bank Amer Ctr, 137 East Franklin Str,Suite 306, Chapel Hill, NC 27517 USA. EM migraff@email.unc.edu RI van Dam, Rob/F-9674-2010; OI van Dam, Rob/0000-0002-7354-8734; Heard-Costa, Nancy/0000-0001-9730-0306; Cupples, L. Adrienne/0000-0003-0273-7965; Sidore, Carlo/0000-0001-7504-7477; sanna, serena/0000-0002-3768-1749; Esko, Tonu/0000-0003-1982-6569; Hayes, Richard/0000-0002-0918-661X FU National Institutes of Health [R01HD057194, HHSN268200625226C, R01-HD012252, R01-HD053685, R01-DK064391, R01-AR052147]; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC- 55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Center for Research Resources (NCRR) [UL1 RR 025005]; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 076113/B/04/Z]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation International (JDRF); EUROSPAN (European Special Populations Research Network); European Commission FP6 STRP [018947, LSHG-CT-2006-01947]; Netherlands Organization for Scientific Research; Erasmus MC; Centre for Medical Systems Biology (CMSB); Netherlands Brain Foundation (HersenStichting Nederland); ENGAGE; OPENGENE; Estonian Government [SF0180142s08]; Estonian Research Roadmap through Estonian Ministry of Education and Research [3.2.0304.11-0312]; Center of Excellence in Genomics (EXCEGEN); University of Tartu [SP1GVARENG]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Department of Medicine at Boston University School of Medicine; Boston Medical Center; NIH [R01HD057194]; National Institutes of Dental and Craniofacial Research [U01-DE018903]; NIDCR [R01-DE 014899]; National Institutes of Health (NIH) [HHSN268200782096C]; NIDCR through CIDR's NIH; National Institutes of Health (Boston Obesity Nutrition Research Center) [HL71981, DK46200]; American Heart Association [0730094N]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; National Institute on Aging (NIA) and National Institutes of Health (NIH) [NO1-AG-1-2109]; [U01 DK062418] FX This work was funded by National Institutes of Health (R01HD057194).; Atherosclerosis Risk in Communities (ARIC). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC- 55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694); National Human Genome Research Institute (U01HG004402); and National Institutes of Health (HHSN268200625226C). Infrastructure was partly supported by a component of the National Institutes of Health and NIH Roadmap for Medical Research (UL1RR025005). The project described was supported by the National Center for Research Resources (NCRR) (UL1 RR 025005).; British 1958 Birth Cohort (B58C). We acknowledge the use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) (http://www.b58cgene.sgul.ac.uk/). Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust (076113/B/04/Z). The B58C-T1DGC genotyping utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418.; Erasmus Rucphen Family (EUROSPAN) (ERF). The genotyping for the ERF study was supported by EUROSPAN (European Special Populations Research Network) and the European Commission FP6 STRP (018947; LSHG-CT-2006-01947). The ERF study was further supported by grants from the Netherlands Organization for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology (CMSB) and the Netherlands Brain Foundation (HersenStichting Nederland).; Estonian Genome Center, University of Tartu (EGCUT). EGCUT received financing by (ENGAGE, OPENGENE), targeted financing from Estonian Government (funding no: SF0180142s08), Estonian Research Roadmap through Estonian Ministry of Education and Research (3.2.0304.11-0312), Center of Excellence in Genomics (EXCEGEN) and Development Fund of University of Tartu (funding no: SP1GVARENG).; Framingham Heart Study (FramHS). This research was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract no: N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses of the Framingham data were supported by subcontract to Boston University under NIH (R01HD057194).; Dental Caries: Whole Genome Association and Gene x Environment Studies (GENEVA Dental Caries). Funding support for the GWAS project was provided by the National Institutes of Dental and Craniofacial Research (U01-DE018903). Data and samples were provided by the Center for Oral Health Research in Appalachia, a collaboration of the University of Pittsburgh and West Virginia University funded by NIDCR (R01-DE 014899); genotyping was done by the Johns Hopkins University Center for Inherited Disease Research (CIDR) which is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University (contract no: HHSN268200782096C). Funds for this project's genotyping were provided by the NIDCR through CIDR's NIH contract. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (www.genevastudy.org; U01-HG004446).; Fels Longitudinal Study (Fels). This work was supported by the National Institutes of Health (R01-HD012252, R01-HD053685, R01-DK064391, R01-AR052147).; The Nurses' Health Study/Health Professionals Follow up Study (NHS/HPFS). This study was supported by National Institutes of Health grants [HL71981 and DK46200 (Boston Obesity Nutrition Research Center)] and by an American Heart Association Scientist Development Award (0730094N).; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO/PLCO2). The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH.; Study of Health in Pomerania (SHIP). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania.; Study of Health in Sardinia, Italy (SardNIA). This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA) and National Institutes of Health (NIH) (NO1-AG-1-2109). NR 40 TC 42 Z9 45 U1 1 U2 16 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 SEP 1 PY 2013 VL 22 IS 17 BP 3597 EP 3607 DI 10.1093/hmg/ddt205 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 198KK UT WOS:000322921400017 PM 23669352 ER PT J AU Sebastiano, C Zhao, XR Deng, FM Das, K AF Sebastiano, Christopher Zhao, Xiangrong Deng, Fang-Ming Das, Kasturi TI Cystic lesions of the adrenal gland: our experience over the last 20 years SO HUMAN PATHOLOGY LA English DT Article DE Adrenal cyst; Pseudocyst; Endothelial cyst; Epithelial cyst; Radiopathologic correlation ID OF-THE-LITERATURE; PSEUDOCYSTS; MANAGEMENT; VARIANTS; PATIENT AB Cystic lesions of the adrenal gland are uncommon, often presenting with nonspecific clinical and radiologic findings, and are thus underrecognized. They are occasionally associated with malignant neoplasms, which can greatly mimic benign lesions and carry detrimental clinical consequences if misdiagnosed. Here we present our 20-year experience (1992-2012) with these lesions at an academic medical center. Among more than 4500 adrenal gland specimens, 31 cases of adrenal lesions with a predominant cystic component were identified in 30 patients with an age range of 34 to 86 years (median, 55.5 years) and a male/female ratio of 13:17. Macroscopic descriptions, available histologic and immunostain slides, and available radiologic records were reviewed for all included cases. Radiologic studies and gross examination correlated well, and hemorrhage (26 cases; 84%) and encapsulation (25 cases; 81%) appeared to be nonspecific radiologic/gross features shared across histologic subtypes. Microscopic review identified 12 cases (39%) of pseudocysts, 2 cases (6%) of endothelium-derived cysts, and 17 cases (55%) of epithelium-derived cysts. Among these 31 cystic adrenal lesions, 2 cases (6%) were malignant neoplasms (1 epithelioid angiosarcoma, 1 adrenocortical carcinoma). Radiologic impression and histopathologic diagnosis were concordant in 11 (73%) of the 15 cases for which radiologic records were available. This study represents the second largest case series to date on cystic adrenal lesions and presents a comprehensive review on their demographic, clinical, radiologic, and gross and microscopic pathologic features, as well as their differential diagnoses. Published by Elsevier Inc. C1 [Sebastiano, Christopher; Zhao, Xiangrong; Deng, Fang-Ming; Das, Kasturi] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10016 USA. RP Zhao, XR (reprint author), NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM xiangrong.zhao@nih.gov NR 29 TC 6 Z9 6 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD SEP PY 2013 VL 44 IS 9 BP 1797 EP 1803 DI 10.1016/j.humpath.2013.02.002 PG 7 WC Pathology SC Pathology GA 214RF UT WOS:000324152500013 PM 23618356 ER PT J AU Smith, CE Ngwa, J Tanaka, T Qi, Q Wojczynski, MK Lemaitre, RN Anderson, JS Manichaikul, A Mikkila, V Van Rooij, FJA Ye, Z Bandinelli, S Frazier-Wood, AC Houston, DK Hu, F Langenberg, C McKeown, NM Mozaffarian, D North, KE Viikari, J Zillikens, MC Djousse, L Hofman, A Kahonen, M Kabagambe, EK Loos, RJF Saylor, GB Forouhi, NG Liu, Y Mukamal, KJ Chen, YDI Tsai, MY Uitterlinden, AG Raitakari, O Van Duijn, CM Arnett, DK Borecki, IB Cupples, LA Ferrucci, L Kritchevsky, SB Lehtimaki, T Qi, L Rotter, JI Siscovick, DS Wareham, NJ Witteman, JCM Ordovas, JM Nettleton, JA AF Smith, C. E. Ngwa, J. Tanaka, T. Qi, Q. Wojczynski, M. K. Lemaitre, R. N. Anderson, J. S. Manichaikul, A. Mikkila, V. Van Rooij, F. J. A. Ye, Z. Bandinelli, S. Frazier-Wood, A. C. Houston, D. K. Hu, F. Langenberg, C. McKeown, N. M. Mozaffarian, D. North, K. E. Viikari, J. Zillikens, M. C. Djousse, L. Hofman, A. Kahonen, M. Kabagambe, E. K. Loos, R. J. F. Saylor, G. B. Forouhi, N. G. Liu, Y. Mukamal, K. J. Chen, Y-D I. Tsai, M. Y. Uitterlinden, A. G. Raitakari, O. Van Duijn, C. M. Arnett, D. K. Borecki, I. B. Cupples, L. A. Ferrucci, L. Kritchevsky, S. B. Lehtimaki, T. Qi, Lu Rotter, J. I. Siscovick, D. S. Wareham, N. J. Witteman, J. C. M. Ordovas, J. M. Nettleton, J. A. TI Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE low-density lipoprotein receptor-related protein 1; SNPs; saturated fatty acids; gene-diet interactions ID GENE-ENVIRONMENT INTERACTIONS; OBESITY-ASSOCIATED GENE; WEIGHT-LOSS DIETS; ADIPOSE-TISSUE; BODY-WEIGHT; ASSOCIATION; MASS; EXPRESSION; COHORT; SAMPLE AB OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids. DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800). RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P - 0.0001), 0.267 cm for waist (interaction P = 0.001) and 0.21 cm for hip (interaction P = 0.001). No other significant interactions were observed. CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits. C1 [Smith, C. E.; McKeown, N. M.; Ordovas, J. M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr & Genom Lab, Boston, MA 02111 USA. [Ngwa, J.; Cupples, L. A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tanaka, T.; Ferrucci, L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Qi, Q.; Hu, F.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Wojczynski, M. K.; Borecki, I. B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Lemaitre, R. N.] Univ Washington, Dept Med, Seattle, WA USA. [Anderson, J. S.; Saylor, G. B.] Wake Forest Sch Med, Cardiol Sect, Dept Internal Med, Winston Salem, NC USA. [Manichaikul, A.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Manichaikul, A.] Univ Virginia, Div Biostat & Epidemiol, Charlottesville, VA USA. [Mikkila, V.] Univ Helsinki, Dept Food & Environm Sci, Helsinki, Finland. [Van Rooij, F. J. A.; Hofman, A.; Uitterlinden, A. G.; Van Duijn, C. M.; Witteman, J. C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Van Rooij, F. J. A.; Zillikens, M. C.; Hofman, A.; Uitterlinden, A. G.; Van Duijn, C. M.; Witteman, J. C. M.] NGI, NCHA, Leiden, Netherlands. [Ye, Z.; Langenberg, C.; Loos, R. J. F.; Forouhi, N. G.; Wareham, N. J.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Bandinelli, S.] Azienda Sanitaria Firenze, Geriatr Rehabil Unit, Florence, Italy. [Frazier-Wood, A. C.; Kabagambe, E. K.; Arnett, D. K.] Univ Alabama Birmingham, Sect Stat Genet, Dept Epidemiol, Birmingham, AL USA. [Frazier-Wood, A. C.; Kabagambe, E. K.; Arnett, D. K.] Univ Alabama Birmingham, Off Energet, Birmingham, AL USA. [Houston, D. K.; Kritchevsky, S. B.] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Hu, F.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hu, F.; Qi, Lu] Harvard Univ, Sch Med, Boston, MA USA. [Mozaffarian, D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mozaffarian, D.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Mozaffarian, D.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Mozaffarian, D.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Mozaffarian, D.] Harvard Univ, Sch Med, Boston, MA USA. [North, K. E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, K. E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Viikari, J.] Univ Turku, Dept Med, Turku, Finland. [Viikari, J.] Turku Univ Hosp, FIN-20520 Turku, Finland. [Zillikens, M. C.; Uitterlinden, A. G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Djousse, L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Djousse, L.] Boston VA Healthcare Syst, Boston, MA USA. [Kahonen, M.] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kahonen, M.] Tampere Univ Hosp, Tampere, Finland. [Liu, Y.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Mukamal, K. J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Chen, Y-D I.; Rotter, J. I.] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Tsai, M. Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Raitakari, O.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, O.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Cupples, L. A.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Lehtimaki, T.] Univ Tampere, Fimlab Labs, Dept Clin Chem, FIN-33101 Tampere, Finland. [Lehtimaki, T.] Tampere Univ Hosp, Tampere, Finland. [Siscovick, D. S.] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, D. S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Ordovas, J. M.] CNIC, Dept Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, J. M.] Estudios Avanzados Alimentac, Inst Madrilenos, Madrid, Spain. [Nettleton, J. A.] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. RP Ordovas, JM (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr & Genom Lab, 711 Washington St, Boston, MA 02111 USA. EM jose.ordovas@tufts.edu RI Djousse, Luc/F-5033-2017; Wood, Lekki/B-8053-2010; OI Djousse, Luc/0000-0002-9902-3047; Wood, Lekki/0000-0001-7616-2119; Forouhi, Nita/0000-0002-5041-248X FU National Heart, Lung and Blood Institute [HHSN268 201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268 201100012C]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C, HL71981, CA055075, CA87969, CA49449]; NIH Roadmap for Medical Research; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [5K01DK 082729-04]; NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129]; NIA [AG-023629, AG-15928, AG-20098, AG-027058, R01 AG032098]; National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Medical Research Council; Cancer Research United Kingdom; Stroke Association; British Heart Foundation; Research Into Ageing; Academy of Medical Science; NIH from NHLBI [R01 HL087700, R01 HL088215]; NIDDK [R01 DK075681, R01 DK8925601]; Wellcome Trust; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; NIH/NIDDK [R01 DK089256-01]; USDA [58-1950-7-707]; US Department of Agriculture Research Service [53-K06-5-10, 58-1950-9-001]; Intramural Research Program of the NIH, National Institute on Aging [N01AG62101, N01AG62103, N01AG62106]; American Heart Association [0730094N]; Italian Ministry of Health; US National Institute on Aging [263 MD 9164, 263 MD 821336]; National Heart, Lung and Blood Institute (NHLBI) [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, N01-HC-95168, N01-HC-95169, RR-024156]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam; Academy of Finland [126925, 121584, 124282, 129378, 117787, 41071]; Social Insurance Institution of Finland, Kuopio, Tampere; Turku University Hospital Medical Funds [9M048, 9N035]; Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; NHLBI. [N02-HL-6-4278, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, R01-HL085251, HL087652, HL105756, N01-HC-25195, U01-HL072524]; [R01HL087641]; [R01HL59367]; [R01HL086694]; [P50 HL105185-01]; [ICS110.1/RF97.71]; [R01HL071051]; [R01HL071205]; [R01HL071250]; [R01HL071251]; [R01HL071252]; [R01HL 071258]; [R01HL071259] FX The Atherosclerosis Risk In Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268 201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268 201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Dr Nettleton is supported by a K01 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (5K01DK 082729-04). Cardiovascular Health Study (CHS) research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI grants HL080295, R01-HL085251 HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. European Prospective Investigation of Cancer Norfolk (EPIC Norfolk): EPIC-Norfolk is supported by grant funding from the Medical Research Council and Cancer Research United Kingdom with additional support from the Stroke Association, British Heart Foundation, Research Into Ageing and the Academy of Medical Science. The Family Heart Study (FamHS) work was supported by NIH grants R01 HL087700, R01 HL088215 (Michael A. Province) from NHLBI; and R01 DK075681 and R01 DK8925601 from NIDDK (Ingrid B. Borecki). The investigators thank the staff and participants of the FamHS for their important contributions. The Fenland Study is funded by the Wellcome Trust and the Medical Research Council. We are grateful to all the volunteers for their time and help and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team, the Field Epidemiology team and the Fenland Study investigators. Biochemical assays were performed by the National Institute for Health Research, Cambridge Biomedical Research Centre, Core Biochemistry Assay Laboratory and the Cambridge University Hospitals NHS Foundation Trust. The Framingham Offspring Study and Framingham Third Generation Study (FHS) were conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (Contract No. N02-HL-6-4278).; A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Dr Cupples and Mr Ngwa are partially supported by NIH/NIDDK grant R01 DK089256-01. Dr Nicola McKeown is supported by the USDA agreement No. 58-1950-7-707. The GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study was funded by the National Heart, Lung and Blood Institute Grant No. U01-HL072524, Genetic and Environmental Determinants of Triglycerides. Dr Smith and Dr Ordovas are partially supported by P50 HL105185-01 and contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research Service. The Health, Aging and Body Composition (Health ABC) study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant R01 AG032098 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Health Professionals Follow-up Study (HPFS): The HPFS was supported by grants HL71981 and CA055075 from the National Institutes of Health. Dr Lu Qi is a recipient of the American Heart Association Scientist Development Award (0730094N). We thank the participants of the HPFS for their continued cooperation. Invecchiare in Chianti (aging in the Chianti area, InCHIANTI) study investigators thank the Intramural Research Program of the NIH, National Institute on Aging who are responsible for the InCHIANTI samples. Investigators also thank the InCHIANTI participants. The InCHIANTI study baseline (1998-2000) was supported as a 'targeted project' (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). MESA and the MESA SHARe project are conducted and supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the National Heart, Lung and Blood Institute (NHLBI). Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL 071258, R01HL071259. We thank the participants of the MESA study, the Coordinating Center, MESA investigators, and study staff for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Nurses Health Study (NHS): The NHS was supported by grants HL71981, CA87969 and CA49449 from the National Institutes of Health. Dr Lu Qi is a recipient of the American Heart Association Scientist Development Award (0730094N). We thank the participants of the NHS for their continued cooperation. Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810.; We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Young Finns Study: The Young Finns Study has been financially supported by the Academy of Finland: grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 and 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (T. L). The authors gratefully acknowledge the statistical analyses provided by Ville Aalto. NR 39 TC 3 Z9 3 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD SEP PY 2013 VL 37 IS 9 BP 1211 EP 1220 DI 10.1038/ijo.2012.215 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 216QX UT WOS:000324300100008 PM 23357958 ER PT J AU Bekelman, JE Schultheiss, T De Gonzalez, B AF Bekelman, Justin E. Schultheiss, Timothy De Gonzalez, Berrington TI Subsequent Malignancies After Photon Versus Proton Radiation Therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID CHILDHOOD-CANCER SURVIVOR; 5-YEAR SURVIVORS; NEOPLASMS C1 [Bekelman, Justin E.] Univ Penn, Dept Radiat Oncol, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Bekelman, Justin E.] Univ Penn, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bekelman, Justin E.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Schultheiss, Timothy] City Hope Canc Ctr, Dept Radiat Oncol, Los Angeles, CA USA. [De Gonzalez, Berrington] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Bekelman, JE (reprint author), Dept Radiat Oncol, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bekelman@uphs.upenn.edu OI Schultheiss, Timothy/0000-0002-8984-196X FU NCI NIH HHS [1K07CA16316-01] NR 9 TC 9 Z9 9 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD SEP 1 PY 2013 VL 87 IS 1 BP 10 EP 12 DI 10.1016/j.ijrobp.2013.05.016 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 216UE UT WOS:000324309500006 PM 23810521 ER PT J AU Reilly, EAO Sharma, S Klinger, R Gubbins, L Kelly, C Lyons, T Maguire, A Aherne, S Barry, M Conlon, S McCaffrey, J Harrison, M Glynn, S McCann, A Kell, M AF Reilly, E. A. O. Sharma, S. Klinger, R. Gubbins, L. Kelly, C. Lyons, T. Maguire, A. Aherne, S. Barry, M. Conlon, S. McCaffrey, J. Harrison, M. Glynn, S. McCann, A. Kell, M. TI Low MAD2 Protein Expression is a Predictor of Poor Outcome After Chemotherapy & Radiotherapy in Oestrogen Receptor Negative Breast Cancer SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Reilly, E. A. O.; Sharma, S.; Klinger, R.; Gubbins, L.; McCann, A.] UCD Sch Med & Med Sci SMMS, UCD Conway Inst Biomol & Biomed Res, Dept Pathol, Belfield, Ireland. [Kelly, C.; Lyons, T.; McCaffrey, J.] Mater Misericordiae Univ Hosp, Dept Oncol, Dublin 1, Ireland. [Maguire, A.; Aherne, S.] St Vincents Univ Hosp, Dept Pathol, Dublin 4, Ireland. [Barry, M.; Kell, M.] Mater Misericordiae Univ Hosp, Dept Surg, Dublin 1, Ireland. [Conlon, S.; Harrison, M.] Mater Misericordiae Univ Hosp, Dept Pathol, Dublin 1, Ireland. [Glynn, S.] NCI, Dept Prostate Canc Inst, NUI Galway, Bethesda, MD 20892 USA. RI Glynn, Sharon/D-7136-2013 OI Glynn, Sharon/0000-0003-1459-2580 NR 0 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD SEP PY 2013 VL 182 SU 7 MA 37 BP S331 EP S331 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 217CX UT WOS:000324335400038 ER PT J AU Ballard-Barbash, R Krebs-Smith, SM Neuhouser, ML AF Ballard-Barbash, Rachel Krebs-Smith, Susan M. Neuhouser, Marian L. TI Potential to Link Dietary Patterns in the Food Supply and Populations to Health SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID EATING INDEX-2005; COLORECTAL-CANCER; RISK C1 [Ballard-Barbash, Rachel; Krebs-Smith, Susan M.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Prevent Ctr, Seattle, WA 98104 USA. RP Ballard-Barbash, R (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, NCI Shady Grove, Rm 3E406,9609 Med Ctr Dr,MSC 9762, Bethesda, MD 20892 USA. EM barbashr@mail.nih.gov NR 14 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2013 VL 105 IS 17 BP 1265 EP 1267 DI 10.1093/jnci/djt220 PG 4 WC Oncology SC Oncology GA 213EW UT WOS:000324038500005 PM 23949328 ER PT J AU Jochmanova, I Yang, CZ Zhuang, ZP Pacak, K AF Jochmanova, Ivana Yang, Chunzhang Zhuang, Zhengping Pacak, Karel TI Hypoxia-Inducible Factor Signaling in Pheochromocytoma: Turning the Rudder in the Right Direction SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID RENAL-CELL-CARCINOMA; ENDOCRINE NEOPLASIA TYPE-2; ENDOTHELIAL GROWTH-FACTOR; HIPPEL-LINDAU-DISEASE; TUMOR-SUPPRESSOR PROTEIN; FACTOR 1-ALPHA HIF-1-ALPHA; SDHD GENE-MUTATIONS; KAPPA-B ACTIVITY; C-MYC; FACTOR-I AB Many solid tumors, including pheochromocytoma (PHEO) and paraganglioma (PGL), are characterized by a (pseudo) hypoxic signature. (Pseudo) hypoxia has been shown to promote both tumor progression and resistance to therapy. The major mediators of the transcriptional hypoxic response are hypoxia-inducible factors (HIFs). High levels of HIFs lead to transcription of hypoxia-responsive genes, which are involved in tumorigenesis. PHEOs and PGLs are catecholamine-producing tumors arising from sympathetic-or parasympathetic-derived chromaffin tissue. In recent years, substantial progress has been made in understanding the metabolic disturbances present in PHEO and PGL, especially because of the identification of some diseases-usceptibility genes. To date, fifteen PHEO and PGL susceptibility genes have been identified. Based on the main transcription signatures of the mutated genes, PHEOs and PGLs have been divided into two clusters, pseudohypoxic cluster 1 and cluster 2, rich in kinase receptor signaling and protein translation pathways. Although these two clusters seem to show distinct signaling pathways, recent data suggest that both clusters are interconnected by HIF signaling as the important driver in their tumorigenesis, and mutations in most PHEO and PGL susceptibility genes seem to affect HIF-alpha regulation and its downstream signaling pathways. HIF signaling appears to play an important role in the development and growth of PHEOs and PGLs, which could suggest new therapeutic approaches for the treatment of these tumors. C1 [Jochmanova, Ivana; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Yang, Chunzhang; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Jochmanova, Ivana] PJ Safarik Univ Kosice, Fac Med, Dept Internal Med 1, Kosice, Slovakia. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH, Bldg 10-CRC,1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Jochmanova, Ivana/I-9011-2016 OI Jochmanova, Ivana/0000-0003-2346-461X NR 244 TC 36 Z9 39 U1 1 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2013 VL 105 IS 17 BP 1270 EP 1283 DI 10.1093/jnci/djt201 PG 14 WC Oncology SC Oncology GA 213EW UT WOS:000324038500007 PM 23940289 ER PT J AU Arem, H Reedy, J Sampson, J Jiao, L Hollenbeck, AR Risch, H Mayne, ST Stolzenberg-Solomon, RZ AF Arem, Hannah Reedy, Jill Sampson, Josh Jiao, Li Hollenbeck, Albert R. Risch, Harvey Mayne, Susan T. Stolzenberg-Solomon, Rachael Z. TI The Healthy Eating Index 2005 and Risk for Pancreatic Cancer in the NIH-AARP Study SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RETIRED-PERSONS DIET; GLYCEMIC LOAD; POSTMENOPAUSAL WOMEN; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; LARGE COHORT; PATTERNS; EPIDEMIOLOGY AB Background Dietary pattern analyses characterizing combinations of food intakes offer conceptual and statistical advantages over food-and nutrient-based analyses of disease risk. However, few studies have examined dietary patterns and pancreatic cancer risk and none focused on the 2005 Dietary Guidelines for Americans. We used the Healthy Eating Index 2005 (HEI-2005) to estimate the association between meeting those dietary guidelines and pancreatic cancer risk. Methods We calculated the HEI-2005 score for 537 218 men and women in the National Institutes of Health-American Association of Retired Persons Diet and Health Study using responses to food frequency questionnaires returned in 1995 and 1996. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of pancreatic cancer according to HEI-2005 quintiles and explored effect modification by known risk factors. P-interaction values were calculated using the Wald test. All statistical tests were two-sided. Results We identified 2383 incident, exocrine pancreatic cancer cases (median = 10.5 years follow-up). Comparing participants who met the most dietary guidelines (Q5) with those who met the fewest guidelines (Q1), we observed a reduced risk of pancreatic cancer (HR = 0.85, 95% CI = 0.74 to 0.97). Among men there was an interaction by body mass index (P-interaction = .03), with a hazard ratio of 0.72 (95% CI = 0.59 to 0.88) comparing Q5 vs Q1 in overweight/obese men (body mass index = 25 kg/m(2)) but no association among normal weight men. Conclusions Our findings support the hypothesis that consuming a high-quality diet, as scored by the HEI-2005, may reduce the risk of pancreatic cancer. C1 [Arem, Hannah; Risch, Harvey; Mayne, Susan T.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Arem, Hannah; Reedy, Jill; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Reedy, Jill] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jiao, Li] Baylor Coll Med, Houston, TX 77030 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Risch, Harvey; Mayne, Susan T.] Yale Canc Ctr, New Haven, CT USA. RP Arem, H (reprint author), 9609 Med Ctr Dr,Rm 6E324, Bethesda, MD 20892 USA. EM Aremhe2@mail.nih.gov FU Yale-NCI predoctoral training grant [T32 CA105666]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported in part by the Yale-NCI predoctoral training grant T32 CA105666 to STM. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 30 TC 21 Z9 21 U1 2 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP PY 2013 VL 105 IS 17 BP 1298 EP 1305 DI 10.1093/jnci/djt185 PG 8 WC Oncology SC Oncology GA 213EW UT WOS:000324038500010 PM 23949329 ER PT J AU Kotani, K Sekine, Y Ishikawa, S Ikpot, IZ Suzuki, K Remaley, AT AF Kotani, Kazuhiko Sekine, Yoshitaka Ishikawa, Shizukiyo Ikpot, Imoh Z. Suzuki, Kazuhiro Remaley, Alan T. TI High-Density Lipoprotein and Prostate Cancer: An Overview SO JOURNAL OF EPIDEMIOLOGY LA English DT Review DE epidemiology; HDL-cholesterol; apoA-I; prostate tumor ID INHIBIT TUMOR-DEVELOPMENT; METABOLIC SYNDROME; HDL CHOLESTEROL; RISK-FACTOR; CELLS; PROLIFERATION; COHORT; HYPERCHOLESTEROLEMIA; CAPABILITY; EXPRESSION AB Prostate cancer is a common disease in modern, developed societies and has a high incidence and mortality. High-density lipoprotein cholesterol (HDL-C) has recently received much attention as a possible risk marker of prostate cancer development and prognosis. In the present article, we summarized findings from epidemiologic studies of the association between HDL-C and prostate cancer. Low HDL-C level was found to be a risk and prognostic factor of prostate cancer in several epidemiologic studies, although the overall linkage between HDL and prostate cancer has not been definitively established. The mechanisms for this association remain uncertain; however, limited data from experimental studies imply a possible role of HDL in the pathophysiology of prostate cancer. More epidemiologic research, in combination with experimental studies, is needed in this field. C1 [Kotani, Kazuhiko; Sekine, Yoshitaka; Ikpot, Imoh Z.; Remaley, Alan T.] NHLBI, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. [Kotani, Kazuhiko] Jichi Med Univ, Dept Clin Lab Med, Shimotsuke, Tochigi 3290498, Japan. [Sekine, Yoshitaka; Suzuki, Kazuhiro] Gunma Univ, Grad Sch Med, Dept Urol, Maebashi, Gumma 371, Japan. [Ishikawa, Shizukiyo] Jichi Med Univ, Ctr Community Med, Div Community & Family Med, Shimotsuke, Tochigi 3290498, Japan. RP Kotani, K (reprint author), Jichi Med Univ, Dept Clin Lab Med, 3311-1 Yakushiji, Shimotsuke, Tochigi 3290498, Japan. EM kazukotani@jichi.ac.jp FU NIH funds from NHLBI FX None declared. Research was in part supported from intramural NIH funds from NHLBI. NR 35 TC 16 Z9 17 U1 1 U2 11 PU JAPAN EPIDEMIOLOGICAL ASSOC PI TOKYO PA C/O UNIBO PRESS, HONGO MT BLDG 4F, 7-2-2 HONGO, BUNKYO-KU, TOKYO, 113-0033, JAPAN SN 0917-5040 J9 J EPIDEMIOL JI J. Epidemiol. PD SEP PY 2013 VL 23 IS 5 BP 313 EP 319 DI 10.2188/jea.JE20130006 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 214PO UT WOS:000324146500001 PM 23985823 ER PT J AU Turcotte, S Gros, A Hogan, K Tran, E Hinrichs, CS Wunderlich, JR Dudley, ME Rosenberg, SA AF Turcotte, Simon Gros, Alena Hogan, Katherine Tran, Eric Hinrichs, Christian S. Wunderlich, John R. Dudley, Mark E. Rosenberg, Steven A. TI Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLORECTAL-CANCER; AUTOLOGOUS TUMOR; PROGNOSTIC-SIGNIFICANCE; TRANSFER IMMUNOTHERAPY; LYMPHOCYTE-CULTURES; LIVER METASTASES; RANDOMIZED TRIAL; DENDRITIC CELLS; GASTRIC-CANCER; EXPRESSION AB Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3(+) T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8(+) cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to similar to 50 x 10(9) T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 +/- 1.4% CD3(+)CD8(+) cells compared with 63 +/- 2.4% from melanoma (p < 0.001). IFN-gamma ELISA demonstrated MHC class I-mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I-mediated up-regulation of CD137 (4-1BB) expression on CD8(+) cells suggested that 0-3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells. C1 [Turcotte, Simon; Gros, Alena; Hogan, Katherine; Tran, Eric; Hinrichs, Christian S.; Wunderlich, John R.; Dudley, Mark E.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, 10 Ctr Dr MSC 1201,CRC Room 3-3940, Bethesda, MD 20892 USA. EM sar@nih.gov OI Gros, Alena/0000-0002-1207-1880 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 45 TC 23 Z9 23 U1 0 U2 14 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2013 VL 191 IS 5 BP 2217 EP 2225 DI 10.4049/jimmunol.1300538 PG 9 WC Immunology SC Immunology GA 204TU UT WOS:000323393300022 PM 23904171 ER PT J AU Kuka, M Munitic, I Torchia, MLG Ashwell, JD AF Kuka, Mirela Munitic, Ivana Torchia, Maria Letizia Giardino Ashwell, Jonathan D. TI CD70 Is Downregulated by Interaction with CD27 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; COSTIMULATORY LIGAND CD70; T-CELL RESPONSES; DENDRITIC CELLS; MEMBRANE-RECEPTORS; MURINE CD70; TNF FAMILY; IN-VIVO; EXPRESSION; MEMBER AB Engagement of the receptor CD27 by CD70 affects the magnitude and quality of T cell responses in a variety of infection models, and exaggerated signaling via this pathway results in enhanced immune responses and autoimmunity. One means by which signaling is regulated is tight control of cell surface CD70, which is expressed on dendritic cells (DCs), T cells, and B cells only upon activation. In this article, we show that a second level of regulation also is present. First, although undetectable on the cell surface by flow cytometry, immature DCs have a small pool of CD70 that continuously recycles from the plasma membrane. In addition, surface levels of CD70 on DCs and T cells were higher in mice deficient in CD27, or on DCs for which the interaction between CD70 and CD27 was precluded by blocking Abs. Binding of CD70 by its receptor resulted in downregulation of CD70 transcription and protein levels, suggesting that CD70-mediated "reverse signals" regulate its own levels. Therefore, the ability of CD70 to trigger costimulation is self-regulated when it binds its complementary receptor. C1 [Kuka, Mirela; Munitic, Ivana; Torchia, Maria Letizia Giardino; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Ctr Canc Res, NIH, Bldg 37,Room 3002C, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov OI KUKA, MIRELA/0000-0001-9418-1559 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 35 TC 9 Z9 10 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2013 VL 191 IS 5 BP 2282 EP 2289 DI 10.4049/jimmunol.1300868 PG 8 WC Immunology SC Immunology GA 204TU UT WOS:000323393300029 PM 23913967 ER PT J AU Takai, S Schlom, J Tucker, J Tsang, KY Greiner, JW AF Takai, Shinji Schlom, Jeffrey Tucker, Joanne Tsang, Kwong Y. Greiner, John W. TI Inhibition of TGF-beta 1 Signaling Promotes Central Memory T Cell Differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; INFLUENZA NUCLEOPROTEIN; LYMPHOCYTES-T; EFFECTOR; GENERATION; IMMUNITY; PHENOTYPE; MIGRATION; DEVELOP AB This study affirmed that isolated CD8(+) T cells express mRNA and produce TGF-beta following cognate peptide recognition. Blockage of endogenous TGF-beta with either a TGF-beta-blocking Ab or a small molecule inhibitor of TGF-beta RI enhances the generation of CD62L(high)/CD44(high) central memory CD8(+) T cells accompanied with a robust recall response. Interestingly, the augmentation within the central memory T cell pool occurs in lieu of cellular proliferation or activation, but with the expected increase in the ratio of the Eomesoderm/T-bet transcriptional factors. Yet, the signal transduction pathway(s) seems to be noncanonical, independent of SMAD or mammalian target of rapamycin signaling. Enhancement of central memory generation by TGF-beta blockade is also confirmed in human PBMCs. The findings underscore the role(s) that autocrine TGF-beta plays in T cell homeostasis and, in particular, the balance of effector/memory and central/memory T cells. These results may provide a rationale to targeting TGF-beta signaling to enhance Ag-specific CD8(+) T cell memory against a lethal infection or cancer. C1 [Takai, Shinji; Schlom, Jeffrey; Tucker, Joanne; Tsang, Kwong Y.; Greiner, John W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greiner, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bldg 10,Room 8B09,10 Ctr Dr, Bethesda, MD 20892 USA. EM jg117s@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 30 TC 5 Z9 7 U1 2 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2013 VL 191 IS 5 BP 2299 EP 2307 DI 10.4049/jimmunol.1300472 PG 9 WC Immunology SC Immunology GA 204TU UT WOS:000323393300031 PM 23904158 ER PT J AU Anuradha, R George, PJ Hanna, LE Chandrasekaran, V Kumaran, P Nutman, TB Babu, S AF Anuradha, Rajamanickam George, Parakkal Jovvian Hanna, Luke E. Chandrasekaran, Vedachalam Kumaran, Paul Nutman, Thomas B. Babu, Subash TI IL-4-, TGF-beta-, and IL-1-Dependent Expansion of Parasite Antigen-Specific Th9 Cells Is Associated with Clinical Pathology in Human Lymphatic Filariasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; DIFFERENTIATION; DISEASE; INTERLEUKIN-9; INFECTION; RESPONSES; PU.1 AB Th9 cells are a subset of CD4(+) T cells, shown to be important in allergy, autoimmunity, and antitumor responses; however, their role in human infectious diseases has not been explored in detail. We identified a population of IL-9 and IL-10 coexpressing cells (lacking IL-4 expression) in normal individuals. These cells respond to antigenic and mitogenic stimulation, but are distinct from IL-9(+) Th2 cells. We also demonstrate that these Th9 cells exhibit Ag-specific expansion in a chronic helminth infection (lymphatic filariasis). Comparison of Th9 responses reveals that individuals with pathology associated with filarial infection exhibit significantly expanded frequencies of filarial Ag-induced Th9 cells, but not of IL9(+)Th2 cells in comparison with filarial-infected individuals without associated disease. Moreover, the per cell production of IL-9 is significantly higher in Th9 cells compared with IL9(+)Th2 cells, indicating that the Th9 cells are the predominant CD4(+) T cell subset producing IL-9 in the context of human infection. This expansion was reflected in elevated Ag-stimulated IL-9 cytokine levels in whole blood culture supernatants. Finally, the frequencies of Th9 cells correlated positively with the severity of lymphedema (and presumed inflammation) in filarial-diseased individuals. This expansion of Th9 cells was dependent on IL-4, TGF-beta, and IL-1 in vitro. We have therefore identified an important human CD4(+) T cell subpopulation coexpressing IL-9 and IL-10, but not IL-4, the expansion of which is associated with disease in chronic lymphatic filariasis and could potentially have an important role in the pathogenesis of other inflammatory disorders. C1 [Anuradha, Rajamanickam; George, Parakkal Jovvian; Babu, Subash] Int Ctr Excellence Res, Natl Inst Hlth, Madras 600031, Tamil Nadu, India. [Hanna, Luke E.; Chandrasekaran, Vedachalam; Kumaran, Paul] Natl Inst Res TB, Madras 600031, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Int Ctr Excellence Res, Natl Inst Res TB, Natl Inst Hlth, Madras 600031, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health 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. NR 35 TC 16 Z9 16 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2013 VL 191 IS 5 BP 2466 EP 2473 DI 10.4049/jimmunol.1300911 PG 8 WC Immunology SC Immunology GA 204TU UT WOS:000323393300048 PM 23913964 ER PT J AU Kole, A He, JP Rivollier, A Silveira, DD Kitamura, K Maloy, KJ Kelsall, BL AF Kole, Abhisake He, JianPing Rivollier, Aymeric Silveira, Danielle D. Kitamura, Kazuya Maloy, Kevin J. Kelsall, Brian L. TI Type I IFNs Regulate Effector and Regulatory T Cell Accumulation and Anti-Inflammatory Cytokine Production during T Cell-Mediated Colitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC INTESTINAL INFLAMMATION; DENDRITIC CELLS; INTERFERON-ALPHA/BETA; LY6C(HI) MONOCYTES; TH17 CELLS; SCID MICE; INDUCTION; ACTIVATION; RECEPTOR; PROMOTE AB We explored the function of endogenous type I IFNs (IFN-1) in the colon using the T cell adoptive transfer model of colitis. Colon mononuclear phagocytes (MPs) constitutively produced IFN-1 in a Toll/IL-1R domain-containing adapter-inducing IFN-beta-dependent manner. Transfer of CD4(+)CD45RB(hi) T cells from wild-type (WT) or IFN-alpha/beta receptor subunit 1 knockout (IFNAR1(-/-)) mice into RAG(-/-) hosts resulted in similar onset and severity of colitis. In contrast, RAG(-/-) x IFNAR1(-/-) double knockout (DKO) mice developed accelerated severe colitis compared with RAG(-/-) hosts when transferred with WT CD4(+)CD45RB(hi) T cells. IFNAR signaling on host hematopoietic cells was required to delay colitis development. MPs isolated from the colon lamina propria of IFNAR1(-/-) mice produced less IL-10, IL-1R antagonist, and IL-27 compared with WT MPs. Accelerated colitis development in DKO mice was characterized by early T cell proliferation and accumulation of CD11b(+)CD103(-) dendritic cells in the mesenteric lymph nodes, both of which could be reversed by systemic administration of IL-1R antagonist (anakinra). Cotransfer of CD4(+) CD25(+) regulatory T cells (Tregs) from WT or IFNAR1(-/-) mice prevented disease caused by CD4(+)CD45RB(hi) T cells. However, WT CD4(+)CD25(+)Foxp3(GFP+) Tregs cotransferred with CD4(+)CD45RB(hi) T cells into DKO hosts failed to expand or maintain Foxp3 expression and gained effector functions in the colon. To our knowledge, these data are the first to demonstrate an essential role for IFN-1 in the production of anti-inflammatory cytokines by gut MPs and the indirect maintenance of intestinal T cell homeostasis by both limiting effector T cell expansion and promoting Treg stability. C1 [Kole, Abhisake; He, JianPing; Rivollier, Aymeric; Silveira, Danielle D.; Kitamura, Kazuya; Kelsall, Brian L.] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Maloy, Kevin J.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. RP Kelsall, BL (reprint author), NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bldg 10,Room 113,10 Ctr Dr,MSC 1886, Bethesda, MD 20892 USA. EM bkelsall@niaid.nih.gov FU Intramural Research Program of the 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 54 TC 25 Z9 25 U1 1 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2013 VL 191 IS 5 BP 2771 EP 2779 DI 10.4049/jimmunol.1301093 PG 9 WC Immunology SC Immunology GA 204TU UT WOS:000323393300077 PM 23913971 ER PT J AU Tan, IL Mowry, EM Steele, SU Pardo, CA McArthur, JC Nath, A Venkatesan, A AF Tan, Ik Lin Mowry, Ellen M. Steele, Sonya U. Pardo, Carlos A. McArthur, Justin C. Nath, Avindra Venkatesan, Arun TI Brainstem encephalitis: etiologies, treatment, and predictors of outcome SO JOURNAL OF NEUROLOGY LA English DT Article DE Rhombencephalitis; Brainstem encephalitis; Brain biopsy; Autoimmune; Inflammatory; Glucose ID HERPES-SIMPLEX ENCEPHALITIS; ACUTE DISSEMINATED ENCEPHALOMYELITIS; INFECTIOUS ENCEPHALITIS; CLINICAL ANALYSIS; DEFINITIONS; DIAGNOSIS; FRANCE AB Brainstem encephalitis (BE) is an uncommon condition. We sought to characterize clinical presentations, etiologies, response to treatment, and predictors of outcome. We performed a retrospective review of non-HIV infected patients diagnosed with BE at Johns Hopkins Hospital (January 1997-April 2010). We characterized clinical and paraclinical features, and used regression models to assess associations with poor outcome. BE was diagnosed in 81 patients. An etiology was identified in 58 of 81 (71.6 %) of cases, most of which were confirmed or probable inflammatory/autoimmune conditions. Of the remaining 23 cases in which a specific diagnosis remained undefined, clinical presentation, CSF, neuroimaging studies, and outcomes were similar to the inflammatory/autoimmune group. Brain biopsy identified a specific diagnosis in 7 of 14 patients (50 %). Fifteen patients (18.5 %) either died or had a poor outcome. In multivariate logistic regression models, a higher CSF protein (per 5 mg/dl, OR = 1.11, 95 % CI: 1.03-1.20), a higher CSF glucose (per 5 mg/dl, OR = 1.36, 95 % CI: 1.09-1.70), and higher serum glucose (per 5 mg/dl, OR = 1.27, 95 % CI: 1.06-1.52) were independently associated with increased odds of poor outcome. Inflammatory and non-infectious conditions accounted for most cases of BE. Higher CSF protein and glucose were independently associated with poor outcome. In immunocompetent patients with BE of undefined etiology despite extensive investigation, a trial of immunosuppressive treatment may be warranted, though deterioration clinically or on magnetic resonance imaging should prompt a brain biopsy. C1 [Tan, Ik Lin; Pardo, Carlos A.; McArthur, Justin C.; Venkatesan, Arun] Johns Hopkins Univ, Sch Med, Johns Hopkins Encephalitis Ctr, Baltimore, MD USA. [Tan, Ik Lin; Mowry, Ellen M.; Steele, Sonya U.; Pardo, Carlos A.; McArthur, Justin C.; Venkatesan, Arun] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Venkatesan, Arun] Johns Hopkins Neuroimmunol & Neuroinfectious Dis, Baltimore, MD 21287 USA. RP Venkatesan, A (reprint author), Johns Hopkins Neuroimmunol & Neuroinfectious Dis, 600 N Wolfe St,Meyer 6-113, Baltimore, MD 21287 USA. EM avenkat2@jhmi.edu FU NIH [K23NS067055]; National MS Society [RG4407A2]; NIH; Biogen-Idec; Gliamed; HHMI; Maryland Stem Cell Research Foundation; National Multiple Sclerosis Society FX Financial disclosure: Ellen M. Mowry: Funding NIH K23NS067055; National MS Society RG4407A2. Receipt of free study medication from Teva Neurological. Justin C. McArthur: Grants from NIH, Biogen-Idec, payment from lectures, speakers' bureau in various universities, book royalties, stock option from Gliamed. Avindra Nath: Consultant to Biogen Idec and Diogenix. Arun Venkatesan: Grants from NIH, HHMI, Maryland Stem Cell Research Foundation, National Multiple Sclerosis Society. Ik Lin Tan, Sonya Steele, Carlos Pardo-Villamizar report no financial disclosure. NR 26 TC 4 Z9 5 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD SEP PY 2013 VL 260 IS 9 BP 2312 EP 2319 DI 10.1007/s00415-013-6986-z PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 213ZL UT WOS:000324099200014 PM 23749332 ER PT J AU Bettencourt, C Morris, HR Singleton, AB Hardy, J Houlden, H AF Bettencourt, Conceicao Morris, Huw R. Singleton, Andrew B. Hardy, John Houlden, Henry TI Exome sequencing expands the mutational spectrum of SPG8 in a family with spasticity responsive to L-DOPA treatment SO JOURNAL OF NEUROLOGY LA English DT Letter ID AUTOSOMAL-DOMINANT; PARAPLEGIA; LOCUS; GENE C1 [Bettencourt, Conceicao; Morris, Huw R.; Hardy, John; Houlden, Henry] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Bettencourt, C (reprint author), UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England. EM c.bettencourt@ucl.ac.uk RI Hardy, John/C-2451-2009; Morris, Huw/B-8527-2008; Singleton, Andrew/C-3010-2009; Houlden, Henry/C-1532-2008 OI Bettencourt, Conceicao/0000-0001-9090-7690; Morris, Huw/0000-0002-5473-3774; Houlden, Henry/0000-0002-2866-7777 FU Medical Research Council [MR/J004758/1, , G0700943, G0802760, G1001253, G108/638, G1100643, MC_G1000735]; Parkinson's UK [G-1107]; Wellcome Trust [, 089698] NR 8 TC 6 Z9 7 U1 0 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 EI 1432-1459 J9 J NEUROL JI J. Neurol. PD SEP PY 2013 VL 260 IS 9 BP 2414 EP 2416 DI 10.1007/s00415-013-7044-6 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 213ZL UT WOS:000324099200031 PM 23881105 ER PT J AU Al-Uzri, A Matheson, M Gipson, DS Mendley, SR Hooper, SR Yadin, O Rozansky, DJ Moxey-Mims, M Furth, SL Warady, BA Gerson, AC AF Al-Uzri, Amira Matheson, Matthew Gipson, Debbie S. Mendley, Susan R. Hooper, Stephen R. Yadin, Ora Rozansky, David J. Moxey-Mims, Marva Furth, Susan L. Warady, Bradley A. Gerson, Arlene C. CA Chronic Kidney Dis Children CKiD TI The Impact of Short Stature on Health-Related Quality of Life in Children with Chronic Kidney Disease SO JOURNAL OF PEDIATRICS LA English DT Article ID GROWTH-HORMONE TREATMENT; SEX-DIFFERENCES; HEIGHT; ADOLESCENCE; COHORT; NAPRTCS; UREMIA AB Objectives To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) and short stature (SS) with that of children with CKD and normal height (NH), to evaluate the impact of catch-up growth and growth hormone (GH) use on HRQoL, and to describe the concordance of perceptions of HRQoL between children with SS and NH and their parents. Study design Four hundred eighty-three children and/or parents enrolled in the multicenter Chronic Kidney Disease in Children study who had completed the Pediatric Quality of Life Inventory (Version 4.0) on at least 2 Chronic Kidney Disease in Children study visits composed this substudy population. Participants were dichotomized into NH or SS groups. The demographic characteristics that varied at baseline (sex, glomerular filtration rate, and parent education) were controlled for in the main analysis evaluating the impact of catch-up growth and use of GH on HRQoL. Results Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and GH use on parent-proxy reports of child physical functioning (P < .05) and social functioning (P < .05). Older children with CKD (15-17 years old) had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old). Conclusion The finding that height gains and GH use are associated with increases in physical and social functioning by parent report provides additional support for interventions to improve height in children with CKD. The importance of evaluating both the parent and child perceptions of HRQoL is supported by our results. C1 [Al-Uzri, Amira; Rozansky, David J.] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA. [Matheson, Matthew] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Gipson, Debbie S.] Mott Childrens Hosp, Dept Pediat, Ann Arbor, MI USA. [Mendley, Susan R.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Hooper, Stephen R.] Univ N Carolina, Sch Med, Carolina Inst Dev Disabil, Chapel Hill, NC USA. [Yadin, Ora] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD 20892 USA. [Furth, Susan L.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Warady, Bradley A.] Childrens Mercy Hosp & Clin, Dept Pediat, Kansas City, MO USA. [Gerson, Arlene C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Al-Uzri, A (reprint author), Oregon Hlth & Sci Univ, Dept Pediat, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97201 USA. FU National Institute of Diabetes and Digestive and Kidney Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute [UO1-DK-66143, UO1-DK-66174, U01-DK-82194, UO1-DK-66116] FX Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute (UO1-DK-66143, UO1-DK-66174, U01-DK-82194, and UO1-DK-66116). The authors are solely responsible for the data analysis, and interpretation of data, in the writing of the report, and the decision to submit the paper for publication. The authors declare no conflicts of interest. NR 29 TC 17 Z9 18 U1 0 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2013 VL 163 IS 3 BP 736 EP + DI 10.1016/j.jpeds.2013.03.016 PG 7 WC Pediatrics SC Pediatrics GA 212LQ UT WOS:000323985300028 PM 23628375 ER PT J AU Chaiworapongsa, T Romero, R Whitten, A Tarca, AL Bhatti, G Draghici, S Chaemsaithong, P Miranda, J Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Whitten, Amy Tarca, Adi L. Bhatti, Gaurav Draghici, Sorin Chaemsaithong, Piya Miranda, Jezid Hassan, Sonia S. TI Differences and similarities in the transcriptional profile of peripheral whole blood in early and late-onset preeclampsia: insights into the molecular basis of the phenotype of preeclampsiaa SO JOURNAL OF PERINATAL MEDICINE LA English DT Article; Proceedings Paper CT 58th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation CY MAR 16-26, 2011 CL Miami Beach, FL SP Soc Gynecol Invest DE Affymetrix; gene expression; H19; microarray; PAX gene; PCR transcriptomic; pregnancy; white blood cell count ID FOR-GESTATIONAL-AGE; BECKWITH-WIEDEMANN-SYNDROME; GENE-EXPRESSION PROFILES; EPITHELIAL MEMBRANE PROTEIN-1; LINKING PLACENTAL ISCHEMIA; MESSENGER-RNA EXPRESSION; AFRICAN-AMERICAN WOMEN; GROWTH-FACTOR RECEPTOR; LONG-TERM MORTALITY; MICROARRAY ANALYSIS AB Objective: Preeclampsia (PE) can be sub-divided into early-and late-onset phenotypes. The pathogenesis of these two phenotypes has not been elucidated. To gain insight into the mechanisms of disease, the transcriptional profiles of whole blood from women with early-and late-onset PE were examined. Methods: A cross-sectional study was conducted to include women with: i) early-onset PE (diagnosed prior to 34 weeks, n = 25); ii) late-onset PE (after 34 weeks, n = 47); and iii) uncomplicated pregnancy (n = 61). Microarray analysis of mRNA expression in peripheral whole blood was undertaken using Affymetrix microarrays. Differential gene expression was evaluated using a moderated t-test (false discovery rate < 0.1 and fold change > 1.5), adjusting for maternal white blood cell count and gestational age. Validation by real-time qRT-PCR was performed in a larger sample size [early PE (n = 31), late PE (n = 72) and controls (n = 99)] in all differentially expressed genes. Gene ontology analysis and pathway analysis were performed. Results: i) 43 and 28 genes were differentially expressed in early-and late-onset PE compared to the control group, respectively; ii) qRT-PCR confirmed the micro-array results for early and late-onset PE in 77% (33/43) and 71% (20/28) of genes, respectively; iii) 20 genes that are involved in coagulation (SERPINI2), immune regulation (VSIG4, CD24), developmental process (H19) and inflammation (S100A10) were differentially expressed in early-onset PE alone. In contrast, only seven genes that encoded proteins involved in innate immunity (LTF, ELANE) and cell-to-cell recognition in the nervous system (CNTNAP3) were differentially expressed in late-onset PE alone. Thirteen genes that encode proteins involved in host defense (DEFA4, BPI, CTSG, LCN2), tight junctions in blood-brain barrier (EMP1) and liver regeneration (ECT2) were differentially expressed in both early-and late-onset PE. Conclusion: Early-and late-onset PE are characterized by a common signature in the transcriptional profile of whole blood. A small set of genes were differentially regulated in early-and late-onset PE. Future studies of the biological function, expression timetable and protein expression of these genes may provide insight into the pathophysiology of PE. C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto; Whitten, Amy; Tarca, Adi L.; Chaemsaithong, Piya; Miranda, Jezid; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto; Whitten, Amy; Tarca, Adi L.; Chaemsaithong, Piya; Miranda, Jezid; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Chaiworapongsa, Tinnakorn; Whitten, Amy; Chaemsaithong, Piya; Miranda, Jezid; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Tarca, Adi L.; Bhatti, Gaurav; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. RP Chaiworapongsa, T (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu; romeror@mail.nih.gov FU Intramural NIH HHS [ZIA HD002400-22]; NICHD NIH HHS [HHSN275201300006C] NR 203 TC 10 Z9 11 U1 0 U2 10 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD SEP PY 2013 VL 41 IS 5 BP 485 EP 504 DI 10.1515/jpm-2013-0082 PG 20 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 213JM UT WOS:000324052900002 PM 23793063 ER PT J AU Lam-Rachlin, J Romero, R Korzeniewski, SJ Schwartz, AG Chaemsaithong, P Hernandez-Andrade, E Dong, Z Yeo, L Hassan, SS Chaiworapongsa, T AF Lam-Rachlin, Jennifer Romero, Roberto Korzeniewski, Steven J. Schwartz, Alyse G. Chaemsaithong, Piya Hernandez-Andrade, Edgar Dong, Zhong Yeo, Lami Hassan, Sonia S. Chaiworapongsa, Tinnakorn TI Infection and smoking are associated with decreased plasma concentration of the anti-aging protein, alpha-klotho SO JOURNAL OF PERINATAL MEDICINE LA English DT Article; Proceedings Paper CT 33rd Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM) CY FEB 11-16, 2013 CL San Francisco, CA SP Soc Maternal Fetal Med DE Inflammation; intrauterine infection; prematurity; preterm labor; preterm prelabor rupture of membranes ID PRETERM PREMATURE RUPTURE; AMNIOTIC-FLUID INTERLEUKIN-6; MATERNAL SERUM INTERLEUKIN-6; FETAL MEMBRANE DISTENSION; SONOGRAPHIC SHORT CERVIX; NECROSIS-FACTOR-ALPHA; PLACEBO-CONTROLLED TRIAL; PROGESTERONE-RECEPTOR-A; PITUITARY-ADRENAL AXIS; WHITE-MATTER LESIONS AB Objective: The objective of this study was to determine whether maternal plasma concentrations of soluble alpha-klotho are different between women with microbial invasion of the intra-amniotic cavity (MIAC) and those without MIAC among preterm labor and intact membranes (PTL) or preterm prelabor rupture of membranes (pPROM). Methods : A cross-sectional study was conducted to include women in the following groups: i) PTL with MIAC (n = 14); ii) PTL without MIAC (n = 79); iii) pPROM with MIAC (n = 30); and iv) pPROM without MIAC (n = 33). MIAC was defined as a positive amniotic fluid culture for microorganisms (aerobic/anaerobic bacteria or genital mycoplasmas). Amniotic fluid samples were obtained within 48 h of maternal blood collection. Plasma concentration of soluble alpha-klotho was determined by ELISA. Results : i) The median plasma concentration (pg/mL) of soluble alpha-klotho was significantly lower in patients with MIAC than in those without MIAC (787.0 vs. 1117.8; P < 0.001). ii) Among patients with PTL, those with MIAC had a lower median plasma concentration (pg/mL) of soluble alpha-klotho than those without MIAC (787.0 vs. 1138.9; P = 0.007). iii) Among patients with pPROM, those with MIAC had a lower median plasma concentration (pg/mL) of soluble alpha-klotho than those without MIAC (766.4 vs. 1001.6; P = 0.045). iv) There was no significant difference in the median plasma concentration of soluble alpha-klotho between PPROM without MIAC and PTL without MIAC (1001.6 pg/mL vs. 1138.9 pg/mL, respectively; P = 0.5). v) After adjustment for potential confounders (maternal age, tobacco use, gestational age at venipuncture), soluble alpha-klotho remained significantly associated with MIAC (P = 0.02); and vi) Among patients without MIAC, smoking was significantly associated with a lower median plasma concentration soluble alpha-klotho than in non-smokers (794.2 pg/mL vs. 1382.0 pg/mL, respectively; P < 0.001); however, this difference was not observed in patients with MIAC. Conclusions : Intra-amniotic infection occurring at preterm gestations (regardless of membrane status) was associated with a decrease in maternal plasma concentrations of soluble a-klotho. Moreover, among patients without infection, the plasma concentration of a-klotho was lower in smokers. C1 [Lam-Rachlin, Jennifer; Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Lam-Rachlin, Jennifer; Romero, Roberto; Korzeniewski, Steven J.; Schwartz, Alyse G.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Dong, Zhong; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Lam-Rachlin, Jennifer; Korzeniewski, Steven J.; Schwartz, Alyse G.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Lam-Rachlin, J (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM jla@med.wayne.edu; romeror@mail.nih.gov FU Intramural NIH HHS [ZIA HD002400-21]; NICHD NIH HHS [HHSN275201300006C] NR 214 TC 7 Z9 7 U1 1 U2 7 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 J9 J PERINAT MED JI J. Perinat. Med. PD SEP PY 2013 VL 41 IS 5 BP 581 EP 594 DI 10.1515/jpm-2013-0084 PG 14 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 213JM UT WOS:000324052900015 PM 23770558 ER PT J AU Wu, XW Subramaniam, S Case, DA Wu, KW Brooks, BR AF Wu, Xiongwu Subramaniam, Sriram Case, David A. Wu, Katherine W. Brooks, Bernard R. TI Targeted conformational search with map-restrained self-guided Langevin dynamics: Application to flexible fitting into electron microscopic density maps SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Self-guided Langevin dynamics; Targeted conformational search; Electron microscopy; Flexible fitting; Map-restraint ID GROUP-II CHAPERONIN; LOW-RESOLUTION MAPS; CRYOELECTRON MICROSCOPY; MOLECULAR-DYNAMICS; ATOMIC STRUCTURES; PROTEIN STRUCTURES; CRYO-EM; ENERGY; MODEL; STATE AB We present a map-restrained self-guided Langevin dynamics (MapSGLD) simulation method for efficient targeted conformational search. The targeted conformational search represents simulations under restraints defined by experimental observations and/or by user specified structural requirements. Through map-restraints, this method provides an efficient way to maintain substructures and to set structure targets during conformational searching. With an enhanced conformational searching ability of self-guided Langevin dynamics, this approach is suitable for simulating large-scale conformational changes, such as the formation of macromolecular assemblies and transitions between different conformational states. Using several examples, we illustrate the application of this method in flexible fitting of atomic structures into density maps derived from cryo-electron microscopy. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved. C1 [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Subramaniam, Sriram] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Case, David A.] Rutgers State Univ, BioMaPS Inst, Piscataway, NJ 08854 USA. [Case, David A.] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Wu, Katherine W.] Thomas Jefferson High Sch Sci & Technol, Alexandria, VA 22312 USA. RP Wu, XW (reprint author), NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,Room T919, Bethesda, MD 20892 USA. EM wuxw@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [Z01 HL001027-30]; National Cancer Institute FX This research was supported by the Intramural Research Programs of National Heart, Lung, and Blood Institute (Z01 HL001027-30) and the National Cancer Institute. NR 49 TC 9 Z9 9 U1 0 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD SEP PY 2013 VL 183 IS 3 BP 429 EP 440 DI 10.1016/j.jsb.2013.07.006 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 217GO UT WOS:000324347900015 PM 23876978 ER PT J AU Ellis, RJ Patel, D Prodanov, T Sadowski, S Nilubol, N Adams, K Steinberg, SM Pacak, K Kebebew, E AF Ellis, Ryan J. Patel, Dhaval Prodanov, Tamara Sadowski, Samira Nilubol, Naris Adams, Karen Steinberg, Seth M. Pacak, Karel Kebebew, Electron TI Response after Surgical Resection of Metastatic Pheochromocytoma and Paraganglioma: Can Postoperative Biochemical Remission Be Predicted? SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID MALIGNANT PHEOCHROMOCYTOMA; GENE-MUTATIONS; SURVIVAL; SDHB AB BACKGROUND: Aggressive surgical resection with intent to cure and surgical debulking procedures are commonly recommended in patients with metastatic pheochromocytoma and paraganglioma. To date there are no data on operative outcomes of patients after surgical resection of metastatic pheochromocytoma and paraganglioma to determine if such an approach is appropriate and what factors may be associated with a favorable outcome. STUDY DESIGN: We performed a retrospective analysis of 30 patients with metastatic pheochromocytoma/paraganglioma who underwent surgical treatment. Clinical characteristics and genetic factors were analyzed as predictors of biochemical response to surgery. RESULTS: Thirty patients underwent a total of 42 operations, with a median follow-up time of 24 months (range 1 to 114 months). Complete disease resection (R0/R1) was achieved in 18 (42.9%) cases; 24 cases (57.1%) were debulking (R2) procedures without intent to cure. Complete biochemical remission was achieved in 10 (23.8%) cases and partial biochemical response was achieved in 23 (54.8%) cases. Patients with disease confined to the abdomen were more likely to achieve and maintain a biochemical response postoperatively than those with extra-abdominal disease (p = 0.0003). Debulking operations were significantly less likely to achieve or maintain biochemical palliation, with only 1 patient maintaining a biochemical response 12 months postoperatively (p < 0.0001). Patients were less likely to obtain pharmacologic independence after debulking (p = 0.0003), with only 2 (8.3%) not requiring pharmacotherapy 6 months after the intervention. Factors not associated with biochemical response to surgery include sex, family history, SDHB mutation status, systemic therapy, and preoperative biochemical profile. CONCLUSIONS: Depending on the extent of disease, patients with metastatic pheochromocytoma/paraganglioma can benefit from aggressive operative intervention and resection with intent to cure. Debulking procedures are unlikely to achieve clinically significant biochemical response, with any biochemical response achieved being very short-lived. ((c) 2013 by the American College of Surgeons) C1 [Ellis, Ryan J.; Patel, Dhaval; Sadowski, Samira; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Bethesda, MD 20892 USA. [Prodanov, Tamara; Adams, Karen; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Ellis, Ryan J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Clin Res Ctr, Bldg 10 CRC,Room 3-5581, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X FU Intramural NIH HHS [Z99 CA999999] NR 31 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2013 VL 217 IS 3 BP 489 EP 496 DI 10.1016/j.jamcollsurg.2013.04.027 PG 8 WC Surgery SC Surgery GA 213GK UT WOS:000324043300013 PM 23891076 ER PT J AU Roschewski, M Farooqui, M Aue, G Wilhelm, F Wiestner, A AF Roschewski, M. Farooqui, M. Aue, G. Wilhelm, F. Wiestner, A. TI Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies SO LEUKEMIA LA English DT Letter ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SMALL-MOLECULE INHIBITOR; SOLID TUMORS; CYCLIN D1; DIAGNOSIS; LYMPHOMA; CRITERIA; CANCER; AGENTS C1 [Roschewski, M.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Roschewski, M.; Farooqui, M.; Aue, G.; Wiestner, A.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wilhelm, F.] Onconova Therapeut Inc, Newtown, PA USA. RP Roschewski, M (reprint author), NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL002346-09] NR 14 TC 7 Z9 7 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2013 VL 27 IS 9 BP 1920 EP 1923 DI 10.1038/leu.2013.79 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 214UT UT WOS:000324162700018 PM 23486532 ER PT J AU Chen, YT Lan, Q Zheng, TZ Zhao, N Holford, TR Lerro, C Dai, M Huang, H Liang, JX Ma, SG Leaderer, B Boyle, P Chanock, S Rothman, N Zhang, YW AF Chen, Yingtai Lan, Qing Zheng, Tongzhang Zhao, Nan Holford, Theodore R. Lerro, Catherine Dai, Min Huang, Huang Liang, Jiaxin Ma, Shuangge Leaderer, Brian Boyle, Peter Chanock, Stephen Rothman, Nathaniel Zhang, Yawei TI Polymorphisms in JAK/STAT signaling pathway genes and risk of non-Hodgkin lymphoma SO LEUKEMIA RESEARCH LA English DT Article DE JAK/STAT signaling pathway; Non-Hodgkin lymphoma; Polymorphism; Case-control study ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENOME-WIDE ASSOCIATION; JAK-STAT PATHWAY; MOLECULAR TARGETS; IFN-GAMMA; SUSCEPTIBILITY; CELLS; CANCER; INFLAMMATION; ACTIVATION AB Impaired function of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway genes leads to immunodeficiency and various hematopoietic disorders. We evaluated the association between genetic polymorphisms (SNPs) in 12 JAK/STAT pathway genes (JAK3, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, SCOS1, SCOS2, SCOS3, and SCOS4) and NHL risk in a population-based case-control study of Connecticut women. We identified three SNPs in STAT3 (rs12949918 and rs6503695) and STAT4 (rs932169) associated with NHL risk after adjustment for multiple comparison. Our results suggest that genetic variation in JAK/STAT pathway genes may play a role in lymphomagenesis and warrants further investigation. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Chen, Yingtai; Dai, Min] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100730, Peoples R China. [Lan, Qing; Chanock, Stephen; Rothman, Nathaniel] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Zheng, Tongzhang; Zhao, Nan; Holford, Theodore R.; Lerro, Catherine; Huang, Huang; Liang, Jiaxin; Ma, Shuangge; Leaderer, Brian; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, 60 Coll St,LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU NIH [CA62006, CA165923, 1D43TW008323, 1D43TW007864, HD70324]; Intramural Research Program of the National Cancer Institute FX This research was supported by the NIH grants CA62006, CA165923, 1D43TW008323, 1D43TW007864, and HD70324, and the Intramural Research Program of the National Cancer Institute. NR 42 TC 6 Z9 7 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD SEP PY 2013 VL 37 IS 9 BP 1120 EP 1124 DI 10.1016/j.leukres.2013.05.003 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 213YW UT WOS:000324097600023 PM 23768868 ER PT J AU Hosgood, HD Chapman, RS He, XZ Hu, W Tian, LW Liu, LZ Lai, H Chen, W Rothman, N Lan, Q AF Hosgood, H. Dean, III Chapman, Robert S. He, Xingzhou Hu, Wei Tian, Linwei Liu, Larry Z. Lai, Hong Chen, Wei Rothman, Nathaniel Lan, Qing TI History of lung disease and risk of lung cancer in a population with high household fuel combustion exposures in rural China SO LUNG CANCER LA English DT Article DE Chronic lung disease; Lung cancer; Never smoking; Xuanwei; China ID INDOOR AIR-POLLUTION; EPIDEMIOLOGIC EVIDENCE; XUAN-WEI; SMOKING; TUBERCULOSIS; IMPROVEMENT AB History of chronic lung diseases and household coal use for heating and cooking are established risk factors of lung cancer; however, few studies have been able to explore these risk factors simultaneously. Xuanwei, China, has some of the highest rates of lung cancer in China and most residents experience substantial in-home coal smoke exposures. Using a population-based case-control study of 498 lung cancer cases and 498 age-matched controls, we evaluated the risk of lung cancer in relation to coal smoke exposure and history of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), chronic bronchitis, and emphysema. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression adjusting for potential confounders. We observed an increased risk of lung cancer with history of any chronic lung disease among males (OR = 14.2; 95%CI = 4.3-46.9), females (OR = 2.6; 95%CI = 1.1-63), smokers (OR = 12.7; 95%CI = 3.5-45.8), and nonsmokers (OR = 2.6; 95%CI = 1.1-6.4). Specifically, TB (OR = 83.7; 95%CI = 11.0-634.7), COPD (OR = 3.2; 95%CI = 1.7-6.0), and emphysema and chronic bronchitis (OR = 3.3; 95%CI = 1.7-6.4) were associated with increased risks. These findings suggest that history of chronic lung diseases may also increase risk of lung cancer in populations with indoor coal smoke exposures. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Hosgood, H. Dean, III; Hu, Wei; Rothman, Nathaniel; Lan, Qing] NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Div Epidemiol, Bronx, NY 10467 USA. [Chapman, Robert S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. [He, Xingzhou] Chinese Ctr Dis Control & Prevent, Inst Environm Hlth & Engn, Beijing, Peoples R China. [Tian, Linwei] Chinese Univ Hong Kong, Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. [Liu, Larry Z.] Cornell Univ, Weill Med Coll, Dept Publ Hlth, New York, NY 10021 USA. [Lai, Hong] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Chen, Wei] Forest Labs Inc, Harborside Financial Ctr, Jersey City, NJ USA. RP Hosgood, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Div Epidemiol, 1300 Morris Pk Ave,Belfer 1309, Bronx, NY 10461 USA. EM dean.hosgood@einstein.yu.edu RI Hu, Wei/M-3524-2013; Tian, Linwei/A-9736-2009 OI Tian, Linwei/0000-0002-4739-1534 FU Chinese Academy of Preventive Medicine; Yunnan Province Antiepidemic Station; U.S. Environmental Protection Agency; Intramural Research Program of the National Institutes of Health FX This research was supported by the Chinese Academy of Preventive Medicine, the Yunnan Province Antiepidemic Station, the U.S. Environmental Protection Agency, and the Intramural Research Program of the National Institutes of Health. NR 23 TC 9 Z9 13 U1 2 U2 19 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD SEP PY 2013 VL 81 IS 3 BP 343 EP 346 DI 10.1016/j.lungcan.2013.06.019 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 217JI UT WOS:000324355400005 PM 23891511 ER PT J AU Choy, JS O'Toole, E Schuster, BM Crisp, MJ Karpova, TS McNally, JG Winey, M Gardner, MK Basrai, MA AF Choy, John S. O'Toole, Eileen Schuster, Breanna M. Crisp, Matthew J. Karpova, Tatiana S. McNally, James G. Winey, Mark Gardner, Melissa K. Basrai, Munira A. TI Genome-wide haploinsufficiency screen reveals a novel role for gamma-TuSC in spindle organization and genome stability SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; KINASE-A PATHWAY; BUDDING YEAST; MITOTIC SPINDLE; POLE BODY; MICROTUBULE ORGANIZATION; ASPERGILLUS-NIDULANS; ELECTRON TOMOGRAPHY; ANAPHASE SPINDLE; GENE DELETION AB How subunit dosage contributes to the assembly and function of multimeric complexes is an important question with implications in understanding biochemical, evolutionary, and disease mechanisms. Toward identifying pathways that are susceptible to decreased gene dosage, we performed a genome-wide screen for haploinsufficient (HI) genes that guard against genome instability in Saccharomyces cerevisiae. This led to the identification of all three genes (SPC97, SPC98, and TUB4) encoding the evolutionarily conserved.-tubulin small complex (gamma-TuSC), which nucleates microtubule assembly. We found that hemizygous gamma-TuSC mutants exhibit higher rates of chromosome loss and increases in anaphase spindle length and elongation velocities. Fluorescence microscopy, fluorescence recovery after photobleaching, electron tomography, and model convolution simulation of spc98/+ mutants revealed improper regulation of interpolar (iMT) and kinetochore (kMT) microtubules in anaphase. The underlying cause is likely due to reduced levels of Tub4, as overexpression of TUB4 suppressed the spindle and chromosome segregation defects in spc98/+ mutants. We propose that gamma-TuSC is crucial for balanced assembly between iMTs and kMTs for spindle organization and accurate chromosome segregation. Taken together, the results show how gene dosage studies provide critical insights into the assembly and function of multisubunit complexes that may not be revealed by using traditional studies with haploid gene deletion or conditional alleles. C1 [Choy, John S.; Crisp, Matthew J.; Basrai, Munira A.] NCI, Genet Branch, Bethesda, MD 20892 USA. [Karpova, Tatiana S.; McNally, James G.] NCI, Fluorescent Imaging Facil, Lab Receptor Biol & Gene Express, Ctr Canc Res, Bethesda, MD 20892 USA. [O'Toole, Eileen; Winey, Mark] Univ Colorado, Dept Cellular & Dev Biol, Boulder, CO 80309 USA. [Schuster, Breanna M.; Gardner, Melissa K.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. RP Basrai, MA (reprint author), NCI, Genet Branch, Bethesda, MD 20892 USA. EM klei0091@umn.edu; basraim@mail.nih.gov FU National Institutes of General Medical Sciences [8P41GM103431]; Biomedical Sciences; National Institutes of Health [GM-100122, GM51312]; National Cancer Institute; National Institutes of Health FX We thank Tom Giddings and Christina Clarissa for electron microscopy specimen preparation; Janet Meehl-Fox for yeast cultures; Charlie Boone, Duncan Clarke, Trisha Davis, and Manuel Mendoza for reagents; Jackie Vogel for critical reading of the manuscript and sharing unpublished results; Hannah Klein for advice on fluctuation analysis; and Basrai laboratory members for discussions. E.O.T. is supported by Grant 8P41GM103431 from the National Institutes of General Medical Sciences to Andreas Hoenger (Department of Molecular, Cellular and Developmental Biology, University of Colorado-Boulder). M.K.G. and B.M.S. are supported by a grant from the Pew Scholars Program in the Biomedical Sciences and National Institutes of Health Grant GM-100122. M.W. is supported by National Institutes of Health Grant GM51312. J.S.C. and M.A.B. are supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 62 TC 3 Z9 3 U1 0 U2 5 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 SEP 1 PY 2013 VL 24 IS 17 BP 2753 EP 2763 DI 10.1091/mbc.E12-12-0902 PG 11 WC Cell Biology SC Cell Biology GA 219GH UT WOS:000324493800015 PM 23825022 ER PT J AU Farley, MN Schmidt, LS Mester, JL Pena-Llopis, S Pavia-Jimenez, A Christie, A Vocke, CD Ricketts, CJ Peterson, J Middelton, L Kinch, L Grishin, N Merino, MJ Metwalli, AR Xing, C Xie, XJ Dahia, PLM Eng, C Linehan, WM Brugarolas, J AF Farley, Megan N. Schmidt, Laura S. Mester, Jessica L. Pena-Llopis, Samuel Pavia-Jimenez, Andrea Christie, Alana Vocke, Cathy D. Ricketts, Christopher J. Peterson, James Middelton, Lindsay Kinch, Lisa Grishin, Nick Merino, Maria J. Metwalli, Adam R. Xing, Chao Xie, Xian-Jin Dahia, Patricia L. M. Eng, Charis Linehan, W. Marston Brugarolas, James TI A Novel Germline Mutation in BAP1 Predisposes to Familial Clear-Cell Renal Cell Carcinoma SO MOLECULAR CANCER RESEARCH LA English DT Article ID UBIQUITIN HYDROLASE; SOMATIC MUTATIONS; UVEAL MELANOMA; KIDNEY CANCER; PARAGANGLIOMA; MESOTHELIOMA AB Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene. (C) 2013 AACR. C1 [Farley, Megan N.; Pena-Llopis, Samuel; Pavia-Jimenez, Andrea; Christie, Alana; Xie, Xian-Jin; Brugarolas, James] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. [Farley, Megan N.] Univ Texas SW Med Ctr Dallas, Dept Clin Genet, Dallas, TX 75390 USA. [Pena-Llopis, Samuel; Pavia-Jimenez, Andrea; Brugarolas, James] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Pena-Llopis, Samuel; Pavia-Jimenez, Andrea; Brugarolas, James] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA. [Kinch, Lisa; Grishin, Nick] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Xing, Chao] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. [Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Dept Med, San Antonio, TX 78229 USA. [Schmidt, Laura S.; Vocke, Cathy D.; Ricketts, Christopher J.; Peterson, James; Middelton, Lindsay; Metwalli, Adam R.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Schmidt, Laura S.] SAIC Frederick Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Mester, Jessica L.; Eng, Charis] Cleveland Clin, Genom Med Inst, Cleveland, OH USA. [Mester, Jessica L.; Eng, Charis] Cleveland Clin, Lerner Res Inst, Cleveland, OH USA. [Mester, Jessica L.; Eng, Charis] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA. [Eng, Charis] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH USA. [Eng, Charis] Case Western Reserve Univ, Sch Med, CASE Comprehens Canc Ctr, Cleveland, OH USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Bldg 10 CRC 1W5940, Bethesda, MD 20892 USA. EM WML@nih.gov; james.brugarolas@utsouthwestern.edu OI Eng, Charis/0000-0002-3693-5145 FU Intramural Research Program of the NIH, NCI, Center for Cancer Research; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; [CPRIT RP101075]; [1P30CA142543] FX This work was supported by private donations in honor of Mr. Thomas M. Green, Sr. and of a second anonymous patient of Dr. J. Brugarolas as well as grants CPRIT RP101075 and 1P30CA142543. In addition, the work was also supported by grants from the Intramural Research Program of the NIH, NCI, Center for Cancer Research, and was funded, in part, with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under Contract HHSN261200800001E (to L. Schmidt). NR 33 TC 46 Z9 46 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2013 VL 11 IS 9 BP 1061 EP 1071 DI 10.1158/1541-7786.MCR-13-0111 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 219RE UT WOS:000324525500010 PM 23709298 ER PT J AU Larocca, C Cohen, JR Fernando, RI Huang, B Hamilton, DH Palena, C AF Larocca, Cecilia Cohen, Joseph R. Fernando, Romaine I. Huang, Bruce Hamilton, Duane H. Palena, Claudia TI An Autocrine Loop between TGF-beta 1 and the Transcription Factor Brachyury Controls the Transition of Human Carcinoma Cells into a Mesenchymal Phenotype SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; CANCER PROGRESSION; STEM-CELLS; GENE; BREAST; DISEASE; MOUSE; SNAIL; EMT AB The epithelial-mesenchymal transition (EMT) is a process associated with the metastasis of solid tumors as well as with the acquisition of resistance to standard anticancer modalities. A major initiator of EMT in carcinoma cells is TGF-beta, which has been shown to induce the expression of several transcription factors ultimately responsible for initiating and maintaining the EMT program. We have previously identified Brachyury, a T-box transcription factor, as an inducer of mesenchymal features in human carcinoma cells. In this study, a potential link between Brachyury and TGF-beta signaling has been investigated. The results show for the first time that Brachyury expression is enhanced during TGF-beta 1-induced EMT in various human cancer cell lines, and that a positive feedback loop is established between Brachyury and TGF-beta 1 in mesenchymal-like tumor cells. In this context, Brachyury overexpression is shown to promote upregulation of TGF-beta 1 at the mRNA and protein levels, an effect mediated by activation of the TGF-beta 1 promoter in the presence of high levels of Brachyury. Furthermore, inhibition of TGF-beta 1 signaling by a small-molecule inhibitor of TGF-beta receptor type I decreases Brachyury expression, induces a mesenchymal-to-epithelial transition, and renders cancer cells more susceptible to chemotherapy. This study thus has implications for the future development of clinical trials using TGF-beta inhibitors in combination with other anticancer agents. (C) 2013 AACR. C1 [Larocca, Cecilia; Cohen, Joseph R.; Fernando, Romaine I.; Huang, Bruce; Hamilton, Duane H.; Palena, Claudia] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B14,MSC 1750, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This work is supported by the funds from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 49 TC 24 Z9 27 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2013 VL 12 IS 9 BP 1805 EP 1815 DI 10.1158/1535-7163.MCT-12-1007 PG 11 WC Oncology SC Oncology GA 214YE UT WOS:000324174600011 PM 23783250 ER PT J AU Nelson, F Salter, A Narayana, P Gustafson, T Conwit, R Wang, J Cofield, SS Cutter, G Lublin, FD Wolinsky, J AF Nelson, Flavia Salter, Amber Narayana, Ponnada Gustafson, Tarah Conwit, Robin Wang, Jing Cofield, Stacey S. Cutter, Gary Lublin, Fred D. Wolinsky, Jerry TI MRI OUTCOMES AND MS DIAGNOSIS CRITERIA IN THE COMBIRX TRIAL SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 18th Annual Meeting of Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS) CY MAY 31-JUN 01, 2013 CL Orlando, FL SP Americas Comm Treatment & Res Multiple Sclerosis DE Epidemiology of MS C1 [Nelson, Flavia; Narayana, Ponnada; Wolinsky, Jerry] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Salter, Amber; Wang, Jing; Cofield, Stacey S.; Cutter, Gary] Univ Alabama Birmingham, Birmingham, AL USA. [Gustafson, Tarah; Lublin, Fred D.] Mt Sinai Sch Med, Corinne Goldsmith Dickinson Ctr Multiple Sclerosi, New York, NY USA. [Conwit, Robin] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2013 VL 19 IS 10 BP 1392 EP 1393 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 208VM UT WOS:000323709300028 ER PT J AU Oh, J Saidha, S Chen, M Smith, S Prince, J Jones, C van Zijl, P Diener-West, M Reich, DS Calabresi, PA AF Oh, Jiwon Saidha, Shiv Chen, Min Smith, Seth Prince, Jerry Jones, Craig van Zijl, Peter Diener-West, Marie Reich, Daniel S. Calabresi, Peter A. TI RELATIVE CLINICAL UTILITY OF QUANTITATIVE MRI MEASURES IN THE SPINAL CORD IN MS PATIENTS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 18th Annual Meeting of Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS) CY MAY 31-JUN 01, 2013 CL Orlando, FL SP Americas Comm Treatment & Res Multiple Sclerosis DE Imaging and MS C1 [Oh, Jiwon; Saidha, Shiv; Chen, Min; Prince, Jerry; Diener-West, Marie; Calabresi, Peter A.] Johns Hopkins Univ, Baltimore, MD USA. [Smith, Seth] Vanderbilt Univ, Inst Imaging Sci, Dept Radiol & Radiol Sci Biomed Engn Phys & Astro, Nashville, TN 37235 USA. [Jones, Craig; van Zijl, Peter] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Jones, Craig; van Zijl, Peter] Kennedy Krieger Inst, FM Kirby Ctr Funct Brain Imaging, Baltimore, MD USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. [Reich, Daniel S.] Johns Hopkins Univ, Bethesda, MD USA. [Reich, Daniel S.] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Bethesda, MD USA. RI Prince, Jerry/A-3281-2010; Reich, Daniel/E-5701-2010 OI Prince, Jerry/0000-0002-6553-0876; Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2013 VL 19 IS 10 BP 1392 EP 1392 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 208VM UT WOS:000323709300027 ER PT J AU Nash, RA Hutton, GJ Racke, MK Popat, U Devine, SM Georges, GE Griffith, LM Muraro, PA Openshaw, H Sayre, P Stuve, O Arnold, DL Spychala, M Lim, N Malhotra, S Phippard, D Wundes, A Kraft, GH Bowen, JD AF Nash, Richard A. Hutton, George J. Racke, Michael K. Popat, Uday Devine, Steven M. Georges, George E. Griffith, Linda M. Muraro, Paolo A. Openshaw, Harry Sayre, Peter Stuve, Olaf Arnold, Douglas L. Spychala, Meagan Lim, Noha Malhotra, Sachin Phippard, Deborah Wundes, Annette Kraft, George H. Bowen, James D. TI 2-YEAR FOLLOW-UP RESULTS OF THE HALT MS CLINICAL TRIAL (ITN033AI) SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 18th Annual Meeting of Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS) CY MAY 31-JUN 01, 2013 CL Orlando, FL SP Americas Comm Treatment & Res Multiple Sclerosis DE Disease-modifying treatments in MS; Imaging and MS; Immunology and MS C1 [Nash, Richard A.] PSL, Colorado Blood Canc Inst, Denver, CO USA. [Hutton, George J.] Baylor Coll Med, Houston, TX 77030 USA. [Racke, Michael K.; Devine, Steven M.] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA. [Popat, Uday] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Georges, George E.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Griffith, Linda M.] NIAID, NIH, Bethesda, MD 20892 USA. [Muraro, Paolo A.] Univ London Imperial Coll Sci Technol & Med, London, England. [Openshaw, Harry] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Sayre, Peter; Phippard, Deborah] Immune Tolerance Network, San Francisco, CA USA. [Stuve, Olaf] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Arnold, Douglas L.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Arnold, Douglas L.] NeuroRx Res, Montreal, PQ, Canada. [Spychala, Meagan] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Lim, Noha; Malhotra, Sachin] Immune Tolerance Network, Boston, MA USA. [Wundes, Annette; Kraft, George H.] Univ Washington, Seattle, WA 98195 USA. [Bowen, James D.] Swedish Med Ctr, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2013 VL 19 IS 10 MA P20 BP 1407 EP 1408 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 208VM UT WOS:000323709300055 ER PT J AU Oh, J Seigo, M Saidha, S Sotirchos, ES Zackowski, KM Chen, M Prince, J Diener-West, M Calabresi, PA Reich, DS AF Oh, Jiwon Seigo, Michaela Saidha, Shiv Sotirchos, Elias S. Zackowski, Kathleen M. Chen, Min Prince, Jerry Diener-West, Marie Calabresi, Peter A. Reich, Daniel S. TI SPINAL CORD NORMALIZATION IN MULTIPLE SCLEROSIS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 18th Annual Meeting of Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS) CY MAY 31-JUN 01, 2013 CL Orlando, FL SP Americas Comm Treatment & Res Multiple Sclerosis DE Imaging and MS C1 [Oh, Jiwon; Seigo, Michaela; Saidha, Shiv; Sotirchos, Elias S.; Chen, Min; Prince, Jerry; Diener-West, Marie] Johns Hopkins Univ, Baltimore, MD USA. [Zackowski, Kathleen M.; Calabresi, Peter A.] Johns Hopkins Sch Med, Baltimore, MD USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. RI Prince, Jerry/A-3281-2010; Reich, Daniel/E-5701-2010 OI Prince, Jerry/0000-0002-6553-0876; Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2013 VL 19 IS 10 MA P22 BP 1408 EP 1409 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 208VM UT WOS:000323709300057 ER PT J AU Bashir, K Cofield, SS Cutter, G Wolinsky, J Gustafson, T Conwit, R Salter, A Wang, J Lublin, FD AF Bashir, Khurram Cofield, Stacey S. Cutter, Gary Wolinsky, Jerry Gustafson, Tarah Conwit, Robin Salter, Amber Wang, Jing Lublin, Fred D. TI CLINICAL OUTCOMES AND MS DIAGNOSIS CRITERIA IN THE COMBIRX TRIAL SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 18th Annual Meeting of Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS) CY MAY 31-JUN 01, 2013 CL Orlando, FL SP Americas Comm Treatment & Res Multiple Sclerosis DE Epidemiology of MS C1 [Bashir, Khurram; Cofield, Stacey S.; Cutter, Gary; Salter, Amber; Wang, Jing] Univ Alabama Birmingham, Birmingham, AL USA. [Wolinsky, Jerry] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Gustafson, Tarah; Lublin, Fred D.] Corinne Goldsmith Dickinson Ctr Multiple Sclerosi, New York, NY USA. [Conwit, Robin] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2013 VL 19 IS 10 MA P42 BP 1418 EP 1419 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 208VM UT WOS:000323709300077 ER PT J AU Jourdan, T Godlewski, G Cinar, R Bertola, A Szanda, G Liu, J Tam, J Han, T Mukhopadhyay, B Skarulis, MC Ju, C Aouadi, M Czech, MP Kunos, G AF Jourdan, Tony Godlewski, Grzegorz Cinar, Resat Bertola, Adeline Szanda, Gergo Liu, Jie Tam, Joseph Han, Tiffany Mukhopadhyay, Bani Skarulis, Monica C. Ju, Cynthia Aouadi, Myriam Czech, Michael P. Kunos, George TI Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes SO NATURE MEDICINE LA English DT Article ID THIOREDOXIN-INTERACTING PROTEIN; INDUCED INSULIN-RESISTANCE; CB1 RECEPTOR ANTAGONIST; DIET-INDUCED OBESITY; CANNABINOID RECEPTORS; NALP3 INFLAMMASOME; ADIPOSE-TISSUE; BODY-WEIGHT; ER STRESS; MICE AB Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat, The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB(1)Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB1R-deficient (Cnr1(-/-)) or Nirp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB1R as a therapeutic target in T2DM. C1 [Jourdan, Tony; Godlewski, Grzegorz; Cinar, Resat; Szanda, Gergo; Liu, Jie; Tam, Joseph; Han, Tiffany; Mukhopadhyay, Bani; Kunos, George] NIAAA, Lab Physiol Studies, US Natl Inst Hlth, Bethesda, MD USA. [Bertola, Adeline] NIAAA, Lab Liver Dis, US Natl Inst Hlth, Bethesda, MD USA. [Skarulis, Monica C.] NIDDK, Diabet Endocrinol & Obes Branch, US Natl Inst Hlth, Bethesda, MD USA. [Ju, Cynthia] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Aouadi, Myriam; Czech, Michael P.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA. RP Jourdan, T (reprint author), NIAAA, Lab Physiol Studies, US Natl Inst Hlth, Bethesda, MD USA. EM jourdant@mail.nih.gov; george.kunos@nih.gov OI CINAR, RESAT/0000-0002-8597-7253; Bertola, Adeline/0000-0002-4885-8423 FU intramural NIH funds; NIH [DK085753, AI046629] FX We thank J.F. McElroy and R.J. Chorvat (Jenrin Discovery) for providing the CB1R antagonist JD5037 and its inactive diastereomer, O. Gavrilova (NIDDK, US National Institutes of Health (NIH)) for advice on pancreatic islet isolation, J. Harvey-White for technical assistance, D. Feng for FACS analyses, R. Kechrid for assistance with the animal studies and P. Staker for collecting human blood specimens. This study was supported by intramural NIH funds. The work from M.P.C.'s laboratory was supported by grants from the NIH (DK085753 and AI046629). NR 59 TC 100 Z9 103 U1 1 U2 34 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2013 VL 19 IS 9 BP 1132 EP 1140 DI 10.1038/nm.3265 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 213TP UT WOS:000324083500027 PM 23955712 ER PT J AU Emblem, KE Mouridsen, K Bjornerud, A Farrar, CT Jennings, D Borra, RJH Wen, PY Ivy, P Batchelor, TT Rosen, BR Jain, RK Sorensen, AG AF Emblem, Kyrre E. Mouridsen, Kim Bjornerud, Atle Farrar, Christian T. Jennings, Dominique Borra, Ronald J. H. Wen, Patrick Y. Ivy, Percy Batchelor, Tracy T. Rosen, Bruce R. Jain, Rakesh K. Sorensen, A. Gregory TI Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy SO NATURE MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MAGNETIC-SUSCEPTIBILITY; ANTIANGIOGENIC THERAPY; GLIOBLASTOMA PATIENTS; TUMOR ANGIOGENESIS; KINASE INHIBITOR; MR CONTRAST; VASCULATURE; MICROCIRCULATION; MECHANISMS AB Measurement of vessel caliber by magnetic resonance imaging (MRI) is a valuable technique for in vivo monitoring of hemodynamic status and vascular development, especially in the brain. Here, we introduce a new paradigm in MRI termed vessel architectural imaging (VAI) that exploits an overlooked temporal shift in the magnetic resonance signal, forming the basis for vessel caliber estimation, and show how this phenomenon can reveal new information on vessel type and function not assessed by any other noninvasive imaging technique. We also show how this biomarker can provide new biological insights into the treatment of patients with cancer. As an example, we demonstrate using VAI that anti-angiogenic therapy can improve microcirculation and oxygen saturation and reduce vessel calibers in patients with recurrent glioblastomas and, more crucially, that patients with these responses have prolonged survival. Thus, VAI has the potential to identify patients who would benefit from therapies. C1 [Emblem, Kyrre E.; Mouridsen, Kim; Farrar, Christian T.; Jennings, Dominique; Borra, Ronald J. H.; Rosen, Bruce R.; Sorensen, A. Gregory] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Emblem, Kyrre E.; Mouridsen, Kim; Farrar, Christian T.; Jennings, Dominique; Borra, Ronald J. H.; Rosen, Bruce R.; Sorensen, A. Gregory] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Emblem, Kyrre E.; Mouridsen, Kim; Farrar, Christian T.; Jennings, Dominique; Borra, Ronald J. H.; Wen, Patrick Y.; Batchelor, Tracy T.; Rosen, Bruce R.; Jain, Rakesh K.; Sorensen, A. Gregory] Harvard Univ, Sch Med, Boston, MA USA. [Emblem, Kyrre E.; Bjornerud, Atle] Oslo Univ Hosp, Intervent Ctr, Oslo, Norway. [Mouridsen, Kim] Univ Aarhus, Ctr Funct Integrat Neurosci, Aarhus, Denmark. [Mouridsen, Kim] Univ Aarhus, MINDLab, Aarhus, Denmark. [Bjornerud, Atle] Univ Oslo, Dept Phys, Oslo, Norway. [Borra, Ronald J. H.] Turku Univ Hosp, Med Imaging Ctr Southwest Finland, FIN-20520 Turku, Finland. [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Ivy, Percy] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Batchelor, Tracy T.; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sorensen, A. Gregory] Siemens Healthcare Hlth Serv, Malvern, PA USA. RP Emblem, KE (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM kyrre@mmr.mgh.harvard.edu RI Emblem, Kyrre/H-6691-2012; OI Emblem, Kyrre/0000-0002-6580-9519; Borra, Ronald/0000-0001-8072-1243 FU US Public Health Service [R21CA117079, S10RR023401, S10RR019307, S10RR019254, S10RR023043, S10RR021110, R01CA137254, R01CA129371, 5R01NS060918, K24CA125440, P0ICA80124, K25AG029415]; US National Cancer Institute [NCT00035656]; SAIC-Frederick Inc. [26XS263]; Norwegian Research Council [191088/F20]; South-Eastern Norway Regional Health Authority Grant [2013069]; Danish Research Foundation (Center of Functionally Integrative Neuroscience); Ministry of Science, Innovation and Technology Denmark (Investment Capital for University Research); Sigrid Juselius Foundation; Instrumentarium Research Foundation; Academy of Finland; Paulo Foundation; Finnish Medical Foundation; Harvard Catalyst Harvard Clinical and Translational Science Center (US National Institutes of Health Award) [UL1 RR 025758, M01-RR-01066]; Harvard University FX The authors thank T. Stylianopoulos (Department of Mechanical and Manufacturing Engineering, University of Cyprus) and J.W. Baish (Department of Mechanical and Biomedical Engineering, Bucknell University) for critical reading of this manuscript. This work was funded by the US Public Health Service (grants R21CA117079, S10RR023401, S10RR019307, S10RR019254, S10RR023043, S10RR021110, R01CA137254, R01CA129371, 5R01NS060918, K24CA125440, P0ICA80124 and K25AG029415), by the US National Cancer Institute (http://www.clinicaltrials.gov/, NCT00035656); SAIC-Frederick Inc. grant 26XS263; Norwegian Research Council grant 191088/F20; South-Eastern Norway Regional Health Authority Grant 2013069; the Danish Research Foundation (Center of Functionally Integrative Neuroscience); the Ministry of Science, Innovation and Technology Denmark (Investment Capital for University Research); the Sigrid Juselius Foundation; the Instrumentarium Research Foundation; the Academy of Finland; the Paulo Foundation; and the Finnish Medical Foundation. This work was conducted with support from Harvard Catalyst Harvard Clinical and Translational Science Center (US National Institutes of Health Award nos. UL1 RR 025758 and M01-RR-01066 and financial contributions from Harvard University and its affiliated academic healthcare centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the US National Center for Research Resources or the US National Institutes of Health. NR 27 TC 58 Z9 59 U1 1 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2013 VL 19 IS 9 BP 1178 EP 1183 DI 10.1038/nm.3289 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 213TP UT WOS:000324083500035 PM 23955713 ER PT J AU Kenworthy, L Yerys, BE Weinblatt, R Abrams, DN Wallace, GL AF Kenworthy, Lauren Yerys, Benjamin E. Weinblatt, Rachel Abrams, Danielle N. Wallace, Gregory L. TI Motor Demands Impact Speed of Information Processing in Autism Spectrum Disorders SO NEUROPSYCHOLOGY LA English DT Article DE autism spectrum disorder; processing speed; motor abilities; communication ID HIGH-FUNCTIONING AUTISM; ASPERGER-SYNDROME; COGNITIVE-ABILITIES; INSPECTION TIME; WISC-IV; CHILDREN; INTELLIGENCE; IMPAIRMENT; DYSPRAXIA; ADHD AB The apparent contradiction between preserved or even enhanced perceptual processing speed on inspection time tasks in autism spectrum disorders (ASD) and impaired performance on complex processing speed tasks that require motor output (e.g., Wechsler Processing Speed Index) has not yet been systematically investigated. This study investigates whether adding motor output demands to an inspection time task impairs ASD performance compared to that of typically developing control (TDC) children. The performance of children with ASD (n = 28; mean Full Scale IQ (FSIQ) = 115) and TDC (n = 25; mean FSIQ = 122) children was compared on processing speed tasks with increasing motor demand. Correlations were run between ASD task performance and Autism Diagnostic Observation Schedule (ADOS) Communication scores. Performance by the ASD and TDC groups on a simple perceptual processing speed task with minimal motor demand was equivalent, though it diverged (ASD worse than TDC) on 2 tasks with the same stimuli but increased motor output demands. ASD performance on the moderate but not the high speeded motor output demand task was negatively correlated with ADOS communication symptoms. These data address the apparent contradiction between preserved inspection time in the context of slowed "processing speed" in ASD. They show that processing speed is preserved when motor demands are minimized, but that increased motor output demands interfere with the ability to act on perceptual processing of simple stimuli. Reducing motor demands (e.g., through the use of computers) may increase the capacity of people with ASD to demonstrate good perceptual processing in a variety of educational, vocational, and social settings. C1 [Kenworthy, Lauren; Yerys, Benjamin E.; Weinblatt, Rachel; Abrams, Danielle N.] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Rockville, MD 20850 USA. [Yerys, Benjamin E.] Childrens Hosp Philadelphia, Ctr Autism Res, Philadelphia, PA 19104 USA. [Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Kenworthy, L (reprint author), Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, 15245 Shady Grove Rd,Suite 350, Rockville, MD 20850 USA. EM lkenwort@cnmc.org OI Wallace, Gregory/0000-0003-0329-5054 FU NIH, National Institute of Mental Health Intramural Research Program; NIH, National Institute of Mental Health [K23MH086111]; Singer Family Foundation; Isadore and Bertha Gudelsky Family Foundation FX We thank the children and families who offered their time for the current study. We also thank Mike Anderson for use of task stimuli. There are no conflicts of interest, financial or otherwise, for the authors involved directly or indirectly with this article. Lauren Kenworthy and Gregory L. Wallace were supported by the NIH, National Institute of Mental Health Intramural Research Program. Benjamin E. Yerys was supported by a K23 Career Development Award from the NIH, National Institute of Mental Health (K23MH086111). Lauren Kenworthy and Benjamin E. Yerys were also supported by awards from The Singer Family Foundation and The Isadore and Bertha Gudelsky Family Foundation. NR 28 TC 5 Z9 5 U1 3 U2 13 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD SEP PY 2013 VL 27 IS 5 BP 529 EP 536 DI 10.1037/a0033599 PG 8 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 212VV UT WOS:000324011800003 PM 23937483 ER PT J AU Yerys, BE Kenworthy, L Jankowski, KF Strang, J Wallace, GL AF Yerys, Benjamin E. Kenworthy, Lauren Jankowski, Kathryn F. Strang, John Wallace, Gregory L. TI Separate Components of Emotional Go/No-Go Performance Relate to Autism Versus Attention Symptoms in Children With Autism SO NEUROPSYCHOLOGY LA English DT Article DE autism; attention-deficit/hyperactivity disorder; cognitive control; response inhibition; emotion ID DEFICIT/HYPERACTIVITY DISORDER; EXECUTIVE FUNCTIONS; SPECTRUM DISORDERS; SUSTAINED ATTENTION; ADHD; HYPERACTIVITY; ENDOPHENOTYPES; INDIVIDUALS; IMPAIRMENT; INTERVIEW AB Objective: The present investigation examined whether higher functioning children with autism would demonstrate impaired response inhibition performance in an emotional go/no-go task, and whether severity of attention-deficit/hyperactivity disorder (ADHD) or autism symptoms correlated with performance. Method: Forty-four children (21 meeting criteria for autism; 23 typically developing controls [TDCs]) completed an emotional go/no-go task in which an emotional facial expression (angry, fearful, happy, or sad) was the go stimulus and a neutral facial expression was the no-go stimulus, and vice versa. Results: The autism group was faster than the TDC group on all emotional go,trials. Moreover, the children in the autism group who had the fastest reaction times on emotional go trials were rated as having the greatest number of symptoms (Autism Diagnostic Observation Schedule Social + Communication score), even after accounting for the association with ADHD symptoms. The autism group also made more impulsive responses (i.e., lower d', more false alarms) than the TDC group on all trials. As d' decreased or false alarms increased, so. did ADHD symptoms. Hyperactivity/impulsivity symptoms were significantly correlated with false alarms, but inattention symptoms were not. There was not a significant relationship between no-go false alarms and autism symptoms; even after partialing out associations with autism symptoms, the significant correlation between ADHD symptoms and no-go false alarms remained. Conclusion: The present findings support a comorbidity model that argues for shared and independent risk factors, because ADHD and autism symptoms related to independent aspects of emotional go/no-go performance. C1 [Yerys, Benjamin E.] Childrens Hosp Philadelphia, Ctr Autism Res, Philadelphia, PA 19104 USA. [Yerys, Benjamin E.; Kenworthy, Lauren; Jankowski, Kathryn F.; Strang, John] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. [Yerys, Benjamin E.; Kenworthy, Lauren; Jankowski, Kathryn F.; Strang, John] Childrens Natl Med Ctr, Childrens Res Inst, Washington, DC 20010 USA. [Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Intramural Res Program, Bethesda, MD 20892 USA. RP Yerys, BE (reprint author), Ctr Autism Res, 3535 Market St,Suite 860, Philadelphia, PA 19104 USA. EM yerysb@email.chop.edu OI Jankowski, Kathryn/0000-0003-3096-0814; Wallace, Gregory/0000-0003-0329-5054 FU Intramural Research Program of the National Institutes of Health, National Institute of Mental Health; Isadore and Bertha Gudelsky Foundation; Elizabeth and Frederick Singer Foundation; National Institute of Mental Health [K23MH086111, R21MH092615] FX We thank the families for volunteering their time and effort to participate in our studies. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health, Isadore and Bertha Gudelsky Foundation, the Elizabeth and Frederick Singer Foundation, and the National Institute of Mental Health Awards K23MH086111 (PI: Benjamin E. Yerys) and R21MH092615 (PI: Benjamin E. Yerys). We thank Rachel Weinblatt and Jennifer Sokoloff from the Center for Autism Spectrum Disorders at Children's National Medical Center for their assistance in data collection. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. NR 43 TC 8 Z9 9 U1 6 U2 37 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD SEP PY 2013 VL 27 IS 5 BP 537 EP 545 DI 10.1037/a0033615 PG 9 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 212VV UT WOS:000324011800004 PM 23937480 ER PT J AU Wong, SJ Campbell, B Massey, B Lynch, DP Cohen, EEW Blair, E Selle, R Shklovskaya, J Jovanovic, BD Skripkauskas, S Dew, A Kulesza, P Parimi, V Bergan, RC Szabo, E AF Wong, Stuart J. Campbell, Bruce Massey, Becky Lynch, Denis P. Cohen, Ezra E. W. Blair, Elizabeth Selle, Rebecca Shklovskaya, Julia Jovanovic, Borko D. Skripkauskas, Silvia Dew, Alexander Kulesza, Peter Parimi, Vamsi Bergan, Raymond C. Szabo, Eva TI A phase I trial of aminolevulinic acid-photodynamic therapy for treatment of oral leukoplakia SO ORAL ONCOLOGY LA English DT Article DE Leukoplakia; Aminolevulinic acid; Photodynamic therapy; Phase I; Laser ID DYSPLASTIC BARRETTS-ESOPHAGUS; TOPICAL 5-AMINOLEVULINIC ACID; LIGHT-EMITTING DIODE; VERRUCOUS HYPERPLASIA; EPITHELIAL DYSPLASIA; INDUCED FLUORESCENCE; CANCER; ERYTHROLEUKOPLAKIA; LESIONS; CAVITY AB Background: Photodynamic therapy with aminolevulinic acid (ALA PDT) for oral leukoplakia has shown promising effects in regression of oral leukoplakia. Although ALA has been extensively studied and is an ideal photosensitizer, the optimal light dose for treatment of oral leukoplakia has not been determined. We conducted a phase I study to determine MTD and DLT of PDT in patients treated with ALA for leukoplakia. Methods: Patients with histologically confirmed oral leukoplakia received a single treatment of ALA PDT in cohorts with escalating doses of light (585 nm). Clinical, histologic, and biologic markers were assessed. Results: Analysis of 11 participants is reported. No significant toxicity from ALA PDT was observed in patients who received ALA with a light dose of up to 4 J/cm(2). One participant experienced transient grade 3 transaminase elevation due to ALA. One participant had a partial clinical response 3 months after treatment. Biologic mucosal risk markers showed no significant associations. Determination of MTD could not be accomplished within a feasible timeframe for completion of the study. Conclusions: ALA PDT could be safely administered with a light dose up to 4 J/cm(2) and demonstrated activity. Larger studies are needed to fully elucidate the MTD and efficacy of ALA-PDT. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Wong, Stuart J.; Campbell, Bruce; Massey, Becky; Selle, Rebecca] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Lynch, Denis P.] Marquette Univ, Sch Dent, Milwaukee, WI 53233 USA. [Cohen, Ezra E. W.; Blair, Elizabeth] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Bergan, Raymond C.] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Chicago, IL 60611 USA. [Szabo, Eva] NCI, Canc Prevent Div, NIH, Chicago, IL USA. RP Wong, SJ (reprint author), Med Coll Wisconsin, Div Hematol Oncol, Dept Med, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. EM swong@mcw.edu RI Parimi, Vamsi/P-5675-2014; OI Campbell, Bruce/0000-0001-9485-5728 FU [N01CN35157] FX Supported by N01CN35157. Stuart Marcus, M. D., Ph. D. (DUSA Pharmaceuticals, Wilmingham, MA) for supplying agent and device, and Judy Smith (DCP) for study support. NR 26 TC 5 Z9 6 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2013 VL 49 IS 9 BP 970 EP 976 DI 10.1016/j.oraloncology.2013.05.011 PG 7 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 213HJ UT WOS:000324046200021 PM 23845699 ER PT J AU Huang, YP Cao, YF Fang, ZZ Zhang, YY Hu, CM Sun, XY Yu, ZW Zhu, X Hong, M Yang, L Sun, HZ AF Huang, Yin-Peng Cao, Yun-Feng Fang, Zhong-Ze Zhang, Yan-Yan Hu, Cui-Min Sun, Xiao-Yu Yu, Zhen-Wen Zhu, Xu Hong, Mo Yang, Lu Sun, Hong-Zhi TI Glycyrrhetinic Acid Exhibits Strong Inhibitory Effects Towards UDP-Glucuronosyltransferase (UGT) 1A3 and 2B7 SO PHYTOTHERAPY RESEARCH LA English DT Article DE licorice; glycyrrhizic acid; glycyrrhetinic acid; UDP-glucuronosyltransferases (UGTs); herb-drug interaction ID DRUG-DRUG INTERACTIONS; HUMAN LIVER; GLUCURONIDATION; POLYMORPHISM; CELLS AB The aim of the present study is to evaluate the inhibitory effects of liver UDP-glucuronosyltransferases (UGTs) by glycyrrhizic acid and glycyrrhetinic acid, which are the bioactive ingredients isolated from licorice. The results showed that glycyrrhetinic acid exhibited stronger inhibition towards all the tested UGT isoforms, indicating that the deglycosylation process played an important role in the inhibitory potential towards UGT isoforms. Furthermore, the inhibition kinetic type and parameters were determined for the inhibition of glycyrrhetinic acid towards UGT1A3 and UGT2B7. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that the inhibition of UGT1A3 and UGT2B7 by glycyrrhetinic acid was best fit to competitive and noncompetitive type, respectively. The second plot using the slopes from Lineweaver-Burk plots versus glycyrrhetinic acid concentrations was employed to calculate the inhibition kinetic parameters (K-i), and the values were calculated to be 0.2 and 1.7M for UGT1A3 and UGT2B7, respectively. All these results remind us the possibility of UGT inhibition-based herb-drug interaction. However, the explanation of these in vitro parameters should be paid more caution due to complicated factors, including the probe substrate-dependent UGT inhibition behaviour, environmental factors affecting the abundance of herbs' ingredients, and individual difference of pharmacokinetic factors. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Huang, Yin-Peng; Sun, Hong-Zhi] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. [Cao, Yun-Feng; Fang, Zhong-Ze; Zhang, Yan-Yan; Sun, Xiao-Yu; Yu, Zhen-Wen; Zhu, Xu; Hong, Mo; Yang, Lu; Sun, Hong-Zhi] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Cao, Yun-Feng; Fang, Zhong-Ze; Zhang, Yan-Yan; Sun, Xiao-Yu; Yu, Zhen-Wen; Zhu, Xu; Hong, Mo; Yang, Lu; Sun, Hong-Zhi] Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China. [Fang, Zhong-Ze; Hu, Cui-Min] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Sun, HZ (reprint author), Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. EM cmushz@163.com FU National Natural Science Foundation of China [81202586] FX This work was supported by the National Natural Science Foundation of China (No. 81202586). NR 25 TC 11 Z9 13 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-418X J9 PHYTOTHER RES JI Phytother. Res. PD SEP PY 2013 VL 27 IS 9 BP 1358 EP 1361 DI 10.1002/ptr.4875 PG 4 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 213AB UT WOS:000324024000016 PM 23148031 ER PT J AU Sutin, AR Costa, PT Evans, MK Zonderman, AB AF Sutin, Angelina R. Costa, Paul T., Jr. Evans, Michele K. Zonderman, Alan B. TI Personality Assessment in a Diverse Urban Sample SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE personality assessment; psychometrics; literacy; Openness to Experience; socioeconomic status ID LIFE-SPAN; STABILITY; EDUCATION; TRAITS AB In the present research, the authors examined the data quality and replicability of the Revised NEO Personality Inventory (NEO-PI-R) factor structure in a sample that varied in ethnicity, socioeconomic status, and literacy. Participants (N = 546), drawn from the Healthy Aging in Neighborhoods of Diversity Across the Life Span study, were African American (58%) and White (42%) urban dwellers living above (49%) and below (51%) 125% of the federal poverty line. The NEO-PI-R, administered via telephone, was evaluated for data quality (percent valid, acquiescence, internal consistency), congruence with the normative factor structure, and readability. All indices of data quality and factor congruence were excellent in the full sample. Literacy was the most consistent predictor of data quality. A slightly worse structure was found for the Openness to Experience and Extraversion factors among lower socioeconomic status African American and White participants. The overall index of factor congruence, however, supports replication of the normative structure well beyond chance levels even among those with lower literacy. Despite the challenges of low literacy, the present findings indicate that personality traits can be assessed reliably in socioeconomically diverse populations that include those living in poverty. C1 [Sutin, Angelina R.] Florida State Univ, Coll Med, Dept Med Humanities & Social Sci, Tallahassee, FL 32306 USA. [Sutin, Angelina R.; Costa, Paul T., Jr.; Evans, Michele K.; Zonderman, Alan B.] NIA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Sutin, AR (reprint author), Florida State Univ, Coll Med, Dept Med Humanities & Social Sci, Tallahassee, FL 32306 USA. EM angelina.sutin@med.fsu.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [Z99 AG999999] NR 21 TC 6 Z9 6 U1 1 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD SEP PY 2013 VL 25 IS 3 BP 1007 EP 1012 DI 10.1037/a0032396 PG 6 WC Psychology, Clinical SC Psychology GA 212PH UT WOS:000323994800030 PM 23815114 ER PT J AU Keck, TM Yang, HJ Bi, GH Huang, Y Zhang, HY Srivastava, R Gardner, EL Newman, AH Xi, ZX AF Keck, Thomas M. Yang, Hong-Ju Bi, Guo-Hua Huang, Yong Zhang, Hai-Ying Srivastava, Ratika Gardner, Eliot L. Newman, Amy Hauck Xi, Zheng-Xiong TI Fenobam sulfate inhibits cocaine-taking and cocaine-seeking behavior in rats: implications for addiction treatment in humans SO PSYCHOPHARMACOLOGY LA English DT Article DE Cocaine; Fenobam; Self-administration; Reinstatement; Cocaine-seeking behavior; Incubation of cocaine craving; mGluR5 ID METABOTROPIC GLUTAMATE RECEPTORS; NEGATIVE ALLOSTERIC MODULATORS; CUE-INDUCED REINSTATEMENT; MGLUR5 ANTAGONIST MPEP; STRESS-INDUCED RELAPSE; NUCLEUS-ACCUMBENS; DRUG-SEEKING; IN-VIVO; SUBSYNAPTIC LOCALIZATION; SQUIRREL-MONKEYS AB Rationale The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be critically involved in drug reward and addiction. Because the mGluR5 negative allosteric modulators (NAMs) 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) significantly inhibit addictive like behaviors of cocaine and other drugs of abuse in experimental animals, it has been suggested that mGluR5 NAMs may have translational potential for treatment of addiction in humans. However, neither MPEP nor MTEP have been evaluated in humans due to their off-target actions and rapid metabolism. Objectives Herein, we evaluate a potential candidate for translational addiction research: a new sulfate salt formulation of fenobam, a selective mGluR5 NAM that has been investigated in humans. Results In rats, fenobam sulfate had superior pharmacokinetics compared to the free base, with improved maximal plasma concentration (C-max) and longer half life. Oral (p.o.) administration of fenobam sulfate (30 or 60 mg/kg) inhibited intravenous (i.v.) cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior, and cocaine-associated cue-induced cocaine-seeking behavior in rats. Fenobam sulfate also inhibited p.o. sucrose self-administration and sucrose-induced reinstatement of sucrose-seeking behavior, but had no effect on locomotion. Conclusions This study provides additional support for the role of mGluR5 signaling in cocaine addiction and suggests that fenobam sulfate may have translational potential in medication development for the treatment of cocaine addiction in humans. C1 [Keck, Thomas M.; Newman, Amy Hauck] Mol Targets & Medicat Discovery Branch, Med Chem Sect, Baltimore, MD 21224 USA. [Yang, Hong-Ju; Bi, Guo-Hua; Zhang, Hai-Ying; Srivastava, Ratika; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Neuropsychopharmacol Sect, Chem Biol Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. [Huang, Yong] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. RP Newman, AH (reprint author), Mol Targets & Medicat Discovery Branch, Med Chem Sect, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov; zxi@mail.nih.gov RI Keck, Thomas/G-9798-2012; OI Keck, Thomas/0000-0003-1845-9373; Srivastava, Rakesh/0000-0002-0065-4069; Zhang, Haiying/0000-0003-0593-5940 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; NIH Postdoctoral Intramural Research Training Associate (IRTA) Fellowship; NIDA [N01DA-9-8883] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. T. M. K. was supported by an NIH Postdoctoral Intramural Research Training Associate (IRTA) Fellowship. Pharmacokinetic data was provided under NIDA Contract, N01DA-9-8883. We thank Drs. Phil Skolnick and Amrat Patel, Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, for providing the fenobam free base and fenobam sulfate, helpful discussions, and critical reading of this manuscript. NR 66 TC 11 Z9 11 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2013 VL 229 IS 2 BP 253 EP 265 DI 10.1007/s00213-013-3106-9 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214OP UT WOS:000324143700005 PM 23615919 ER PT J AU Tanda, G Li, SM Mereu, M Thomas, AM Ebbs, AL Chun, LE Tronci, V Green, JL Zou, MF Kopajtic, TA Newman, AH Katz, JL AF Tanda, Gianluigi Li, Su Min Mereu, Maddalena Thomas, Alexandra M. Ebbs, Aaron L. Chun, Lauren E. Tronci, Valeria Green, Jennifer L. Zou, Mu-Fa Kopajtic, Theresa A. Newman, Amy Hauck Katz, Jonathan L. TI Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change SO PSYCHOPHARMACOLOGY LA English DT Article DE Dopamine transporter conformation; Accumbens shell; Drug abuse; Dopamine microdialysis; Place preference; Benztropine analogs; Cocaine ID UPTAKE INHIBITORS; INTRAVENOUS COCAINE; NUCLEUS-ACCUMBENS; 3-ALPHA-DIPHENYLMETHOXYTROPANE ANALOGS; EXTRACELLULAR DOPAMINE; BENZTROPINE ANALOGS; IN-VIVO; BINDING; AMPHETAMINE; TRANSMISSION AB Rationale Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change. Methods We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place conditioning in rats among cocaine and four BZT analogs with Cl substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring. Results Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, i.p.), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning. Conclusions The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast, BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse. C1 [Tanda, Gianluigi; Li, Su Min; Mereu, Maddalena; Thomas, Alexandra M.; Ebbs, Aaron L.; Chun, Lauren E.; Tronci, Valeria; Green, Jennifer L.; Kopajtic, Theresa A.; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zou, Mu-Fa; Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, 251 Bayview Blvd,NIDA Suite 200, Baltimore, MD 21224 USA. EM jkatz@mail.nih.gov RI Tanda, Gianluigi/B-3318-2009; OI Tanda, Gianluigi/0000-0001-9526-9878; Katz, Jonathan/0000-0002-1068-1159 FU NIDA Intramural Research Program FX The present report was funded by NIDA Intramural Research Program. NR 48 TC 7 Z9 8 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2013 VL 229 IS 2 BP 307 EP 321 DI 10.1007/s00213-013-3109-6 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214OP UT WOS:000324143700010 PM 23612854 ER PT J AU Phillips, SM Wojcicki, TR McAuley, E AF Phillips, Siobhan M. Wojcicki, Thomas R. McAuley, Edward TI Physical activity and quality of life in older adults: an 18-month panel analysis SO QUALITY OF LIFE RESEARCH LA English DT Article DE Physical activity; Quality of life; Self-efficacy; Older adults ID MAXIMUM-LIKELIHOOD-ESTIMATION; STRUCTURAL EQUATION MODELS; SELF-EFFICACY; ACTIVITY SCALE; ELDERLY PASE; MISSING DATA; SATISFACTION; HEALTH; PARTICIPATION; MAINTENANCE AB Although physical activity has been associated with quality of life (QOL), the empirical evidence regarding the mechanisms underlying this relationship is limited. In the present study, we examined the mediating roles played by self-efficacy and health status in the physical activity-QOL relationship from baseline to 18-month follow-up in a sample of community-dwelling older adults. Community-dwelling adults (N = 321, M age = 63.8 years) were recruited to participate in a cross-sectional study and were later contacted to participate in an 18-month follow-up. Individuals completed a battery of questionnaires assessing physical activity, self-efficacy, physical self-worth, disability limitations, and quality of life. A panel analysis within a covariance modeling framework was used to analyze the data. Overall, the model was a good fit to the data (chi(2) = 61.00, df = 29, p < 0.001, standardized root mean residual = 0.05, Comparative Fit Index = 0.97) with changes in physical activity indirectly influencing change in life satisfaction from baseline to 18 months via changes in exercise self-efficacy, physical self-worth, and disability limitations independent of baseline relationships and demographic factors. Specifically, increases in physical activity were associated with increases in exercise self-efficacy which, in turn, was associated with higher physical self-worth and fewer disability limitations which were associated with greater life satisfaction. The findings from this study suggest the relationship between physical activity and global QOL in older adults may be mediated by more proximal modifiable outcomes that can be targeted in physical activity programs and interventions. C1 [Phillips, Siobhan M.; Wojcicki, Thomas R.; McAuley, Edward] Univ Illinois, Dept Kinesiol & Community Hlth, Urbana, IL 61801 USA. [Phillips, Siobhan M.] NCI, Ctr Canc Training, Bethesda, MD 20892 USA. RP Phillips, SM (reprint author), NCI, Ctr Canc Training, 6120 Execut Blvd,Suite 150E, Bethesda, MD 20892 USA. EM smphillips19@gmail.com OI Wojcicki, Thomas/0000-0001-6320-413X FU National Institute on Aging [AG020118]; University of Illinois Urbana Champaign FX This study was funded in part by a grant from the National Institute on Aging (AG020118) and a Shahid and Ann Carlson Khan Professorship in Applied Health Sciences at the University of Illinois Urbana Champaign. NR 43 TC 9 Z9 9 U1 2 U2 32 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD SEP PY 2013 VL 22 IS 7 BP 1647 EP 1654 DI 10.1007/s11136-012-0319-z PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 214BL UT WOS:000324105100013 PM 23161331 ER PT J AU Sarkin, AJ Groessl, EJ Carlson, JA Tally, SR Kaplan, RM Sieber, W Ganiats, TG AF Sarkin, Andrew J. Groessl, Erik J. Carlson, Jordan A. Tally, Steven R. Kaplan, Robert M. Sieber, William J. Ganiats, Theodore G. TI Development and validation of a mental health subscale from the Quality of Well-Being Self-Administered SO QUALITY OF LIFE RESEARCH LA English DT Article DE QWB-SA; Quality of life; Mental health; Mental illness; Mental health screening ID OF-LIFE; MAJOR DEPRESSION; IQOLA PROJECT; SURVEY SF-36; ILLNESS; SCHIZOPHRENIA; INDEXES; SYSTEM; MODEL; SCALE AB The purpose of this study was to create and validate a mental health subscale for the Quality of Well-Being Self-Administered (QWB-SA). The QWB-SA and other measures such as the Profile of Mood States (POMS), Medical Outcomes Study 36 Item Short Form (SF-36), EuroQOL 5D (EQ-5D), and Health Utilities Index Mark 2 (HUI) were administered to three samples: a general population (N = 3,844), a non-psychiatric medical population (N = 535), and a psychiatric population (N = 915). Independent expert ratings of which items represented the construct of mental health were used along with psychometric methods to develop and validate a 10-item QWB-SA mental health scale. The mental health scale demonstrated high internal consistency (Cronbach's alpha = 0.827-0.842) and strong correlations with other measures of mental health, such as the POMS (r = -0.77), mental health scale from the SF-36 (r = 0.72), EQ-5D mood item (r = 0.61), and HUI Emotion Scale (r = 0.59). It was not highly correlated with measures of physical health. Among the psychiatric population, the new mental health scale was moderately correlated with indicators of psychiatric problem severity. It is now possible to report outcomes and relationships with mental health in studies that use the QWB-SA. This new mental health subscale can also be used with the large volume of previously collected data using the QWB-SA to examine the impact of illnesses and interventions on mental health-related quality of life. C1 [Sarkin, Andrew J.; Groessl, Erik J.; Carlson, Jordan A.; Tally, Steven R.; Ganiats, Theodore G.] Univ Calif San Diego, Hlth Serv Res Ctr, La Jolla, CA 92093 USA. [Sarkin, Andrew J.; Sieber, William J.; Ganiats, Theodore G.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Kaplan, Robert M.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Sarkin, AJ (reprint author), Univ Calif San Diego, Hlth Serv Res Ctr, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM asarkin@ucsd.edu FU NIA NIH HHS [P01 AG020679] NR 46 TC 3 Z9 3 U1 1 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD SEP PY 2013 VL 22 IS 7 BP 1685 EP 1696 DI 10.1007/s11136-012-0296-2 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 214BL UT WOS:000324105100017 PM 23104088 ER PT J AU Weickert, TW Mattay, VS Das, S Bigelow, LB Apud, JA Egan, MF Weinberger, DR Goldberg, TE AF Weickert, Thomas W. Mattay, Venkata S. Das, Saumitra Bigelow, Llewellyn B. Apud, Jose A. Egan, Michael F. Weinberger, Daniel R. Goldberg, Terry E. TI Dopaminergic therapy removal differentially effects learning in schizophrenia and Parkinson's disease SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Parkinson's disease; Frontal-striatal circuitry; Dopamimetics; Probabilistic association learning; Antipsychotics ID EMISSION COMPUTERIZED-TOMOGRAPHY; CAUDATE-NUCLEUS; MEMORY-SYSTEMS; HUNTINGTONS-DISEASE; NEURAL RESPONSES; COGNITIVE SKILL; BASAL GANGLIA; REWARD; CLASSIFICATION; RECEPTOR AB Studies of patients with Parkinson's disease receiving dopamimetics report conflicting evidence for early learning of probabilistic cue-outcome associations that elicits frontal-striatal activity. Previous studies of probabilistic association learning in patients with schizophrenia administered antipsychotics have displayed conflicting evidence for normal and abnormal learning. The role of dopaminergic treatment (dopamimetic versus dopamine antagonistic) effects on probabilistic association learning in these diseases that directly impact the dopamine system is not fully understood. The current study examined the effects of dopaminergic therapies on probabilistic association learning in 13 patients with schizophrenia and 8 patients with Parkinson's disease under two conditions: after withdrawal from dopaminergic treatment and following administration of appropriate dopaminergic treatment. Medication order was counterbalanced in both groups. Patients with Parkinson's disease failed to demonstrate any significant improvement over 150 trials, under both conditions (receiving or withdrawn from dopamimetics). Patients with schizophrenia withdrawn from antipsychotics displayed significant improvement during later trials only. These results demonstrate an effect of dopamine (DA) signaling on probabilistic association learning in that: (1) dopamine replacement therapy in Parkinson's disease is insufficient to significantly improve probabilistic association learning and (2) DA receptor blockade impairs and removal of DA receptor blockade significantly improves frontal-striatal-dependent probabilistic association learning in schizophrenia, which is a novel finding and is opposite to the effects shown following removal of DA receptor blockade on other cognitive domains reported previously. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved. C1 [Weickert, Thomas W.; Mattay, Venkata S.; Das, Saumitra; Bigelow, Llewellyn B.; Apud, Jose A.; Egan, Michael F.; Weinberger, Daniel R.; Goldberg, Terry E.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Weickert, TW (reprint author), Univ New S Wales, Sch Psychiat, Neurosci Res Australia, Barker St, Randwick, NSW 2031, Australia. EM t.weickert@unsw.edu.au FU NIMH; Weinberger Lab. FX This work was supported by the NIMH Intramural Research Program with direct funding from the Weinberger Lab. This organization had no further role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 41 TC 7 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2013 VL 149 IS 1-3 BP 162 EP 166 DI 10.1016/j.schres.2013.06.028 PG 5 WC Psychiatry SC Psychiatry GA 211UQ UT WOS:000323937200025 PM 23830543 ER PT J AU Sadowski, SM Kebebew, E AF Sadowski, Samira M. Kebebew, Electron TI Which Hemostatic Surgical Devices Should Be Used for Thyroid Surgery, or Should We Just Continue to Clamp and Tie? SO THYROID LA English DT Editorial Material ID LIGASURE C1 [Sadowski, Samira M.; Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Bldg 10 CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov NR 11 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD SEP 1 PY 2013 VL 23 IS 9 BP 1047 EP 1048 DI 10.1089/thy.2013.0286 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 213LT UT WOS:000324059400001 PM 23688251 ER PT J AU Bisoffi, Z Buonfrate, D Sequi, M Mejia, R Cimino, RO Krolewiecki, AJ Albonico, M Gobbo, M Bonafini, S Requena-Mendez, A Munoz, J Nutman, TB AF Bisoffi, Z. Buonfrate, D. Sequi, M. Mejia, R. Cimino, R. O. Krolewiecki, A. J. Albonico, M. Gobbo, M. Bonafini, S. Requena-Mendez, A. Munoz, J. Nutman, T. B. TI Comparison of diagnostic accuracy of five serodiagnostic tests for strongyloidiasis SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Meeting Abstract C1 [Bisoffi, Z.; Buonfrate, D.; Sequi, M.; Albonico, M.; Gobbo, M.; Bonafini, S.] Sacro Cuore Hosp, Ctr Trop Dis, Verona, Italy. [Mejia, R.; Nutman, T. B.] NIAID, NIH, Bethesda, MD 20892 USA. [Cimino, R. O.; Krolewiecki, A. J.] Natl Univ Salta, Salta, Argentina. [Requena-Mendez, A.; Munoz, J.] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, E-08007 Barcelona, Spain. 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 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD SEP PY 2013 VL 18 SU 1 SI SI BP 57 EP 57 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 213BS UT WOS:000324029000145 ER PT J AU Clark, C Bhat, S Talaat, K Babu, S Swaminathan, S Kumarasamy, N Nutman, T AF Clark, C. Bhat, S. Talaat, K. Babu, S. Swaminathan, S. Kumarasamy, N. Nutman, T. TI Bystander impairment of HIV-specific immune responses by co-incident filarial (W. bancrofti) infection SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Meeting Abstract C1 [Clark, C.; Nutman, T.] NIAID, NIH, Bethesda, MD 20892 USA. [Bhat, S.; Babu, S.] NIRT Int Ctr Excellence Res, Natl Inst Hlth, Madras, Tamil Nadu, India. [Talaat, K.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Swaminathan, S.] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Kumarasamy, N.] YRG Care, Madras, Tamil Nadu, India. 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 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD SEP PY 2013 VL 18 SU 1 SI SI BP 175 EP 175 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 213BS UT WOS:000324029000473 ER PT J AU Steagall, WK Pacheco-Rodriguez, G Glasgow, CG Ikeda, Y Lin, JP Zheng, G Moss, J AF Steagall, Wendy K. Pacheco-Rodriguez, Gustavo Glasgow, Connie G. Ikeda, Yoshihiko Lin, Jing-Ping Zheng, Gang Moss, Joel TI Osteoprotegerin Contributes to the Metastatic Potential of Cells with a Dysfunctional TSC2 Tumor-Suppressor Gene SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID BONE-MINERAL DENSITY; TRAIL-INDUCED APOPTOSIS; KAPPA-B LIGAND; TUBEROUS SCLEROSIS COMPLEX; CORONARY-ARTERY-DISEASE; PROSTATE-CANCER CELLS; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; RECEPTOR ACTIVATOR; ENDOTHELIAL-CELLS; SURVIVAL FACTOR AB In addition to its effects on bone metabolism, osteoprotegerin (OPG), a soluble member of the tumor necrosis factor family of receptors, promotes smooth muscle cell proliferation and migration and may act as a survival factor for tumor cells. We hypothesized that these cellular mechanisms of OPG may be involved in the growth and proliferation of lymphangioleiomyomatosis (LAM) cells, abnormal smooth muscle-like cells with mutations in one of the tuberous sclerosis complex tumor-suppressor genes (TSC1/TSC2) that cause LAM, a multisystem disease characterized by cystic lung destruction, lymphatic infiltration, and abdominal tumors. Herein, we show that OPG stimulated proliferation of cells cultured from explanted LAM lungs, and selectively induced migration of LAM cells identified by the loss of heterozygosity for TSC2. Consistent with these observations, cells with TSC2 toss of heterozygosity expressed the OPG receptors, receptor activator of NF-kappa B ligand, syndecan-1, and syndecan-2. LAM lung nodules showed reactivities to antibodies to tumor necrosis factor related apoptosis-inducing ligand, receptor activator of NF-kappa B ligand, syndecan-1, and syndecan-2. LAM Lung nodules also produced OPG, as shown by expression of OPG mRNA and colocalization of reactivities to anti-OPG and anti-gp100 (HMB45) antibodies in LAM lung nodules. Serum OPG was significantly higher in LAM patients than in normal volunteers. Based on these data, it appears that OPG may have tumor-promoting roles in the pathogenesis of lymphangioleiomyomatosis, perhaps acting as both autocrine and paracrine factors. C1 [Steagall, Wendy K.; Pacheco-Rodriguez, Gustavo; Glasgow, Connie G.; Ikeda, Yoshihiko; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Lin, Jing-Ping; Zheng, Gang] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NIH, 9000 Rockville Pike,Bldg 10 Room 6D05, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU Intramural Research Program; NIH; National Heart, Lung, and Blood Institute; Oak Ridge Institute for Science and Education senior fellowship FX Supported by the Intramural Research Program, the NIH, the National Heart, Lung, and Blood Institute, and an Oak Ridge Institute for Science and Education senior fellowship (Y.I.). NR 66 TC 1 Z9 1 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2013 VL 183 IS 3 BP 938 EP 950 DI 10.1016/j.ajpath.2013.05.024 PG 13 WC Pathology SC Pathology GA 210WP UT WOS:000323866000027 PM 23867796 ER PT J AU Lee, D Vandrey, R Milman, G Bergamaschi, M Mendu, DR Murray, JA Barnes, AJ Huestis, MA AF Lee, Dayong Vandrey, Ryan Milman, Garry Bergamaschi, Mateus Mendu, Damodara R. Murray, Jeannie A. Barnes, Allan J. Huestis, Marilyn A. TI Oral fluid/plasma cannabinoid ratios following controlled oral THC and smoked cannabis administration SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Cannabis; Marijuana; Delta9-tetrahydrocannabinol; Oral fluid; Plasma; Ratio ID 2-DIMENSIONAL GAS-CHROMATOGRAPHY; MOTOR-VEHICLE CRASHES; SIMULTANEOUS QUANTIFICATION; PHARMACOKINETIC PROPERTIES; MASS-SPECTROMETRY; WHOLE-BLOOD; FLUID; PLASMA; DELTA(9)-TETRAHYDROCANNABINOL; DRUGS AB Oral fluid (OF) is a valuable biological alternative for clinical and forensic drug testing. Evaluating OF to plasma (OF/P) cannabinoid ratios provides important pharmacokinetic data on the disposition of drug and factors influencing partition between matrices. Eleven chronic cannabis smokers resided on a closed research unit for 51 days. There were four 5-day sessions of 0, 30, 60, and 120 mg oral a dagger(9)-tetrahydrocannabinol (THC)/day followed by a five-puff smoked cannabis challenge on Day 5. Each session was separated by 9 days ad libitum cannabis smoking. OF and plasma specimens were analyzed for THC and metabolites. During ad libitum smoking, OF/P THC ratios were high (median, 6.1; range, 0.2-348.5) within 1 h after last smoking, decreasing to 0.1-20.7 (median, 2.1) by 13.0-17.1 h. OF/P THC ratios also decreased during 5-days oral THC dosing, and after the smoked cannabis challenge, median OF/P THC ratios decreased from 1.4 to 5.5 (0.04-245.6) at 0.25 h to 0.12 to 0.17 (0.04-5.1) at 10.5 h post-smoking. In other studies, longer exposure to more potent cannabis smoke and oromucosal cannabis spray was associated with increased OF/P THC peak ratios. Median OF/P 11-nor-9-carboxy-THC (THCCOOH) ratios were 0.3-2.5 (range, 0.1-14.7) ng/mu g, much more consistent in various dosing conditions over time. OF/P THC, but not THCCOOH, ratios were significantly influenced by oral cavity contamination after smoking or oromucosal spray of cannabinoid products, followed by time-dependent decreases. Establishing relationships between OF and plasma cannabinoid concentrations is essential for making inferences of impairment or other clinical outcomes from OF concentrations. C1 [Lee, Dayong; Milman, Garry; Bergamaschi, Mateus; Mendu, Damodara R.; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Vandrey, Ryan; Murray, Jeannie A.] Johns Hopkins Univ, Sch Med, Behav Biol Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd Suite 200, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse [R01 DA025044]; National Institute on Drug Abuse, NIH FX This research was funded by grant R01 DA025044 from the National Institute on Drug Abuse and by the Intramural Research Program, National Institute on Drug Abuse, NIH. The funding sources had no role in study design, data collection and analysis, or presentation of results. This study was registered on clinicaltrials.gov (NCT00893074). NR 37 TC 12 Z9 12 U1 2 U2 35 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD SEP PY 2013 VL 405 IS 23 BP 7269 EP 7279 DI 10.1007/s00216-013-7159-8 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 208CJ UT WOS:000323653400012 PM 23831756 ER PT J AU Arem, H Mayne, ST Sampson, J Risch, H Stolzenberg-Solomon, RZ AF Arem, Hannah Mayne, Susan T. Sampson, Joshua Risch, Harvey Stolzenberg-Solomon, Rachael Z. TI Dietary fat intake and risk of pancreatic cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Dietary fats; Cohort studies; Pancreatic neoplasms; Epidemiology ID FUNCTIONAL DYSPEPSIA; CARCINOGENESIS; MEAT; SMOKING; INSULIN; SMOKERS; MODELS; COHORT; HEALTH; ACIDS AB Purpose: Epidemiologic and experimental studies suggest that dietary fat intake may affect risk of pancreatic cancer, but published results are inconsistent. Methods: We examined risk associations for specific types of dietary fat intakes and related food sources among 111,416 participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We used Cox proportional hazards regression to examine associations between fat intake and pancreatic cancer risk. Results: Over a mean 8.4 years of follow-up, 411 pancreatic cancer cases were identified. We observed an inverse association between saturated fat intake and pancreatic cancer risk (hazard ratio [HR], 0.64 comparing extreme quintiles; 95% confidence interval [CI], 0.46-0.88), but the association became weaker and nonsignificant when individuals with fewer than 4 years of follow-up were excluded to avoid possible reverse causation (HR, 0.88; 95% CI, 0.58-1.33). Total fat intake showed a similar pattern of association, whereas intakes of monounsaturated and polyunsaturated fats and fats from animal or plant sources showed no associations with risk. Conclusions: These results do not support the hypothesis of increased pancreatic cancer risk with higher fat consumption overall or by specific fat type or source. Dietary changes owing to undetected disease may explain the observed inverse association with saturated fat. Published by Elsevier Inc. C1 [Arem, Hannah; Mayne, Susan T.; Risch, Harvey] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Arem, Hannah; Sampson, Joshua; Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mayne, Susan T.; Risch, Harvey] Yale Canc Ctr, New Haven, CT USA. RP Arem, H (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 9609 Med Ctr Dr,Room 6E324, Bethesda, MD 20892 USA. EM aremhe2@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, DHHS; [T32 CA105666] FX This work was supported in part by the training grant T32 CA105666. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. This research was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, DHHS. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc. Most important, we acknowledge the study participants for their contributions to making this study possible. NR 31 TC 9 Z9 10 U1 0 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD SEP PY 2013 VL 23 IS 9 BP 571 EP 575 DI 10.1016/j.annepidem.2013.06.006 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 210TE UT WOS:000323856700008 PM 23890797 ER PT J AU Kamper-Jorgensen, M Rostgaard, K Glaser, SL Zahm, SH Cozen, W Smedby, KE Sanjose, S Chang, ET Zheng, T La Vecchia, C Serraino, D Monnereau, A Kane, EV Miligi, L Vineis, P Spinelli, JJ McLaughlin, JR Pahwa, P Dosman, JA Vornanen, M Foretova, L Maynadie, M Staines, A Becker, N Nieters, A Brennan, P Boffetta, P Cocco, P Hjalgrim, H AF Kamper-Jorgensen, M. Rostgaard, K. Glaser, S. L. Zahm, S. H. Cozen, W. Smedby, K. E. Sanjose, S. Chang, E. T. Zheng, T. La Vecchia, C. Serraino, D. Monnereau, A. Kane, E. V. Miligi, L. Vineis, P. Spinelli, J. J. McLaughlin, J. R. Pahwa, P. Dosman, J. A. Vornanen, M. Foretova, L. Maynadie, M. Staines, A. Becker, N. Nieters, A. Brennan, P. Boffetta, P. Cocco, P. Hjalgrim, H. TI Cigarette smoking and risk of Hodgkin lymphoma and its subtypes: a pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph) SO ANNALS OF ONCOLOGY LA English DT Review DE Hodgkin lymphoma; case-control; cigarette smoking; epidemiology; Epstein-Barr virus; individual patient data meta-analysis ID CHILDHOOD SOCIAL-ENVIRONMENT; SOFT-TISSUE SARCOMA; ALCOHOL-DRINKING; INFECTIOUS-MONONUCLEOSIS; SOCIOECONOMIC-STATUS; LOGISTIC-REGRESSION; MALIGNANT-LYMPHOMAS; TOBACCO SMOKING; UNITED-STATES; FOLLOW-UP AB The etiology of Hodgkin lymphoma (HL) remains incompletely characterized. Studies of the association between smoking and HL have yielded ambiguous results, possibly due to differences between HL subtypes. Through the InterLymph Consortium, 12 case-control studies regarding cigarette smoking and HL were identified. Pooled analyses on the association between smoking and HL stratified by tumor histology and Epstein-Barr virus (EBV) status were conducted using random effects models adjusted for confounders. Analyses included 3335 HL cases and 14 278 controls. Overall, 54.5% of cases and 57.4% of controls were ever cigarette smokers. Compared with never smokers, ever smokers had an odds ratio (OR) of HL of 1.10 [95% confidence interval (CI) 1.01-1.21]. This increased risk reflected associations with mixed cellularity cHL (OR = 1.60, 95% CI 1.29-1.99) and EBV-positive cHL (OR = 1.81, 95% CI 1.27-2.56) among current smokers, whereas risk of nodular sclerosis (OR = 1.09, 95% CI 0.90-1.32) and EBV-negative HL (OR = 1.02, 95% CI 0.72-1.44) was not increased. These results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. Even if not relevant to all subtypes, our study emphasizes that cigarette smoking should be added to the few modifiable HL risk factors identified. C1 [Kamper-Jorgensen, M.] Univ Copenhagen, Dept Publ Hlth, DK-1014 Copenhagen K, Denmark. [Kamper-Jorgensen, M.; Rostgaard, K.; Hjalgrim, H.] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Glaser, S. L.] Canc Prevent Inst Calif, Dept Res, Fremont, CA USA. [Zahm, S. H.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Cozen, W.] Univ So Calif, Dept Prevent Med & Pathol, Los Angeles, CA USA. [Smedby, K. E.] Karolinska Inst, Unit Clin Epidemiol, Dept Med, Stockholm, Sweden. [Sanjose, S.] Inst Catala Oncol, Unit Infect & Canc, Barcelona, Spain. [Chang, E. T.] Exponent Inc, Hlth Sci Practice, Menlo Pk, CA USA. [Glaser, S. L.; Chang, E. T.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Foretova, L.] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [La Vecchia, C.] Ist Ric Farmacol Mario Negri IRCCS, Dept Epidemiol, Chieti, Italy. [La Vecchia, C.] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Serraino, D.] IRCCS Ctr Riferimento Oncol, Sci Directorate, Epidemiol & Biostatist Unit, Aviano, Italy. [Monnereau, A.] Ctr Res Epidemiol & Populat Hlth CESP, INSERM, Environmental Epidemiol Canc Grp, U1018, Villejuif, France. [Monnereau, A.] Registry Hematol Malignancies Gironde, Dept Clin Res & Med Informat, Bergonie Inst, Bordeaux, France. [Miligi, L.] ISPO Canc Prevent & Res Inst, Environm & Occupat Epidemiol Unit, Florence, Italy. [Vineis, P.] Univ London Imperial Coll Sci Technol & Med, London, England. [Spinelli, J. J.] BC Canc Agcy, Vancouver, BC, Canada. [Spinelli, J. J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [McLaughlin, J. R.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [McLaughlin, J. R.] Mt Sinai Hosp Joseph & Wolf Lebov Hlth Complex, Samuel Lunenfeld Res Inst, Toronto, ON, Canada. [Pahwa, P.] Univ Saskatchewan, Dept Community Hlth & Epidemiol, Saskatoon, SK, Canada. [Zheng, T.] Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Becker, N.] German Canc Res Ctr, Dept Canc Epidemiol, Heidelberg, Germany. [Cocco, P.] Univ Cagliari, Dept Publ Hlth, Monserrato, Italy. [Nieters, A.] Univ Freiburg Klinikum, Dept Canc Epidemiol & Genet, Freiburg, Germany. [Maynadie, M.] Univ Burgundy, Registre Hemopathies Malignes Cote Or EA4184, Dijon, France. [Maynadie, M.] Univ Hosp, Dijon, France. [Brennan, P.] Int Agcy Res Canc, Genet Sect, F-69372 Lyon, France. [Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst & Inst Translat Epidemiol, New York, NY USA. [Boffetta, P.] Int Prevent Res Inst, Lyon, France. [Vornanen, M.] Fimlab Labs, Dept Pathol, Tampere, Finland. RP Kamper-Jorgensen, M (reprint author), Univ Copenhagen, Dept Publ Hlth, Oster Farimagsgade 5,Postbox 2099, DK-1014 Copenhagen K, Denmark. EM maka@sund.ku.dk RI Spinelli, John/B-6210-2013; Monnereau, Alain/L-1249-2014; OI Monnereau, Alain/0000-0002-5056-1397; Kamper-Jorgensen, Mads/0000-0001-6393-5258; Staines, Anthony/0000-0001-9161-1357; Serraino, Diego/0000-0003-0565-8920; La Vecchia, Carlo/0000-0003-1441-897X; Rostgaard, Klaus/0000-0001-6220-9414 FU NIH [5 ROI CA 69269]; Nordic Cancer Union; Plan Danmark [16-02-D]; Italian Association for Cancer Research FX The study was supported by NIH (grant number 5 ROI CA 69269), Nordic Cancer Union (no grant number), Plan Danmark grant number is 16-02-D, and the Italian Association for Cancer Research (no grant number). NR 60 TC 11 Z9 11 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2013 VL 24 IS 9 BP 2245 EP 2255 DI 10.1093/annonc/mdt218 PG 11 WC Oncology SC Oncology GA 212DT UT WOS:000323963100006 PM 23788758 ER PT J AU Ando, H Sato, T Tomaru, U Yoshida, M Utsunomiya, A Yamauchi, J Araya, N Yagishita, N Coler-Reilly, A Shimizu, Y Yudoh, K Hasegawa, Y Nishioka, K Nakajima, T Jacobson, S Yamano, Y AF Ando, Hitoshi Sato, Tomoo Tomaru, Utano Yoshida, Mari Utsunomiya, Atae Yamauchi, Junji Araya, Natsumi Yagishita, Naoko Coler-Reilly, Ariella Shimizu, Yukiko Yudoh, Kazuo Hasegawa, Yasuhiro Nishioka, Kusuki Nakajima, Toshihiro Jacobson, Steven Yamano, Yoshihisa TI Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy SO BRAIN LA English DT Article DE HTLV-1; HAM/TSP; CXCL10; CXCR3; astrocyte ID I-ASSOCIATED MYELOPATHY; T-CELL LEUKEMIA; TROPICAL SPASTIC PARAPARESIS; SPINAL-CORD LESIONS; HTLV-I; PROVIRAL LOAD; PERIPHERAL-BLOOD; CYTOKINE EXPRESSION; MONONUCLEAR-CELLS; INTERFERON-GAMMA AB Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease characterized by chronic inflammation in the spinal cord. We hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that patients with HAM/TSP have extraordinarily high levels of the chemokine CXCL10 (also known as IP-10) and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of patients with HAM/TSP. Co-culture of human astrocytoma cells with CD4(+) T cells from patients with HAM/TSP revealed that astrocytes produce CXCL10 in response to IFN-gamma secreted by CD4(+) T cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system and that anti-CXCL10 neutralizing antibody can disrupt this migration. In short, we inferred that human T-lymphotropic virus type 1-infected cells in the central nervous system produce IFN-gamma that induces astrocytes to secrete CXCL10, which recruits more infected cells to the area via CXCR3, constituting a T helper type 1-centric positive feedback loop that results in chronic inflammation. C1 [Ando, Hitoshi; Sato, Tomoo; Yamauchi, Junji; Araya, Natsumi; Yagishita, Naoko; Coler-Reilly, Ariella; Shimizu, Yukiko; Yamano, Yoshihisa] St Marianna Univ, Sch Med, Inst Med Sci, Dept Rare Dis Res, Kawasaki, Kanagawa 2168512, Japan. [Tomaru, Utano] Hokkaido Univ, Grad Sch Med, Dept Pathol, Sapporo, Hokkaido, Japan. [Yoshida, Mari] Aichi Med Univ, Inst Med Sci Ageing, Aichi, Japan. [Utsunomiya, Atae] Imamura Bun In Hosp, Dept Haematol, Kagoshima, Japan. [Yudoh, Kazuo] St Marianna Univ, Sch Med, Inst Med Sci, Kawasaki, Kanagawa 2168512, Japan. [Hasegawa, Yasuhiro] St Marianna Univ, Sch Med, Dept Neurol, Kawasaki, Kanagawa 2168512, Japan. [Nishioka, Kusuki; Nakajima, Toshihiro] Tokyo Med Univ, Inst Med Sci, Tokyo 1608402, Japan. [Jacobson, Steven] NIH, Viral Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP Yamano, Y (reprint author), St Marianna Univ, Sch Med, Inst Med Sci, Dept Rare Dis Res,Miyamae Ku, 2-16-1 Sugao, Kawasaki, Kanagawa 2168512, Japan. EM yyamano@marianna-u.ac.jp FU project "Research on Measures for Intractable Disease"; Ministry of Health Labour and Welfare; Ministry of Education, Culture, Sports, Science and Technology; MEXT FX This work was partly supported by project "Research on Measures for Intractable Disease," a matching fund subsidy from the Ministry of Health Labour and Welfare, a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2008-2012. NR 55 TC 17 Z9 17 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD SEP PY 2013 VL 136 BP 2876 EP 2887 DI 10.1093/brain/awt183 PN 9 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 212EM UT WOS:000323965100024 PM 23892452 ER PT J AU Wu, T Hallett, M AF Wu, Tao Hallett, Mark TI Reply: The cerebellum in Parkinson's disease and parkinsonism in cerebellar disorders SO BRAIN LA English DT Letter ID SCA2 PARKINSONISM C1 [Wu, Tao] Capital Med Univ, Beijing Inst Geriatr, Key Lab Neurodegenerat Disorders, Dept Neurobiol,Minist Educ,Xuanwu Hosp, Beijing 100053, 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, Beijing Inst Geriatr, Key Lab Neurodegenerat Disorders, Dept Neurobiol,Minist Educ,Xuanwu Hosp, Beijing 100053, Peoples R China. EM wutao69@gmail.com NR 8 TC 3 Z9 3 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD SEP PY 2013 VL 136 BP E249 EP U18 DI 10.1093/brain/awt100 PN 9 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 212EM UT WOS:000323965100004 PM 23739172 ER PT J AU Li, WQ Park, Y Wu, JW Ren, JS Goldstein, AM Taylor, PR Hollenbeck, AR Freedman, ND Abnet, CC AF Li, Wen-Qing Park, Yikyung Wu, Jennifer W. Ren, Jian-Song Goldstein, Alisa M. Taylor, Philip R. Hollenbeck, Albert R. Freedman, Neal D. Abnet, Christian C. TI Index-based Dietary Patterns and Risk of Esophageal and Gastric Cancer in a Large Cohort Study SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Food Habits; Esophageal Neoplasms; Stomach Neoplasms ID SQUAMOUS-CELL CARCINOMA; MEDITERRANEAN DIET; NATIONAL INSTITUTES; VEGETABLE INTAKE; QUALITY SCORES; ADENOCARCINOMA; POPULATION; FRUIT; INFLAMMATION; CONSUMPTION AB BACKGROUND & AIMS: Diet could affect risk for esophageal and gastric cancers, but associations have been inconsistent. The diet is complex, so studies of dietary patterns, rather than studies of individual foods, might be more likely to identify cancer risk factors. There is limited research on index-based dietary patterns and esophageal and gastric cancers. We prospectively evaluated associations between the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet (aMED) scores and risk of esophageal and gastric cancers. METHODS: We analyzed data from 494,968 participants in the National Institutes of Health-AARP Diet and Health study, in which AARP members (age, 51-70 y) completed a self-administered baseline food frequency questionnaire between 1995 and 1996. Their answers were used to estimate scores for each index. RESULTS: During the follow-up period (1995-2006), participants developed 215 esophageal squamous cell carcinomas (ESCCs), 633 esophageal adenocarcinomas (EACs), 453 gastric cardia adenocarcinomas, and 501 gastric noncardia adenocarcinomas. Higher scores from the HEI-2005 were associated with a reduced risk of ESCC (comparing the highest quintile with the lowest quintile: hazard ratio, 0.51; 95% confidence interval, 0.31-0.86; P-trend = .001) and EAC (hazard ratio, 0.75; 95% confidence interval, 0.57-0.98; P-trend = .01). We observed an inverse association between ESCC, but not EAC, and a higher aMED score (meaning a higher-quality diet). HEI-2005 and aMED scores were not associated significantly with gastric cardia or noncardia adenocarcinomas. CONCLUSIONS: By using data collected from 1995 through 2006 from the National Institutes of Health-AARP Diet and Health Study, HEI-2005 and aMED scores were associated inversely with risk for esophageal cancers, particularly ESCC. Adherence to dietary recommendations might help prevent esophageal cancers. C1 [Li, Wen-Qing; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Park, Yikyung; Wu, Jennifer W.; Ren, Jian-Song; Freedman, Neal D.; Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Li, WQ (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM liw9@mail.nih.gov RI Li, Wenqing/N-2293-2014; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; OI Li, Wenqing/0000-0002-1283-4091; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The study sponsor was not involved in the study design, data collection, data analysis, manuscript writing, or review. NR 28 TC 17 Z9 18 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD SEP PY 2013 VL 11 IS 9 BP 1130 EP U136 DI 10.1016/j.cgh.2013.03.023 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 210FU UT WOS:000323816100018 PM 23591281 ER PT J AU Hernaez, R McLean, J Lazo, M Brancati, FL Hirschhorn, JN Borecki, IB Harris, TB Nguyen, T Kamel, IR Bonekamp, S Eberhardt, MS Clark, JM Kao, WHL Speliotes, EK AF Hernaez, Ruben McLean, Jody Lazo, Mariana Brancati, Frederick L. Hirschhorn, Joel N. Borecki, Ingrid B. Harris, Tamara B. Thutrang Nguyen Kamel, Ihab R. Bonekamp, Susanne Eberhardt, Mark S. Clark, Jeanne M. Kao, Wen Hong Linda Speliotes, Elizabeth K. CA Genetics Obesity-Related Liver Dis TI Association Between Variants in or Near PNPLA3, GCKR, and PPP1R3B With Ultrasound-Defined Steatosis Based on Data From the Third National Health and Nutrition Examination Survey SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Nonalcoholic Fatty Liver Disease; Replication; Candidate Gene Study; Genome-wide Association Study; SNP ID FATTY LIVER-DISEASE; GENOME-WIDE ASSOCIATION; US ADULTS; SUSCEPTIBILITY LOCI; METABOLIC SYNDROME; FASTING GLUCOSE; IDENTIFIES LOCI; PREVALENCE; METAANALYSIS; GLYCOGEN AB BACKGROUND & AIMS: A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. METHODS: We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. RESULTS: The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. CONCLUSIONS: We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations. C1 [Hernaez, Ruben; Lazo, Mariana; Brancati, Frederick L.; Clark, Jeanne M.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Kamel, Ihab R.; Bonekamp, Susanne] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD USA. [Hernaez, Ruben; Lazo, Mariana; Brancati, Frederick L.; Clark, Jeanne M.; Kao, Wen Hong Linda] Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Brancati, Frederick L.; Clark, Jeanne M.; Kao, Wen Hong Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Hernaez, Ruben] Georgetown Univ Hosp, Washington Hosp Ctr, Dept Med, Washington, DC 20007 USA. [McLean, Jody] NOVA Res Co, Bethesda, MD USA. [Hirschhorn, Joel N.; Thutrang Nguyen] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Thutrang Nguyen] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Thutrang Nguyen] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Thutrang Nguyen; Speliotes, Elizabeth K.] Broad Inst, Cambridge, MA USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Harris, Tamara B.] NIH, Natl Inst Aging, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Eberhardt, Mark S.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. RP Speliotes, EK (reprint author), Univ Michigan, 6520 MSRBI,SPC 5682,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM espeliot@med.umich.edu RI Hernaez, Ruben/C-4039-2014; OI Hernaez, Ruben/0000-0002-1518-4020; Bonekamp, Susanne/0000-0001-5847-5656 FU American Diabetes Association [7-07-MN-08]; Doris Duke Medical Foundation; National Institutes of Health [K23DK080145-01, R01DK075787, 5R01DK075681, R01 DK083393] FX Supported by the American Diabetes Association Mentor-Based Fellowship Program 7-07-MN-08 (R.H., M.L., F.L.B.), Doris Duke Medical Foundation (E.K.S.), National Institutes of Health grants K23DK080145-01 (E.K.S.), R01DK075787 (J.N.H.), 5R01DK075681 (I.B.B.), and R01 DK083393 (J.M.C., R.H., M.L., F.L.B., I.R.H., S.B., W.H.L.K.). NR 32 TC 35 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD SEP PY 2013 VL 11 IS 9 BP 1183 EP U203 DI 10.1016/j.cgh.2013.02.011 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 210FU UT WOS:000323816100027 PM 23416328 ER PT J AU Lukacs, B Cornu, JN Aout, M Tessier, N Hodee, C Haab, F Cussenot, O Merliere, Y Moysan, V Vicaut, E AF Lukacs, Bertrand Cornu, Jean-Nicolas Aout, Mounir Tessier, Natacha Hodee, Christophe Haab, Francois Cussenot, Olivier Merliere, Yvon Moysan, Veronique Vicaut, Eric TI Management of Lower Urinary Tract Symptoms Related to Benign Prostatic Hyperplasia in Real-life Practice in France: A Comprehensive Population Study SO EUROPEAN UROLOGY LA English DT Article DE 5 alpha-Reductase inhibitors; alpha(1)-Blockers; Benign prostatic obstruction; Claim database; Epidemiology; Phytotherapy; Population study ID TRIUMPH PROJECT; SAW PALMETTO; PRIMARY-CARE; MEN; GUIDELINES; THERAPY; PREVALENCE; PATTERNS; BPH; AUA AB Background: Male lower urinary tract symptoms (LUTS) are one of the most treated diseases, but little is known about patient trajectories in current clinical practice. Objective: To describe the dynamic treatment patterns of LUTS presumably due to benign prostatic obstruction (BPO). Design, settings, and participants: All prescriptions of alpha(1)-adrenergic receptor blocking agents (alpha(1)-blockers), 5 alpha-reductase inhibitors (5-ARIs), and phytotherapy, and all surgeries related to BPO performed in France from 2004 to 2008 were identified using two distinct administrative claim databases maintained by the National Health Insurance system that covers the entire population. After linking the two data sets, all consecutive treatment events were analyzed for each patient. Outcome measurements and statistical analysis: Drug prescription details were assessed for each year, region, and prescriber qualification. Medical treatment initiation, interruption, evolution, and events after surgical management (hospital stay, reoperation, complication rates, and subsequent medical prescriptions) were also investigated. Results and limitations: Overall, 2 620 269 patients were treated within 5 yr, with important geographic variations. Medical treatment was interrupted for approximately 16% of patients. The alpha(1)-blockers were prescribed most frequently, but phytotherapy surprisingly accounted for 27% of all monotherapies and 54% of all combination therapies. General practitioners and urologists (92% and 3.7% of overall prescribers, respectively) exhibited a similar prescription profile. Treatment initiation was medical in 95.4% of cases, consisting primarily of mono- therapy using alpha(1)-blockers (60.3%), phytotherapy (31.8%), or 5-ARIs (7.9%). Treatment was modified at extremely high rates within 12 mo of initiation (8.7%, 14.6%, and 12.9%, respectively). The median hospital stay for surgical management was far higher than in clinical trials. Long-term surgical complications and reoperation rates favored open prostatectomy. Incidence of pharmacologic treatment after surgery was as high as 13.8% at 12 mo. Conclusions: This unique dynamic evaluation of clinical practice revealed unexpected results that contrast with previously published evidence from clinical trials. This approach may merit monitored and targeted measures to improve the level of care in the field. (C) 2013 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Lukacs, Bertrand; Cornu, Jean-Nicolas; Haab, Francois; Cussenot, Olivier] Univ Paris 06, Tenon Hosp, AP HP, Dept Urol, Paris, France. [Cornu, Jean-Nicolas] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Aout, Mounir; Tessier, Natacha; Vicaut, Eric] Univ Paris 07, Lariboisiere Fernand Widal Hosp, AP HP, Clin Res Unit, Paris, France. [Hodee, Christophe] AP HP, Dept Informat, Paris, France. [Merliere, Yvon] Ctr Rech Etud & Observat Condit Vie CREDOC, Paris, France. [Merliere, Yvon; Moysan, Veronique] CNAMTS, Paris, France. [Moysan, Veronique] CNAMTS, Bordeaux, France. RP Lukacs, B (reprint author), Tenon Hosp, Dept Urol, 4 Rue Chine, F-75020 Paris, France. EM bertrand.lukacs@tnn.aphp.fr; jncornu@hotmail.fr FU Clinical Research Unit, Lariboisiere Fernand Widal Hospital, Assistance Publique - Hopitaux de Paris, University Denis Diderot, Paris, France; Association Nationale des Malades du Cancer de la Prostate FX This study was financed by the Clinical Research Unit, Lariboisiere Fernand Widal Hospital, Assistance Publique - Hopitaux de Paris, University Denis Diderot, Paris, France. A grant was received from the Association Nationale des Malades du Cancer de la Prostate. This academic study was designed, conducted, analyzed, and written completely independently of any sponsor. The Association Nationale des Malades du Cancer de la Prostate did not participate in the design or conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. NR 35 TC 21 Z9 21 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD SEP PY 2013 VL 64 IS 3 BP 493 EP 501 DI 10.1016/j.eururo.2013.02.026 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 211VF UT WOS:000323938700037 PM 23465519 ER PT J AU Shallom, SJ Gardina, PJ Myers, TG Sebastian, Y Conville, P Calhoun, LB Tettelin, H Olivier, KN Uzel, G Sampaio, EP Holland, SM Zelazny, AM AF Shallom, Shamira J. Gardina, Paul J. Myers, Timothy G. Sebastian, Yinong Conville, Patricia Calhoun, Leslie B. Tettelin, Herve Olivier, Kenneth N. Uzel, Gulbu Sampaio, Elizabeth P. Holland, Steven M. Zelazny, Adrian M. TI New Rapid Scheme for Distinguishing the Subspecies of the Mycobacterium abscessus Group and Identifying Mycobacterium massiliense Isolates with Inducible Clarithromycin Resistance SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID DESORPTION IONIZATION-TIME; FLIGHT MASS-SPECTROMETRY; GROWING MYCOBACTERIA; TAXONOMIC STATUS; CYSTIC-FIBROSIS; CULTURE-MEDIA; IDENTIFICATION; CHELONAE; BOLLETII; OUTBREAK AB Mycobacterium abscessus (M. abscessus sensu lato, or the M. abscessus group) comprises three closely related taxa whose taxonomic statuses are under revision, i.e., M. abscessus sensu stricto, Mycobacterium bolletii, and Mycobacterium massiliense. We describe here a simple, robust, and cost-effective PCR-based method for distinguishing among M. abscessus, M. massiliense, and M. bolletii. Based on the M. abscessus ATCC 19977(T) genome, regions that discriminated between M. abscessus and M. massiliense were identified through array-based comparative genomic hybridization. A typing scheme using PCR primers designed for four of these locations was applied to 46 well-characterized clinical isolates comprising 29 M. abscessus, 15 M. massiliense, and 2 M. bolletii isolates previously identified by multitarget sequencing. Interestingly, 2 isolates unequivocally identified as M. massiliense were shown to have a full-length erm(41) gene instead of the expected gene deletion and showed inducible clarithromycin resistance after 14 days. We propose using this PCR-based typing scheme combined with erm(41) PCR for straightforward identification of M. abscessus, M. massiliense, and M. bolletii and the assessment of inducible clarithromycin resistance. This method can be easily integrated into a routine workflow to provide subspecies-level identification within 24 h after isolation of the M. abscessus group. C1 [Shallom, Shamira J.; Conville, Patricia; Calhoun, Leslie B.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Gardina, Paul J.; Myers, Timothy G.; Sebastian, Yinong] NIAID, Genom Technol Sect, Res Technol Branch, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Tettelin, Herve] Univ Maryland, Sch Med, Inst Genome Sci, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Olivier, Kenneth N.; Uzel, Gulbu; Sampaio, Elizabeth P.; Holland, Steven M.; Zelazny, Adrian M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.] Inst Oswaldo Cruz, Leprosy Lab, BR-20001 Rio De Janeiro, Brazil. RP Zelazny, AM (reprint author), NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov FU NIH; NIH Clinical Center; National Institute of Allergy and Infectious Diseases; National Institute of Allergy and Infectious Diseases, National Institutes of Health [HHSN272200900007C] FX The Intramural Research Program of the NIH, the NIH Clinical Center, and the National Institute of Allergy and Infectious Diseases supported this research. H.T. was supported in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (contract HHSN272200900007C). NR 30 TC 32 Z9 32 U1 0 U2 7 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 2013 VL 51 IS 9 BP 2943 EP 2949 DI 10.1128/JCM.01132-13 PG 7 WC Microbiology SC Microbiology GA 202KL UT WOS:000323214200022 PM 23804391 ER PT J AU Balaban, RS AF Balaban, Robert S. TI Evaluation of scientific productivity and excellence in the NHLBI Division of Intramural Research SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20824 USA. RP Balaban, RS (reprint author), NHLBI, Bethesda, MD 20824 USA. NR 1 TC 1 Z9 1 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD SEP PY 2013 VL 142 IS 3 BP 177 EP 178 DI 10.1085/jgp.201311076 PG 2 WC Physiology SC Physiology GA 207ZJ UT WOS:000323643300002 PM 23980190 ER PT J AU Stern, MD Rios, E Maltsev, VA AF Stern, Michael D. Rios, Eduardo Maltsev, Victor A. TI Life and death of a cardiac calcium spark SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID POLYMORPHIC VENTRICULAR-TACHYCARDIA; INDUCED CA2+ RELEASE; IN MOUSE MODEL; RYANODINE RECEPTOR; SARCOPLASMIC-RETICULUM; LUMINAL CA2+; SKELETAL-MUSCLE; MYOCYTES; TERMINATION; LEAK AB Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium-induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium. Spark termination by local SR depletion was not robust: under some conditions, sparks could be greatly and variably prolonged, terminating by stochastic attrition-a phenomenon we dub "spark metastability." Spark fluorescence rise time was not a good surrogate for the duration of calcium release. Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates. The conditions for spark metastability resemble those produced by known mutations of RyR2 and CASQ2 that cause life-threatening triggered arrhythmias, and spark metastability may be mitigated by altering the kinetics of the RyR in a manner similar to the effects of drugs known to prevent those arrhythmias. The model was unable to explain the distributions of spark amplitudes and rise times seen in chemically skinned cat atrial myocytes, suggesting that such sparks may be more complex events involving heterogeneity of couplons or local propagation among sub-clusters of RyRs. C1 [Stern, Michael D.; Maltsev, Victor A.] NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Rios, Eduardo] Rush Univ, Dept Mol Biophys & Physiol, Chicago, IL 60612 USA. RP Stern, MD (reprint author), NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM SternMi@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). NR 46 TC 23 Z9 23 U1 1 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD SEP PY 2013 VL 142 IS 3 BP 257 EP 274 DI 10.1085/jgp.201311034 PG 18 WC Physiology SC Physiology GA 207ZJ UT WOS:000323643300009 PM 23980195 ER PT J AU Stampalija, T Chaiworapongsa, T Romero, R Chaemsaithong, P Korzeniewski, SJ Schwartz, AG Ferrazzi, EM Dong, Z Hassan, SS AF Stampalija, Tamara Chaiworapongsa, Tinnakorn Romero, Roberto Chaemsaithong, Piya Korzeniewski, Steven J. Schwartz, Alyse G. Ferrazzi, Enrico M. Dong, Zhong Hassan, Sonia S. TI Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Biomarker; interleukin-33; pregnancy; sflt-1; Th2 immune response; VEGFR-1 ID LATE-ONSET PREECLAMPSIA; UTERINE ARTERY DOPPLER; FOR-GESTATIONAL-AGE; INTRAUTERINE GROWTH RESTRICTION; FACTOR RECEPTOR-1 CONCENTRATION; PREGNANCY-INDUCED HYPERTENSION; ENDOTHELIAL-CELL DYSFUNCTION; LINKING PLACENTAL ISCHEMIA; ATRIAL-NATRIURETIC-PEPTIDE; TYPE-2 CYTOKINE PRODUCTION AB Objectives: Angiogenic/anti-angiogenic factors have emerged as one of the promising biomarkers for the prediction of preeclampsia. Since not all patients with preeclampsia can be identified by these analytes, the search for additional biomarkers continues. The soluble form of ST2 (sST2), a protein capable of binding to interleukin (IL)-33 and thus contributing to a Th1-biased immune response, has been reported to be elevated in maternal plasma of women with preeclampsia. The aims of this study were to examine: (1) differences in maternal plasma concentrations of sST2 and IL-33 between women diagnosed with preeclampsia and those having uncomplicated pregnancies; (2) the relationship between sST2, umbilical and uterine artery Doppler velocimetry, and the severity of preeclampsia; and (3) the performance of sST2 and angiogenic/anti-angiogenic factors in identifying patients with preeclampsia at the time of diagnosis. Methods: This cross-sectional study included women with preeclampsia (n = 106) and women with an uncomplicated pregnancy (n = 131). Plasma concentrations of sST2, IL-33, soluble vascular endothelial growth factor receptor (sVEGFR)-1, soluble endoglin (sEng) and placental growth factor (PlGF) were determined by enzyme linked immune sorbent assay. Area under the receiver operating characteristic curve (AUC) for the identification of preeclampsia was examined for each analyte. Results: (1) Patients with preeclampsia had a higher mean plasma concentrations of sST2 than those with an uncomplicated pregnancy (p < 0.0001), while no significant difference in the mean plasma concentration of IL-33 between the two groups was observed; (2) the magnitude of this difference was greater in early-onset, compared to late-onset disease, and in severe compared to mild preeclampsia; (3) sST2 plasma concentrations did not correlate with the results of uterine or umbilical artery Doppler velocimetry (p = 0.7 and p = 1, respectively) among women with preeclampsia; (4) sST2 correlated positively with plasma concentrations of sVEGFR1-1 and sEng (Spearman's Rho = 0.72 and 0.63; each p < 0.0001), and negatively with PlGF (Spearman's Rho = -0.56, p < 0.0001); and (5) while the AUC achieved by sST2 and angiogenic/anti-angiogenic factors in identifying women with preeclampsia at the time of diagnosis were non-significantly different prior to term (<37 weeks of gestation), thereafter the AUC achieved by sST2 was significantly less than that achieved by angiogenic/anti-angiogenic factors. Conclusions: Preeclampsia is associated with increased maternal plasma concentrations of sST2. The findings that sST2 concentrations do not correlate with uterine or umbilical artery Doppler velocimetry in women with preeclampsia suggest that elevated maternal plasma sST2 concentrations in preeclampsia are not related to the increased impedance to flow in the utero-placental circulation. The performance of sST2 in identifying preeclampsia at the time of diagnosis prior to 37 weeks of gestation was comparable to that of angiogenic/anti-angiogenic factors. It remains to be elucidated if an elevation of maternal plasma sST2 concentrations in pregnancy is specific to preeclampsia. C1 [Stampalija, Tamara; Chaiworapongsa, Tinnakorn; Romero, Roberto; Chaemsaithong, Piya; Korzeniewski, Steven J.; Schwartz, Alyse G.; Dong, Zhong; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Stampalija, Tamara; Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Korzeniewski, Steven J.; Schwartz, Alyse G.; Hassan, Sonia S.] Wayne State Univ, Detroit Med Ctr, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Stampalija, Tamara; Ferrazzi, Enrico M.] Univ Milan, Childrens Hosp Buzzi, Dept Obstet Gynecol, Milan, Italy. 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 romeror@mail.nih.gov RI Stampalija, Tamara/K-4900-2014 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C. NR 177 TC 15 Z9 15 U1 0 U2 10 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD SEP PY 2013 VL 26 IS 14 BP 1359 EP 1370 DI 10.3109/14767058.2013.784256 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 203ZI UT WOS:000323333300001 PM 23488689 ER PT J AU Stampalija, T Romero, R Korzeniewski, SJ Chaemsaithong, P Miranda, J Yeo, L Dong, Z Hassan, SS Chaiworapongsa, T AF Stampalija, Tamara Romero, Roberto Korzeniewski, Steven J. Chaemsaithong, Piya Miranda, Jezid Yeo, Lami Dong, Zhong Hassan, Sonia S. Chaiworapongsa, Tinnakorn TI Soluble ST2 in the fetal inflammatory response syndrome: in vivo evidence of activation of the anti-inflammatory limb of the immune response SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Funisitis; IL-10; inflammation; intra-amniotic infection/inflammation; preterm labor ID PRETERM PREMATURE RUPTURE; TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID INFECTION; TOLL-LIKE RECEPTORS; BLOOD-CELL COUNT; T-HELPER-CELL; INHIBITS CYTOKINE PRODUCTION; POLYMERASE-CHAIN-REACTION; HERPES-SIMPLEX INFECTION; CENTRAL-NERVOUS-SYSTEM AB Objective: Inflammation is a mechanism of host response to infection, which can be harmful when inappropriately modulated. Soluble ST2 (sST2) is a decoy receptor of interleukin (IL)-33, and this complex modulates the balance in the Th1/Th2 immune response. Moreover, sST2 inhibits the production of pro-inflammatory cytokines in cooperation with an anti-inflammatory cytokine, IL-10. The objectives of this study were to: (1) determine whether umbilical cord plasma sST2 concentration differs between preterm neonates with and without funisitis and between those with and without the fetal inflammatory response syndrome (FIRS); and (2) evaluate the relationship between sST2 and IL-10 among neonates with funisitis and/or FIRS. Methods: Umbilical cord plasma was collected from neonates delivered prematurely due to preterm labor or preterm prelabor rupture of membranes with (n = 36), and without funisitis (n = 30). FIRS (umbilical cord IL-6 concentration >= 17.5 pg/mL) was identified in 29 neonates. Plasma sST2 and IL-10 concentrations were determined by enzyme linked immune sorbent assay. Results: The median umbilical cord plasma sST2 concentration was 6.7-fold higher in neonates with FIRS than in those without FIRS (median 44.6 ng/mL, interquartile range (IQR) 13.8-80.3 ng/mL versus median 6.7 ng/mL, IQR 5.6-20.1 ng/mL; p < 0.0001). Similarly, the median umbilical cord plasma sST2 concentration was 2.7-fold higher in neonates with funisitis than in those without funisitis (median 19.1 ng/mL; IQR 7.1-75.0 ng/mL versus median 7.2 ng/mL; IQR 5.9-23.1 ng/mL; p = 0.008). There was a strong positive correlation between sST2 and IL-10 in neonates with funisitis and/or FIRS (Spearman's Rho = 0.7, p < 0.0001). Conclusion: FIRS and funisitis are associated with an elevation of umbilical cord plasma concentrations of soluble ST2. This protein represents an important mediator of the immune response in neonates diagnosed with FIRS by promoting an anti-inflammatory effect in association with IL-10. C1 [Stampalija, Tamara; Romero, Roberto; Korzeniewski, Steven J.; Chaemsaithong, Piya; Miranda, Jezid; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Stampalija, Tamara; Romero, Roberto; Korzeniewski, Steven J.; Chaemsaithong, Piya; Miranda, Jezid; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Stampalija, Tamara; Korzeniewski, Steven J.; Chaemsaithong, Piya; Miranda, Jezid; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet Gynecol, Detroit, MI 48201 USA. [Stampalija, Tamara] Univ Milan, Dept Biol & Clin Sci, Milan, Italy. 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 romeror@mail.nih.gov RI Stampalija, Tamara/K-4900-2014 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [HHSN275201300006C] FX This project has been funded in whole or in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201300006C. NR 202 TC 9 Z9 9 U1 0 U2 6 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 2013 VL 26 IS 14 BP 1384 EP 1393 DI 10.3109/14767058.2013.784258 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 203ZI UT WOS:000323333300004 PM 23488731 ER PT J AU Floreani, A Caroli, D Lazzari, R Memmo, A Vidali, E Colavito, D D'Arrigo, A Leon, A Romero, R Gervasi, MT AF Floreani, Annarosa Caroli, Diego Lazzari, Roberta Memmo, Alessia Vidali, Elisa Colavito, Davide D'Arrigo, Antonello Leon, Alberta Romero, Roberto Gervasi, Maria Teresa TI Intrahepatic cholestasis of pregnancy: new insights into its pathogenesis SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Genetics; intrahepatic cholestsis of pregnancy; microarray ID PHOSPHOLIPID TRANSFER PROTEIN; MDR3 GENE; MUTATION; PRURITUS; GABAPENTIN; TRANSPORT; VARIANTS; PROFILES; WOMEN; BURNS AB Aim: To search a specific gene expression profile in women with intrahepatic cholestasis of pregnancy (ICP) and to evaluate the maternal and foetal outcome. Methods: We consecutively enrolled 12 women with ICP and 12 healthy pregnant controls. The gene expression profile was assayed with the microarray technique including a panel of 5541 human genes. Microarray data were validated by real-time PCR technique. Results: Caesarean delivery was performed in eight patients with ICP versus three controls (p = 0.05). ICP women delivered at earlier gestational age than control (p < 0.001). Foetal distress was recorded in two babies, but we failed to find any correlation between bile salt concentration and foetal distress. Twenty genes potentially correlated with ICP were found differentially expressed (p < 0.05). Among these, three belong to genetic classes involved in pathogenic mechanisms of ICP: (1) pathophysiology of pruritus (GABRA2, cases versus controls = 2, upregulated gene); (2) lipid metabolism and bile composition (HLPT, cases versus controls = 0.6, down-regulated gene) and (3) protein trafficking and cytoskeleton arrangement (KIFC3, cases versus controls = 0.5, down-regulated gene). Conclusions: Different gene expression may contribute to the complex pathogenesis of ICP. An upregulation of GABRA2 receptor may indicate that GABA may play a role in the pathogenesis of pruritus in this condition. C1 [Floreani, Annarosa; Caroli, Diego; Lazzari, Roberta] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy. [Memmo, Alessia; Vidali, Elisa; Gervasi, Maria Teresa] Azienda Osped, Dept Obstet & Gynaecol, Padua, Italy. [Colavito, Davide; D'Arrigo, Antonello; Leon, Alberta] Res & Innovat, Padua, Italy. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] Wayne State Univ, Sch Med, Dept Obstet & Gynaecol, Detroit, MI USA. RP Floreani, A (reprint author), Dept Surg & Gastroenterol Sci, Via Giustiniani 2, I-35128 Padua, Italy. EM annarosa.floreani@unipd.it FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX The authors report no conflict of interest. The research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS and by a Ministerial grant (ex 60% fund). NR 35 TC 10 Z9 12 U1 0 U2 4 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 2013 VL 26 IS 14 BP 1410 EP 1415 DI 10.3109/14767058.2013.783810 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 203ZI UT WOS:000323333300008 PM 23480690 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, HHS, OD, OLAW,OER, Bethesda, MD 20892 USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, HHS, OD, OLAW,OER, Bethesda, MD 20892 USA. NR 1 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 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD SEP PY 2013 VL 42 IS 9 BP 318 EP 318 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 211AO UT WOS:000323876700015 PM 23965560 ER PT J AU Hughes, L AF Hughes, LaTesa TI Training initiatives for non-native English speakers in Laboratory animal care SO LAB ANIMAL LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Hughes, L (reprint author), NIH, Bldg 10, 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 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD SEP PY 2013 VL 42 IS 9 BP 335 EP 335 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 211AO UT WOS:000323876700020 PM 23965567 ER PT J AU Key, TJ Appleby, PN Reeves, GK Travis, RC Alberg, AJ Barricarte, A Berrino, F Krogh, V Sieri, S Brinton, LA Dorgan, JF Dossus, L Dowsett, M Eliassen, AH Fortner, RT Hankinson, SE Helzlsouer, KJ Hoffman-Bolton, J Comstock, GW Kaaks, R Kahle, LL Koenig, K Zeleniuch-Jacquotte, A Muti, P Overvad, K Peeters, PHM Riboli, E Rinaldi, S Rollison, DE Stanczyk, FZ Trichopoulos, D Tworoger, SS Tworoger, SS Vineis, P AF Key, T. J. Appleby, P. N. Reeves, G. K. Travis, R. C. Alberg, A. J. Barricarte, A. Berrino, F. Krogh, V. Sieri, S. Brinton, L. A. Dorgan, J. F. Dossus, L. Dowsett, M. Eliassen, A. H. Fortner, R. T. Hankinson, S. E. Helzlsouer, K. J. Hoffman-Bolton, J. Comstock, George W. Kaaks, R. Kahle, L. L. Koenig, K. Zeleniuch-Jacquotte, A. Muti, P. Overvad, K. Peeters, P. H. M. Riboli, E. Rinaldi, S. Rollison, D. E. Stanczyk, F. Z. Trichopoulos, D. Tworoger, S. S. Tworoger, S. S. Vineis, P. TI Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies SO LANCET ONCOLOGY LA English DT Article ID GROWTH-FACTOR LEVELS; POSTMENOPAUSAL WOMEN; ENDOGENOUS HORMONES; SERUM ANDROGENS; TESTOSTERONE; NUTRITION; ESTRADIOL; ESTROGENS; ETIOLOGY; DISEASE AB Background Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. Methods Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. Findings We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1.19, 95% CI 1.06-1.35), calculated free oestradiol (1.17, 1.03-1.33), oestrone (1.27, 1.05-1.54), androstenedione (1.30, 1.10-1.55), dehydroepiandrosterone sulphate (1.17, 1.04-1.32), testosterone (1.18, 1.03-1.35), and calculated free testosterone (1.08, 0.97-1.21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1.00, 95% CI 0.92-1.09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. Interpretation Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women. C1 [Key, T. J.; Appleby, P. N.; Reeves, G. K.; Travis, R. C.] Univ Oxford, Canc Epidemiol Unit, Nuffi eld Dept Populat Hlth, Oxford, England. [Alberg, A. J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Alberg, A. J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Barricarte, A.] Navarre Publ Hlth Inst, Pamplona, Spain. [Berrino, F.; Krogh, V.; Sieri, S.] Fondazione IRCCS Ist Nazl Tumori, Milan, Italy. [Brinton, L. A.] Natl Canc Inst, Bethesda, MD USA. [Dorgan, J. F.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Dossus, L.] INSERM, Ctr Res Epidemiol & Populat Hlth, CESP, Nutr Hormones & Womens Hlth Team, Villejuif, France. [Dowsett, M.] Inst Canc Res, London SW3 6JB, England. [Eliassen, A. H.] Harvard Univ, Sch Med, Channing Div Network Med, Dept Med, Boston, MA USA. [Eliassen, A. H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Eliassen, A. H.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Fortner, R. T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Fortner, R. T.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hankinson, S. E.] Harvard Univ, Sch Med, Boston, MA USA. [Hankinson, S. E.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. [Hankinson, S. E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trichopoulos, D.] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, D.] Hellen Hlth Fdn, Athens, Greece. [Tworoger, S. S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Tworoger, S. S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Vineis, P.] HuGeF Fdn, Turin, Italy. [Vineis, P.] Imperial Coll, London, England. RP Key, TJ (reprint author), Univ Oxford, Nuffield Dept Populat Hlth, Endogenous Hormones & Breast Canc Collaborat Grp, Canc Epidemiol Unit, Richard Doll Bldg, Oxford OX3 7LF, England. EM tim.key@ceu.ox.ac.uk RI Brinton, Louise/G-7486-2015; Krogh, Vittorio/K-2628-2016; Sieri, Sabina/K-4667-2016; OI Brinton, Louise/0000-0003-3853-8562; Krogh, Vittorio/0000-0003-0122-8624; Sieri, Sabina/0000-0001-5201-172X; Fortner, Renee/0000-0002-1426-8505 FU Cancer Research UK FX Funding Cancer Research UK. NR 39 TC 49 Z9 49 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2013 VL 14 IS 10 BP 1009 EP 1019 DI 10.1016/S1470-2045(13)70301-2 PG 11 WC Oncology SC Oncology GA 211WM UT WOS:000323942500047 ER PT J AU Griebel, G Holmes, A AF Griebel, Guy Holmes, Andrew TI 50 years of hurdles and hope in anxiolytic drug discovery SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID ANXIETY-LIKE BEHAVIOR; CORTICOTROPIN-RELEASING-FACTOR; NATIONAL-COMORBIDITY-SURVEY; GLUTAMIC-ACID DECARBOXYLASE; SEROTONIN 5-HT1A RECEPTOR; CB1 CANNABINOID RECEPTORS; ELEVATED PLUS-MAZE; DSM-IV DISORDERS; NULL MUTANT MICE; FEAR-POTENTIATED STARTLE AB Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (gamma-aminobutyric acid)-benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future. C1 [Griebel, Guy] Sanofi, Exploratory Unit, F-91385 Chilly Mazarin, France. [Holmes, Andrew] US Natl Inst Alcohol Abuse & Alcoholism, Lab Behav & Genom Neurosci, US Natl Inst Hlth, Rockville, MD 20852 USA. RP Griebel, G (reprint author), Sanofi, Exploratory Unit, F-91385 Chilly Mazarin, France. EM Guy.Griebel@sanofi.com RI Griebel, Guy/F-8752-2014 OI Griebel, Guy/0000-0002-6052-9438 FU Intramural NIH HHS [ZIA AA000411-10] NR 286 TC 84 Z9 88 U1 8 U2 46 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2013 VL 12 IS 9 BP 667 EP 687 DI 10.1038/nrd4075 PG 21 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 211EF UT WOS:000323887000018 PM 23989795 ER PT J AU Eisenberg, DP Kleinman, J Berman, KF AF Eisenberg, Daniel Paul Kleinman, Joel Berman, Karen F. TI Commentary on "Synergistic Effects of COMT and TPH2 on Social Cognition" Epistasis and Complex Neuropsychiatric Phenotypes SO PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES LA English DT Editorial Material C1 [Eisenberg, Daniel Paul; Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, NIH, Intramural Res Program,DHHS, Bethesda, MD 20892 USA. [Kleinman, Joel] NIMH, Neuropathol Sect, NIH, Intramural Res Program,DHHS, Bethesda, MD 20892 USA. RP Eisenberg, DP (reprint author), NIMH, Sect Integrat Neuroimaging, NIH, 9000 Rockville Pike,Bldg 10,Room 3C209, Bethesda, MD 20892 USA. EM eisenbergd@mail.nih.gov RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 FU Intramural NIH HHS [Z01 MH002717-13] NR 5 TC 0 Z9 0 U1 0 U2 1 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0033-2747 J9 PSYCHIATRY JI Psychiatry-Interpers. Biol. Process. PD FAL PY 2013 VL 76 IS 3 BP 295 EP 297 PG 3 WC Psychiatry SC Psychiatry GA 210TD UT WOS:000323856600008 PM 23965266 ER PT J AU Kozmin, SG Schaaper, RM AF Kozmin, Stanislav G. Schaaper, Roel M. TI Genetic characterization of moaB mutants of Escherichia coli SO RESEARCH IN MICROBIOLOGY LA English DT Article DE Molybdenum cofactor; moaABCDE operon; mogA gene; 6-N-Hydroxylaminopurine; Chlorate resistance ID MOLYBDENUM-COFACTOR BIOSYNTHESIS; HYDROXYLATED BASE ANALOGS; RESISTANCE; K-12; COLLECTION; REDUCTASE; STRAINS AB The moaABCDE operon of Escherichia coli encodes enzymes essential for the biosynthesis of the molybdenum cofactor (Moco). However, the role of the moaB gene within this operon has remained enigmatic. Here, we have investigated the effect of moaB defects on two phenotypes diagnostic for Moco-deficiency: chlorate-resistance and sensitivity to the base analog 6-N-hydroxylaminopurine (HAP). We found that transposon insertions in moaB caused partial Moco-deficiency associated with chlorate-resistance, but not for HAP-sensitivity. On the other hand, in-frame deletions of moaB, or moaB overexpression, had no effect on either phenotype. Our combined data are consistent with the lack of any role for MoaB in Moco biosynthesis in E. coli. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Kozmin, Stanislav G.; Schaaper, Roel M.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Schaaper, RM (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM stanislav.kozmin@duke.edu; schaaper@niehs.nih.gov RI Kozmin, Stanislav/J-6849-2012 OI Kozmin, Stanislav/0000-0002-4128-4447 FU National Institute of Environmental Health Sciences (NIEHS) [ES050170] FX We thank Drs. K. Chan and M. Itsko of the NIEHS for their helpful comments on the manuscript for this paper. This work was supported by project ES050170 of the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS). NR 21 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0923-2508 J9 RES MICROBIOL JI Res. Microbiol. PD SEP PY 2013 VL 164 IS 7 BP 689 EP 694 DI 10.1016/j.resmic.2013.05.001 PG 6 WC Microbiology SC Microbiology GA 212VL UT WOS:000324010800001 PM 23680484 ER PT J AU Szabo, S Xu, Y Romero, R Fule, T Karaszi, K Bhatti, G Varkonyi, T Varkonyi, I Krenacs, T Dong, Z Tarca, AL Chaiworapongsa, T Hassan, SS Papp, Z Kovalszky, I Than, NG AF Szabo, Szilvia Xu, Yi Romero, Roberto Fule, Tibor Karaszi, Katalin Bhatti, Gaurav Varkonyi, Tibor Varkonyi, Ildiko Krenacs, Tibor Dong, Zhong Tarca, Adi L. Chaiworapongsa, Tinnakorn Hassan, Sonia S. Papp, Zoltan Kovalszky, Ilona Than, Nandor Gabor TI Changes of placental syndecan-1 expression in preeclampsia and HELLP syndrome SO VIRCHOWS ARCHIV LA English DT Article DE Cell signaling; Pregnancy; Proteoglycan; Syncytiotrophoblast; Systemic inflammation; Virtual microscopy ID INTRAUTERINE GROWTH RESTRICTION; ELEVATED LIVER-ENZYMES; FOR-GESTATIONAL-AGE; CELL-SURFACE; SERUM CONCENTRATIONS; HEPARAN-SULFATE; PREGNANCY; PROTEOGLYCANS; TRANSMEMBRANE; MICROARRAY AB Preeclampsia is characterized by maternal systemic anti-angiogenic and pro-inflammatory states. Syndecan-1 is a cell surface proteoglycan expressed by the syncytiotrophoblast, which plays an important role in angiogenesis and resolution of inflammation. Our aim was to examine placental syndecan-1 expression in preeclampsia with or without hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Placentas were obtained from women in the following groups: (1) late-onset preeclampsia (n=8); (2) early-onset preeclampsia without (n=7) and (3) with HELLP syndrome (n=8); (4) preterm controls (n=5); and (5) term controls (n=9). Tissue microarrays (TMAs) were constructed from paraffin-embedded placentas. TMA slides were immunostained for syndecan-1 and evaluated using microscopy, virtual microscopy, and semi-automated image analysis. Maternal sera from patients with preeclampsia (n=49) and controls (n=32) were immunoassayed for syndecan-1. BeWo cells were treated with Forskolin or Latrunculin B or kept in ischemic conditions. SDC1 expression and syndecan-1 production were investigated with qRT-PCR, confocal microscopy, and immunoassays. Syndecan-1 was localized to the syncytiotrophoblast apical membrane in normal placentas. Syndecan-1 immunoscores were higher in late-onset preeclampsia (p=0.0001) and early-onset preeclampsia with or without HELLP syndrome (p=0.02 for both) than in controls. Maternal serum syndecan-1 concentration was lower in preeclampsia (median, 673 ng/ml; interquartile range, 459-1,161 ng/ml) than in controls (1,158 ng/ml; 622-1,480 ng/ml). SDC1 expression and syndecan-1 immunostainings in BeWo cells and syndecan-1 concentrations in supernatants increased during cell differentiation. Disruption of the actin cytoskeleton with Latrunculin B decreased syndecan-1 release, while ischemic conditions increased it. Syncytiotrophoblastic syndecan-1 expression depends on the differentiation of villous trophoblasts, and trophoblastic syndecan-1 release is decreased in preeclampsia and HELLP syndrome. This phenomenon may be related to the disturbed syncytiotrophoblastic cortical actin cytoskeleton and associated with maternal anti-angiogenic and pro-inflammatory states in these syndromes. C1 [Szabo, Szilvia] Semmelweis Univ, Fac Hlth Sci, Dept Morphol & Physiol, H-1085 Budapest, Hungary. [Xu, Yi; Romero, Roberto; Bhatti, Gaurav; Dong, Zhong; Tarca, Adi L.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Than, Nandor Gabor] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Fule, Tibor; Karaszi, Katalin; Krenacs, Tibor; Kovalszky, Ilona] Semmelweis Univ, Fac Med, Dept Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. [Varkonyi, Tibor; Papp, Zoltan; Than, Nandor Gabor] Semmelweis Univ, Fac Med, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary. [Papp, Zoltan; Than, Nandor Gabor] Matern Private Clin Obstet, Budapest, Hungary. [Varkonyi, Ildiko] Sundsvall Hosp, Dept Pathol & Cytol, Sundsvall, Sweden. [Tarca, Adi L.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Than, Nandor Gabor] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. EM romeror@mail.nih.gov; koval@korb1.sote.hu; gabor_than@yahoo.com FU European Union FP6 [Pregenesys 037244]; Hungarian Scientific Research Fund (OTKA) [67925]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services FX The authors are grateful to Dr. Noemi Mihalik, Edit Parsch, Levente Ficsor, and Gabor Kiszler (Budapest), and to Rona Wang, Yang Jiang, Olesya Plazyo, Mary Olive, Sandy Field, Ted Price, and Gerardo Rodriguez (Detroit) for their helpful technical assistance, and to Maureen McGerty and Andrea Bernard (Wayne State University) for their critical readings of the manuscript. Figure 6 was adapted from Riquelme et al. [59] with kind permission from Springer Science and Business Media. This research has been supported in part by the following grants: the European Union FP6 Grant "Pregenesys 037244" (to N.G.T.), the Hungarian Scientific Research Fund (OTKA) Grant 67925 (to N.G.T.), and the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services. NR 67 TC 6 Z9 7 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD SEP PY 2013 VL 463 IS 3 BP 445 EP 458 DI 10.1007/s00428-013-1426-0 PG 14 WC Pathology SC Pathology GA 211KB UT WOS:000323904700010 PM 23807541 ER PT J AU Garrison, AR Radoshitzky, SR Kota, KP Pegoraro, G Ruthel, G Kuhn, JH Altamura, LA Kwilas, SA Bavari, S Haucke, V Schmaljohn, CS AF Garrison, Aura R. Radoshitzky, Sheli R. Kota, Krishna P. Pegoraro, Gianluca Ruthel, Gordon Kuhn, Jens H. Altamura, Louis A. Kwilas, Steven A. Bavari, Sina Haucke, Volker Schmaljohn, Connie S. TI Crimean-Congo hemorrhagic fever virus utilizes a clathrin- and early endosome-dependent entry pathway SO VIROLOGY LA English DT Article DE Bunyavirus; CCHF; Crimean-Congo hemorrhagic fever; Nairovirus; Virus entry ID RECEPTOR-MEDIATED ENDOCYTOSIS; CELL-FUSION; CONFORMATIONAL-CHANGES; MAMMALIAN-CELLS; HOST-CELLS; GLYCOPROTEIN; PSEUDOVIRIONS; ACIDIFICATION; REPLICATION; TRAFFICKING AB The early events in Crimean-Congo hemorrhagic fever virus (CCHFV) have not been completely characterized. Earlier work indicated that CCHFV likely enters cells by clathrin-mediated endocytosis (CME). Here we provide confirmatory evidence for CME entry by showing that CCHFV infection is inhibited in cells treated with Pitstop 2, a drug that specifically and reversibly interferes with the dynamics of clathrin-coated pits. Additionally, we show that CCHFV infection is inhibited by siRNA depletion of the clathrin pit associated protein AP-2. Following CME entry, we show that CCHFV has a pH-dependent entry step, with virus inactivation occurring at pH 6.0 and below. To more precisely define the endosomal trafficking of CCHFV, we show for the first time that overexpression of the dominant negative forms of Rab5 protein but not Rab7 protein inhibits CCHFV infection. These results indicate that CCHFV likely enters cells through the early endosomal compalunent. Published by Elsevier Inc. C1 [Garrison, Aura R.; Radoshitzky, Sheli R.; Kota, Krishna P.; Pegoraro, Gianluca; Ruthel, Gordon; Altamura, Louis A.; Kwilas, Steven A.; Bavari, Sina; Schmaljohn, Connie S.] US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Ft Detrick, MD USA. [Haucke, Volker] Leibniz Inst Mol Pharmakol FMP, Berlin, Germany. RP Schmaljohn, CS (reprint author), US Army Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD USA. EM connie.schmaljohn@us.army.mil RI Kuhn, Jens H./B-7615-2011; OI Kuhn, Jens H./0000-0002-7800-6045; Pegoraro, Gianluca/0000-0003-2843-9464; Haucke, Volker/0000-0003-3119-6993 FU Military Infectious Diseases Research Program; NIAID [HHSN272200200016I]; German Funding Agency DFG [SFB765/B04] FX This work was funded by the Military Infectious Diseases Research Program. JHK performed this work as an employee of Tunnell Government Services, a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, under Contract no. HHSN272200200016I. V.H. gratefully acknowledges support by the German Funding Agency DFG (SFB765/B04). NR 60 TC 18 Z9 18 U1 0 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP PY 2013 VL 444 IS 1-2 BP 45 EP 54 DI 10.1016/j.virol.2013.05.030 PG 10 WC Virology SC Virology GA 210ZJ UT WOS:000323873600007 PM 23791227 ER PT J AU Vasilakis, N Widen, S Mayer, SV Seymour, R Wood, TG Popov, V Guzman, H da Rosa, APAT Ghedin, E Holmes, EC Walker, PJ Tesh, RB AF Vasilakis, Nikos Widen, Steven Mayer, Sandra V. Seymour, Robert Wood, Thomas G. Popov, Vsevolov Guzman, Hilda da Rosa, Amelia P. A. Travassos Ghedin, Elodie Holmes, Edward C. Walker, Peter J. Tesh, Robert B. TI Niakha virus: A novel member of the family Rhabdoviridae isolated from phlebotomine sandflies in Senegal SO VIROLOGY LA English DT Article DE Niakha virus (NIAV); Rhabdoviridae; Phlebotomine sandflies; Complement fixation; West Africa ID VESICULAR STOMATITIS-VIRUS; GLYCOPROTEIN-G; ARBOVIRUSES; PHYLOGENIES; ALIGNMENT; GENES; SMART; FORM AB Members of the family Rhabdoviridae have been assigned to eight genera but many remain unassigned. Rhabdoviruses have a remarkably diverse host range that includes terrestrial and marine animals, invertebrates and plants. Transmission of some rhabdoviruses often requires an arthropod vector, such as mosquitoes, midges, sandflies, ticks, aphids and leafhoppers, in which they replicate. Herein we characterize Niakha virus (NIAV), a previously uncharacterized rhabdovirus isolated from phebotomine sandflies in Senegal. Analysis of the 11,124 nt genome sequence indicates that it encodes the five common rhabdovirus proteins with alternative ORFs in the M, G and L genes. Phylogenetic analysis of the L protein indicate that NIAV's closest relative is Oak Vale rhabdovirus, although in this analysis NIAV is still so phylogenetically distinct that it might be classified as distinct from the eight currently recognized Rhabdoviridae genera. This observation highlights the vast, and yet not fully recognized diversity, of this family. (C) 2013 Elsevier Inc. All rights reserved. C1 [Vasilakis, Nikos; Mayer, Sandra V.; Seymour, Robert; Popov, Vsevolov; Guzman, Hilda; da Rosa, Amelia P. A. Travassos; Tesh, Robert B.] Ctr Biodef & Emerging Infect Dis, Galveston, TX USA. [Vasilakis, Nikos; Mayer, Sandra V.; Seymour, Robert; Popov, Vsevolov; Guzman, Hilda; da Rosa, Amelia P. A. Travassos; Tesh, Robert B.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Ctr Trop Dis, Galveston, TX 77555 USA. [Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Widen, Steven; Wood, Thomas G.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Ghedin, Elodie] Univ Pittsburgh, Dept Computat & Syst Biol, Ctr Vaccine Res, Pittsburgh, PA 15261 USA. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Walker, Peter J.] CSIRO Anim Food & Hlth Sci, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. RP Vasilakis, N (reprint author), Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, 2-138D Keiller Bldg,301 Univ Blvd, Galveston, TX 77555 USA. EM nivasila@utmb.edu RI Walker, Peter/H-6059-2013; OI Walker, Peter/0000-0003-1851-642X; Holmes, Edward/0000-0001-9596-3552 FU Department of Pathology; Institute for Human Infection and Immunity; NIH [HHSN272201000040I/HHSN27200004/D04]; NHMRC Australia Fellowship FX The authors are grateful to the late Jean Pierre Digoutte for providing Niakha virus strain DakArD 88909, to Gerald Campbell for his assistance in the histological evaluation of stained brain sections, and to Frederick A. Murphy for help in interpreting the electron micrographs of the virus. This work was supported in part by the Department of Pathology start up funds and a grant from the Institute for Human Infection and Immunity to NV and NIH contract HHSN272201000040I/HHSN27200004/D04 to RBT. ECH is supported by an NHMRC Australia Fellowship. The authors have no conflicting financial interests. NR 28 TC 12 Z9 12 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP PY 2013 VL 444 IS 1-2 BP 80 EP 89 DI 10.1016/j.virol.2013.05.035 PG 10 WC Virology SC Virology GA 210ZJ UT WOS:000323873600011 PM 23773405 ER PT J AU Satheshkumar, PS Chavre, J Moss, B AF Satheshkumar, P. S. Chavre, James Moss, Bernard TI Role of the vaccinia virus O3 protein in cell entry can be fulfilled by its Sequence flexible transmembrane domain SO VIROLOGY LA English DT Article DE Poxvirus entry; Membrane fusion; Entry-fusion complex; Transmembrane protein; Mutagenesis ID SURFACE HEPARAN-SULFATE; MEMBRANE-PROTEIN; FUSION COMPLEX; ESSENTIAL COMPONENT; POXVIRUS ENTRY; MATURE VIRIONS; HOST-CELLS; L1 PROTEIN; GENE; BINDS AB The vaccinia virus O3 protein, a component of the entry-fusion complex, is encoded by all chordopox-viruses. We constructed truncation mutants and demonstrated that the transmembrane domain, which comprises two-thirds of this 35 amino acid protein, is necessary and sufficient for interaction with the entry-fusion complex and function in cell entry. Nevertheless, neither single amino acid substitutions nor alanine scanning mutagenesis revealed essential amino acids within the transmembrane domain. Moreover, replication-competent mutant viruses were generated by randomization of 10 amino acids of the transmembrane domain. Of eight unique viruses, two contained only two amino acids in common with wild type and the remainder contained one or none within the randomized sequence. Although these mutant viruses formed normal size plaques, the entry-fusion complex did not co-purify with the mutant O3 proteins suggesting a less stable interaction. Thus, despite low specific sequence requirements, the transmembrane domain is sufficient for function in entry. Published by Elsevier Inc. C1 [Satheshkumar, P. S.; Chavre, James; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Catherine Cotter for cell culture and Jason Laliberte and Karl Erlandson for helpful discussions. The research was supported by intramural funds of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 31 TC 4 Z9 6 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP PY 2013 VL 444 IS 1-2 BP 148 EP 157 DI 10.1016/j.virol.2013.06.003 PG 10 WC Virology SC Virology GA 210ZJ UT WOS:000323873600018 PM 23816434 ER PT J AU Dunn, LL Boyer, PL Clark, PK Hughes, SH AF Dunn, Linda L. Boyer, Paul L. Clark, Patrick K. Hughes, Stephen H. TI Mutations in HIV-1 reverse transcriptase cause misfolding and miscleavage by the viral protease SO VIROLOGY LA English DT Article DE HIV-1; Reverse transcriptase; Protease; Stability; Differential scanning fluorescence ID IMMUNODEFICIENCY-VIRUS TYPE-1; RIBONUCLEASE-H ACTIVITY; DIMERIZATION; INSTABILITY; SUBUNIT; VIRIONS AB Previous work on mutations in the thumb of HIV-1 reverse transcriptase (RT) showed that the majority of the mutant RTs were degraded (by the viral protease) to various extents in virions. This degradation was, in most cases, temperature sensitive, and presumably was due to a partial unfolding of the protein at 37 degrees C. We used recombinant proteins to investigate the effects of the mutations on the thermal stability and proteolytic degradation of RT. Both subunits contribute to the stability of RT. In general, the differences in stability between the mutants and WT were greater if the mutation was in p51 rather than p66. Expressing the Pol polyprotein containing the RT mutants in Escherichia coli produced results similar to what was seen in virions; the mutant RTs were misfolded and/or degraded at 37 degrees C, but were better folded and processed at 30 degrees C. Published by Elsevier Inc. C1 [Dunn, Linda L.; Boyer, Paul L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Clark, Patrick K.] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Ctr Canc Res, NIH, POB B, Frederick, MD 21702 USA. EM dunnli@mail.nih.gov; boyerp@mail.nih.gov; clarkpk@mail.nih.gov; hughesst@mail.nih.gov FU National Cancer Institute, NIH [HHSN26120080001E]; Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E. NR 19 TC 5 Z9 5 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP PY 2013 VL 444 IS 1-2 BP 241 EP 249 DI 10.1016/j.virol.2013.06.017 PG 9 WC Virology SC Virology GA 210ZJ UT WOS:000323873600028 PM 23850459 ER PT J AU Changula, K Yoshida, R Noyori, O Marzi, A Miyamoto, H Ishijima, M Yokoyama, A Kajihara, M Feldmann, H Mweene, AS Takada, A AF Changula, Katendi Yoshida, Reiko Noyori, Osamu Marzi, Andrea Miyamoto, Hiroko Ishijima, Mari Yokoyama, Ayaka Kajihara, Masahiro Feldmann, Heinz Mweene, Aaron S. Takada, Ayato TI Mapping of conserved and species-specific antibody epitopes on the Ebola virus nucleoprotein SO VIRUS RESEARCH LA English DT Article DE Ebola virus; Nucleoprotein; Antibody epitope; Monoclonal antibody; Synthetic peptide ID LINKED-IMMUNOSORBENT-ASSAY; MONOCLONAL-ANTIBODIES; MARBURG VIRUSES; GLYCOPROTEIN; PARTICLES; ANTIGEN; COMPLEX; VP40 AB Filoviruses (viruses in the genus Ebolavirus and Marburgvirus in the family Filoviridae) cause severe haemorrhagic fever in humans and nonhuman primates. Rapid, highly sensitive, and reliable filovirus-specific assays are required for diagnostics and outbreak control. Characterisation of antigenic sites in viral proteins can aid in the development of viral antigen detection assays such immunochromatography-based rapid diagnosis. We generated a panel of mouse monoclonal antibodies (mAbs) to the nucleoprotein (NP) of Ebola virus belonging to the species Zaire ebolavirus. The mAbs were divided into seven groups based on the profiles of their specificity and cross-reactivity to other species in the Ebolavirus genus. Using synthetic peptides corresponding to the Ebola virus NP sequence, the mAb binding sites were mapped to seven antigenic regions in the C-terminal half of the NP, including two highly conserved regions among all five Ebolavirus species currently known. Furthermore, we successfully produced species-specific rabbit antisera to synthetic peptides predicted to represent unique filovirus B-cell epitopes. Our data provide useful information for the development of Ebola virus antigen detection assays. (C) 2013 Elsevier B.V. All rights reserved. C1 [Changula, Katendi; Mweene, Aaron S.; Takada, Ayato] Univ Zambia, Sch Vet Med, Lusaka, Zambia. [Changula, Katendi] SACIDS, Morogoro, Tanzania. [Yoshida, Reiko; Noyori, Osamu; Miyamoto, Hiroko; Ishijima, Mari; Yokoyama, Ayaka; Kajihara, Masahiro; Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido 0010020, Japan. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Takada, A (reprint author), Hokkaido Univ, Res Ctr Zoonosis Control, Kita Ku, Kita 20 Nishi 10, Sapporo, Hokkaido 0010020, Japan. EM atakada@czc.hokudai.ac.jp RI YOSHIDA, Reiko/F-6883-2012 FU Japan Science and Technology Agency within the framework of the Science and Technology Research Partnership for Sustainable Development (SATREPS); Japan Initiative for Global Research Network on Infectious Diseases (J-GRID); Ministry of Health, Labour and Welfare of Japan; National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). FX We thank Dr. Hideki Ebihara (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories) for valuable advice and Kim Barrymore for editing the manuscript: This work was supported by the Japan Science and Technology Agency within the framework of the Science and Technology Research Partnership for Sustainable Development (SATREPS) and by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID). Funding was also provided by a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan, and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 23 TC 8 Z9 8 U1 7 U2 37 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD SEP PY 2013 VL 176 IS 1-2 BP 83 EP 90 DI 10.1016/j.virusres.2013.05.004 PG 8 WC Virology SC Virology GA 210TV UT WOS:000323858500010 PM 23702199 ER PT J AU Levitt, AL Singh, R Cox-Foster, DL Rajotte, E Hoover, K Ostiguy, N Holmes, EC AF Levitt, Abby L. Singh, Rajwinder Cox-Foster, Diana L. Rajotte, Edwin Hoover, Kelli Ostiguy, Nancy Holmes, Edward C. TI Cross-species transmission of honey bee viruses in associated arthropods SO VIRUS RESEARCH LA English DT Article DE Deformed wing virus (DWV); Phylogenetic analysis; Virus detection; Apis mellifera ID DEFORMED-WING-VIRUS; MITES VARROA-DESTRUCTOR; ACUTE PARALYSIS VIRUS; APIS-MELLIFERA L.; RNA VIRUSES; EVOLUTIONARY GENETICS; POPULATION BIOLOGY; MUTATION-RATES; EMERGENCE; INFECTION AB There are a number of RNA virus pathogens that represent a serious threat to the health of managed honey bees (Apis mellifera). That some of these viruses are also found in the broader pollinator community suggests the wider environmental spread of these viruses, with the potential for a broader impact on ecosystems. Studies on the ecology and evolution of these viruses in the arthropod community as a whole may therefore provide important insights into these potential impacts. We examined managed A. mellifera colonies, nearby non-Apis hymenopteran pollinators, and other associated arthropods for the presence of five commonly occurring picorna-like RNA viruses of honey bees - black queen cell virus, deformed wing virus, Israeli acute paralysis virus, Kashmir bee virus and sacbrood virus. Notably, we observed their presence in several arthropod species. Additionally, detection of negative-strand RNA using strand-specific RT-PCR assays for deformed wing virus and Israeli acute paralysis virus suggests active replication of deformed wing virus in at least six non-Apis species and active replication of Israeli acute paralysis virus in one non-Apis species. Phylogenetic analysis of deformed wing virus also revealed that this virus is freely disseminating across the species sampled in this study. In sum, our study indicates that these viruses are not specific to the pollinator community and that other arthropod species have the potential to be involved in disease transmission in pollinator populations. (C) 2013 Elsevier B.V. All rights reserved. C1 [Levitt, Abby L.] Penn State Univ, Huck Inst Life Sci, Intercoll Program Genet, University Pk, PA 16802 USA. [Singh, Rajwinder; Cox-Foster, Diana L.; Rajotte, Edwin; Hoover, Kelli; Ostiguy, Nancy] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Hoover, K (reprint author), Penn State Univ, Dept Entomol, 501 ASI Bldg, University Pk, PA 16802 USA. EM kxh25@psu.edu OI Holmes, Edward/0000-0001-9596-3552 FU Alphawood Foundation; Pennsylvania Department of Agriculture [ME 446716]; Haagen Dazs Graduate Fellowship in Pollinator Health; NHMRC Australia Fellowship FX We thank Jeremy Fitzgerald and Christina Grozinger's group at the Department of Entomology at The Pennsylvania State University for assistance in collecting samples and the Penn State Genomics Core Facility, University Park, PA for sequencing services. Funding provided by the Alphawood Foundation, the Pennsylvania Department of Agriculture (Grant No. ME 446716), and the Haagen Dazs Graduate Fellowship in Pollinator Health. ECH is supported by an NHMRC Australia Fellowship. NR 50 TC 26 Z9 30 U1 8 U2 96 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD SEP PY 2013 VL 176 IS 1-2 BP 232 EP 240 DI 10.1016/j.virusres.2013.06.013 PG 9 WC Virology SC Virology GA 210TV UT WOS:000323858500027 PM 23845302 ER PT J AU Ozarslan, E Koay, CG Shepherd, TM Komlosh, ME Irfanoglu, MO Pierpaoli, C Basser, PJ AF Oezarslan, Evren Koay, Cheng Guan Shepherd, Timothy M. Komlosh, Michal E. Irfanoglu, M. Okan Pierpaoli, Carlo Basser, Peter J. TI Mean apparent propagator (MAP) MRI: A novel diffusion imaging method for mapping tissue microstructure SO NEUROIMAGE LA English DT Article DE Diffusion; Propagator; ODF; Return-to-origin; Non-Gaussianity; Anisotropy; Volume; Hermite; SHORE; Generalized DTI; GDTI ID NON-GAUSSIAN DIFFUSION; GENERALIZED DIFFUSION; FIELD GRADIENT; WEIGHTED MRI; SPHERICAL DECONVOLUTION; PROBABILITY DENSITY; RAT HIPPOCAMPUS; AXON DIAMETER; SPIN ECHOES; HUMAN BRAIN AB Diffusion-weighted magnetic resonance (MR) signals reflect information about underlying tissue microstructure and cytoarchitecture. We propose a quantitative, efficient, and robust mathematical and physical framework for representing diffusion-weighted MR imaging (MRI) data obtained in "q-space," and the corresponding "mean apparent propagator (MAP)" describing molecular displacements in "r-space." We also define and map novel quantitative descriptors of diffusion that can be computed robustly using this MAP-MRI framework. We describe efficient analytical representation of the three-dimensional q-space MR signal in a series expansion of basis functions that accurately describes diffusion in many complex geometries. The lowest order term in this expansion contains a diffusion tensor that characterizes the Gaussian displacement distribution, equivalent to diffusion tensor MRI (DTI). Inclusion of higher order terms enables the reconstruction of the true average propagator whose projection onto the unit "displacement" sphere provides an orientational distribution function (ODF) that contains only the orientational dependence of the diffusion process. The representation characterizes novel features of diffusion anisotropy and the non-Gaussian character of the three-dimensional diffusion process. Other important measures this representation provides include the return-to-the-origin probability (RTOP), and its variants for diffusion in one- and two-dimensions-the return-to-the-plane probability (RTPP), and the return-to-the-axis probability (RTAP), respectively. These zero net displacement probabilities measure the mean compartment (pore) volume and cross-sectional area in distributions of isolated pores irrespective of the pore shape. MAP-MRI represents a new comprehensive framework to model the three-dimensional q-space signal and transform it into diffusion propagators. Experiments on an excised marmoset brain specimen demonstrate that MAP-MRI provides several novel, quantifiable parameters that capture previously obscured intrinsic features of nervous tissue microstructure. This should prove helpful for investigating the functional organization of normal and pathologic nervous tissue. (C) 2013 Elsevier Inc. All rights reserved. C1 [Oezarslan, Evren; Komlosh, Michal E.; Irfanoglu, M. Okan; Pierpaoli, Carlo; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. [Oezarslan, Evren; Komlosh, Michal E.; Irfanoglu, M. Okan] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Oezarslan, Evren] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02215 USA. [Koay, Cheng Guan] Univ Wisconsin, Dept Med Phys, Madison, WI 53705 USA. [Shepherd, Timothy M.] NYU, Dept Radiol, Langone Med Ctr, New York, NY 10016 USA. RP Ozarslan, E (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02215 USA. EM evren@bwh.harvard.edu RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH); Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM); Henry M. Jackson Foundation (HJF); NIH [IRCMH090912-01, R01MH074794] FX The authors gratefully acknowledge Drs. John D. Newman and Afonso C. Silva for the marmoset brain specimen and Liz Salak for editing the manuscript. Special thanks to Jian Cheng for pointing out an error in (Ozarslan et al., 2009c). Support for this work included funding from: (i) the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health (NIH), and (ii) the Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) and the Henry M. Jackson Foundation (HJF). (iii) CGK was supported in part by NIH grant no. IRCMH090912-01. (iv) EO was supported in part by NIH R01MH074794. NR 74 TC 49 Z9 49 U1 2 U2 36 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 2013 VL 78 BP 16 EP 32 DI 10.1016/j.neuroimage.2013.04.016 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 165MV UT WOS:000320488900003 PM 23587694 ER PT J AU Warren, K AF Warren, K. TI FETAL ALCOHOL SPECTRUM DISORDERS: STRANGE BEGINNINGS TO CUTTING EDGE RESEARCH ESBRA & ISBRA JOINT SYMPOSIUM SO ALCOHOL AND ALCOHOLISM LA English DT Meeting Abstract C1 [Warren, K.] NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP PY 2013 VL 48 SU 1 BP 18 EP 19 PG 2 WC Substance Abuse SC Substance Abuse GA 204EP UT WOS:000323348200079 ER PT J AU Leggio, L AF Leggio, L. TI STUDYING THE ROLE OF FEEDING-RELATED PATHWAYS IN ALCOHOLISM VIA HUMAN LABORATORY STUDIES SO ALCOHOL AND ALCOHOLISM LA English DT Meeting Abstract C1 [Leggio, L.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. RI Leggio, Lorenzo/M-2972-2016 NR 0 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP PY 2013 VL 48 SU 1 BP 27 EP 27 PG 1 WC Substance Abuse SC Substance Abuse GA 204EP UT WOS:000323348200119 ER PT J AU Ramchandani, V AF Ramchandani, V. TI CHARACTERIZATION OF OPERANT INTRAVENOUS ALCOHOL SELF-ADMINISTRATION IN HUMANS SO ALCOHOL AND ALCOHOLISM LA English DT Meeting Abstract C1 [Ramchandani, V.] NIAAA, Lab Clin & Translat Studies, Sect Human Psychopharmacol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP PY 2013 VL 48 SU 1 BP 27 EP 27 PG 1 WC Substance Abuse SC Substance Abuse GA 204EP UT WOS:000323348200118 ER PT J AU van Meurs, JBJ Pare, G Schwartz, SM Hazra, A Tanaka, T Vermeulen, SH Cotlarciuc, I Yuan, X Malarstig, A Bandinelli, S Bis, JC Morn, H Brown, MJ Chen, C Chen, YD Clarke, RJ Dehghan, A Erdmann, J Ferrucci, L Hamsten, A Hofman, A Hunten, DJ Goel, A Johnson, AD Kathiresan, S Kampman, E Kiel, DP Kiemeney, LA Chambers, JC Kraft, P Lindemans, J McKnight, B Nelson, CP O'Donnell, CJ Psaty, BM Ridken, PM Rivadeneira, F Rose, LM Seedoif, U Siscovick, DS Schunkert, H Selhub, J Ueland, PM Vollenweiden, P Waeben, G Waterworth, DM Watkins, H Witteman, JCM den Heijen, M Jacques, P Uitterlinden, AG Koonet, JS Rader, DJ Reilly, MP Moose, V Chasman, DI Samani, NJ Ahmadi, KR AF van Meurs, Joyce B. J. Pare, Guillaume Schwartz, Stephen M. Hazra, Aditi Tanaka, Toshiko Vermeulen, Sita H. Cotlarciuc, Ioana Yuan, Xin Malarstig, Anders Bandinelli, Stefania Bis, Joshua C. Morn, Henk Brown, Morris J. Chen, Constance Chen, Yii-Der Clarke, Robert J. Dehghan, Abbas Erdmann, Jeanette Ferrucci, Luigi Hamsten, Anders Hofman, Albert Hunten, David J. Goel, Anuj Johnson, Andrew D. Kathiresan, Secar Kampman, Ellen Kiel, Douglas P. Kiemeney, Lamberius Aim Chambers, John C. Kraft, Peter Lindemans, Jan McKnight, Barbara Nelson, Christopher P. O'Donnell, Christopher J. Psaty, Bruce M. Ridken, Paul M. Rivadeneira, Fernando Rose, Lynda M. Seedoif, Udo Siscovick, David S. Schunkert, Heribert Selhub, Jacob Ueland, Per M. Vollenweiden, Peter Waeben, Gerard Waterworth, Dawn M. Watkins, Hugh Witteman, Jacqueline C. M. den Heijen, Martin Jacques, Paul Uitterlinden, Andre G. Koonet, Jaspal S. Rader, Dan J. Reilly, Muredach P. Moose, Vincent Chasman, Daniel I. Samani, Nilesh J. Ahmadi, Kourosh R. TI Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID GENOME-WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; MENDELIAN RANDOMIZATION; HEART-DISEASE; EXPRESSION; METAANALYSIS; MTHFR; POLYMORPHISM; WOMEN; IDENTIFICATION AB Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteinelowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. Objective: We tested whether common genetic polymorphisms associated with variation in tlicy are also associated with CAD. Design: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymolphisms associated with tHcy (P < 10(-8)) were tested for association with CAD in 31,400 cases and 92,927 controls. Results: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 X 10(-9)), SLC17A3 (1.0 x 10(-8)), GTPB10 (1.7 X 10(-8)), CUBN (7.5 X 10(-1)), HNFlA (1.2 x 10(-12)), and FUT2 (6.6 x 10(-9)), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-gmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 X 10(-36)). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). Conclusions: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHey concentrations and tHcy-related pathways for CAD. C1 [van Meurs, Joyce B. J.; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Dehghan, Abbas; Hofman, Albert; Rivadeneira, Fernando; Witteman, Jacqueline C. M.; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Meurs, Joyce B. J.; Rivadeneira, Fernando] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Pare, Guillaume] McMaster Univ, Dept Pathol, Hamilton, ON, Canada. [Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Hazra, Aditi; Chen, Constance; Hunten, David J.; Kraft, Peter] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dep Med, Boston, MA 02115 USA. [Hazra, Aditi; Chen, Constance; Hunten, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, Nijmegen, Netherlands. [Cotlarciuc, Ioana; Ahmadi, Kourosh R.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Yuan, Xin; Waterworth, Dawn M.; Moose, Vincent] GlaxoSmithKline, Div Genet, King Of Prussia, PA USA. [Yuan, Xin; Vollenweiden, Peter; Waeben, Gerard; Waterworth, Dawn M.; Moose, Vincent] Univ Lausanne, Dept Med, Div Internal Med, Lausanne, Switzerland. [Yuan, Xin; Vollenweiden, Peter; Waeben, Gerard; Waterworth, Dawn M.; Moose, Vincent] Univ Lausanne, Ctr Hosp Univ Vaudois, Lausanne, Switzerland. [Malarstig, Anders; Hamsten, Anders] Karolinska Inst, Atherosclerosis Res Unit, Stockholm, Sweden. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Brown, Morris J.] Univ Cambridge, Clin Pharmacol Unit, Cambridge, England. [Chen, Yii-Der] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Clarke, Robert J.] Univ Oxford, Clin Trial Serv Unit, Oxford OX1 2JD, England. [Clarke, Robert J.] Univ Oxford, Epidemiol Studies Unit, Oxford OX1 2JD, England. [Erdmann, Jeanette; Schunkert, Heribert] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Goel, Anuj; Watkins, Hugh] Univ Oxford, Dept Cardiovasc Med, Oxford OX1 2JD, England. [Selhub, Jacob; Jacques, Paul] Tufts Univ, Vitamin Metab & Aging Lab, Boston, MA 02111 USA. [Selhub, Jacob; Jacques, Paul] Tufts Univ, Nutrit Epidemiol Program, Boston, MA 02111 USA. [Johnson, Andrew D.; Kiel, Douglas P.; O'Donnell, Christopher J.; Jacques, Paul] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kathiresan, Secar] Cardiovasc Res Ctr, Boston, MA USA. [Kathiresan, Secar] Div Cardiol, Boston, MA USA. [Kampman, Ellen] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Kiel, Douglas P.] Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA USA. [Koonet, Jaspal S.] Natl Heart & Lung Inst, Bethesda, MD USA. [McKnight, Barbara] Imperial Coll London, London, England. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, NIHR, Leicester Cardiovascular Biomed Res Unit, Leicester, Leics, England. [Reilly, Muredach P.] Univ Washington, Cardiovascular Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovascular Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovascular Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Ridken, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Dept Prevent Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Seedoif, Udo] Univ Munster, Inst Arterioskleroseforsch, D-48149 Munster, Germany. [Ueland, Per M.] Univ Bergen Haukeland, Bergen, Norway. [Ueland, Per M.] Bergen Univ Hosp, Bergen, Norway. [Rader, Dan J.; Reilly, Muredach P.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Rader, Dan J.; Reilly, Muredach P.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Samani, Nilesh J.] Leicester NTHR Biomed Res Unit Cardiovasc Dis, Leicester, Leics, England. [Erdmann, Jeanette; Schunkert, Heribert] Univ Lubeck, Deutsch Zentrum Herz Kreislauf Forschung, Lubeck, Germany. [den Heijen, Martin] Vrije Univ Amsterdam Med Ctr, Dept Internal Med, Amsterdam, Netherlands. [Ahmadi, Kourosh R.] Univ Surrey, Dept Nutr & Metab, Fac Hlth & Med Sci, Guildford GU2 5XH, Surrey, England. RP Ahmadi, KR (reprint author), Univ Surrey, Dept Nutr & Metab, Fac Hlth & Med Sci, Guildford GU2 5XH, Surrey, England. EM k.ahmadi@surrey.co.uk RI Colaus, PsyColaus/K-6607-2013; Kiemeney, Lambertus/D-3357-2009; Erdmann, Jeanette/P-7513-2014; Ueland, Per/C-7340-2013; den Heijer, Martin/J-8036-2015; Kampman, E./H-8057-2014; Rivadeneira, Fernando/O-5385-2015; Vermeulen, H.H.M./L-4716-2015; Johnson, Andrew/G-6520-2013; OI Kiemeney, Lambertus/0000-0002-2368-1326; Erdmann, Jeanette/0000-0002-4486-6231; Kiel, Douglas/0000-0001-8474-0310; den Heijer, Martin/0000-0003-3620-5617; Rivadeneira, Fernando/0000-0001-9435-9441; Blom, Henk/0000-0001-5202-9241; Schwartz, Stephen/0000-0001-7499-8502; Seedorf, Udo/0000-0003-4652-5358; Watkins, Hugh/0000-0002-5287-9016; Dehghan, Abbas/0000-0001-6403-016X FU Netherlands Consortium for Healthy Aging, Rotterdam, Leiden the Netherlands; Department of Pathology; McMaster University, Hamilton, Canada; Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA; Channing Laboratory, Department of Medicine, Brigham; Women's Hospital, Harvard Medical School and Department of Epidemiology, Harvard School of Public Health, Boston; Clinical Research Branch, National Institute on Aging, Baltimore, MD; Department for Health Evidence, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; Genetics Division, GlaxoSmithKline, King of Prussia, PA; Department of Medicine, Division of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland FX From the Departments of Internal Medicine (JBJvM, FR, and AGU), Epidemiology (AD, A Hofman, FR, JCMVV, and AGU), and Clinical Chemistry (IL), Erasmus MC, Rotterdam, the Netherlands; the Netherlands Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Aging, Rotterdam, Leiden the Netherlands (JBJvM and FR); the Department of Pathology, McMaster University, Hamilton, Canada (GP); the Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA (SMS); the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School and Department of Epidemiology, Harvard School of Public Health, Boston (AH, CC, DJH, and PK); the Clinical Research Branch, National Institute on Aging, Baltimore, MD (TT, and LF); the Department for Health Evidence, Radboud University Medical Centre, Nijmegen, the Netherlands (SHY and LALMK); the Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom (IC and KRA); the Genetics Division, GlaxoSmithKline, King of Prussia, PA (XY, DMW, and VM); the Department of Medicine, Division of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland (XY, PV, GW, DIVIW, and VM); the Atherosclerosis Research Unit, Karolinska Institute, Stockholm, Sweden (AM and A Hamsten); the Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy (SB); the VU Medical Centre, Amsterdam, the Netherlands (HB); the Clinical Pharmacology Unit, University of Cambridge, Cambridge, United Kingdom (MJB); the Medical Genetics Research Institute, Cedars-Sinai Medical Centre, Los Angeles, CA (Y-DC); the Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, United Kingdom (RJC); Medizinische Klinik It, Universitat zu Liibeck, Liibeck, Germany (JE and HS); the Department of Cardiovascular Medicine, University of Oxford, United Kingdom (AG and HW); the Vitamin Metabolism and Aging Laboratory and Nutritional Epidemiology Program, Tufts University, Boston, MA (JS and PJ); the Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA (ADJ, DPK, CJO, and PJ); the Cardiovascular Research Center and Cardiology Division, Boston, MA (SK); the Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands (EK); the Hebrew Senior Life Institute for Aging Research and Harvard Medical School, Boston, MA (DPK); the Department of Epidemiology and Biostatistics (JCC) and the National Heart and Lung Institute (JSK), Imperial College of London, United Kingdom; the Department of Biostatistics, University of Washington, Seattle, WA (BM); the Department of Cardiovascular Sciences, University of Leicester, Leicester (CPN and NJS) and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (CPN and NJS); the Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington and the Group Health Research Institute, Group Health Cooperative, Seattle, WA (BMP); the Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (PMR, LMR, and DIC); the Institut fur Arterioskleroseforschung an der Universitat Miinster, Miinster, Germany (US); the University of Bergen/ Haukeland, University Hospital Bergen, Bergen, Norway (PMU); the Cardiovascular Institute and Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia; , PA (DJR and MPR); Leicester NTHR Biomedical Research Unit in Cardiovascular Disease, Leicester, United Kingdom (NJS); the Deutsches Zentrum fur Herz-Kreislauf-Forschung, Universitat zu Liibeck, Lubeck, Germany (TB and HS); the Department of Internal Medicine, VU Medical Center, Amsterdam, the Netherlands (MdH); and the Department of Nutrition and Metabolism, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (KRA). NR 47 TC 40 Z9 40 U1 0 U2 17 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2013 VL 98 IS 3 BP 668 EP 676 DI 10.3945/ajcn.112.044545 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 206OT UT WOS:000323532700007 PM 23824729 ER PT J AU Miller, PE Cross, AJ Subar, AF Krebs-Smith, SM Park, Y Powell-Wiley, T Hollenbeck, A Reedy, J AF Miller, Paige E. Cross, Amanda J. Subar, Amy F. Krebs-Smith, Susan M. Park, Yikyung Powell-Wiley, Tiffany Hollenbeck, Albert Reedy, Jill TI Comparison of 4 established DASH diet indexes: examining associations of index scores and colorectal cancer SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRES; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; NATIONAL-INSTITUTES; BLOOD-PRESSURE; HYPERTENSION; RISK; PATTERNS; ADHERENCE; DISEASE AB Background: Multiple diet indexes have been developed to capture the Dietary Approaches to Stop Hypertension (DASH) dietary pattern and examine relations with health outcomes but have not been compared within the same study population to our knowledge. Objective: We compared 4 established DASH indexes and examined associations with colorectal cancer. Design: Scores were generated from a food-frequency questionnaire in the NIH-AARP Diet and Health Study (n = 491,841). Separate indexes defined by Dixon (7 food groups, saturated fat, and alcohol), Mellen (9 nutrients), Fung (7 food groups and sodium), and Gunther (8 food groups) were used. HRs and 95% CIs for colorectal cancer were generated by using Cox proportional hazard models. Results: From 1995 through 2006, 6752 incident colorectal cancer cases were ascertained. In men, higher scores were associated with reduced colorectal cancer incidence by comparing highest to lowest quintiles for all indexes as follows: Dixon (HR: 0.77; 95% CI: 0.69, 0.87), Mellen (HR: 0.78; 95% CI: 031, 0.86), Fung (HR: 0.75; 95% CI: 0.68, 0.83), and Gunther (HR: 0.81; 95% CI: 0.74, 0.90). Higher scores in women were inversely associated with colorectal cancer incidence by using methods defined by Mellen (HR: 0.79; 95% CI: 0.68, 0.91), Fung (HR: 0.84; 95% CI: 0.73, 0.96), and Gunther (HR: 0.84; 95% CI: 0.73.0.97) but not Dixon (BR: 1.01; 95% CI: 0.80, 1.28). Conclusion: The consistency in findings, particularly in men, suggests that all indexes capture an underlying construct inherent in the DASH dietary pattern, although the specific index used can affect results. C1 [Miller, Paige E.] NCI, Canc Prevent Fellowship Program, Rockville, MD USA. [Cross, Amanda J.; Park, Yikyung] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Subar, Amy F.; Krebs-Smith, Susan M.; Reedy, Jill] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Miller, Paige E.] Exponent Inc, Ctr Epidemiol Biostat & Computat Biol, Chicago, IL USA. [Powell-Wiley, Tiffany] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Miller, PE (reprint author), Exponent Inc, 525 West Monroe St,Suite 1050, Chicago, IL 60661 USA. EM pmiller@exponent.com OI Park, Yikyung/0000-0002-6281-489X FU Cancer Prevention Fellowship Program; Intramural Research Program, National Cancer Institute, NIH FX Supported by the Cancer Prevention Fellowship Program and the Intramural Research Program, National Cancer Institute, NIH. NR 30 TC 18 Z9 18 U1 0 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2013 VL 98 IS 3 BP 794 EP 803 DI 10.3945/ajcn.113.063602 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 206OT UT WOS:000323532700022 PM 23864539 ER PT J AU Folio, LR Sandouk, A Huang, JX Solomon, JM Apolo, AB AF Folio, Les R. Sandouk, Aline Huang, Jiaxin Solomon, Jeffrey M. Apolo, Andrea B. TI Consistency and Efficiency of CT Analysis of Metastatic Disease: Semiautomated Lesion Management Application Within a PACS SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE metastatic cancer; quantitative imaging; RECIST; tumor assessment; volumetric measurements ID IMAGE REGISTRATION; TUMOR SEGMENTATION; SOLID TUMORS; LUNG-CANCER; CLASSIFICATION; VARIABILITY; PULMONARY; SCANS AB OBJECTIVE. The purpose of this study was to evaluate the success, consistency, and efficiency of a semiautomated lesion management application within a PACS in the analysis of metastatic lesions in serial CT examinations of cancer patients. MATERIALS AND METHODS. Two observers using baseline and follow-up CT data independently reviewed 93 target lesions (17 lung, five liver, 71 lymph node) in 50 patients with either metastatic bladder or prostate cancer. The observers measured the longest axis (or short axis for lymph nodes) of each lesion and made Response Evaluation Criteria in Solid Tumors (RECIST) determinations using manual and lesion management application methods. The times required for examination review, RECIST calculations, and data input were recorded. The Wilcoxon signed rank test was used to assess time differences, and Bland-Altman analysis was used to assess interobserver agreement within the manual and lesion management application methods. Percentage success rates were also reported. RESULTS. With the lesion management application, most lung and liver lesions were semiautomatically segmented. Comparison of the lesion management application and manual methods for all lesions showed a median time saving of 45% for observer 1 (p < 0.05) and 28% for observer 2 (p = 0.05) on follow-up scans versus 28% for observer 1 (p < 0.05) and 9% for observer 2 (p = 0.087) on baseline scans. Variability of measurements showed mean percentage change differences of only 8.9% for the lesion management application versus 26.4% for manual measurements. CONCLUSION. With the lesion management application method, most lung and liver lesions were successfully segmented semiautomatically; the results were more consistent between observers; and assessment of tumor size was faster than with the manual method. C1 [Folio, Les R.; Sandouk, Aline; Huang, Jiaxin; Solomon, Jeffrey M.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Solomon, Jeffrey M.] Expert Image Anal LLC, Potomac, MD USA. [Apolo, Andrea B.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Folio, LR (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm 1C340, Bethesda, MD 20892 USA. EM les.folio@nih.gov FU Intramural Research Program of the National Institutes of Health FX Supported in part by the Intramural Research Program of the National Institutes of Health. NR 31 TC 7 Z9 7 U1 2 U2 11 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD SEP PY 2013 VL 201 IS 3 BP 618 EP 625 DI 10.2214/AJR.12.10136 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 207LP UT WOS:000323601500041 PM 23971455 ER PT J AU Lennartz, F Hoenen, T Lehmann, M Groseth, A Garten, W AF Lennartz, Frank Hoenen, Thomas Lehmann, Maria Groseth, Allison Garten, Wolfgang TI The role of oligomerization for the biological functions of the arenavirus nucleoprotein SO ARCHIVES OF VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; VIRAL-RNA SYNTHESIS; MATRIX PROTEIN-Z; LASSA-VIRUS; IMMUNE SUPPRESSION; TERMINAL REGION; REPLICATION; NP; TRANSCRIPTION; REVEALS AB The Lassa virus nucleoprotein (NP) is a multifunctional protein that plays an essential role in many aspects of the viral life cycle, including RNA encapsidation, viral transcription and replication, recruitment of ribonucleoprotein complexes to viral budding sites, and inhibition of the host cell interferon response. While it is known that NP is capable of forming oligomers, both the oligomeric state of NP in mammalian cells and the significance of NP oligomerization for its various functions remain unclear. Here, we demonstrate that Lassa virus NP solely forms trimers upon expression in mammalian cells. Using a minigenome assay we show that mutants that are not able to form stable trimers are no longer functional during transcription and/or replication of the minigenome, indicating that NP trimerization is essential for transcription and/or replication of the viral genome. However, mutations leading to destabilization of the NP trimer did not impact the incorporation of NP into virus-like particles or its ability to suppress interferon-induced gene expression, two important functions of arenavirus NP. C1 [Lennartz, Frank; Hoenen, Thomas; Groseth, Allison; Garten, Wolfgang] Univ Marburg, Inst Virol, D-35043 Marburg, Germany. [Hoenen, Thomas; Groseth, Allison] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Lehmann, Maria] Bernhard Nocht Inst Trop Med, Dept Virol, D-20359 Hamburg, Germany. RP Garten, W (reprint author), Univ Marburg, Inst Virol, Hans Meerwein Str 2, D-35043 Marburg, Germany. EM garten@staff.uni-marburg.de OI Hoenen, Thomas/0000-0002-5829-6305 FU Deutsche Forschungsgemeinschaft [SPP1175, SFB593]; Stiftung zur Forderung von Forschung und Lehre am Fachbereich Medizin der Philipps-Universitat Marburg; Studienstiftung des deutschen Volkes; Schering Foundation; Canadian Institutes of Health Research; NIH, NIAID FX We thank Thomas Strecker for critical manuscript review and Petra Neubauer-Radel for expert technical assistance. We further thank Stephan Becker (Philipps University Marburg), Thomas Strecker (Philipps University Marburg) and Takashi Fujita (Kyoto University) for kindly providing plasmids. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SPP1175 and SFB593), the "Stiftung zur Forderung von Forschung und Lehre am Fachbereich Medizin der Philipps-Universitat Marburg", the "Studienstiftung des deutschen Volkes" (F. L.), the Schering Foundation (T. H.), the Canadian Institutes of Health Research (A. G.), and in part by the Intramural Research Program of the NIH, NIAID. NR 35 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD SEP PY 2013 VL 158 IS 9 BP 1895 EP 1905 DI 10.1007/s00705-013-1684-9 PG 11 WC Virology SC Virology GA 208CS UT WOS:000323654600007 PM 23553456 ER PT J AU Lorenzo, FR Yang, CZ Lanikova, L Butros, L Zhuang, ZP Prchal, JT AF Lorenzo, Felipe R. Yang, Chunzhang Lanikova, Lucie Butros, Linda Zhuang, Zhengping Prchal, Josef T. TI Novel compound VHL heterozygosity (VHL T124A/L188V) associated with congenital polycythaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE polycythaemia; erythrocytosis; mutations; molecular haematology; genetics ID CHUVASH POLYCYTHEMIA; MUTATION; ERYTHROPOIETIN; ERYTHROCYTOSIS; PARAGANGLIOMA; RECEPTOR; GENE C1 [Lorenzo, Felipe R.; Lanikova, Lucie; Prchal, Josef T.] Univ Utah, Div Hematol, Salt Lake City, UT 84112 USA. [Lorenzo, Felipe R.; Lanikova, Lucie; Prchal, Josef T.] VA Hlth Care, Salt Lake City, UT USA. [Yang, Chunzhang; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lanikova, Lucie] Palacky Univ, Fac Med & Dent, Dept Biol, CR-77147 Olomouc, Czech Republic. [Butros, Linda] Univ New Mexico, Albuquerque, NM 87131 USA. RP Lorenzo, FR (reprint author), Univ Utah, Div Hematol, Salt Lake City, UT 84112 USA. EM josef.prchal@hsc.utah.edu RI Lanikova, Lucie/F-7720-2013 FU NCI NIH HHS [P01 CA108671, P01CA108671] NR 10 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2013 VL 162 IS 6 BP 851 EP 853 DI 10.1111/bjh.12431 PG 3 WC Hematology SC Hematology GA 209BL UT WOS:000323728600018 PM 23772956 ER PT J AU Kolesar, JM Traynor, AM Holen, KD Hoang, T Seo, S Kim, K Alberti, D Espinoza-Delgado, I Wright, JJ Wilding, G Bailey, HH Schelman, WR AF Kolesar, Jill M. Traynor, Anne M. Holen, Kyle D. Hoang, Tien Seo, Songwon Kim, KyungMann Alberti, Dona Espinoza-Delgado, Igor Wright, John J. Wilding, George Bailey, Howard H. Schelman, William R. TI Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE SAHA; Vorinostat; PS-341; Bortezomib; Phase I ID SUBEROYLANILIDE HYDROXAMIC ACID; T-CELL LYMPHOMA; DOWN-REGULATION; HDAC INHIBITOR; EXPRESSION; APOPTOSIS; DEACETYLASES; TUMORS; KIT AB Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis. Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples. In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49-1.04 (p < 0.001); 0.28 (0.15-0.7) (p < 0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) (p < 0.01); 0.44 (0.25-1.3) (p < 0.01), respectively. The ChIP assay demonstrated a protein-DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients. Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3. C1 [Kolesar, Jill M.; Traynor, Anne M.; Holen, Kyle D.; Hoang, Tien; Seo, Songwon; Kim, KyungMann; Alberti, Dona; Wilding, George; Bailey, Howard H.; Schelman, William R.] Univ Wisconsin, Carbone Comprehens Canc Ctr, Madison, WI 53792 USA. [Seo, Songwon; Kim, KyungMann] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53792 USA. [Espinoza-Delgado, Igor; Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Kolesar, JM (reprint author), Univ Wisconsin, Carbone Comprehens Canc Ctr, 600 Highland Ave,K4-554 CSC, Madison, WI 53792 USA. EM jmkolesar@pharmacy.wisc.edu FU Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis, NCI; CTEP Translational Research Initiative [UO1 CA062491]; Clinical and Translational Science Award, National Center for Research Resources, NIH [1UL 1RR025011]; NIH/NCI [P30 CA014520] FX We thank the University of Wisconsin Carbone Cancer Center (UWCCC) Analytical Instrumentation Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics (3P Lab) for acquisition of gene expression and chromatin precipitation data for this research. We also thank the patients who participated in this clinical trial, and the nurses and research specialist of the UWCCC Phase I Program for their efforts in conducting and managing this trial. UO1 CA062491, Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis, NCI; CTEP Translational Research Initiative, Contract; and 1UL 1RR025011, Clinical and Translational Science Award, National Center for Research Resources, NIH. The authors would like to thank the University of Wisconsin Carbone Cancer Center (UWCCC) for use of its Shared Services to complete this research. This work is supported in part by NIH/NCI P30 CA014520 to the UW Carbone Cancer Center. NR 17 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2013 VL 72 IS 3 BP 661 EP 667 DI 10.1007/s00280-013-2242-6 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 208CK UT WOS:000323653600018 PM 23903894 ER PT J AU Gulley, JL Heery, CR Madan, RA Walter, BA Merino, MJ Dahut, WL Tsang, KY Schlom, J Pinto, PA AF Gulley, James L. Heery, Christopher R. Madan, Ravi A. Walter, Beatriz A. Merino, Maria J. Dahut, William L. Tsang, Kwong-Yok Schlom, Jeffrey Pinto, Peter A. TI Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Cancer vaccine; Immunotherapy; PROSTVAC; Intratumoral vaccine; Prostate cancer ID DIVERSIFIED SUBCUTANEOUS/INTRATUMORAL VACCINATION; MULTIPLE COSTIMULATORY MOLECULES; TUMOR-INFILTRATING LYMPHOCYTES; COLONY-STIMULATING FACTOR; CD8(+) T-CELLS; COMBINATION THERAPY; CUTANEOUS MELANOMA; PROGNOSTIC-FACTOR; DENDRITIC CELLS; GENE-THERAPY AB The primary end point of this study was to determine the safety and feasibility of intraprostatic administration of PSA-TRICOM vaccine [encoding transgenes for prostate-specific antigen (PSA) and 3 costimulatory molecules] in patients with locally recurrent or progressive prostate cancer. This trial was a standard 3 + 3 dose escalation with 6 patients each in cohorts 4 and 5 to gather more immunologic data. Nineteen of 21 patients enrolled had locally recurrent prostate cancer after definitive radiation therapy, and 2 had no local therapy. All cohorts received initial subcutaneous vaccination with recombinant vaccinia (rV)-PSA-TRICOM and intraprostatic booster vaccinations with recombinant fowlpox (rF)-PSA-TRICOM. Cohorts 3-5 also received intraprostatic rF-GM-CSF. Cohort 5 received additional subcutaneous boosters with rF-PSA-TRICOM and rF-GM-CSF. Patients had pre- and post-treatment prostate biopsies, and analyses of peripheral and intraprostatic immune cells were performed. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. The most common grade 2 adverse events were fever (38 %) and subcutaneous injection site reactions (33 %); the single grade 3 toxicity was transient fever. Overall, 19 of 21 patients on trial had stable (10) or improved (9) PSA values. There was a marked increase in CD4(+) (p = 0.0002) and CD8(+) (p = 0.0002) tumor infiltrates in post- versus pre-treatment tumor biopsies. Four of 9 patients evaluated had peripheral immune responses to PSA or NGEP. Intraprostatic administration of PSA-TRICOM is safe and feasible and can generate a significant immunologic response. Improved serum PSA kinetics and intense post-vaccination inflammatory infiltrates were seen in the majority of patients. Clinical trials examining clinical end points are warranted. C1 [Gulley, James L.; Heery, Christopher R.; Madan, Ravi A.; Tsang, Kwong-Yok; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Walter, Beatriz A.; Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dahut, William L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,8B09 MSC 1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Grant support was provided by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors thank Benedetto Farsaci and Caroline Jochems for their helpful discussions, Diane J. Poole for her technical assistance, and Bonnie L. Casey and Debra Weingarten for their editorial assistance in the preparation of this manuscript. NR 44 TC 15 Z9 15 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD SEP PY 2013 VL 62 IS 9 BP 1521 EP 1531 DI 10.1007/s00262-013-1448-0 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA 208DS UT WOS:000323657500008 PM 23836412 ER PT J AU Weissman, AM AF Weissman, Allan M. TI Ubiquitin and Drug Discovery: Challenges and Opportunities INTRODUCTION SO CELL BIOCHEMISTRY AND BIOPHYSICS LA English DT Editorial Material C1 NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. EM amw@nih.gov FU Intramural NIH HHS [ZIA BC010292-15] NR 0 TC 0 Z9 0 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1085-9195 J9 CELL BIOCHEM BIOPHYS JI Cell Biochem. Biophys. PD SEP PY 2013 VL 67 IS 1 SI SI BP 1 EP 2 DI 10.1007/s12013-013-9620-x PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 208FR UT WOS:000323663300001 PM 23754620 ER PT J AU Kotlarz, A Tukaj, S Krzewski, K Brycka, E Lipinska, B AF Kotlarz, Agnieszka Tukaj, Stefan Krzewski, Konrad Brycka, Elzbieta Lipinska, Barbara TI Human Hsp40 proteins, DNAJA1 and DNAJA2, as potential targets of the immune response triggered by bacterial DnaJ in rheumatoid arthritis SO CELL STRESS & CHAPERONES LA English DT Article DE Anti-Hsp40 autoantibodies; Hsp40 in rheumatoid arthritis; Cross-reactivity of anti-Hsp40 antibodies; Anti-DNAJ monoclonal antibodies; Molecular mimicry ID HEAT-SHOCK-PROTEIN; T-CELL REGULATION; HUMAN HOMOLOG; INFLAMMATION; HSP70; CHAPERONE; IMPORT; DJ2 AB Hsp40 proteins of bacterial and human origin are suspected to be involved in the pathogenesis of rheumatoid arthritis (RA). It has been shown that sera of RA patients contain increased levels of antibodies directed to bacterial and human Hsp40s. The aim of this work was to explore immunological similarities between the bacterial (DnaJ) and human (DNAJA1 and DNAJA2) Hsp40 proteins in relation to their possible involvement in the RA. Using polyclonal antibodies directed against a full-length DnaJ or its domains, against DNAJA1 and DNAJA2, as well as monoclonal anti-DnaJ antibodies, we found immunological similarities between the bacterial and human Hsp40s. Both ELISA and Western blotting showed that these similarities were not restricted to the conserved J domains but were also present in the C-terminal variable regions. We also found a positive correlation between the levels of the anti-DnaJ and anti-DNAJA1 antibodies in the sera of RA patients. This finding supports the molecular mimicry hypothesis that human Hsp40 could be the targets of antibodies originally directed against bacterial DnaJ in RA. C1 [Kotlarz, Agnieszka; Krzewski, Konrad; Lipinska, Barbara] Univ Gdansk, Dept Biochem, PL-80308 Gdansk, Poland. [Tukaj, Stefan] Univ Gdansk, Dept Plant Physiol & Biotechnol, PL-80308 Gdansk, Poland. [Brycka, Elzbieta] Univ Gdansk, Dept Mol Virol, PL-80822 Gdansk, Poland. [Brycka, Elzbieta] Med Univ Gdansk, PL-80822 Gdansk, Poland. [Krzewski, Konrad] NIAID, NIH, Rockville, MD USA. RP Lipinska, B (reprint author), Univ Gdansk, Dept Biochem, Wita Stwosza 59, PL-80308 Gdansk, Poland. EM lipinska@biotech.ug.gda.pl RI Tukaj, Stefan/G-6746-2014 FU Polish Ministry of Science and Higher Education [1610/B/P01/2008/35] FX We would like to express our thanks to Dr. B. Szewczyk for his help with overproducing proteins in the baculovirus system. We are very grateful to Dr. Kazutoyo Terada for his generous gift of the pMal-c2x/hdj2 and pVL1393/hdj3 plasmids. This work was supported by a grant from the Polish Ministry of Science and Higher Education (no. 1610/B/P01/2008/35) to BL. NR 26 TC 4 Z9 4 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1355-8145 J9 CELL STRESS CHAPERON JI Cell Stress Chaperones PD SEP PY 2013 VL 18 IS 5 BP 653 EP 659 DI 10.1007/s12192-013-0407-1 PG 7 WC Cell Biology SC Cell Biology GA 203GI UT WOS:000323279300010 PM 23408083 ER PT J AU Dehdashti, SJ Zheng, W Gever, JR Wilhelm, R Nguyen, DT Sittampalam, G McKew, JC Austin, CP Prusiner, SB AF Dehdashti, Seameen J. Zheng, Wei Gever, Joel R. Wilhelm, Robert Dac-Trung Nguyen Sittampalam, Gurusingham McKew, John C. Austin, Christopher P. Prusiner, Stanley B. TI A High-Throughput Screening Assay for Determining Cellular Levels of Total Tau Protein SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Alzheimer's disease; FRET-based assay; high-throughput screening assay; prions; neurodegenerative diseases; tau protein ID ALZHEIMERS-DISEASE; BRAIN-INJURY; PHOSPHORYLATION; DEGRADATION; PROPAGATION; INHIBITORS; TAUOPATHY; MELATONIN; DEMENTIA; FTDP-17 AB The microtubule-associated protein (MAP) tau has been implicated in the pathology of numerous neurodegenerative diseases. In the past decade, the hyperphosphorylated and aggregated states of tau protein have been important targets in the drug discovery field for the potential treatment of Alzheimer's disease. Although several compounds have been reported to reduce the hyperphosphorylated state of tau or impact the stabilization of tau, their therapeutic activities are remain to be validated. Recently, reduction of total cellular tau protein has emerged as an alternate intervention point for drug development and a potential treatment of tauopathies. We have developed and optimized homogenous assays, using the AlphaLISA and HTRF assay technologies, for the quantification of total cellular tau protein levels in the SH-SY5Y neuroblastoma cell line. The signal-to-basal ratios were 375 and 5.3, and the Z' factors were 0.67 and 0.60 for the AlphaLISA and HTRF tau assays, respectively. The clear advantages of these homogeneous tau assays over conventional total tau assays, such as ELISA and Western blot, are the elimination of plate wash steps and miniaturization of the assay into 1536-well plate format for the ultra-high-throughput screening of large compound libraries. C1 [Dehdashti, Seameen J.; Zheng, Wei; Dac-Trung Nguyen; Sittampalam, Gurusingham; McKew, John C.; Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Gever, Joel R.; Wilhelm, Robert; Prusiner, Stanley B.] Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. [Gever, Joel R.; Wilhelm, Robert; Prusiner, Stanley B.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Zheng, W (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov FU National Center for Advancing Translational Sciences, National Institutes of Health; NIH [AG021601, AG031220]; Tau Consortium; Sherman Fairchild Foundation; Rainwater Charitable Foundation FX This work was supported by the Intramural Research Program of the Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, National Institutes of Health. We thank the compound management team in NCATS for their support. This work was also supported by research grants from the NIH to S. B. P. (AG021601 and AG031220). Additionally, S. B. P. gratefully acknowledges the support of the Tau Consortium, the Sherman Fairchild Foundation, and the Rainwater Charitable Foundation. NR 36 TC 9 Z9 9 U1 1 U2 17 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 EI 1875-5828 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD SEP PY 2013 VL 10 IS 7 BP 679 EP 687 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 211ET UT WOS:000323888500002 PM 23905996 ER PT J AU Kreitman, RJ AF Kreitman, Robert J. TI Hairy Cell Leukemia-New Genes, New Targets SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Article DE BL22; BRAF; CD22; Dabrafenib; HCL variant; IGHV4-34; Immunotoxin; MAPK; Melanoma; Moxetumomab pasudotox; Purine analog; Recombinant immunotoxin; Trametinib; V600E; Vemurafenib ID BRAF V600E MUTATION; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; TERM-FOLLOW-UP; ANTI-CD20 MONOCLONAL-ANTIBODY; CHRONIC LYMPHOCYTIC-LEUKEMIA; NATIONAL-CANCER-INSTITUTE; MINIMAL RESIDUAL DISEASE; LOW-DOSE VEMURAFENIB; PHASE-II TRIAL; RECOMBINANT IMMUNOTOXIN AB Hairy cell leukemia (HCL), a B cell malignancy comprising 2 % of all leukemias, has become quite exciting recently with regard to the development of new targets for therapy. This review will focus on advancements made within the past 1-2 years in targeted therapy for this disease. These advances may be grouped into two very difference categories, namely targeting of CD22 with the recombinant immunotoxin moxetumomab pasudotox, and targeting of the mutated BRAF component of the MAP kinase pathway. Moxetumomab pasudotox in phase I testing was recently reported to be associated with an overall response rate of 86 % and a complete remission (CR) rate of 46 % in 28 patients with relapsed and refractory HCL. Many of the CRs are without minimal residual disease (MRD). Severe or dose limiting toxicity was not observed on this trial, but a completely reversible and largely asymptomatic form of grade 2 hemolytic uremic syndrome occurred in two patients during retreatment. This agent has commenced phase III multicenter testing to validate its phase I results. An extensive number of studies have documented the V600E mutation in nearly all HCL patients, but not in similar hematologic malignancies. The thymidine kinase inhibitor vemurafenib, which inhibits the V600E mutant of BRAF, was reported to induce a CR in multiply relapsed and refractory HCL, with nearly complete clearing of MRD. One additional partial and one additional complete remission were subsequently reported. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, NIH, 37-5124B,37 CONVENT DR MSC 4255, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov NR 134 TC 8 Z9 8 U1 0 U2 7 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD SEP PY 2013 VL 8 IS 3 BP 184 EP 195 DI 10.1007/s11899-013-0167-0 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 209EI UT WOS:000323736700003 PM 23892906 ER PT J AU Duncan, WC Zarate, CA AF Duncan, Wallace C., Jr. Zarate, Carlos A., Jr. TI Ketamine, Sleep, and Depression: Current Status and New Questions SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Ketamine; NMDAantagonist; Sleep; Major depressive disorder; MDD; Synaptic plasticity; Slow wave sleep; Slow wave activity; SWA; AMPA; Mood; Rapid antidepressant response; Neurotrophic factors; Brain-derived neurotrophic factor; BDNF; Treatment-resistant depression; Bipolar depression; Sleep disorders; Psychiatry ID RESISTANT MAJOR DEPRESSION; ACTIVITY-DEPENDENT SECRETION; GLYCOGEN-SYNTHASE KINASE-3; NMDA RECEPTOR BLOCKADE; D-ASPARTATE ANTAGONIST; SLOW-WAVE SLEEP; STAR-ASTERISK-D; VAL66MET POLYMORPHISM; NEUROTROPHIC FACTOR; LITHIUM-CARBONATE AB Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has well-described rapid antidepressant effects in clinical studies of individuals with treatment-resistant major depressive disorder (MDD). Preclinical studies investigating the effects of ketamine on brain-derived neurotrophic factor (BDNF) and on sleep slow wave activity (SWA) support its use as a prototype for investigating the neuroplastic mechanisms presumably involved in the mechanism of rapidly acting antidepressants. This review discusses human EEG slow wave sleep parameters and plasma BDNF as central and peripheral surrogate markers of plasticity, and their use in assessing ketamine's effects. Acutely, ketamine elevates BDNF levels, as well as early night SWA and high-amplitude slow waves; each of these measures correlates with change in mood in depressed patients who respond to ketamine. The slow wave effects are limited to the first night post-infusion, suggesting that their increase is part of an early cascade of events triggering improved mood. Increased total sleep and decreased waking occur during the first and second night post infusion, suggesting that these measures are associated with the enduring treatment response observed with ketamine. C1 [Duncan, Wallace C., Jr.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural NIH HHS [ZIA MH002857-08, ZIA MH002927-03] NR 65 TC 11 Z9 12 U1 3 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD SEP PY 2013 VL 15 IS 9 AR 394 DI 10.1007/s11920-013-0394-z PG 7 WC Psychiatry SC Psychiatry GA 208DI UT WOS:000323656400001 PM 23949569 ER PT J AU Vereb, G Lockett, SJ AF Vereb, Gyoergy Lockett, Stephen J. TI Microscopy of molecular interactions SO CYTOMETRY PART A LA English DT Editorial Material C1 [Vereb, Gyoergy] Univ Debrecen, Dept Biophys & Cell Biol, Med & Hlth Sci Ctr, Debrecen, Hungary. [Vereb, Gyoergy] Univ Debrecen, MTA DE Cell Biol & Signaling Res Grp, Med & Hlth Sci Ctr, Debrecen, Hungary. [Lockett, Stephen J.] SAIC Frederick Inc, Opt Microscopy & Anal Lab, Adv Technol Program, Frederick, MD USA. [Lockett, Stephen J.] Frederick Natl Lab Canc Res, Frederick, MD USA. RP Vereb, G (reprint author), Univ Debrecen, Dept Biophys & Cell Biol, Med & Hlth Sci Ctr, Debrecen, Hungary. EM vereb@med.unideb.hu; locketts@mail.nih.gov RI Vereb, Gyorgy/A-4241-2008 OI Vereb, Gyorgy/0000-0003-2157-3265 NR 0 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD SEP PY 2013 VL 83 IS 9 SI SI BP 763 EP 764 DI 10.1002/cyto.a.22339 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 205YF UT WOS:000323480200001 PM 24038840 ER PT J AU Renz, M AF Renz, Malte TI Fluorescence microscopy-A historical and technical perspective SO CYTOMETRY PART A LA English DT Review DE fluorescence microscopy; historical perspective; diffraction-limited microscopy; super-resolution microscopy ID STRUCTURED-ILLUMINATION MICROSCOPY; LASER-SCANNING-MICROSCOPE; PHOTOACTIVATED LOCALIZATION MICROSCOPY; OPTICAL RECONSTRUCTION MICROSCOPY; INTERNAL-REFLECTION FLUORESCENCE; DIGITAL IMAGING MICROSCOPY; PHOTON-COUNTING HISTOGRAM; LOW-DENSITY-LIPOPROTEIN; CORRELATION SPECTROSCOPY; PHOTOBLEACHING RECOVERY AB For a little more than a century, fluorescence microscopy has been an essential source of major discoveries in cell biology. Recent developments improved both visualization and quantification by fluorescence microscopy imaging and established a methodology of fluorescence microscopy. By outlining basic principles and their historical development, I seek to provide insight into and understanding of the ever-growing tools of fluorescence microscopy. Thereby, this synopsis may help the interested researcher to choose a fluorescence microscopic method capable of addressing a specific scientific question. (c) 2013 International Society for Advancement of Cytometry C1 [Renz, Malte] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. [Renz, Malte] Eunice Kennedy Shriver Inst Child Hlth & Human De, NIH, Bethesda, MD 20892 USA. RP Renz, M (reprint author), Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. EM mrenz@montefiore.org NR 139 TC 7 Z9 8 U1 15 U2 96 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD SEP PY 2013 VL 83 IS 9 SI SI BP 767 EP 779 DI 10.1002/cyto.a.22295 PG 13 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 205YF UT WOS:000323480200003 PM 23585290 ER PT J AU Fisher, L Hessler, D Glasgow, RE Arean, PA Masharani, U Naranjo, D Strycker, LA AF Fisher, Lawrence Hessler, Danielle Glasgow, Russell E. Arean, Patricia A. Masharani, Umesh Naranjo, Diana Strycker, Lisa A. TI REDEEM: A Pragmatic Trial to Reduce Diabetes Distress SO DIABETES CARE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MANAGEMENT SUPPORT PROGRAM; SELF-MANAGEMENT; GLYCEMIC CONTROL; DEPRESSIVE SYMPTOMS; INTERVENTION; OUTCOMES; SCALE; RECRUITMENT; THERAPY AB OBJECTIVE To compare three interventions to reduce diabetes distress (DD) and improve self-management among non-clinically depressed adults with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODS In REDEEM, 392 adults with T2DM and DD were randomized to computer-assisted self-management (CASM), CASM plus DD-specific problem solving (CAPS), or a computer-administered minimal supportive intervention. Primary outcomes were Diabetes Distress Scale (DDS) total, the Emotional Burden (EB) and Regimen Distress (RD) DDS subscales, and diet, exercise, and medication adherence.RESULTS Significant and clinically meaningful reductions in DD (DDS, EB, and RD) and self-management behaviors occurred in all three conditions (P < 0.001), with no significant between-group differences. There was, however, a significant group x baseline distress interaction (P < 0.02), in which patients with high baseline RD in the CAPS condition displayed significantly larger RD reductions than those in the other two conditions. RD generated the most distress and displayed the greatest distress reduction as a result of intervention. The pace of DD reduction varied by patient age: older patients demonstrated significant reductions in DD early in the intervention, whereas younger adults displayed similar reductions later. Reductions in DD were accompanied by significant improvements in healthy eating, physical activity, and medication adherence, although not by change in HbA(1c).CONCLUSIONS DD is malleable and highly responsive to intervention. Interventions that enhance self-management also reduce DD significantly, but DD-specific interventions may be necessary for patients with high initial levels of DD. Future research should identify the minimal, most cost-effective interventions to reduce DD and improve self-management. C1 [Fisher, Lawrence; Hessler, Danielle; Arean, Patricia A.; Masharani, Umesh; Naranjo, Diana] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Strycker, Lisa A.] Oregon Res Inst, Eugene, OR 97403 USA. RP Fisher, L (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM fisherl@fcm.ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK061937] FX This research was funded by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant DK061937. NR 39 TC 52 Z9 55 U1 0 U2 15 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2013 VL 36 IS 9 BP 2551 EP 2558 DI 10.2337/dc12-2493 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205CZ UT WOS:000323420200038 PM 23735726 ER PT J AU Jasuja, GK Travison, TG Davda, M Rose, AJ Zhang, AQ Kushnir, MM Rockwood, AL Meikle, W Coviello, AD D'Agostino, R Vasan, RS Bhasin, S AF Jasuja, Guneet Kaur Travison, Thomas G. Davda, Maithili Rose, Adam J. Zhang, Anqi Kushnir, Mark M. Rockwood, Alan L. Meikle, Wayne Coviello, Andrea D. D'Agostino, Ralph Vasan, Ramachandran S. Bhasin, Shalender TI Circulating Estrone Levels Are Associated Prospectively With Diabetes Risk in Men of the Framingham Heart Study SO DIABETES CARE LA English DT Article ID HORMONE-BINDING GLOBULIN; TANDEM MASS-SPECTROMETRY; ENDOGENOUS SEX-HORMONES; MIDDLE-AGED MEN; POSTMENOPAUSAL WOMEN; INSULIN CONCENTRATIONS; REPLACEMENT THERAPY; GLUCOSE-TOLERANCE; GLYCEMIC CONTROL; ESTRADIOL LEVELS AB OBJECTIVE In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS).RESEARCH DESIGN AND METHODS Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998-2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography-tandem mass spectrometry, and free estradiol and estrone were calculated.RESULTS In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02-1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8.CONCLUSIONS Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol. C1 [Jasuja, Guneet Kaur; D'Agostino, Ralph] Boston Univ, Dept Math, Boston, MA 02215 USA. [Jasuja, Guneet Kaur; Rose, Adam J.; D'Agostino, Ralph] Bedford VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Travison, Thomas G.; Davda, Maithili; Zhang, Anqi; Coviello, Andrea D.; Bhasin, Shalender] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Travison, Thomas G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Rose, Adam J.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Kushnir, Mark M.; Rockwood, Alan L.; Meikle, Wayne] Univ Utah, ARUP Labs, Salt Lake City, UT USA. [Coviello, Andrea D.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Jasuja, GK (reprint author), Boston Univ, Dept Math, Boston, MA 02215 USA. EM guneetk@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health [1RO1-AG-31206, 5R01-DK-092938]; Boston Claude D. Pepper Older Americans Independence Center from the National Institute on Aging [5P30-AG-031679]; Centers for Disease Control and Prevention Foundation; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This project was supported primarily by National Institutes of Health grants 1RO1-AG-31206 and 5R01-DK-092938 to R. S. V. and S. B. Additional support was provided by the Boston Claude D. Pepper Older Americans Independence Center Grant 5P30-AG-031679 from the National Institute on Aging and by a grant from the Centers for Disease Control and Prevention Foundation. The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study contract N01-HC-25195. NR 34 TC 8 Z9 8 U1 3 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2013 VL 36 IS 9 BP 2591 EP 2596 DI 10.2337/dc12-2477 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205CZ UT WOS:000323420200044 PM 23690532 ER PT J AU Cheng, YLJ Imperatore, G Geiss, LS Wang, J Saydah, SH Cowie, CC Gregg, EW AF Cheng, Yiling J. Imperatore, Giuseppina Geiss, Linda S. Wang, Jing Saydah, Sharon H. Cowie, Catherine C. Gregg, Edward W. TI Secular Changes in the Age-Specific Prevalence of Diabetes Among US Adults: 1988-2010 SO DIABETES CARE LA English DT Article ID BODY-MASS INDEX; TO-HEIGHT RATIO; WAIST CIRCUMFERENCE; CARDIOMETABOLIC RISK; EXPERT COMMITTEE; UNITED-STATES; TRENDS; OBESITY; POPULATION; MORTALITY AB OBJECTIVE To examine the age-specific changes of prevalence of diabetes among U.S. adults during the past 2 decades.RESEARCH DESIGN AND METHODS This study included 22,586 adults sampled in three periods of the National Health and Nutrition Examination Survey (1988-1994, 1999-2004, and 2005-2010). Diabetes was defined as having self-reported diagnosed diabetes or having a fasting plasma glucose level 126 mg/dL or HbA(1c) 6.5% (48 mmol/mol).RESULTS The number of adults with diabetes increased by 75% from 1988-1994 to 2005-2010. After adjusting for sex, race/ethnicity, and education level, the prevalence of diabetes increased over the two decades across all age-groups. Younger adults (20-34 years of age) had the lowest absolute increase in diabetes prevalence of 1.0%, followed by middle-aged adults (35-64) at 2.7% and older adults (65) at 10.0% (all P < 0.001). Comparing 2005-2010 with 1988-1994, the adjusted prevalence ratios (PRs) by age-group were 2.3, 1.3, and 1.5 for younger, middle-aged, and older adults, respectively (all P < 0.05). After additional adjustment for body mass index (BMI), waist-to-height ratio (WHtR), or waist circumference (WC), the adjusted PR remained statistically significant only for adults 65 years of age.CONCLUSIONS During the past two decades, the prevalence of diabetes increased across all age-groups, but adults 65 years of age experienced the largest increase in absolute change. Obesity, as measured by BMI, WHtR, or WC, was strongly associated with the increase in diabetes prevalence, especially in adults <65. C1 [Cheng, Yiling J.; Imperatore, Giuseppina; Geiss, Linda S.; Wang, Jing; Saydah, Sharon H.; Gregg, Edward W.] Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Cowie, Catherine C.] NIDDK, NIH, Bethesda, MD USA. RP Cheng, YLJ (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM ycheng@cdc.gov NR 38 TC 74 Z9 74 U1 0 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2013 VL 36 IS 9 BP 2690 EP 2696 DI 10.2337/dc12-2074 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205CZ UT WOS:000323420200058 PM 23637354 ER PT J AU Rosenquist, KJ Massaro, JM Pencina, KM D'Agostino, RB Beiser, A O'Connor, GT O'Donnell, CJ Wolf, PA Polak, JF Seshadri, S Fox, CS AF Rosenquist, Klara J. Massaro, Joseph M. Pencina, Karol M. D'Agostino, Ralph B. Beiser, Alexa O'Connor, George T. O'Donnell, Christopher J. Wolf, Philip A. Polak, Joseph F. Seshadri, Sudha Fox, Caroline S. TI Neck Circumference, Carotid Wall Intima-Media Thickness, and Incident Stroke SO DIABETES CARE LA English DT Letter C1 [Rosenquist, Klara J.; Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Rosenquist, Klara J.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Rosenquist, Klara J.; Massaro, Joseph M.; D'Agostino, Ralph B.; Beiser, Alexa; O'Connor, George T.; O'Donnell, Christopher J.; Wolf, Philip A.; Seshadri, Sudha; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rosenquist, Klara J.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Rosenquist, Klara J.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Massaro, Joseph M.; Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Pencina, Karol M.; D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Beiser, Alexa; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Polak, Joseph F.] Tufts Med Ctr, Dept Radiol, Boston, MA USA. RP Fox, CS (reprint author), Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812; Seshadri, Sudha/0000-0001-6135-2622; Beiser, Alexa/0000-0001-8551-7778 FU NHLBI NIH HHS [HL081352, N01-HC-25195, N01HC25195, R01 HL069003, R01 HL081352, T32 HL007224]; NIA NIH HHS [R01 AG008122, R01 AG033193]; NINDS NIH HHS [R01 NS017950, R01 NS17950]; PHS HHS [R01 031287, R01 033193, R01 08122, R01 33040] NR 5 TC 8 Z9 8 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2013 VL 36 IS 9 BP E153 EP E154 DI 10.2337/dc13-0379 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205CZ UT WOS:000323420200011 PM 23970728 ER PT J AU Guirguis, E Hockman, S Chung, YW Ahmad, F Gavrilova, O Raghavachari, N Yang, YQ Niu, G Chen, XY Yu, ZX Liu, SW Degerman, E Manganiello, V AF Guirguis, Emilia Hockman, Steven Chung, Youn Wook Ahmad, Faiyaz Gavrilova, Oksana Raghavachari, Nalini Yang, Yanqin Niu, Gang Chen, Xiaoyuan Yu, Zu Xi Liu, Shiwei Degerman, Eva Manganiello, Vincent TI A Role for Phosphodiesterase 3B in Acquisition of Brown Fat Characteristics by White Adipose Tissue in Male Mice SO ENDOCRINOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; INSULIN-RESISTANCE; ADIPOCYTE DIFFERENTIATION; ENERGY HOMEOSTASIS; PPAR-GAMMA; TRANSCRIPTIONAL COMPLEX; MITOCHONDRIAL-FUNCTION; SKELETAL-MUSCLE; DEFICIENT MICE; OBESITY AB Obesity is linked to various diseases, including insulin resistance, diabetes, and cardiovascular disorders. The idea of inducing white adipose tissue (WAT) to assume characteristics of brown adipose tissue (BAT), and thus gearing it to fat burning instead of storage, is receiving serious consideration as potential treatment for obesity and related disorders. Phosphodiesterase 3B (PDE3B) links insulin-and cAMP-signaling networks in tissues associated with energy metabolism, including WAT. We used C57BL/6 PDE3B knockout (KO) mice to elucidate mechanisms involved in the formation of BAT in epididymal WAT (EWAT) depots. Examination of gene expression profiles in PDE3B KO EWAT revealed increased expression of several genes that block white and promote brown adipogenesis, such as C-terminal binding protein, bone morphogenetic protein 7, and PR domain containing 16, but a clear BAT-like phenotype was not completely induced. However, acute treatment of PDE3B KO mice with the beta 3-adrenergic agonist, CL316243, markedly increased the expression of cyclooxygenase-2, which catalyzes prostaglandin synthesis and is thought to be important in the formation of BAT in WAT and the elongation of very long-chain fatty acids 3, which is linked to BAT recruitment upon cold exposure, causing a clear shift toward fat burning and the induction of BAT in KO EWAT. These data provide insight into the mechanisms of BAT formation in mouse EWAT, suggesting that, in a C57BL/6 background, an increase in cAMP, caused by ablation of PDE3B and administration of CL316243, may promote differentiation of prostaglandin-responsive progenitor cells in the EWAT stromal vascular fraction into functional brown adipocytes. C1 [Guirguis, Emilia; Hockman, Steven; Chung, Youn Wook; Ahmad, Faiyaz; Liu, Shiwei; Manganiello, Vincent] NHLBI, Pulm Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. [Raghavachari, Nalini; Yang, Yanqin] NHLBI, Genom Core, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, NIH, Bethesda, MD 20892 USA. [Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Yu, Zu Xi] NIH, Pathol Core, Bethesda, MD 20892 USA. [Degerman, Eva] Lund Univ, Dept Expt Med Sci, Div Diabet Metab & Endocrinol, SE-22184 Lund, Sweden. RP Guirguis, E (reprint author), NHLBI, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM emilia.guirguis@nih.gov; manganiv@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Biomedical Imaging and Bioengineering Intramural Research Programs; Swedish Research Council [3362] FX This work was supported by the National Heart, Lung, and Blood Institute (to E. G., S. H., Y.W.C., F. A., N.R., Y.Y., S. L., Z.X.Y., V. M.), the National Institute of Diabetes and Digestive and Kidney Diseases (to O.G.), the National Institute of Biomedical Imaging and Bioengineering Intramural Research Programs (to G.N., X. C.), and the Swedish Research Council Project 3362 (to E. D.). NR 77 TC 10 Z9 10 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2013 VL 154 IS 9 BP 3152 EP 3167 DI 10.1210/en.2012-2185 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 207RE UT WOS:000323620100020 PM 23766131 ER PT J AU Murthy, SRK Thouennon, E Li, WS Cheng, Y Bhupatkar, J Cawley, NX Lane, M Merchenthaler, I Loh, YP AF Murthy, S. R. K. Thouennon, E. Li, W. -S. Cheng, Y. Bhupatkar, J. Cawley, N. X. Lane, M. Merchenthaler, I. Loh, Y. P. TI Carboxypeptidase E Protects Hippocampal Neurons During Stress in Male Mice by Up-regulating Pro-survival BCL2 Protein Expression SO ENDOCRINOLOGY LA English DT Article ID CHRONIC PSYCHOSOCIAL STRESS; CENTRAL-NERVOUS-SYSTEM; MESSENGER-RNA; RAT-BRAIN; SPATIAL MEMORY; GLUCOCORTICOIDS; MORPHOLOGY; PRETREATMENT; COMBINATION; ISCHEMIA AB Prolonged chronic stress causing elevated plasma glucocorticoids leads to neurodegeneration. Adaptation to stress (allostasis) through neuroprotective mechanisms can delay this process. Studies on hippocampal neurons have identified carboxypeptidase E (CPE) as a novel neuroprotective protein that acts extracellularly, independent of its enzymatic activity, although the mechanism of action is unclear. Here, we aim to determine if CPE plays a neuroprotective role in allostasis in mouse hippocampus during chronic restraint stress (CRS), and the molecular mechanisms involved. Quantitative RT-PCR/in situ hybridization and Western blots were used to assay for mRNA and protein. After mild CRS (1 h/d for 7 d), CPE protein and mRNA were significantly elevated in the hippocampal CA3 region, compared to naive littermates. In addition, luciferase reporter assays identified a functional glucocorticoid regulatory element within the cpe promoter that mediated the up-regulation of CPE expression in primary hippocampal neurons following dexamethasone treatment, suggesting that circulating plasma glucocorticoids could evoke a similar effect on CPE in the hippocampus in vivo. Overexpression of CPE in hippocampal neurons, or CRS in mice, resulted in elevated prosurvival BCL2 protein/mRNA and p-AKT levels in the hippocampus; however, CPE-/- mice showed a decrease. Thus, during mild CRS, CPE expression is up-regulated, possibly contributed by glucocorticoids, to mediate neuroprotection of the hippocampus by enhancing BCL2 expression through AKT signaling, and thereby maintaining allostasis. C1 [Murthy, S. R. K.; Thouennon, E.; Cheng, Y.; Bhupatkar, J.; Cawley, N. X.; Loh, Y. P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Li, W. -S.] Sun Yat Sen Univ, Sch Life Sci, Guangzhou 510275, Guangdong, Peoples R China. [Lane, M.; Merchenthaler, I.] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. RP Loh, YP (reprint author), NIH, 49 Convent Dr,Bldg 49,Room 5A-22, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov OI Cheng, Yong/0000-0002-7529-4408 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 38 TC 7 Z9 7 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD SEP PY 2013 VL 154 IS 9 BP 3284 EP 3293 DI 10.1210/en.2013-1118 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 207RE UT WOS:000323620100032 PM 23825125 ER PT J AU Liu, JF Tolaney, SM Birrer, M Fleming, GF Buss, MK Dahlberg, SE Lee, H Whalen, C Tyburski, K Winer, E Ivy, P Matulonis, UA AF Liu, Joyce F. Tolaney, Sara M. Birrer, Michael Fleming, Gini F. Buss, Mary K. Dahlberg, Suzanne E. Lee, Hang Whalen, Christin Tyburski, Karin Winer, Eric Ivy, Percy Matulonis, Ursula A. TI A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Olaparib; PARP-inhibitor; Cediranib; Anti-angiogenic; Ovarian; Breast; Phase 1 ID HOMOLOGOUS RECOMBINATION; DOWN-REGULATION; SOLID TUMORS; DNA-REPAIR; BEVACIZUMAB; HYPOXIA; RAD51; BRCA1; CELLS AB Background: Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). Methods: Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. Results: 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia >= 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) >24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for >24 weeks. Interpretation: The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Liu, Joyce F.; Tolaney, Sara M.; Whalen, Christin; Tyburski, Karin; Winer, Eric; Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Birrer, Michael] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Fleming, Gini F.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Buss, Mary K.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Ivy, Percy] NIH, Canc Therapy Evaluat Program, Bethesda, MD USA. RP Liu, JF (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM joyce_liu@dfci.harvard.edu FU Cancer Therapy Evaluation Program of the National Cancer Institute; National Institutes of Health [3 U01 CA062490-16S2] FX This study was sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute and supported by a Grant through the National Institutes of Health (3 U01 CA062490-16S2). The funding source had no role in the conduct, data collection or analysis of the study. NR 23 TC 51 Z9 59 U1 2 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 IS 14 BP 2972 EP 2978 DI 10.1016/j.ejca.2013.05.020 PG 7 WC Oncology SC Oncology GA 207MM UT WOS:000323604700003 PM 23810467 ER PT J AU Tandle, AT Kramp, T Kil, WJ Halthore, A Gehlhaus, K Shankavaram, U Tofilon, PJ Caplen, NJ Camphausen, K AF Tandle, Anita T. Kramp, Tamalee Kil, Whoon J. Halthore, Aditya Gehlhaus, Kristen Shankavaram, Uma Tofilon, Philip J. Caplen, Natasha J. Camphausen, Kevin TI Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Glioblastoma multiforme; PLK1; GSK461364A; siRNA; Radiation ID DNA-DAMAGE CHECKPOINT; ADJUVANT TEMOZOLOMIDE; THERAPEUTIC TARGET; CANCER-THERAPY; CELL-LINES; RNAI; RADIOTHERAPY; GROWTH; BRAIN; PLK1 AB Glioblastoma multiforme (GBM) is the most common primary brain tumour in the United States of America (USA) with a median survival of approximately 14 months. Low survival rates are attributable to the aggressiveness of GBM and a lack of understanding of the molecular mechanisms underlying GBM. The disruption of signalling pathways regulated either directly or indirectly by protein kinases is frequently observed in cancer cells and thus the development of inhibitors of specific kinases has become a major focus of drug discovery in oncology. To identify protein kinases required for the survival of GBM we performed a siRNA-based RNAi screen focused on the human kinome in GBM. Inhibition of the polo-like kinase 1 (PLK1) induced a reduction in the viability in two different GBM cell lines. To assess the potential of inhibiting PLK1 as a treatment strategy for GBM we examined the effects of a small molecule inhibitor of PLK1, GSK461364A, on the growth of GBM cells. PLK1 inhibition arrested cells in the mitotic phase of the cell cycle and induced cell kill by mitotic catastrophe. GBM engrafts treated with GSK461364A showed statistically significant inhibition of tumour growth. Further, exposure of different GBM cells to RNAi or GSK461364A prior to radiation resulted in an increase in their radiosensitivity with dose enhancement factor ranging from 1.40 to 1.53 with no effect on normal cells. As a measure of DNA double strand breaks, gamma H2AX levels were significantly higher in the combined modality as compared to the individual treatments. This study suggests that PLK1 is an important therapeutic target for GBM and can enhance radiosensitivity in GBM. Published by Elsevier Ltd. C1 [Tandle, Anita T.; Kramp, Tamalee; Kil, Whoon J.; Halthore, Aditya; Shankavaram, Uma; Tofilon, Philip J.; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Gehlhaus, Kristen; Caplen, Natasha J.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr B2-3561, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 37 TC 21 Z9 22 U1 0 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 IS 14 BP 3020 EP 3028 DI 10.1016/j.ejca.2013.05.013 PG 9 WC Oncology SC Oncology GA 207MM UT WOS:000323604700009 PM 23790466 ER PT J AU Morris, CP Torrero, MN Larson, D Evans, H Shi, YH Cox, RT Mitre, E AF Morris, C. Paul Torrero, Marina N. Larson, David Evans, Holly Shi, Yinghui Cox, Rachel T. Mitre, Edward TI Vaccination with intestinal tract antigens does not induce protective immunity in a permissive model of filariasis SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Filaria; Litomosoides sigmodontis; Vaccine; Hidden; Antigen; Intestine; Helminth ID ASPARAGINYL ENDOPEPTIDASE SM32; CHRONIC LYMPHATIC FILARIASIS; JIRDS MERIONES-UNGUICULATUS; H-GAL-GP; HAEMONCHUS-CONTORTUS; LITOMOSOIDES-SIGMODONTIS; BRUGIA-MALAYI; DIROFILARIA-IMMITIS; HOOKWORM INFECTION; NEUTRALIZING ANTIBODIES AB Antigens obtained from the intestinal tract of filarial nematodes have been proposed as potential safe and effective vaccine candidates. Because they may be 'hidden' from the immune response during natural infection, yet accessible by antibodies induced by vaccination, intestinal antigens may have a low potential for eliciting allergic responses when vaccinating previously infected individuals. Despite prior promising data, vaccination with intestinal antigens has yet to be tested in a permissive model of filariasis. In this study we investigated the efficacy of vaccination with filarial intestinal antigens in the permissive Litomosoides sigmodontis BALB/c model of filariasis, and we evaluated the extent to which these antigens are recognized by the immune system during and after infection. Infected BALB/c mice developed lower IgG antibody responses to soluble intestinal antigens (GutAg) than to soluble antigens of whole worms (LsAg). Similarly, GutAg induced less proliferation and less production of IL-4 and IFN gamma from splenocytes of infected mice than LsAg. In contrast to these differences, active infection resulted in equivalent levels of circulating GutAg-specific IgE and LsAg-specific IgE levels. Consistent with this, basophil activation, as assessed by flow cytometric staining of intracellular basophil IL-4 expression, was equivalent in response to GutAg and LsAg. Vaccination with GutAg adsorbed to CpG/alum induced GutAg specific IgG1 and IgG2A production, with GutAg specific IgG titers greater than 5-fold higher than those measured in previously infected animals. Despite this response to GutAg vaccination, vaccinated mice harbored similar parasite burdens 8 weeks post infection when compared to non-vaccinated controls. These studies demonstrate that soluble antigens obtained from the intestinal tracts of L. sigmodontis have some qualities of 'hidden' antigens, but they still sensitize mice to allergic reactions and fail to protect against future infection when given as a vaccine adsorbed to alum/CPG. Published by Elsevier Inc. C1 [Morris, C. Paul; Torrero, Marina N.; Larson, David; Evans, Holly; Shi, Yinghui; Mitre, Edward] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, Bethesda, MD 20852 USA. [Cox, Rachel T.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Biochem, Bethesda, MD 20852 USA. [Morris, C. Paul] NIAID, NIH, Bethesda, MD 20892 USA. RP Mitre, E (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM edward.mitre@usuhs.edu OI Morris, Christopher/0000-0002-5989-3638 FU Uniformed Services University of the Health Sciences [R073UE] FX We thank Karen Wolcott and Kateryna Lund at the Uniformed Services University Biomedical Instrumentation Center for support with Flow Cytometry. This work was supported by the Uniformed Services University of the Health Sciences grant number R073UE. NR 45 TC 2 Z9 2 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 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD SEP PY 2013 VL 135 IS 1 BP 87 EP 95 DI 10.1016/j.exppara.2013.05.018 PG 9 WC Parasitology SC Parasitology GA 207UD UT WOS:000323629200013 PM 23792131 ER PT J AU Simeonov, A AF Simeonov, Anton TI Recent developments in the use of differential scanning fluorometry in protein and small molecule discovery and characterization SO EXPERT OPINION ON DRUG DISCOVERY LA English DT Review DE chemical chaperones; differential scanning fluorometry; fluorescence thermal shift; inhibitor mechanism of action; pharmacological chaperones; thermal stabilization ID THERMAL SHIFT ASSAYS; DRUG DISCOVERY; MONOCLONAL-ANTIBODY; LIGAND-BINDING; STABILITY; IDENTIFICATION; FLUORESCENCE; AFFINITY; INHIBITORS; THERMODYNAMICS AB Introduction: Despite tremendous advances in the application of biophysical methods in drug discovery, the preponderance of instruments and techniques still require sophisticated analyses by dedicated personnel and/or large amounts of frequently hard-to-produce proteins. A technique which carries the promise of simplicity and relatively low protein consumption is the differential scanning fluorometry (DSF). This technique monitors protein through the use of environmentally sensitive fluorescent dye, in a temperature-ramp regime by observing the gradual exposure to the solvent of otherwise buried hydrophobic faces of protein domains. Areas covered: This review describes recent developments in the field of DSF. This article pays a particular emphasis on the advances published during the 2010 - 2013 period. Expert opinion: There has been a significant diversification of DSF applications beyond initial small molecule discovery into areas such as protein therapeutic development, formulation studies and various mechanistic investigations. This serves as a further indication of the broad penetration of the technique. In the small molecule arena, DSF has expanded toward sophisticated co-dependency MOA tests, demonstrating the wealth of information which the technique can provide. Importantly, the first public deposition of a large screening dataset may enable the use of thermal stabilization data in refining in silico models for small molecule binding. C1 NIH, Natl Ctr Adv Translat Sci, Div Discovery Innovat, Bethesda, MD 20892 USA. RP Simeonov, A (reprint author), NIH, Natl Ctr Adv Translat Sci, Div Discovery Innovat, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM asimeono@mail.nih.gov FU US National Institutes of Health FX A Simeonov is supported by the US National Institutes of Health. NR 70 TC 9 Z9 10 U1 5 U2 52 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1746-0441 J9 EXPERT OPIN DRUG DIS JI Expert. Opin. Drug Discov. PD SEP PY 2013 VL 8 IS 9 BP 1071 EP 1082 DI 10.1517/17460441.2013.806479 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 206FA UT WOS:000323502200003 PM 23738712 ER PT J AU Kim, KH Dmitriev, IP Saddekni, S Kashentseva, EA Harris, RD Aurigemma, R Bae, S Singh, KP Siegal, GP Curiel, DT Alvarez, RD AF Kim, Kenneth H. Dmitriev, Igor P. Saddekni, Souheil Kashentseva, Elena A. Harris, Raymond D. Aurigemma, Rosemarie Bae, Sejong Singh, Karan P. Siegal, Gene P. Curiel, David T. Alvarez, Ronald D. TI A phase I clinical trial of Ad5/3-Delta 24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE CRAd; Gene therapy; Infectivity-enhanced adenoviral vectors; Ovarian cancer ID ONCOLYTIC ADENOVIRUS; GENE-TRANSFER; THERAPEUTIC-EFFICACY; STAGE-III; PACLITAXEL; CISPLATIN; RECEPTOR; TROPISM; DISEASES; ONYX-015 AB Objective. The conditionally replicative adenovirus Ad5/3-Delta 24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Delta 24 achieves significant oncolysis and anti-tumor activity in ovarian cancer models. The purpose of this study was to evaluate in a phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-Delta 24 in recurrent ovarian cancer patients. Methods. Eligible patients were treated with IP Ad5/3-Delta 24 for 3 consecutive days in one of three dose cohorts ranging 1 x 10(10)-1 x 10(12) vp. Toxicity was assessed utilizing CfC grading and efficacy with RECIST. Ascites, serum, and other samples were obtained to evaluate gene transfer, generation of wildtype virus, viral shedding, and antibody response. Results. Nine of 10 patients completed treatment per protocol. A total of 15 vector-related adverse events were experienced in 5 patients. These events included fever or chills, nausea, fatigue, and myalgia. All were grades 1-2 in nature, transient, and medically managed. Of the 8 treated patients evaluable for response, six patients had stable disease and 2 patients had progressive disease. Three patients had decreased, FA-125 from pretreatment levels one month after treatment Ancillary biologic studies indicated Ad5/3-Delta 24 replication in patients in the higher dose cohorts. All patients experienced an anti-adenoviral neutralizing antibody, effect. Conclusions. This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-Delta 24, as a potential therapeutic option for recurrent ovarian cancer patients. (C) 2013 Elsevier Inc. All rights reserved. C1 [Kim, Kenneth H.] Univ N Carolina, Div Gynecol Oncol, Chapel Hill, NC 27515 USA. [Dmitriev, Igor P.; Kashentseva, Elena A.; Curiel, David T.] Washington Univ, Sch Med, Div Canc Biol, St Louis, MO 63130 USA. [Saddekni, Souheil] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL 35249 USA. [Harris, Raymond D.] NIAID, Off Biodef Res Affairs, DMID, NIH, Bethesda, MD USA. [Aurigemma, Rosemarie] NCI, Biol Resources Branch, Bethesda, MD 20892 USA. [Bae, Sejong; Singh, Karan P.] Univ Alabama Birmingham, Biostat & Informat Shared Facil BBSF, Birmingham, AL 35249 USA. [Siegal, Gene P.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35249 USA. [Alvarez, Ronald D.] Univ Alabama Birmingham, Div Gynecol Oncol, Birmingham, AL 35249 USA. RP Alvarez, RD (reprint author), Univ Alabama Birmingham, Div Gynecol Oncol, 176F Rm 10250,619 19th St South, Birmingham, AL 35249 USA. EM rdalvarez@uab.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; UAB Comprehensive Cancer Center's Clinical Protocol and Data Management Shared Facility [P30 CA013148] FX Financial support: This project has been funded in whole or in part with funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of polities of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was also supported by the UAB Comprehensive Cancer Center's Clinical Protocol and Data Management Shared Facility (P30 CA013148). NR 31 TC 25 Z9 26 U1 2 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2013 VL 130 IS 3 BP 518 EP 524 DI 10.1016/j.ygyno.2013.06.003 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 208OB UT WOS:000323687900023 PM 23756180 ER PT J AU Luhn, P Houldsworth, J Cahill, L Schiffman, M Castle, PE Zuna, RE Dunn, ST Gold, MA Walker, J Wentzensen, N AF Luhn, Patricia Houldsworth, Jane Cahill, Lynnette Schiffman, Mark Castle, Philip E. Zuna, Rosemary E. Dunn, S. Terence Gold, Michael A. Walker, Joan Wentzensen, Nicolas TI Chromosomal gains measured in cytology samples from women with abnormal cervical cancer screening results SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Cervical cancer; Genomic gains; 3q26; FISH; HPV ID TELOMERASE GENE TERC; GENOMIC AMPLIFICATION; CENTROSOME DUPLICATION; UTERINE CERVIX; COPY NUMBER; PAP-SMEARS; CELL-LINES; HPV TYPE; IN-SITU; CARCINOMA AB Objective. Chromosomal gains at 3q26, 5p15 and 20q13 have been described in cervical precancer and cancer. We evaluated a novel fluorescence in situ hybridization (FISH) assay that detects gains at these three loci simultaneously as a possible biomarker for detecting cervical precancer. Methods. Chromosomal copy numbers at 3q26, 5p15, 20q13 and the centromere of chromosome7 (cen7) in liquid-based cytology specimens from 168 women enrolled in the Biopsy Study were determined by FISH. The number of cells with >= 3 or >= 4 signals for a genomic locus was enumerated and diagnostic test performance measures were calculated using receiver operating characteristic (ROC) analyses. Sensitivity and specificity values were determined for the detection of CIN2 + and/or HSIL. Results. The median number of cells with >= 3 signals increased with the severity of cervical lesion for each genomic locus (p-trend < 0.02 for each locus). ROC analysis for the number of cells with >= 3 signals resulted in area under the curve values of 0.70 (95% CI: 0.54-0.86), 0.67 (0.52-0.83), 0.67 (0.51-0.83) and 0.78 (0.64-0.92) for 3q26, 5p15, 20q13 and cen7, respectively, for the detection of CIN2 + and/or HSIL. Positivity for gains at multiple loci resulted in only slightly better test performance measures than those for the individual probes for four distinct combinations of probes. Conclusions. Chromosomal gains at 3q26, 5p15, 20q13 and cen7 are associated with severity of cervical lesions. Further studies are required to quantify risk stratification of FISH assays for cervical cancer screening. Published by Elsevier Inc. C1 [Luhn, Patricia; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Epidemiol & Genet, Rockville, MD USA. [Luhn, Patricia] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD USA. [Houldsworth, Jane; Cahill, Lynnette] Canc Genet Inc, Rutherford, NJ USA. [Castle, Philip E.] Albert Einstein Coll Med, New York, NY USA. [Zuna, Rosemary E.; Dunn, S. Terence] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Gold, Michael A.] Univ Oklahoma, Sch Community Med, Tulsa Canc Inst, Dept Obstet & Gynecol, Tulsa, OK USA. [Walker, Joan] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. RP Luhn, P (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM luhnpa@mail.nih.gov FU National Institutes of Health [R44CA139667] FX This research was funded, in part, by the National Institutes of Health (R44CA139667) (JH). NR 31 TC 11 Z9 11 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2013 VL 130 IS 3 BP 595 EP 600 DI 10.1016/j.ygyno.2013.06.005 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 208OB UT WOS:000323687900035 PM 23769811 ER PT J AU Bundorf, MK Mata, R Schoenbaum, M Bhattacharya, J AF Bundorf, M. Kate Mata, Rui Schoenbaum, Michael Bhattacharya, Jay TI Are Prescription Drug Insurance Choices Consistent With Expected Utility Theory? SO HEALTH PSYCHOLOGY LA English DT Article DE expected utility maximization; prospect theory; Medicare Part D; risk; information ID MEDICARE PART-D; DECISION-MAKING; RISK AVOIDANCE; PLAN CHOICE; HEALTH-RISK; GRAPHS; METAANALYSIS; DISPLAYS; BEHAVIOR; SCALE AB Objective: To determine the extent to which people make choices inconsistent with expected utility theory when choosing among prescription drug insurance plans and whether tabular or graphical presentation format influences the consistency of their choices. Method: Members of an Internet-enabled panel chose between two Medicare prescription drug plans. The "low variance" plan required higher out-of-pocket payments for the drugs respondents usually took but lower out-of-pocket payments for the drugs they might need if they developed a new health condition than the "high variance" plan. The probability of a change in health varied within subjects and the presentation format (text vs. graphical) and the affective salience of the clinical condition (abstract vs. risk related to specific clinical condition) varied between subjects. Respondents were classified based on whether they consistently chose either the low or high variance plan. Logistic regression models were estimated to examine the relationship between decision outcomes and task characteristics. Results: The majority of respondents consistently chose either the low or high variance plan, consistent with expected utility theory. Half of respondents consistently chose the low variance plan. Respondents were less likely to make discrepant choices when information was presented in graphical format. Conclusions: Many people, although not all, make choices consistent with expected utility theory when they have information on differences among plans in the variance of out-of-pocket spending. Medicare beneficiaries would benefit from information on the extent to which prescription drug plans provide risk protection. C1 [Bundorf, M. Kate] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Mata, Rui] Univ Basel, Dept Psychol, Basel, Switzerland. [Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Bhattacharya, Jay] Stanford Univ, Sch Med, Ctr Primary Care & Outcomes Res, Stanford, CA 94305 USA. RP Bundorf, MK (reprint author), Stanford Univ, Sch Med, HRP Redwood Bldg,259 Campus Dr, Stanford, CA 94305 USA. EM bundorf@stanford.edu RI Mata, Rui/K-8138-2015 OI Mata, Rui/0000-0002-1679-906X FU Stanford Center on Longevity FX This research was supported in part by the Stanford Center on Longevity. The views expressed in this article do not necessarily reflect the opinions of the National Institutes of Health, the Department of Health and Human Services, or the federal government. NR 31 TC 3 Z9 3 U1 5 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD SEP PY 2013 VL 32 IS 9 SI SI BP 986 EP 994 DI 10.1037/a0033517 PG 9 WC Psychology, Clinical; Psychology SC Psychology GA 209ZO UT WOS:000323799300008 PM 24001249 ER PT J AU Gubin, M Techasintana, P Chen, J Calaluce, R Magee, J Martindale, J Gorospe, M Casolaro, V Stellato, C Atasoy, U AF Gubin, Matt Techasintana, Pat Chen, Jing Calaluce, Robert Magee, Joe Martindale, Jennifer Gorospe, Myriam Casolaro, Vincenzo Stellato, Christiana Atasoy, Ulus TI RNA-BINDING PROTEIN HUR COORDINATELY REGULATES GATA-3, CD4+TH2 AND TH17 CYTOKINE GENE EXPRESSION IN DOSE-DEPENDENT MANNER SO INTERNAL MEDICINE JOURNAL LA English DT Meeting Abstract C1 [Gubin, Matt; Techasintana, Pat; Chen, Jing; Calaluce, Robert; Magee, Joe; Atasoy, Ulus] Univ Missouri, Columbia, MO USA. [Martindale, Jennifer; Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. [Casolaro, Vincenzo; Stellato, Christiana] Johns Hopkins Univ, Baltimore, MD USA. RI Casolaro, Vincenzo/E-9144-2010; Stellato, Cristiana/P-3001-2015 OI Casolaro, Vincenzo/0000-0001-9810-0488; Stellato, Cristiana/0000-0002-1294-8355 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 1444-0903 J9 INTERN MED J JI Intern. Med. J. PD SEP PY 2013 VL 43 SU 4 SI SI BP 2 EP 2 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 208NG UT WOS:000323685200006 ER PT J AU Junttila, IS Watson, C Kummola, L Chen, X Hu-Li, J Guo, LY Yagi, R Paul, WE AF Junttila, Ilkka S. Watson, Cynthia Kummola, Laura Chen, Xi Hu-Li, Jane Guo, Liying Yagi, Ryoji Paul, William E. TI Efficient cytokine-induced IL-13 production by mast cells requires both IL-33 and IL-3 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Mast cells; basophils; allergic inflammation; cytokines; signal transducer and activator of transcription 5; tyrosine phosphorylation; BAC transgenic mouse; DsRed fluorochrome ID EXPRESSION; LIPOPOLYSACCHARIDE AB Background: IL-13 is a critical effector cytokine for allergic inflammation. It is produced by several cell types, including mast cells, basophils, and T(H)2 cells. In mast cells and basophils its induction can be stimulated by cross-linkage of immunoglobulin receptors or cytokines. The IL-1 family members IL-33 and IL-18 have been linked to induction of IL-13 production by mast cells and basophils. In CD4 T(H)2 cells IL-33-mediated production of IL-13 requires simultaneous signal transducer and activator of transcription (STAT) 5 activation. Objective: Here we have addressed whether cytokine-induced IL-13 production in mast cells and basophils follows the same logic as in T(H)2 cells: requirement of 2 separate signals. Methods: By generating a bacterial artificial chromosome (BAC) transgenic IL-13 reporter mouse, we measured IL-13 production in mast cells and basophils. Results: In mast cells harvested from peritoneal cavities, 2 cytokine signals are required for IL-13 production: IL-33 and IL-3. In bone marrow mast cells IL-13 production requires IL-33, but the requirement for a STAT5 inducer is difficult to evaluate because these cells require the continuous presence of IL-3 (a STAT5 activator) for survival. Poorer STAT5 inducers in culture (IL-4 or stem cell factor) result in less IL-13 production on IL-33 challenge, but the addition of exogenous IL-3 enhances IL-13 production. This implies that bone marrow-derived mast cells, like peritoneal mast cells and T(H)2 cells, require stimulation both by an IL-1 family member and a STAT5 inducer to secrete IL-13. Basophils follow the same rule; splenic basophils produce IL-13 in response to IL-18 or IL-33 plus IL-3. Conclusion: Optimal IL-13 production from mast cells and basophils requires 2 cytokine signals. C1 [Junttila, Ilkka S.; Watson, Cynthia; Chen, Xi; Hu-Li, Jane; Guo, Liying; Yagi, Ryoji; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Junttila, Ilkka S.; Kummola, Laura] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Junttila, Ilkka S.] Pirkanmaa Hosp Dist, Fimlab Labs, Tampere, Finland. RP Junttila, IS (reprint author), Biokatu 4,Rm C-306, Tampere 33520, Finland. EM ilkka.junttila@uta.fi; wpaul@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases Intramural Program; Finnish Medical Foundation; Competitive Research Funding of the Tampere University Hospital [9N018]; Sigrid Juselius Foundation; Fimlab laboratories [X51409]; Competitive Research Funding of Tampere University Hospital; Fimlab Laboratories; Sigrig Juselius Foundation FX Supported by the National Institute of Allergy and Infectious Diseases Intramural Program (to I.S.J., C.W., X.C., J.H.-L., L.G., R.Y., and W.E.P.), the Finnish Medical Foundation (to I.S.J.), Competitive Research Funding of the Tampere University Hospital (grant 9N018, to I.S.J.), the Sigrid Juselius Foundation (to I.S.J. and L.K.), and Fimlab laboratories (grant X51409, to I.S.J.).; I. S. Junttila has been supported by one or more grants from Competitive Research Funding of Tampere University Hospital, Fimlab Laboratories, and the Sigrid Juselius Foundation. L. Kummola has been supported by one or more grants from the Sigrig Juselius Foundation. The rest of the authors declare that they have no relevant conflicts of interest. NR 22 TC 21 Z9 22 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD SEP PY 2013 VL 132 IS 3 BP 704 EP + DI 10.1016/j.jaci.2013.03.033 PG 19 WC Allergy; Immunology SC Allergy; Immunology GA 207OS UT WOS:000323612000023 PM 23683462 ER PT J AU van der Schot, G Zhang, ZY Vernon, R Shen, Y Vranken, WF Baker, D Bonvin, AMJJ Lange, OF AF van der Schot, Gijs Zhang, Zaiyong Vernon, Robert Shen, Yang Vranken, Wim F. Baker, David Bonvin, Alexandre M. J. J. Lange, Oliver F. TI Improving 3D structure prediction from chemical shift data SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Nuclear magnetic resonance; Protein structure calculation; CS-ROSETTA; Sparse data ID PROTEIN-STRUCTURE DETERMINATION; NMR STRUCTURE DETERMINATION; STRUCTURE GENERATION; ROSETTA; PLUS AB We report advances in the calculation of protein structures from chemical shift nuclear magnetic resonance data alone. Our previously developed method, CS-Rosetta, assembles structures from a library of short protein fragments picked from a large library of protein structures using chemical shifts and sequence information. Here we demonstrate that combination of a new and improved fragment picker and the iterative sampling algorithm RASREC yield significant improvements in convergence and accuracy. Moreover, we introduce improved criteria for assessing the accuracy of the models produced by the method. The method was tested on 39 proteins in the 50-100 residue size range and yields reliable structures in 70 % of the cases. All structures that passed the reliability filter were accurate (< 2 RMSD from the reference). C1 [van der Schot, Gijs; Bonvin, Alexandre M. J. J.] Univ Utrecht, Bijvoet Ctr Biomol Res, Fac Sci Chem, NL-3584 CH Utrecht, Netherlands. [Zhang, Zaiyong; Lange, Oliver F.] Tech Univ Munich, Biomol NMR, D-85747 Garching, Germany. [Zhang, Zaiyong; Lange, Oliver F.] Tech Univ Munich, Dept Chem, Munich Ctr Integrated Prot Sci, D-85747 Garching, Germany. [Vernon, Robert; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Shen, Yang] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Vranken, Wim F.] VIB, Dept Biol Struct, B-1050 Brussels, Belgium. [Vranken, Wim F.] Vrije Univ Brussel, Struct Biol Brussels, B-1050 Brussels, Belgium. [Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Lange, Oliver F.] Helmholtz Zentrum Munchen, Inst Biol Struct, D-85764 Neuherberg, Germany. RP Bonvin, AMJJ (reprint author), Univ Utrecht, Bijvoet Ctr Biomol Res, Fac Sci Chem, Padualaan 8, NL-3584 CH Utrecht, Netherlands. EM a.m.j.j.bonvin@uu.nl; oliver.lange@tum.de RI Bonvin, Alexandre/A-5420-2009; Shen, Yang/C-3064-2008; Baker, David/K-8941-2012; Vranken, Wim/J-5051-2016 OI Bonvin, Alexandre/0000-0001-7369-1322; Shen, Yang/0000-0003-1408-8034; Baker, David/0000-0001-7896-6217; Vranken, Wim/0000-0001-7470-4324 FU German Science Foundation (DFG) [LA 1817/3-1]; Brussels Institute for Research and Innovation (Innoviris) [BB2B 2010-1-12]; NIDDK; European Grid Initiative (EGI) through the national GRID Initiative of Belgium [261572]; European Grid Initiative (EGI) through the national GRID Initiative of France; European Grid Initiative (EGI) through the national GRID Initiative of Italy; European Grid Initiative (EGI) through the national GRID Initiative of Germany; European Grid Initiative (EGI) through the national GRID Initiative of Netherlands (via the Dutch BiG Grid project); European Grid Initiative (EGI) through the national GRID Initiative of Portugal; European Grid Initiative (EGI) through the national GRID Initiative of Spain; European Grid Initiative (EGI) through the national GRID Initiative of UK; European Grid Initiative (EGI) through the national GRID Initiative of South Africa; European Grid Initiative (EGI) through the national GRID Initiative of Malaysia; European Grid Initiative (EGI) through the national GRID Initiative of Taiwan FX This work was supported by the German Science Foundation (DFG) Grant LA 1817/3-1 (to Z. Z. and O. F. L.), the Brussels Institute for Research and Innovation (Innoviris) grant BB2B 2010-1-12 (to W. F. V.), and the Intramural Research Program of the NIDDK (to Y. S.). The WeNMR project (European FP7 e-Infrastructure Grant, Contract No. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands (via the Dutch BiG Grid project), Portugal, Spain, UK, South Africa, Malaysia, Taiwan and the Latin America GRID infrastructure via the Gisela project is acknowledged for the use of web portals, computing and storage facilities. NR 22 TC 15 Z9 15 U1 1 U2 24 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD SEP PY 2013 VL 57 IS 1 BP 27 EP 35 DI 10.1007/s10858-013-9762-6 PG 9 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 208JH UT WOS:000323673800004 PM 23912841 ER PT J AU Jean-Pierre, P Winters, PC Clark, JA Warren-Mears, V Wells, KJ Post, DM LaVerda, N Van Duyn, MA Fiscella, K AF Jean-Pierre, Pascal Winters, Paul C. Clark, Jack A. Warren-Mears, Victoria Wells, Kristen J. Post, Douglas M. LaVerda, Nancy Van Duyn, Mary Ann Fiscella, Kevin CA Patient Nav Res Program Grp TI Do Better-Rated Navigators Improve Patient Satisfaction with Cancer-Related Care? SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Patient navigation; Cancer disparities; Patient Satisfaction with Interpersonal Relationship with Navigators; Patient Satisfaction with Cancer-Related Care ID HEALTH DISPARITIES; RESEARCH-PROGRAM AB Patient navigation has emerged as a promising strategy for addressing racial-ethnic and socioeconomic disparities in cancer-related care. However, little is known about the impact of patients' perception of the quality of navigation on patient outcomes. We examined the impact of better-rated navigators on patients' satisfaction with cancer-related care. The sample included 1,593 adults (85.8 % with abnormal cancer screening and 14.2 % with confirmed cancer diagnosis) who received patient navigation. We defined better-rated navigators as those scoring above the first quartile of mean scores on the Patient Satisfaction with Interpersonal Relationship with Navigator scale. We defined patient satisfaction based on scores above or below the median of the Patient Satisfaction with Cancer-Related Care (PSCC) scale. We controlled for patient and site characteristics using backward selection logistic regression analyses. Among patients with abnormal screening, having a better-rated navigator was associated with higher score on the PSCC (p < 0.05). After controlling for other bivariate predictors of satisfaction (e.g., age, race, income, and household size), navigation by better-rated navigators was associated with a greater likelihood of having higher patient satisfaction [odds ratio (OR), 1.38; 95 % confidence interval (CI), 1.05-1.82]. Similar findings between better-rated navigators and score on the PSCC were found for participants with diagnosed cancer (OR, 3.06; 95 % CI, 1.56-6.0). Patients navigated by better-rated navigators reported higher satisfaction with their cancer-related care. C1 [Jean-Pierre, Pascal] Harper Canc Res Inst, Notre Dame, IN USA. [Winters, Paul C.; Fiscella, Kevin] Univ Rochester, Med Ctr, Dept Family Med, Rochester, NY 14642 USA. [Clark, Jack A.] Boston Univ, Sch Publ Hlth, Ctr Hlth Qual Outcomes & Econ Res VA HSR&D, Boston, MA USA. [Warren-Mears, Victoria] Tribal Epidemiol Ctr, Northwest Portland Area Indian Hlth Board, Portland, OR USA. [Wells, Kristen J.] Univ S Florida, Coll Med, Ctr Evidence Based Med & Hlth Outcomes Res, Tampa, FL USA. [Post, Douglas M.] Ohio State Wexner Med Ctr, Dept Family Med, Columbus, OH USA. [LaVerda, Nancy] George Washington Univ, Med Ctr, Inst Canc, Washington, DC 20037 USA. [Van Duyn, Mary Ann] NCI, Ctr Reduce Canc Hlth Dispar, Rockville, MD USA. [Jean-Pierre, Pascal] Univ Notre Dame, Dept Psychol, Notre Dame, IN 46556 USA. RP Jean-Pierre, P (reprint author), Univ Notre Dame, Dept Psychol, 109 Haggar Hall, Notre Dame, IN 46556 USA. EM PJeanpierre@nd.edu RI Wells, Kristen/J-1838-2012; OI Clark, Jack/0000-0002-7424-1670 FU Walther Cancer Foundation; National Cancer Institute Center to Reduce Cancer Health Disparities [3U01CA116924-03S1, U01 CA116924 01, 1R25CA10261801A1, U01CA116892, U01CA117281, U01CA116903, U01CA116937, U01CA116885, U01CA116875, U01CA116925]; American Cancer Society [SIRSG-05-253-01] FX Dr. Pascal Jean-Pierre wishes to acknowledge the support of the Walther Cancer Foundation. This study was supported by grants from the National Cancer Institute Center to Reduce Cancer Health Disparities (3U01CA116924-03S1, U01 CA116924 01, 1R25CA10261801A1, U01CA116892, U01CA117281, U01CA116903, U01CA116937, U01CA116885, U01CA116875, and U01CA116925) and the American Cancer Society (SIRSG-05-253-01). NR 23 TC 2 Z9 2 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD SEP PY 2013 VL 28 IS 3 BP 527 EP 534 DI 10.1007/s13187-013-0498-5 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 206JN UT WOS:000323516400022 PM 23807598 ER PT J AU van der Veen, JW Shen, J AF van der Veen, Jan Willem Shen, Jun TI Regional difference in GABA levels between medial prefrontal and occipital cortices SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE N-acetylaspartate (NAA); creatine; glutamate + glutamine (Glx); gamma-aminobutyric acid (GABA); prefrontal cortex; occipital cortex; white matter; gray matter ID MAGNETIC-RESONANCE-SPECTROSCOPY; GAMMA-AMINOBUTYRIC-ACID; HUMAN BRAIN; IN-VIVO; DEPRESSED-PATIENTS; DISORDER; CORTEX AB Purpose: To avoid the confounding effects of variations in tissue composition this study measured regional GABA differences using two voxels with the same tissue composition. Materials and Methods: Eighteen healthy adult volunteers were scanned using a 3 Tesla GE clinical scanner with a J-coupling based editing sequence. Spectroscopy voxels were placed in the medial prefrontal (MPFC) and occipital cortex (OCC) with essentially the same gray and white matter fractions. Results: A 16% (P = 0.0001) significantly higher GABA to creatine ratio was found in the OCC (0.1103 +/- 0.0050) compared with the MPFC (0.0953 +/- 0.0041). When normalized to tissue water, GABA concentrations in the OCC were 14% higher than in the MPFC. Conclusion: A difference in GABA concentration was found between the OCC and MPFC voxels in healthy subjects which is attributable to differences other than tissue composition. J. Magn. Reson. Imaging 2013;38:745-750. (c) 2013 Wiley Periodicals, Inc. C1 [van der Veen, Jan Willem; Shen, Jun] NIMH, Magnet Resonance Spectroscopy Core Facil, Bethesda, MD 20892 USA. [Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP van der Veen, JW (reprint author), NIMH, Magnet Resonance Spectroscopy Core Facil, Bldg 10,Room 2D50,9000 Rockville Pike, Bethesda, MD 20892 USA. EM veen@nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX Contract grant sponsor: the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). NR 30 TC 10 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD SEP PY 2013 VL 38 IS 3 BP 745 EP 750 DI 10.1002/jmri.24009 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 208TL UT WOS:000323702500031 PM 23349060 ER PT J AU Yu, FS Wang, ZF Tanaka, M Chiu, CT Leeds, P Zhang, YM Chuang, DM AF Yu, Fengshan Wang, Zhifei Tanaka, Mikiei Chiu, Chi-Tso Leeds, Peter Zhang, Yumin Chuang, De-Maw TI Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice with traumatic brain injury Laboratory investigation SO JOURNAL OF NEUROSURGERY LA English DT Article DE traumatic brain injury; lithium; valproate; neuroprotection; acetylhistone H3; mouse ID MOOD STABILIZERS LITHIUM; BIPOLAR DISORDER; MOUSE MODEL; ACID; INHIBITION; NEURODEGENERATION; DEFICITS; DISEASE; ROLES; HDAC AB Object. Although traumatic brain injury (TBI) is the leading cause of death and morbidity in young adults, no effective pharmaceutical treatment is available. By inhibiting glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs), respectively, lithium and valproate (VPA) have beneficial effects in diverse neurodegenerative diseases. Furthermore, in an excitotoxic neuronal model and in animal models of amyotrophic lateral sclerosis, Huntington disease, and stroke, combined treatment with lithium and VPA produces more robust neuroprotective effects than treatment with either agent alone. Building on previous work that establishes that therapeutic doses of either lithium or VPA have beneficial effects in mouse models of TBI, this study evaluated the effects of combined treatment with subeffective doses of lithium and VPA in a mouse model of TBI. Methods. Male C57BL/6 mice underwent TBI and were subsequently treated with lithium, VPA, or a combination of lithium and VPA 15 minutes post-TBI and once daily thereafter for up to 3 weeks; all doses were subeffective (1 mEq/kg of lithium and 200 mg/kg of VPA). Assessed parameters included lesion volume via H & E staining; blood-brain bather (BBB) integrity via immunoglobulin G extravasation; neurodegeneration via Fluoro-Jade B staining; motor coordination via a beam-walk test; and protein levels of acetylhistone H3, phospho-GSK-3 beta, and beta-catenin via Western blotting. Results. Posttrauma treatment with combined subeffective doses of lithium and VPA significantly reduced lesion volume, attenuated BBB disruption, and mitigated hippocampal neurodegeneration 3 days after TBI. As expected, subeffective doses of lithium or VPA alone did not have these beneficial effects. Combined treatment also improved motor coordination starting from Day 7 and persisting at least 21 days after TBI. Acetylation of histone H3, an index of HDAC inhibition, was robustly increased by the combined treatment 3 days after TBI. Conclusions. Cotreatment with subeffective doses of lithium and VPA significantly attenuated TBI-induced brain lesion, BBB disruption, and neurodegeneration, and robustly improved long-term functional recovery. These findings suggest that potentiating histone acetylation by HDAC inhibition is probably part of the mechanism underlying the beneficial effects associated with this combined treatment for TBI. Because both lithium and VPA have a long history of safe clinical use, the results suggest that using a combination of these 2 agents at subtherapeutic doses to treat patients with TBI may also reduce side effects and enhance tolerability. C1 [Yu, Fengshan; Wang, Zhifei; Chiu, Chi-Tso; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Yu, Fengshan; Zhang, Yumin; Chuang, De-Maw] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Yu, Fengshan; Tanaka, Mikiei; Zhang, Yumin] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU Center for Neuroscience and Regenerative Medicine of the Department of Defense; Blast Lethality Injury and Research Program; Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This work was funded in part by the Center for Neuroscience and Regenerative Medicine of the Department of Defense, the Blast Lethality Injury and Research Program, and the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). The authors have no conflicts of interest to disclose, financial or otherwise. NR 28 TC 23 Z9 23 U1 0 U2 14 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2013 VL 119 IS 3 BP 766 EP 773 DI 10.3171/2013.6.JNS13135 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 204IJ UT WOS:000323358700029 PM 23848820 ER PT J AU Zamora-Ros, R Rabassa, M Cherubini, A Urpi-Sarda, M Bandinelli, S Ferrucci, L Andres-Lacueva, C AF Zamora-Ros, Raul Rabassa, Montserrat Cherubini, Antonio Urpi-Sarda, Mireia Bandinelli, Stefania Ferrucci, Luigi Andres-Lacueva, Cristina TI High Concentrations of a Urinary Biomarker of Polyphenol Intake Are Associated with Decreased Mortality in Older Adults SO JOURNAL OF NUTRITION LA English DT Article ID NUTRITION EPIC-SPAIN; CARDIOVASCULAR-DISEASE; DIETARY FLAVONOIDS; CANCER-RISK; MEDITERRANEAN DIET; PHENOLIC-ACIDS; SPANISH COHORT; HUMANS; FOOD; EXCRETION AB Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy. TUP concentrations were measured at enrolment (1998-2000) using the Folin-Ciocalteau assay after a solid-phase extraction. TDPs were also estimated at baseline throughout a validated food frequency questionnaire and using our database based on USDA and Phenol-Explorer databases. We modeled associations using Kaplan-Meier survival and Cox proportional hazards models, with adjustment for potential confounders. During the 12-y follow-up, 274 participants (34%) died. At enrollment, TUP excretion adjusted for age and sex tended to be greater in participants who survived 1163 +/- 62 mg gallic acid equivalents (GAE)/d)I than in those who died (143 +/- 63 mg GAE/d) (P = 0.07). However, no significant differences were observed for TDPs. In the multivariable Cox model, participants in the highest tertile of TUP at enrolment had a lower mortality rate than those in the lowest tertile [HR = 0.70 (95% Cl: 0.49-0.99); P-trend = 0.045], whereas no significant associations were found between TDP and overall mortality. TUP is an independent risk factor for mortality among community-dwelling older adults, suggesting that high dietary intake of polyphenols may be associated with longevity. C1 [Zamora-Ros, Raul; Rabassa, Montserrat; Urpi-Sarda, Mireia; Andres-Lacueva, Cristina] Univ Barcelona, Dept Nutr & Food Sci, XaRTA INSA, INGENIO CONSOLIDER Program,Pharm Sch, Barcelona, Spain. [Zamora-Ros, Raul] Bellvitge Biomed Res Inst, Catalan Inst Oncol, Unit Nutr Environm & Canc, Barcelona, Spain. [Cherubini, Antonio] Univ Perugia, Sch Med, Dept Clin & Expt Med, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Cherubini, A (reprint author), Italian Natl Res Ctr Aging, Geriatr Hosp, Ancona, Italy. EM a.cherubini@inrca.it RI Urpi-Sarda, Mireia/D-5937-2013; Andres-Lacueva, Cristina/J-3377-2012; OI Urpi-Sarda, Mireia/0000-0002-4064-5175; Andres-Lacueva, Cristina/0000-0002-8494-4978; Cherubini, Antonio/0000-0003-0261-9897 FU Italian Ministry of Health; United States National Institute on Aging; Spanish Ministry of Science and Innovation [AGL2009-13906-C02-01]; Mapfre Foundation; University of Barcelona; Barcelona Knowledge Campus; Campus of International Excellence program of the Spanish Ministry of Education, Culture and Sport; MICINN; European Social Funds; Spanish postdoctoral programme Fondo de Investigacion Sanitaria [CD09/00133] FX Supported in part by the Italian Ministry of Health and by the United States National Institute on Aging. This study was also supported by grants from the Spanish Ministry of Science and Innovation (INGENIO-CONSOLIDER program, FUN-C-Food CSD2007-063, AGL2009-13906-C02-01), the Mapfre Foundation, and the University of Barcelona, Barcelona Knowledge Campus, Campus of International Excellence program of the Spanish Ministry of Education, Culture and Sport. Further support was from MICINN and the European Social Funds [to the Ramon y Cajal contract (Ramon y Cajal Programme)] and the Spanish postdoctoral programme Fondo de Investigacion Sanitaria (no. CD09/00133). NR 44 TC 12 Z9 12 U1 1 U2 20 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD SEP PY 2013 VL 143 IS 9 BP 1445 EP 1450 DI 10.3945/jn.113.177121 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 205SX UT WOS:000323466200012 PM 23803472 ER PT J AU MacKillop, J Acker, JD Bollinger, J Clifton, A Miller, JD Campbell, WK Goodie, AS AF MacKillop, James Acker, John D. Bollinger, Jared Clifton, Allan Miller, Joshua D. Campbell, W. Keith Goodie, Adam S. TI Brief Report: The Brief Alcohol Social Density Assessment (BASDA): Convergent, Criterion-Related, and Incremental Validity SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID ADOLESCENT SUBSTANCE USE; DRINKING MOTIVES; CONSTRUCT-VALIDITY; COLLEGE-STUDENTS; NETWORK ANALYSIS; YOUNG ADULTHOOD; UNITED-STATES; ABUSE; SWITZERLAND; INVOLVEMENT AB Objective: Alcohol misuse is substantially influenced by social factors, but systematic assessments of social network drinking are typically lengthy. The goal of the present study was to provide further validation of a brief measure of social network alcohol use, the Brief Alcohol Social Density Assessment (BASDA), in a sample of emerging adults. Specifically, the study sought to examine the BASDA's convergent, criterion, and incremental validity in relation to well-established measures of drinking motives and problematic drinking. Method: Participants were 354 undergraduates who were assessed using the BASDA, the Alcohol Use Disorders Identification Test (AUDIT), and the Drinking Motives Questionnaire. Results: Significant associations were observed between the BASDA index of alcohol-related social density and alcohol misuse, social motives, and conformity motives, supporting convergent validity Criterion-related validity was supported by evidence that significantly greater alcohol involvement was present in the social networks of individuals scoring at or above an AUDIT score of 8, a validated criterion for hazardous drinking. Finally, the BASDA index was significantly associated with alcohol misuse above and beyond drinking motives in relation to AUDIT scores, supporting incremental validity. Conclusions: Taken together, these findings provide further support for the BASDA as an efficient measure of drinking in an individual's social network. Methodological considerations as well as recommendations for future investigations in this area are discussed. C1 [MacKillop, James; Acker, John D.; Miller, Joshua D.; Campbell, W. Keith; Goodie, Adam S.] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [MacKillop, James] Brown Univ, Dept Behav & Social Sci, Providence, RI 02912 USA. [Bollinger, Jared] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD USA. [Clifton, Allan] Vassar Coll, Dept Psychol, Poughkeepsie, NY 12601 USA. RP MacKillop, J (reprint author), Univ Georgia, Dept Psychol, 100 Hooper St, Athens, GA 30602 USA. EM jmackill@uga.edu FU National Institutes of Health [K23 AA016936]; National Center for Responsible Gaming FX This research was supported by National Institutes of Health Grant K23 AA016936 (J.M.) and the National Center for Responsible Gaming (A.S.G., A.C., J.D.M., W.K.C.). NR 34 TC 1 Z9 1 U1 2 U2 10 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD SEP PY 2013 VL 74 IS 5 BP 810 EP 815 PG 6 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 206OG UT WOS:000323531400019 PM 23948542 ER PT J AU Chuang, GY Acharya, P Schmidt, SD Yang, YP Louder, MK Zhou, TQ Do Kwon, Y Pancera, M Bailer, RT Doria-Rose, NA Nussenzweig, MC Mascola, JR Kwong, PD Georgiev, IS AF Chuang, Gwo-Yu Acharya, Priyamvada Schmidt, Stephen D. Yang, Yongping Louder, Mark K. Zhou, Tongqing Do Kwon, Young Pancera, Marie Bailer, Robert T. Doria-Rose, Nicole A. Nussenzweig, Michel C. Mascola, John R. Kwong, Peter D. Georgiev, Ivelin S. TI Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains SO JOURNAL OF VIROLOGY LA English DT Article ID STRUCTURAL BASIS; MONOCLONAL-ANTIBODIES; POTENT NEUTRALIZATION; RATIONAL DESIGN; BINDING; VIRUS; BROAD; GP120; RECOGNITION; CD4 AB Delineation of antibody epitopes at the residue level is key to understanding antigen resistance mutations, designing epitope-specific probes for antibody isolation, and developing epitope-based vaccines. Ideally, epitope residues are determined in the context of the atomic-level structure of the antibody-antigen complex, though structure determination may in many cases be impractical. Here we describe an efficient computational method to predict antibody-specific HIV-1 envelope (Env) epitopes at the residue level, based on neutralization panels of diverse viral strains. The method primarily utilizes neutralization potency data over a set of diverse viral strains representing the antigen, and enhanced accuracy could be achieved by incorporating information from the unbound structure of the antigen. The method was evaluated on 19 HIV-1 Env antibodies with neutralization panels comprising 181 diverse viral strains and with available antibody-antigen complex structures. Prediction accuracy was shown to improve significantly over random selection, with an average of greater-than-8-fold enrichment of true positives at the 0.05 false-positive rate level. The method was used to prospectively predict epitope residues for two HIV-1 antibodies, 8ANC131 and 8ANC195, for which we experimentally validated the predictions. The method is inherently applicable to antigens that exhibit sequence diversity, and its accuracy was found to correlate inversely with sequence conservation of the epitope. Together the results show how knowledge inherent to a neutralization panel and unbound antigen structure can be utilized for residue-level prediction of antibody epitopes. C1 [Chuang, Gwo-Yu; Acharya, Priyamvada; Schmidt, Stephen D.; Yang, Yongping; Louder, Mark K.; Zhou, Tongqing; Do Kwon, Young; Pancera, Marie; Bailer, Robert T.; Doria-Rose, Nicole A.; Mascola, John R.; Kwong, Peter D.; Georgiev, Ivelin S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. RP Georgiev, IS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ivelin.georgiev@nih.gov RI Zhou, Tongqing/A-6880-2010; Kwon, Young Do/A-6957-2010; Schmidt, Stephen/B-5398-2012 OI Zhou, Tongqing/0000-0002-3935-4637; FU Intramural Research Program of the Vaccine Research Center, NIAID; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; Office of AIDS Research, NIH; Bill and Melinda Gates Foundation [38619s]; NIH [AI 100663-01, AI 100148-01] FX This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium, the Office of AIDS Research, NIH, and the following grants to M.C.N.: Bill and Melinda Gates Foundation grant 38619s and NIH grants AI 100663-01 and AI 100148-01. M.C.N. is an HHMI investigator. NR 55 TC 25 Z9 25 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10047 EP 10058 DI 10.1128/JVI.00984-13 PG 12 WC Virology SC Virology GA 205DE UT WOS:000323420800009 PM 23843642 ER PT J AU Stokes, KL Currier, MG Sakamoto, K Lee, S Collins, PL Plemper, RK Moore, ML AF Stokes, Kate L. Currier, Michael G. Sakamoto, Kaori Lee, Sujin Collins, Peter L. Plemper, Richard K. Moore, Martin L. TI The Respiratory Syncytial Virus Fusion Protein and Neutrophils Mediate the Airway Mucin Response to Pathogenic Respiratory Syncytial Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; IN-VITRO; MEMBRANE-FUSION; TNF-ALPHA; INFLAMMATORY PROTEIN-2; EPITHELIAL-CELLS; DISEASE SEVERITY; GENE-EXPRESSION; INFLUENZA-VIRUS; ALLERGIC-ASTHMA AB Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown that infection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater airway necrosis, and higher levels of interleukin-13 (IL-13) and airway mucin expression than infection with RSV laboratory strain A2. We hypothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor. In vitro, the fusion activity of 2-20 F but not that of A2 F was enhanced by expression of RSV G. We generated a recombinant F-chimeric RSV by replacing the F gene of A2 with the F gene of 2-20, generating A2-2-20F. Similar to the results obtained with the parent 2-20 strain, infection of BALB/cJ mice with A2-2-20F resulted in a higher early viral load and higher levels of subsequent pulmonary mucin expression than infection with the A2 strain. A2-2-20F infection induced greater necrotic airway damage and neutrophil infiltration than A2 infection. We hypothesized that the neutrophil response to A2-2-20F infection is involved in mucin expression. Antibody-mediated depletion of neutrophils in RSV-infected mice resulted in lower tumor necrosis factor alpha levels, fewer IL-13-expressing CD4 T cells, and less airway mucin production in the lung. Our data are consistent with a model in which the F and attachment (G) glycoprotein functional interaction leads to enhanced fusion and F is a key factor in airway epithelium infection, pathogenesis, and subsequent airway mucin expression. C1 [Stokes, Kate L.; Currier, Michael G.; Lee, Sujin; Plemper, Richard K.; Moore, Martin L.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Stokes, Kate L.; Currier, Michael G.; Lee, Sujin; Plemper, Richard K.; Moore, Martin L.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Sakamoto, Kaori] Univ Georgia, Coll Vet Med, Dept Pathol, Athens, GA 30602 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Moore, ML (reprint author), Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. EM martin.moore@emory.edu FU NIH [1R01AI087798, 1U19AI095227] FX This work was supported by the following grants: NIH 1R01AI087798 and NIH 1U19AI095227. NR 72 TC 29 Z9 31 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10070 EP 10082 DI 10.1128/JVI.01347-13 PG 13 WC Virology SC Virology GA 205DE UT WOS:000323420800011 PM 23843644 ER PT J AU Samal, S Khattar, SK Paldurai, A Palaniyandi, S Zhu, XP Collins, PL Samal, SK AF Samal, Sweety Khattar, Sunil K. Paldurai, Anandan Palaniyandi, Senthilkumar Zhu, Xiaoping Collins, Peter L. Samal, Siba K. TI Mutations in the Cytoplasmic Domain of the Newcastle Disease Virus Fusion Protein Confer Hyperfusogenic Phenotypes Modulating Viral Replication and Pathogenicity SO JOURNAL OF VIROLOGY LA English DT Article ID HEMAGGLUTININ-NEURAMINIDASE PROTEIN; RESPIRATORY-SYNCYTIAL-VIRUS; POLARIZED EPITHELIAL-CELLS; PARAMYXOVIRUS-F-PROTEIN; AMINO-ACID CHANGE; MEMBRANE-FUSION; SORTING SIGNALS; TERMINAL REGION; COILED-COIL; GLYCOPROTEIN AB The Newcastle disease virus (NDV) fusion protein (F) mediates fusion of viral and host cell membranes and is a major determinant of NDV pathogenicity. In the present study, we demonstrate the effects of functional properties of F cytoplasmic tail (CT) amino acids on virus replication and pathogenesis. Out of a series of C-terminal deletions in the CT, we were able to rescue mutant viruses lacking two or four residues (r Delta 2 and r Delta 4). We further rescued viral mutants with individual amino acid substitutions at each of these four terminal residues (rM553A, rK552A, rT551A, and rT550A). In addition, the NDV F CT has two conserved tyrosine residues (Y524 and Y527) and a dileucine motif (LL536-537). In other paramyxoviruses, these residues were shown to affect fusion activity and are central elements in basolateral targeting. The deletion of 2 and 4 CT amino acids and single tyrosine substitution resulted in hyperfusogenic phenotypes and increased viral replication and pathogenesis. We further found that in rY524A and rY527A viruses, disruption of the targeting signals did not reduce the expression on the apical or basolateral surface in polarized Madin-Darby canine kidney cells, whereas in double tyrosine mutant, it was reduced on both the apical and basolateral surfaces. Interestingly, in rL536A and rL537A mutants, the F protein expression was more on the apical than on the basolateral surface, and this effect was more pronounced in the rL537A mutant. We conclude that these wild-type residues in the NDV F CT have an effect on regulating F protein biological functions and thus modulating viral replication and pathogenesis. C1 [Samal, Sweety; Khattar, Sunil K.; Paldurai, Anandan; Palaniyandi, Senthilkumar; Zhu, Xiaoping; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Palaniyandi, Senthilkumar/B-9575-2016 FU NIAID [N01A060009]; NIAID, NIH Intramural Research Program FX This research was supported by NIAID contract no. N01A060009 (85% support) and NIAID, NIH Intramural Research Program (15% support). NR 61 TC 10 Z9 11 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10083 EP 10093 DI 10.1128/JVI.01446-13 PG 11 WC Virology SC Virology GA 205DE UT WOS:000323420800012 PM 23843643 ER PT J AU Martin, C Buckler-White, A Wollenberg, K Kozak, CA AF Martin, Carrie Buckler-White, Alicia Wollenberg, Kurt Kozak, Christine A. TI The Avian XPR1 Gammaretrovirus Receptor Is under Positive Selection and Is Disabled in Bird Species in Contact with Virus-Infected Wild Mice SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA VIRUSES; CELL-SURFACE RECEPTOR; MOUSE XENOTROPIC GAMMARETROVIRUSES; MUS-MUSCULUS-MOLOSSINUS; HOST-RANGE; HOUSE MICE; LABORATORY MOUSE; RETROVIRUS XMRV; C VIRUSES; ORIGIN AB Xenotropic mouse leukemia viruses (X-MLVs) are broadly infectious for mammals except most of the classical strains of laboratory mice. These gammaretroviruses rely on the XPR1 receptor for entry, and the unique resistance of laboratory mice is due to two mutations in different putative XPR1 extracellular loops. Cells from avian species differ in susceptibility to X-MLVs, and 2 replacement mutations in the virus-resistant chicken XPR1 (K496Q and Q579E) distinguish it from the more permissive duck and quail receptors. These substitutions align with the two mutations that disable the laboratory mouse XPR1. Mutagenesis of the chicken and duck genes confirms that residues at both sites are critical for virus entry. Among 32 avian species, the 2 disabling XPR1 mutations are found together only in the chicken, an omnivorous, ground-dwelling fowl that was domesticated in India and/or Southeast Asia, which is also where X-MLV-infected house mice evolved. The receptor-disabling mutations are also present separately in 5 additional fowl and raptor species, all of which are native to areas of Asia populated by the virus-infected subspecies Mus musculus castaneus. Phylogenetic analysis showed that the avian XPR1 gene is under positive selection at sites implicated in receptor function, suggesting a defensive role for XPR1 in the avian lineage. Contact between bird species and virus-infected mice may thus have favored selection of mouse virus-resistant receptor orthologs in the birds, and our data suggest that similar receptor-disabling mutations were fixed in mammalian and avian species exposed to similar virus challenges. C1 [Martin, Carrie; Buckler-White, Alicia; Kozak, Christine A.] NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov OI Blanchard, Carrie/0000-0002-1236-4245 FU Intramural Research Program of the NIAID, NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. NR 71 TC 8 Z9 8 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10094 EP 10104 DI 10.1128/JVI.01327-13 PG 11 WC Virology SC Virology GA 205DE UT WOS:000323420800013 PM 23843647 ER PT J AU Pastrana, DV Ray, U Magaldi, TG Schowalter, RM Cuburu, N Buck, CB AF Pastrana, Diana V. Ray, Upasana Magaldi, Thomas G. Schowalter, Rachel M. Cuburu, Nicolas Buck, Christopher B. TI BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism SO JOURNAL OF VIROLOGY LA English DT Article ID HIGH-THROUGHPUT; VIRUS; SEQUENCE; VP1; IDENTIFICATION; GANGLIOSIDES; VARIABILITY; POPULATIONS; REACTIVITY; MUTATIONS AB BK polyomavirus (BKV) causes significant urinary tract pathogenesis in immunosuppressed individuals, including kidney and bone marrow transplant recipients. It is currently unclear whether BKV-neutralizing antibodies can moderate or prevent BKV disease. We developed reporter pseudoviruses based on seven divergent BKV isolates and performed neutralization assays on sera from healthy human subjects. The results demonstrate that BKV genotypes I, II, III, and IV are fully distinct serotypes. While nearly all healthy subjects had BKV genotype I-neutralizing antibodies, a majority of subjects did not detectably neutralize genotype III or IV. Surprisingly, BKV subgenotypes Ib1 and Ib2 can behave as fully distinct serotypes. This difference is governed by as few as two residues adjacent to the cellular glycan receptor-binding site on the virion surface. Serological analysis of mice given virus-like particle (VLP)-based BKV vaccines confirmed these findings. Mice administered a multivalent VLP vaccine showed high-titer serum antibody responses that potently cross-neutralized all tested BKV genotypes. Interestingly, each of the neutralization serotypes bound a distinct spectrum of cell surface receptors, suggesting a possible connection between escape from recognition by neutralizing antibodies and cellular attachment mechanisms. The finding implies that different BKV genotypes have different cellular tropisms and pathogenic potentials in vivo. Individuals who are infected with one BKV serotype may remain humorally vulnerable to other BKV serotypes after implementation of T cell immunosuppression. Thus, prevaccinating organ transplant recipients with a multivalent BKV VLP vaccine might reduce the risk of developing posttransplant BKV disease. C1 [Pastrana, Diana V.; Ray, Upasana; Magaldi, Thomas G.; Schowalter, Rachel M.; Cuburu, Nicolas; Buck, Christopher B.] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Buck, CB (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM BuckC@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU Intramural Research Program of the NIH; Center for Cancer Research; NCI Director's Intramural Innovation Award Program FX This work was by the Intramural Research Program of the NIH, with support from the Center for Cancer Research and the NCI Director's Intramural Innovation Award Program. NR 42 TC 25 Z9 25 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10105 EP 10113 DI 10.1128/JVI.01189-13 PG 9 WC Virology SC Virology GA 205DE UT WOS:000323420800014 PM 23843634 ER PT J AU Acharya, P Luongo, TS Georgiev, IS Matz, J Schmidt, SD Louder, MK Kessler, P Yang, YP McKee, K O'Dell, S Chen, L Baty, D Chames, P Martin, L Mascola, JR Kwong, PD AF Acharya, Priyamvada Luongo, Timothy S. Georgiev, Ivelin S. Matz, Julie Schmidt, Stephen D. Louder, Mark K. Kessler, Pascal Yang, Yongping McKee, Krisha O'Dell, Sijy Chen, Lei Baty, Daniel Chames, Patrick Martin, Loic Mascola, John R. Kwong, Peter D. TI Heavy Chain-Only IgG2b Llama Antibody Effects Near-Pan HIV-1 Neutralization by Recognizing a CD4-Induced Epitope That Includes Elements of Coreceptor- and CD4-Binding Sites SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4 BINDING-SITE; ENVELOPE GLYCOPROTEINS; STRUCTURAL BASIS; POTENT NEUTRALIZATION; BROAD NEUTRALIZATION; DOMAIN ANTIBODIES; RECEPTOR-BINDING; GP120 CORE; IMMUNOGENICITY AB The conserved HIV-1 site of coreceptor binding is protected from antibody-directed neutralization by conformational and steric restrictions. While inaccessible to most human antibodies, the coreceptor site has been shown to be accessed by antibody fragments. In this study, we used X-ray crystallography, surface plasmon resonance, and pseudovirus neutralization to characterize the gp120-envelope glycoprotein recognition and HIV-1 neutralization of a heavy chain-only llama antibody, named JM4. We describe full-length IgG2b and IgG3 versions of JM4 that target the coreceptor-binding site and potently neutralize over 95% of circulating HIV-1 isolates. Contrary to established trends that show improved access to the coreceptor-binding region by smaller antibody fragments, the single-domain (VHH) version of JM4 neutralized less well than the full-length IgG2b version of JM4. The crystal structure at 2.1-angstrom resolution of VHH JM4 bound to HIV-1 YU2 gp120 stabilized in the CD4-bound state by the CD4-mimetic miniprotein, M48U1, revealed a JM4 epitope that combined regions of coreceptor recognition (including the gp120 bridging sheet, V3 loop, and beta 19 strand) with gp120 structural elements involved in recognition of CD4 such as the CD4-binding loop. The structure of JM4 with gp120 thus defines a novel CD4-induced site of vulnerability involving elements of both co-receptor- and CD4-binding sites. The potently neutralizing JM4 IgG2b antibody that targets this newly defined site of vulnerability adds to the expanding repertoire of broadly neutralizing antibodies that effectively neutralize HIV-1 and thereby potentially provides a new template for vaccine development and target for HIV-1 therapy. C1 [Acharya, Priyamvada; Luongo, Timothy S.; Georgiev, Ivelin S.; Schmidt, Stephen D.; Louder, Mark K.; Yang, Yongping; McKee, Krisha; O'Dell, Sijy; Chen, Lei; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Matz, Julie; Baty, Daniel; Chames, Patrick] INSERM, U1068, CRCM, F-13258 Marseille, France. [Kessler, Pascal; Martin, Loic] CEA, IBiTecS, Serv Ingn Mol Prot, Gif Sur Yvette, France. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM acharyap@mail.nih.gov; pdkwong@nih.gov RI Schmidt, Stephen/B-5398-2012; MARTIN, loic/E-1627-2011; Chames, Patrick/R-1800-2016; OI MARTIN, loic/0000-0002-7940-2955; Chames, Patrick/0000-0002-6104-6286; Baty, Daniel/0000-0001-8443-4444 FU Intramural AIDS Targeted Anti-retroviral Program (IATAP), NIH; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH; Framework Program [242135]; Agence Nationale de Recherche sur le SIDA (ANRS); ANRS; INSERM transfert; OSEO; FP7 program NAMDIATREAM; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX Support for this work was provided by the Intramural AIDS Targeted Anti-retroviral Program (IATAP), NIH, the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, the Framework Program (FP7/2010-2014) under grant agreement no. 242135 (CHAARM), and Agence Nationale de Recherche sur le SIDA (ANRS). J.M. was supported by a fellowship from ANRS. D.B. and P.C. are members of the IBiSA nanobody platform of CRCM, supported by INSERM transfert, OSEO, and FP7 program NAMDIATREAM. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. NR 49 TC 9 Z9 9 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10173 EP 10181 DI 10.1128/JVI.01332-13 PG 9 WC Virology SC Virology GA 205DE UT WOS:000323420800020 PM 23843638 ER PT J AU Maruri-Avidal, L Weisberg, AS Moss, B AF Maruri-Avidal, Liliana Weisberg, Andrea S. Moss, Bernard TI Association of the Vaccinia Virus A11 Protein with the Endoplasmic Reticulum and Crescent Precursors of Immature Virions SO JOURNAL OF VIROLOGY LA English DT Article ID NASCENT VIRAL MEMBRANES; ENVELOPE PROTEIN; EXTERNAL SCAFFOLD; F10 KINASE; MORPHOGENESIS; BIOGENESIS; RIFAMPICIN; INSERTION; ENCODES; CELLS AB The apparent de novo formation of viral membranes within cytoplasmic factories is a mysterious, poorly understood first step in poxvirus morphogenesis. Genetic studies identified several viral proteins essential for membrane formation and the assembly of immature virus particles. Their repression results in abortive replication with the accumulation of dense masses of viroplasm. In the present study, we further characterized one of these proteins, A11, and investigated its association with cellular and viral membranes under normal and abortive replication conditions. We discovered that A11 colocalized in cytoplasmic factories with the endoplasmic reticulum (ER) and L2, another viral protein required for morphogenesis. Confocal microscopy and subcellular fractionation indicated that A11 was not membrane associated in uninfected cells, whereas L2 still colocalized with the ER. Cellfree transcription and translation experiments indicated that both A11 and L2 are tail-anchored proteins that associate post-translationally with membranes and likely require specific cytoplasmic targeting chaperones. Transmission electron microscopy indicated that A11, like L2, associated with crescent membranes and immature virions during normal infection and with vesicles and tubules near masses of dense viroplasm during abortive infection in the absence of the A17 or A14 protein component of viral membranes. When the synthesis of A11 was repressed, "empty" immature-virion-like structures formed in addition to masses of viroplasm. The immature-virion-like structures were labeled with antibodies to A17 and to the D13 scaffold protein and were closely associated with calnexin-labeled ER. These studies revealed similarities and differences between A11 and L2, both of which may be involved in the recruitment of the ER for virus assembly. C1 [Maruri-Avidal, Liliana; Weisberg, Andrea S.; Moss, Bernard] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX The research was supported by the Division of Intramural Research, NIAID, NIH. NR 50 TC 8 Z9 9 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10195 EP 10206 DI 10.1128/JVI.01601-13 PG 12 WC Virology SC Virology GA 205DE UT WOS:000323420800023 PM 23864611 ER PT J AU Maldarelli, F Kearney, M Palmer, S Stephens, R Mican, J Polis, MA Davey, RT Kovacs, J Shao, W Rock-Kress, D Metcalf, JA Rehm, C Greer, SE Lucey, DL Danley, K Alter, H Mellors, JW Coffin, JM AF Maldarelli, Frank Kearney, Mary Palmer, Sarah Stephens, Robert Mican, JoAnn Polis, Michael A. Davey, Richard T. Kovacs, Joseph Shao, Wei Rock-Kress, Diane Metcalf, Julia A. Rehm, Catherine Greer, Sarah E. Lucey, Daniel L. Danley, Kristen Alter, Harvey Mellors, John W. Coffin, John M. TI HIV Populations Are Large and Accumulate High Genetic Diversity in a Nonlinear Fashion SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; DRUG-RESISTANCE MUTATIONS; DYNAMICS IN-VIVO; CHRONIC INFECTION; REVERSE-TRANSCRIPTASE; PERIPHERAL-BLOOD; VIRAL LOAD; EVOLUTION; TYPE-1 AB HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence and to estimate replicating population sizes in a group of treatment-naive HIV-infected individuals sampled at single (n = 22) or multiple, longitudinal (n = 11) time points. Analysis of single genome sequences revealed nonlinear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30-fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were low relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1,000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift. C1 [Maldarelli, Frank; Kearney, Mary; Palmer, Sarah; Danley, Kristen; Coffin, John M.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Stephens, Robert; Shao, Wei] SAIC, ISP Adv Biomed Comp Ctr, Frederick, MD USA. [Mican, JoAnn; Polis, Michael A.; Davey, Richard T.; Rock-Kress, Diane; Metcalf, Julia A.; Rehm, Catherine] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph] NIH, Dept Crit Care, Bethesda, MD 20892 USA. [Greer, Sarah E.; Alter, Harvey] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Lucey, Daniel L.] Washington Hosp Ctr, Div Infect Dis, Washington, DC 20010 USA. [Mellors, John W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Maldarelli, F (reprint author), NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. EM fmalli@mail.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU F.M. Kirby Foundation FX J.M.C. was a research professor of the American Cancer Society with support from the F.M. Kirby Foundation. NR 61 TC 25 Z9 27 U1 2 U2 24 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 18 BP 10313 EP 10323 DI 10.1128/JVI.01225-12 PG 11 WC Virology SC Virology GA 205DE UT WOS:000323420800033 PM 23678164 ER PT J AU Drosten, C Seilmaier, M Corman, VM Hartmann, W Scheible, G Sack, S Guggemos, W Kallies, R Muth, D Junglen, S Muller, MA Haas, W Guberina, N Rohnisch, T Schmid-Wendtner, M Aldabbagh, S Dittmer, U Gold, H Graf, P Bonin, F Rambaut, A Wendtner, CM AF Drosten, Christian Seilmaier, Michael Corman, Victor M. Hartmann, Wulf Scheible, Gregor Sack, Stefan Guggemos, Wolfgang Kallies, Rene Muth, Doreen Junglen, Sandra Muller, Marcel A. Haas, Walter Guberina, Nana Rohnisch, Tim Schmid-Wendtner, Monika Aldabbagh, Souhaib Dittmer, Ulf Gold, Hermann Graf, Petra Bonin, Frank Rambaut, Andrew Wendtner, Clemens-Martin TI Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection SO LANCET INFECTIOUS DISEASES LA English DT Article ID VIRUS; EMC; TROPISM; ASSAY; PCR AB Background The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus involved in cases and case clusters of severe acute respiratory infection in the Arabian Peninsula, Tunisia, Morocco, France, Italy, Germany, and the UK. We provide a full description of a fatal case of MERS-CoV infection and associated phylogenetic analyses. Methods We report data for a patient who was admitted to the Klinikum Schwabing (Munich, Germany) for severe acute respiratory infection. We did diagnostic RT-PCR and indirect immunofluorescence. From time of diagnosis, respiratory, faecal, and urine samples were obtained for virus quantification. We constructed a maximum likelihood tree of the five available complete MERS-CoV genomes. Findings A 73-year-old man from Abu Dhabi, United Arab Emirates, was transferred to Klinikum Schwabing on March 19, 2013, on day 11 of illness. He had been diagnosed with multiple myeloma in 2008, and had received several lines of treatment. The patient died on day 18, due to septic shock. MERS-CoV was detected in two samples of bronchoalveolar fluid. Viral loads were highest in samples from the lower respiratory tract (up to 1.2x10(6) copies per mL). Maximum virus concentration in urine samples was 2691 RNA copies per mL on day 13; the virus was not present in the urine after renal failure on day 14. Stool samples obtained on days 12 and 16 contained the virus, with up to 1031 RNA copies per g (dose to the lowest detection limit of the assay). One of two oronasal swabs obtained on day 16 were positive, but yielded little viral RNA (5370 copies per mL). No virus was detected in blood. The full virus genome was combined with four other available full genome sequences in a maximum likelihood phylogeny, correlating branch lengths with dates of isolation. The time of the common ancestor was halfway through 2011. Addition of novel genome data from an unlinked case treated 6 months previously in Essen, Germany, showed a clustering of viruses derived from Qatar and the United Arab Emirates. Interpretation We have provided the first complete viral load profile in a case of MERS-CoV infection. MERS-CoV might have shedding patterns that are different from those of severe acute respiratory syndrome and so might need alternative diagnostic approaches. C1 [Drosten, Christian; Corman, Victor M.; Kallies, Rene; Muth, Doreen; Junglen, Sandra; Muller, Marcel A.; Aldabbagh, Souhaib] Univ Bonn, Med Ctr, Inst Virol, D-53105 Bonn, Germany. [Seilmaier, Michael; Hartmann, Wulf; Scheible, Gregor; Sack, Stefan; Guggemos, Wolfgang; Schmid-Wendtner, Monika] Klinikum Schwabing, D-80804 Munich, Germany. [Haas, Walter] Robert Koch Inst, Dept Infect Epidemiol, Berlin, Germany. [Guberina, Nana] Univ Duisburg Essen, Dept Internal Med, Essen, Germany. [Dittmer, Ulf] Univ Duisburg Essen, Inst Virol, Essen, Germany. [Rohnisch, Tim; Schmid-Wendtner, Monika] Interdisziplinares Onkol Zentrum, Munich, Germany. [Gold, Hermann; Graf, Petra] Dept Hlth & Environm, Munich, Germany. [Bonin, Frank] Ruhrlandklinik, Dept Intens Care, Essen, Germany. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Forgarty Int Ctr, Bethesda, MD 20892 USA. RP Drosten, C (reprint author), Univ Bonn, Med Ctr, Inst Virol, D-53105 Bonn, Germany. EM drosten@virology-bonn.de; clemens.wendtner@klinikum-muenchen.de RI Junglen, Sandra/I-3033-2012; OI Mueller, Marcel/0000-0003-2242-5117; Corman, Victor Max/0000-0002-3605-0136; Rambaut, Andrew/0000-0003-4337-3707 FU European research project on emerging diseases detection and response (EMPERIE) [223498]; German Centre for Infection Research and Education; German research council [01KIO701, DR 772/3-1] FX This work was supported by a European research project on emerging diseases detection and response (EMPERIE; contract No 223498). CD has received infrastructural support from the German Centre for Infection Research, which included full funding of the position of VC. Virological analyses were partly support by the German Ministry for Research and Education and the German research council (grants 01KIO701 and DR 772/3-1). We thank Tobias BIeicker, Sebastian Brunink, Monika Eschbach-Bludau, Stephan Kallies, Heike Kirberg, Tobias Klant, Ingrid Kroning, and Astrid Schneider (Institute of Virology, Bonn, Germany) for excellent technical assistance. NR 25 TC 142 Z9 150 U1 6 U2 44 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD SEP PY 2013 VL 13 IS 9 BP 745 EP 751 DI 10.1016/S1473-3099(13)70154-3 PG 7 WC Infectious Diseases SC Infectious Diseases GA 205SU UT WOS:000323465900019 PM 23782859 ER PT J AU Subramanian, S Chandramouli, GVR McMillan, A Gullapalli, RP Devasahayam, N Mitchell, JB Matsumoto, S Krishna, MC AF Subramanian, Sankaran Chandramouli, Gadisetti V. R. McMillan, Alan Gullapalli, Rao P. Devasahayam, Nallathamby Mitchell, James B. Matsumoto, Shingo Krishna, Murali C. TI Evaluation of partial k-space strategies to speed up time-domain EPR imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; time-domain EPR imaging; partial Fourier; partial k-space acquisition; conjugate symmetry; single-point imaging; homodyne detection; projection onto convex sets (POCS) ID ELECTRON-PARAMAGNETIC-RESONANCE; TUMOR OXYGENATION; RECONSTRUCTION; MRI; RESOLUTION; OPTIMIZATION; TRAJECTORIES; DESIGN; IMAGES; FMRI AB Narrow-line spin probes derived from the trityl radical have led to the development of fast in vivo time-domain EPR imaging. Pure phase-encoding imaging modalities based on the single-point imaging scheme have demonstrated the feasibility of three-dimensional oximetric images with functional information in minutes. In this article, we explore techniques to improve the temporal resolution and circumvent the relatively short biological half-lives of trityl probes using partial k-space strategies. There are two main approaches: one involves the use of the Hermitian character of the k-space by which only part of the k-space is measured and the unmeasured part is generated using the Hermitian symmetry. This approach is limited in success by the accuracy of numerical estimate of the phase roll in the k-space that corrupts the Hermiticy. The other approach is to measure only a judicially chosen reduced region of k-space (a centrosymmetric ellipsoid region) that more or less accounts for >70% of the k-space energy. Both of these aspects were explored in Fourier transform-EPR imaging with a doubling of scan speed demonstrated by considering ellipsoid geometry of the k-space. Partial k-space strategies help improve the temporal resolution in studying fast dynamics of functional aspects in vivo with infused spin probes. Magn Reson Med 70:745-753, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Subramanian, Sankaran; Devasahayam, Nallathamby; Mitchell, James B.; Matsumoto, Shingo; Krishna, Murali C.] NCI, Radiat Biol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Chandramouli, Gadisetti V. R.] GenEpria Consulting Inc, Columbia, MD USA. [McMillan, Alan; Gullapalli, Rao P.] Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, CCR, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM murali@helix.nih.gov FU Intramural NIH HHS [Z01 BC010476-05] NR 32 TC 4 Z9 4 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD SEP PY 2013 VL 70 IS 3 BP 745 EP 753 DI 10.1002/mrm.24508 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 206SU UT WOS:000323543600016 PM 23045171 ER PT J AU Hiraishi, H Shin, BS Udagawa, T Nemoto, N Chowdhury, W Graham, J Cox, C Reid, M Brown, SJ Asano, K AF Hiraishi, Hiroyuki Shin, Byung-Sik Udagawa, Tsuyoshi Nemoto, Naoki Chowdhury, Wasimul Graham, Jymie Cox, Christian Reid, Megan Brown, Susan J. Asano, Katsura TI Interaction between 25S rRNA A Loop and Eukaryotic Translation Initiation Factor 5B Promotes Subunit Joining and Ensures Stringent AUG Selection SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID START CODON SELECTION; IN-VIVO; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; SITE SELECTION; DNA-DAMAGE; COMPLEX; YEAST; BINDING; GCN4 AB In yeast, 25S rRNA makes up the major mass and shape of the 60S ribosomal subunit. During the last step of translation initiation, eukaryotic initiation factor 5B (eIF5B) promotes the 60S subunit joining with the 40S initiation complex (IC). Malfunctional 60S subunits produced by misfolding or mutation may disrupt the 40S IC stalling on the start codon, thereby altering the stringency of initiation. Using several point mutations isolated by random mutagenesis, here we studied the role of 25S rRNA in start codon selection. Three mutations changing bases near the ribosome surface had strong effects, allowing the initiating ribosomes to skip both AUG and non-AUG codons: C2879U and U2408C, altering the A loop and P loop, respectively, of the peptidyl transferase center, and G1735A, mapping near a Eukarya-specific bridge to the 40S subunit. Overexpression of eIF5B specifically suppressed the phenotype caused by C2879U, suggesting functional interaction between eIF5B and the A loop. In vitro reconstitution assays showed that C2879U decreased eIF5B-catalyzed 60S subunit joining with a 40S IC. Thus, eIF5B interaction with the peptidyl transferase center A loop increases the accuracy of initiation by stabilizing the overall conformation of the 80S initiation complex. This study provides an insight into the effect of ribosomal mutations on translation profiles in eukaryotes. C1 [Hiraishi, Hiroyuki; Udagawa, Tsuyoshi; Nemoto, Naoki; Chowdhury, Wasimul; Graham, Jymie; Cox, Christian; Reid, Megan; Brown, Susan J.; Asano, Katsura] Kansas State Univ, Div Biol, Mol Cellular & Dev Biol Program, Manhattan, KS 66506 USA. [Brown, Susan J.] Kansas State Univ, Div Biol, Arthropod Genom Ctr, Manhattan, KS 66506 USA. [Shin, Byung-Sik] Eunice Kennedy Shriver NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. RP Asano, K (reprint author), Kansas State Univ, Div Biol, Mol Cellular & Dev Biol Program, Manhattan, KS 66506 USA. EM kasano@ksu.edu FU NIH [GM64781]; Kansas COBRE PSF pilot grant; KSU Terry Johnson Cancer Center; KSU Division of Biology; NCRR [5P20RR016475]; NIGMS [8P20GM103418]; Intramural Research Program of the National Institutes of Health; NIH, ARRA FX This work was supported by NIH R01 grant GM64781 and its ARRA supplement (K. A.), a Kansas COBRE PSF pilot grant (K. A.), an Innovative Award from KSU Terry Johnson Cancer Center (K. A.), an internal grant from the KSU Division of Biology (K. A.), and grants from NCRR (5P20RR016475) and NIGMS (8P20GM103418) (S.J.B.) and, in part, by the Intramural Research Program of the National Institutes of Health (B.-S.S. and Thomas E. Dever). NR 44 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2013 VL 33 IS 18 BP 3540 EP 3548 DI 10.1128/MCB.00771-13 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208BQ UT WOS:000323651200001 PM 23836883 ER PT J AU Lee, BS Gapud, EJ Zhang, SC Dorsett, Y Bredemeyer, A George, R Callen, E Daniel, JA Osipovich, O Oltz, EM Bassing, CH Nussenzweig, A Lees-Miller, S Hammel, M Chen, BPC Sleckman, BP AF Lee, Baeck-Seung Gapud, Eric J. Zhang, Shichuan Dorsett, Yair Bredemeyer, Andrea George, Rosmy Callen, Elsa Daniel, Jeremy A. Osipovich, Oleg Oltz, Eugene M. Bassing, Craig H. Nussenzweig, Andre Lees-Miller, Susan Hammel, Michal Chen, Benjamin P. C. Sleckman, Barry P. TI Functional Intersection of ATM and DNA-Dependent Protein Kinase Catalytic Subunit in Coding End Joining during V(D)J Recombination SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DOUBLE-STRAND-BREAK; TELANGIECTASIA MUTATED ATM; ATAXIA-TELANGIECTASIA; SIGNAL JOINT; LYMPHOCYTE DEVELOPMENT; GENOMIC INSTABILITY; NONSENSE MUTATION; CELL-LINES; PKCS; REPAIR AB V(D)J recombination is initiated by the RAG endonuclease, which introduces DNA double-strand breaks (DSBs) at the border between two recombining gene segments, generating two hairpin-sealed coding ends and two blunt signal ends. ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are serine-threonine kinases that orchestrate the cellular responses to DNA DSBs. During V(D) J recombination, ATM and DNA-PKcs have unique functions in the repair of coding DNA ends. ATM deficiency leads to instability of postcleavage complexes and the loss of coding ends from these complexes. DNA-PKcs deficiency leads to a nearly complete block in coding join formation, as DNA-PKcs is required to activate Artemis, the endonuclease that opens hairpin-sealed coding ends. In contrast to loss of DNA-PKcs protein, here we show that inhibition of DNA-PKcs kinase activity has no effect on coding join formation when ATM is present and its kinase activity is intact. The ability of ATM to compensate for DNA-PKcs kinase activity depends on the integrity of three threonines in DNA-PKcs that are phosphorylation targets of ATM, suggesting that ATM can modulate DNA-PKcs activity through direct phosphorylation of DNA-PKcs. Mutation of these threonine residues to alanine (DNA-PKcs(3A)) renders DNA-PKcs dependent on its intrinsic kinase activity during coding end joining, at a step downstream of opening hairpin-sealed coding ends. Thus, DNA-PKcs has critical functions in coding end joining beyond promoting Artemis endonuclease activity, and these functions can be regulated redundantly by the kinase activity of either ATM or DNA-PKcs. C1 [Lee, Baeck-Seung; Gapud, Eric J.; Dorsett, Yair; Bredemeyer, Andrea; George, Rosmy; Osipovich, Oleg; Oltz, Eugene M.; Sleckman, Barry P.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Zhang, Shichuan; Chen, Benjamin P. C.] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Div Mol Radiat Biol, Dallas, TX 75390 USA. [Callen, Elsa; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Daniel, Jeremy A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark. [Bassing, Craig H.] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Ctr Childhood Canc Res,Div Canc Pathobiol, Philadelphia, PA 19104 USA. [Bassing, Craig H.] Univ Penn, Dept Pathol & Lab Med, Abramson Family Canc Res Inst, Philadelphia, PA USA. [Bassing, Craig H.] Univ Penn, Immunol Grad Grp, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lees-Miller, Susan] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada. [Lees-Miller, Susan] Univ Calgary, Southern Alberta Canc Res Inst, Calgary, AB, Canada. [Hammel, Michal] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA. RP Sleckman, BP (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. EM sleckman@immunology.wustl.edu RI Daniel, Jeremy/S-4729-2016; OI Daniel, Jeremy/0000-0002-1981-5571; Bredemeyer, Andrea/0000-0003-2970-5998 FU National Institutes of Health [CA136470, AI074953, AI47829, CA92584, GM105404]; Lawrence Berkeley National Lab IDAT program; CIHR [691369] FX This work was supported by National Institutes of Health grants CA136470 (B. P. S.), AI074953 (B. P. S.), AI47829 (B. P. S.), CA92584 (S. L.-M. and M. H.), and GM105404 (M. H.). M. H. was also supported by the Lawrence Berkeley National Lab IDAT program, and S. L.-M. was supported by CIHR grant 691369. NR 64 TC 12 Z9 14 U1 0 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2013 VL 33 IS 18 BP 3568 EP 3579 DI 10.1128/MCB.00308-13 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208BQ UT WOS:000323651200003 PM 23836881 ER PT J AU Fogel, AI Dlouhy, BJ Wang, CX Ryu, SW Neutzner, A Hasson, SA Sideris, DP Abeliovich, H Youle, RJ AF Fogel, Adam I. Dlouhy, Brian J. Wang, Chunxin Ryu, Seung-Wook Neutzner, Albert Hasson, Samuel A. Sideris, Dionisia P. Abeliovich, Hagai Youle, Richard J. TI Role of Membrane Association and Atg14-Dependent Phosphorylation in Beclin-1-Mediated Autophagy SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID III PHOSPHATIDYLINOSITOL 3-KINASE; BECLIN 1; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM; TUMOR-SUPPRESSOR; BINDING; PROTEIN; DOMAIN; YEAST; GENE AB During autophagy, a double membrane envelops cellular material for trafficking to the lysosome. Human beclin-1 and its yeast homologue, Atg6/Vps30, are scaffold proteins bound in a lipid kinase complex with multiple cellular functions, including autophagy. Several different Atg6 complexes exist, with an autophagy-specific form containing Atg14. However, the roles of Atg14 and beclin-1 in the activation of this complex remain unclear. We here addressed the mechanism of beclin-1 complex activation and reveal two critical steps in this pathway. First, we identified a unique domain in beclin-1, conserved in the yeast homologue Atg6, which is involved in membrane association and, unexpectedly, controls autophagosome size and number in yeast. Second, we demonstrated that human Atg14 is critical in controlling an autophagy-dependent phosphorylation of beclin-1. We map these novel phosphorylation sites to serines 90 and 93 and demonstrate that phosphorylation at these sites is necessary for maximal autophagy. These results help clarify the mechanism of beclin-1 and Atg14 during autophagy. C1 [Fogel, Adam I.; Dlouhy, Brian J.; Wang, Chunxin; Ryu, Seung-Wook; Neutzner, Albert; Hasson, Samuel A.; Sideris, Dionisia P.; Abeliovich, Hagai; Youle, Richard J.] NINDS, Biochem Sect, NIH, Bethesda, MD 20892 USA. [Dlouhy, Brian J.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. [Ryu, Seung-Wook] Korea Adv Inst Sci & Technol, Cell Signaling & Bioimaging Lab, Dept Bio & Brain Engn, KAIST Inst BioCentury, Taejon, South Korea. [Abeliovich, Hagai] Hebrew Univ Jerusalem, Inst Biochem Food Sci & Nutr, IL-76100 Rehovot, Israel. RP Youle, RJ (reprint author), NINDS, Biochem Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov RI Wang, Chunxin/B-9312-2016; OI Wang, Chunxin/0000-0001-6015-6806; Neutzner, Albert/0000-0001-9254-5558 FU NINDS; National Institutes of Health; Israel Science Fund [1016/07] FX This work was supported by the NINDS, National Institutes of Health, and by Israel Science Fund grant 1016/07 (to H.A.). NR 39 TC 28 Z9 34 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2013 VL 33 IS 18 BP 3675 EP 3688 DI 10.1128/MCB.00079-13 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208BQ UT WOS:000323651200011 PM 23878393 ER PT J AU Taylor, JE Pacheco, MA Bacon, DJ Beg, MA Machado, RL Fairhurst, RM Herrera, S Kim, JY Menard, D Povoa, MM Villegas, L Mulyanto Snounou, G Cui, LW Zeyrek, FY Escalante, AA AF Taylor, Jesse E. Pacheco, M. Andreina Bacon, David J. Beg, Mohammad A. Machado, Ricardo Luiz Fairhurst, Rick M. Herrera, Socrates Kim, Jung-Yeon Menard, Didier Povoa, Marinete Marins Villegas, Leopoldo Mulyanto Snounou, Georges Cui, Liwang Zeyrek, Fadile Yildiz Escalante, Ananias A. TI The Evolutionary History of Plasmodium vivax as Inferred from Mitochondrial Genomes: Parasite Genetic Diversity in the Americas SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE molecular clock; population structure; demographic history ID HUMAN MALARIA PARASITE; ANCIENT POPULATION EXPANSION; DNA POLYMORPHISM DATA; SOUTH-AMERICA; FALCIPARUM; ORIGIN; AMAZON; ASIA; ELIMINATION; HUMANS AB Plasmodium vivax is the most prevalent human malaria parasite in the Americas. Previous studies have contrasted the genetic diversity of parasite populations in the Americas with those in Asia and Oceania, concluding that New World populations exhibit low genetic diversity consistent with a recent introduction. Here we used an expanded sample of complete mitochondrial genome sequences to investigate the diversity of P. vivax in the Americas as well as in other continental populations. We show that the diversity of P. vivax in the Americas is comparable to that in Asia and Oceania, and we identify several divergent clades circulating in South America that may have resulted from independent introductions. In particular, we show that several haplotypes sampled in Venezuela and northeastern Brazil belong to a clade that diverged from the other P. vivax lineages at least 30,000 years ago, albeit not necessarily in the Americas. We propose that, unlike in Asia where human migration increases local genetic diversity, the combined effects of the geographical structure and the low incidence of vivax malaria in the Americas has resulted in patterns of low local but high regional genetic diversity. This could explain previous views that P. vivax in the Americas has low genetic diversity because these were based on studies carried out in limited areas. Further elucidation of the complex geographical pattern of P. vivax variation will be important both for diversity assessments of genes encoding candidate vaccine antigens and in the formulation of control and surveillance measures aimed at malaria elimination. C1 [Taylor, Jesse E.; Pacheco, M. Andreina; Escalante, Ananias A.] Arizona State Univ, Biodesign Inst, Ctr Evolutionary Med & Informat, Tempe, AZ 85287 USA. [Bacon, David J.] Naval Res Lab, Washington, DC USA. [Beg, Mohammad A.] Aga Khan Univ, Dept Pathol & Microbiol, Karachi, Pakistan. [Machado, Ricardo Luiz] Fac Med Sao Jose do Rio Preto, Ctr Invest Microrganismos, Dept Doencas Dermatol Infecciosas & Parasitarias, Sao Paulo, Brazil. [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Herrera, Socrates] Univ Valle, Caucaseco Sci Res Ctr, Inst Immunol, Cali, Colombia. [Kim, Jung-Yeon] Korea Ctr Dis Control & Prevent, Div Malaria & Parasit Dis, Osong, South Korea. [Menard, Didier] Inst Pasteur Cambodge, Phnom Penh, Cambodia. [Povoa, Marinete Marins] Evandro Chagas Inst, Belem, Para, Brazil. [Villegas, Leopoldo] ICF Int, Int Hlth & Dev Div, Calverton, MD USA. [Mulyanto] Univ Mataram, Fac Med, Immunobiol Lab, Mataram, Indonesia. [Snounou, Georges] Univ Paris 06, Paris, France. [Snounou, Georges] INSERM, Paris, France. [Cui, Liwang] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Zeyrek, Fadile Yildiz] Harran Univ, Sch Med, Dept Microbiol, Sanliurfa, Turkey. [Escalante, Ananias A.] Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA. RP Escalante, AA (reprint author), Arizona State Univ, Biodesign Inst, Ctr Evolutionary Med & Informat, Tempe, AZ 85287 USA. EM Ananias.Escalante@asu.edu RI Menard, Didier/O-3294-2013; Dantas Machado, Ricardo Luiz/P-1288-2014 OI Menard, Didier/0000-0003-1357-4495; Dantas Machado, Ricardo Luiz/0000-0002-8955-3204 FU US National Institutes of Health [R01 GM080586]; Latin American Center for Malaria Research and Control [U19AI089702]; National Institute of Allergy and Infectious Diseases FX The authors thank the DNA laboratory at the School of Life Sciences for their technical support. This work was supported by the US National Institutes of Health (R01 GM080586 to A.A.E., the Latin American Center for Malaria Research and Control U19AI089702, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases to R.M.F.). The content of this article is solely the responsibility of the authors and does not represent the views of the US National Institutes of Health. NR 61 TC 32 Z9 32 U1 1 U2 33 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD SEP PY 2013 VL 30 IS 9 BP 2050 EP 2064 DI 10.1093/molbev/mst104 PG 15 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 207QE UT WOS:000323616600006 PM 23733143 ER PT J AU Tarazona-Santos, E Machado, M Magalhaes, WCS Chen, R Lyon, F Burdett, L Crenshaw, A Fabbri, C Pereira, L Pinto, L Redondo, RAF Sestanovich, B Yeager, M Chanock, SJ AF Tarazona-Santos, Eduardo Machado, Moara Magalhaes, Wagner C. S. Chen, Renee Lyon, Fernanda Burdett, Laurie Crenshaw, Andrew Fabbri, Cristina Pereira, Latife Pinto, Laelia Redondo, Rodrigo A. F. Sestanovich, Ben Yeager, Meredith Chanock, Stephen J. TI Evolutionary Dynamics of the Human NADPH Oxidase Genes CYBB, CYBA, NCF2, and NCF4: Functional Implications SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE innate immunity; immunogenetics; chronic granulomatous disease ID NATURAL-SELECTION; HUMAN GENOME; POPULATION-GENETICS; DNA-SEQUENCE; DISEASE; POLYMORPHISM; ASSOCIATION; MAP; SUSCEPTIBILITY; MUTATIONS AB The phagocyte NADPH oxidase catalyzes the reduction of O-2 to reactive oxygen species with microbicidal activity. It is composed of two membrane-spanning subunits, gp91-phox and p22-phox (encoded by CYBB and CYBA, respectively), and three cytoplasmic subunits, p40-phox, p47-phox, and p67-phox (encoded by NCF4, NCF1, and NCF2, respectively). Mutations in any of these genes can result in chronic granulomatous disease, a primary immunodeficiency characterized by recurrent infections. Using evolutionary mapping, we determined that episodes of adaptive natural selection have shaped the extracellular portion of gp91-phox during the evolution of mammals, which suggests that this region may have a function in host-pathogen interactions. On the basis of a resequencing analysis of approximately 35 kb of CYBB, CYBA, NCF2, and NCF4 in 102 ethnically diverse individuals (24 of African ancestry, 31 of European ancestry, 24 of Asian/Oceanians, and 23 US Hispanics), we show that the pattern of CYBA diversity is compatible with balancing natural selection, perhaps mediated by catalase-positive pathogens. NCF2 in Asian populations shows a pattern of diversity characterized by a differentiated haplotype structure. Our study provides insight into the role of pathogen-driven natural selection in an innate immune pathway and sheds light on the role of CYBA in endothelial, nonphagocytic NADPH oxidases, which are relevant in the pathogenesis of cardiovascular and other complex diseases. C1 [Tarazona-Santos, Eduardo; Chen, Renee; Sestanovich, Ben; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD USA. [Tarazona-Santos, Eduardo; Machado, Moara; Magalhaes, Wagner C. S.; Lyon, Fernanda; Pereira, Latife; Pinto, Laelia] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, Belo Horizonte, MG, Brazil. [Burdett, Laurie; Crenshaw, Andrew; Yeager, Meredith] NCI FCRDC, Intramural Res Support Program, SAIC Frederick, Frederick, MD USA. [Burdett, Laurie; Crenshaw, Andrew; Yeager, Meredith] NCI, Core Genotype Facil, NIH, Gaithersburg, MD USA. [Fabbri, Cristina] Univ Bologna, Dipartimento Biol Evoluzionist Sperimentale, Bologna, Italy. [Redondo, Rodrigo A. F.] IST Austria, A-3400 Klosterneuburg, Austria. RP Tarazona-Santos, E (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD USA. EM edutars@icb.ufmg.br; chanocks@mail.nih.gov RI Magalhaes, Wagner/D-8822-2015 FU National Cancer Institute (NCI); National Institutes of Health (NIH); University of Bologna; Fogarty International Center; National Cancer Institute [1R01TW007894]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazil) [307556/2012-3] FX S.J.C. conceived the study; E. T.-S., M. M., F. L., R. C., A. C., C. F., L. P., and B. S. generated the data/analyzed the sequences; L. B., A. C., W. C. S. M., and M.Y. provided tools for data generation and analyses; E. T.-S., M. M., F. L., W. C. S. M., and R. R. performed population genetics analyses; E. T.-S. and M. M. prepared tables and figures; E. T.-S. and S.J.C. wrote the manuscript. All the authors contributed with discussions about the results. The authors are grateful to Silvia Fuselli for discussions of our results, to Fernando Levi Soares for technical assistance with the figures and the Sequencing Group of the Core Genotyping Facility (National Cancer Institute) for their technical assistance. This work was supported by the Intramural Research Program of the National Cancer Institute (NCI) and National Institutes of Health (NIH). C. F. was supported by the University of Bologna. E. T-S., M. M., W. C. S. M., and F. L. were supported by the Fogarty International Center and National Cancer Institute (1R01TW007894), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazil, Grant 307556/2012-3), Fundacao de Amparo a Pesquisa de Minas Gerais (Brazil, CBB PPM 00265/12) and the Brazilian Ministry of Education (CAPES Agency, grant PNPD 02567/09-1). NR 59 TC 5 Z9 5 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD SEP PY 2013 VL 30 IS 9 BP 2157 EP 2167 DI 10.1093/molbev/mst119 PG 11 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 207QE UT WOS:000323616600014 PM 23821607 ER PT J AU Shrivastav, S Zhang, LY Okamoto, K Lee, H Lagranha, C Abe, Y Balasubramanyam, A Lopaschuk, GD Kino, T Kopp, JB AF Shrivastav, Shashi Zhang, Liyan Okamoto, Koji Lee, Hewang Lagranha, Claudia Abe, Yoshifusa Balasubramanyam, Ashok Lopaschuk, Gary D. Kino, Tomoshige Kopp, Jeffrey B. TI HIV-1 Vpr Enhances PPAR beta/delta-Mediated Transcription, Increases PDK4 Expression, and Reduces PDC Activity SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTORS; VIRAL PROTEIN-R; PYRUVATE-DEHYDROGENASE COMPLEX; FATTY-ACIDS; SKELETAL-MUSCLE; METABOLISM; MECHANISMS; DELTA; GAMMA; RESPONSES AB HIV infection and its therapy are associated with disorders of lipid metabolism and bioenergetics. Previous work has suggested that viral protein R (Vpr) may contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients. In adipocytes, Vpr suppresses mRNA expression of peroxisomal proliferator-activating receptor-gamma (PPAR gamma)-responsive genes and inhibits differentiation. We investigated whether Vpr might interact with PPAR beta/delta and influence its transcriptional activity. In the presence of PPAR beta/delta, Vpr induced a 3.3-fold increase in PPAR response element-driven transcriptional activity, a 1.9-fold increase in pyruvate dehydrogenase kinase 4 (PDK4) protein expression, and a 1.6-fold increase in the phosphorylated pyruvate dehydrogenase subunit E1 alpha leading to a 47% decrease in the activity of the pyruvate dehydrogenase complex in HepG2 cells. PPAR beta/delta knockdown attenuated Vpr-induced enhancement of endogenous PPAR beta/delta-responsive PDK4 mRNA expression. Vpr induced a 1.3-fold increase in mRNA expression of both carnitine palmitoyltransferase vertical bar (CPT1) and acetyl-coenzyme A acyltransferase 2 (ACAA2) and doubled the activity of beta-hydroxylacyl coenzyme A dehydrogenase (HADH). Vpr physically interacted with the ligand-binding domain of PPAR beta/delta in vitro and in vivo. Consistent with a role in energy expenditure, Vpr increased state-3 respiration in isolated mitochondria (1.16-fold) and basal oxygen consumption rate in intact HepG2 cells (1.2-fold) in an etomoxir-sensitive manner, indicating that the oxygen consumption rate increase is beta-oxidation-dependent. The effects of Vpr on PPAR response element activation, pyruvate dehydrogenase complex activity, and beta-oxidation were reversed by specific PPAR beta/delta antagonists. These results support the hypothesis that Vpr contributes to impaired energy metabolism and increased energy expenditure in HIV patients. C1 [Shrivastav, Shashi; Okamoto, Koji; Lee, Hewang; Abe, Yoshifusa; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Bethesda, MD 20892 USA. [Lagranha, Claudia] NHLBI, Lab Cardiac Physiol, Bethesda, MD 20892 USA. [Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Zhang, Liyan; Lopaschuk, Gary D.] Univ Alberta, Mazankowski Alberta Heart Inst, Cardiovasc Res Ctr, Edmonton, AB, Canada. [Balasubramanyam, Ashok] Baylor Coll Med, Diabet Res Ctr, Div Diabet Endocrinol & Metab, Houston, TX 77030 USA. [Lee, Hewang] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. RP Kopp, JB (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM jbkopp@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Heart Lung and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine Diabetes Research Center [P30-DK079638, 5P01HL074940-08]; University of Maryland School of Medicine; Children's National Medical Center; [R01-DK081553] FX This study was funded in part by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart Lung and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Support was also provided by R01-DK081553 (to A. B.) and the Baylor College of Medicine Diabetes Research Center P30-DK079638 and by 5P01HL074940-08 (principal investigator, R. A. Felder; Project 3 principal investigator, P. A. Jose), University of Maryland School of Medicine Start-up Funds, and Children's National Medical Center Intramural Avery award (to H.L.). NR 38 TC 6 Z9 6 U1 1 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2013 VL 27 IS 9 BP 1564 EP 1576 DI 10.1210/me.2012-1370 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 209NN UT WOS:000323765200016 PM 23842279 ER PT J AU Rodriguez-Gil, JL Larson, DM Wassif, CA Yanjanin, NM Anderson, SM Kirby, MR Trivedi, NS Porter, FD Pavan, WJ AF Rodriguez-Gil, Jorge L. Larson, Denise M. Wassif, Christopher A. Yanjanin, Nicole M. Anderson, Stacie M. Kirby, Martha R. Trivedi, Niraj S. Porter, Forbes D. Pavan, William J. TI A somatic cell defect is associated with the onset of neurological symptoms in a lysosomal storage disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Niemann-Pick disease, type C1; NPC1; Lysosomal storage disorders; Neurodegenerative disorders ID NIEMANN-PICK-DISEASE; CHOLESTEROL REDUCTION AB Mutations in individuals with the lysosomal storage disorder Niemann-Pick disease, type C1 (NPC1) are heterogeneous, not localized to specific protein domains, and not correlated to time of onset or disease severity. We demonstrate direct correlation of the time of neurological symptom onset with the severity of lysosomal defects in NPC1 patient-derived fibroblasts. This is a novel assay for NPC1 individuals that may be predictive of NPC1 disease progression and broadly applicable to other lysosomal disorders. Published by Elsevier Inc. C1 [Rodriguez-Gil, Jorge L.; Larson, Denise M.; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wassif, Christopher A.; Yanjanin, Nicole M.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Anderson, Stacie M.; Kirby, Martha R.] NHGRI, Flow Cytometry Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Trivedi, Niraj S.] NHGRI, Genome Technol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr,Room 4A82, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU National Human Genome Research Institute, National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Ara Parseghian Medical Research Foundation; Office of Rare Diseases; National Institutes of Health Clinical Center FX We thank Cynthia J. Tifft for helpful discussions, Laura Baxter for editing the manuscript Stephen Wincovitch for support in imaging/microscopy, Larry N. Singh for assistance in mutation analysis software and the contributions of the caretakers, patients, and their families who participated in this study. This work was supported by the intramural research program of the National Human Genome Research Institute, National Institutes of Health, the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Ara Parseghian Medical Research Foundation, and a Bench to Bedside award from the Office of Rare Diseases and the National Institutes of Health Clinical Center. NR 10 TC 1 Z9 1 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2013 VL 110 IS 1-2 BP 188 EP 190 DI 10.1016/j.ymgme.2013.06.010 PG 3 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 209ZP UT WOS:000323799400028 PM 23850077 ER PT J AU Gold, PW AF Gold, P. W. TI Evidence that stress per se has a role in the precipitation and natural history of depressive illness SO MOLECULAR PSYCHIATRY LA English DT Editorial Material ID MAJOR DEPRESSION; HIPPOCAMPAL NEUROGENESIS; LIFE EVENTS; BIOCHEMICAL MANIFESTATIONS; SIGNALING PATHWAYS; BLOOD-COAGULATION; SOCIAL SUPPORT; SERUM-LEVELS; WOMEN; DISORDER C1 NIMH, Bethesda, MD 20892 USA. RP Gold, PW (reprint author), NIMH, Bethesda, MD 20892 USA. EM PhilipGold@mail.nih.gov NR 29 TC 2 Z9 2 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2013 VL 18 IS 9 BP 954 EP 956 DI 10.1038/mp.2013.85 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 207JS UT WOS:000323595300002 PM 23969379 ER PT J AU Grillon, C Krimsky, M Charney, DR Vytal, K Ernst, M Cornwell, B AF Grillon, C. Krimsky, M. Charney, D. R. Vytal, K. Ernst, M. Cornwell, B. TI Oxytocin increases anxiety to unpredictable threat SO MOLECULAR PSYCHIATRY LA English DT Letter ID CENTRAL AMYGDALA; FEAR; HUMANS C1 [Grillon, C.; Krimsky, M.; Charney, D. R.; Vytal, K.; Cornwell, B.] NIMH, Neurobiol Fear & Anxiety Sect, Intramural Res Program, Bethesda, MD 20892 USA. [Ernst, M.] NIMH, Emot Dev & Affect Neurosci Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, Neurobiol Fear & Anxiety Sect, Intramural Res Program, Bethesda, MD 20892 USA. EM christian.grillon@nih.gov FU Intramural NIH HHS [ZIA MH002798-12]; NIMH NIH HHS [Z01 MH002798] NR 10 TC 43 Z9 43 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2013 VL 18 IS 9 BP 958 EP 960 DI 10.1038/mp.2012.156 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 207JS UT WOS:000323595300004 PM 23147382 ER PT J AU Silverman, MN Mukhopadhyay, P Belyavskaya, E Tonelli, LH Revenis, BD Doran, JH Ballard, BE Tam, J Pacher, P Sternberg, EM AF Silverman, M. N. Mukhopadhyay, P. Belyavskaya, E. Tonelli, L. H. Revenis, B. D. Doran, J. H. Ballard, B. E. Tam, J. Pacher, P. Sternberg, E. M. TI Glucocordwticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice SO MOLECULAR PSYCHIATRY LA English DT Article DE cytokine; depression; hippocampus; HPA axis; hypothalamus; thermoregulation ID PITUITARY-ADRENAL AXIS; CENTRAL-NERVOUS-SYSTEM; ENDOGENOUS GLUCOCORTICOIDS PROTECT; INNATE IMMUNE-SYSTEM; GENE-EXPRESSION; KAPPA-B; MAJOR DEPRESSION; VIRAL-INFECTION; DNA-BINDING; PHYSIOLOGICAL-RESPONSES AB Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-a (TNF alpha)), enhanced early expression of brain TNF alpha, IL-1 beta and IL-6 mRNA levels, and impaired later central TNFa mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNF alpha expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine-and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state. C1 [Silverman, M. N.; Belyavskaya, E.; Revenis, B. D.; Doran, J. H.; Ballard, B. E.; Sternberg, E. M.] NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Bethesda, MD 20892 USA. [Mukhopadhyay, P.; Tam, J.; Pacher, P.] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Tonelli, L. H.] Univ Maryland, Sch Med, Dept Psychiat, Mood & Anxiety Program, Baltimore, MD 21201 USA. [Sternberg, E. M.] Univ Arizona, Coll Med, Arizona Ctr Integrat Med, Tucson, AZ 85724 USA. RP Sternberg, EM (reprint author), Univ Arizona, Coll Med, Arizona Ctr Integrat Med, POB 245153, Tucson, AZ 85724 USA. EM esternberg@email.arizona.edu RI Pacher, Pal/B-6378-2008; MUKHOPADHYAY, PARTHA/G-3890-2010 OI Pacher, Pal/0000-0001-7036-8108; MUKHOPADHYAY, PARTHA/0000-0002-1178-1274 FU NIH (National Institute of Mental Health (NIMH)); NIH (National Institute on Alcohol Abuse and Alcoholism (NIAAA)); Henry M Jackson Foundation (Bethesda, MD, USA); Center for Neuroscience and Regenerative Medicine (Uniformed Services University of the Health Sciences, Bethesda, MD, USA) FX This work was supported by the NIH (intramural funds from the National Institute of Mental Health (NIMH) to EM Sternberg and from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to P Pacher). Additional support was received by the Henry M Jackson Foundation (Bethesda, MD, USA-MNS salary) and the Center for Neuroscience and Regenerative Medicine (Uniformed Services University of the Health Sciences, Bethesda, MD, USA). We thank Dr Gunther Schutz (German Cancer Research Centre, Heidelberg, Germany) for providing homozygous GRdim mouse breeder pairs to Taconic Farms (Rockville, MD, USA). We also thank Laura Tucker (Uniformed Services University of the Health Sciences, Center for Neuroscience and Regenerative Medicine, Mouse Behavioral Assessment Core, Bethesda, MD, USA) for instruction on the ANY-maze software used to analyze our open field data and Dr Sandor Batkai (Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA) for setting up the metabolic chambers. NR 106 TC 15 Z9 16 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2013 VL 18 IS 9 BP 1006 EP 1017 DI 10.1038/mp.2012.131 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 207JS UT WOS:000323595300011 PM 23089634 ER PT J AU Lee, SH Ripke, S Neale, BM Faraone, SV Purcell, SM Perlis, RH Mowry, BJ Thapar, A Goddard, ME Witte, JS Absher, D Agartz, I Akil, H Amin, F Andreassen, OA Anjorin, A Anney, R Anttila, V Arking, DE Asherson, P Azevedo, MH Backlund, L Badner, JA Bailey, AJ Banaschewski, T Barchas, JD Barnes, MR Barrett, TB Bass, N Battaglia, A Bauer, M Bayes, M Bellivier, F Bergen, SE Berrettini, W Betancur, C Bettecken, T Biederman, J Binder, EB Black, DW Blackwood, DHR Bloss, CS Boehnke, M Boomsma, DI Breen, G Breuer, R Bruggeman, R Cormican, P Buccola, NG Buitelaar, JK Bunney, WE Buxbaum, JD Byerley, WF Byrne, EM Caesar, S Cahn, W Cantor, RM Casas, M Chakravarti, A Chambert, K Choudhury, K Cichon, S Cloninger, CR Collier, DA Cook, EH Coon, H Cormand, B Corvin, A Coryell, WH Craig, DW Craig, IW Crosbie, J Cuccaro, ML Curtis, D Czamara, D Datta, S Dawson, G Day, R De Geus, EJ Degenhardt, F Djurovic, S Donohoe, GJ Doyle, AE Duan, JB Dudbridge, F Duketis, E Ebstein, RP Edenberg, HJ Elia, J Ennis, S Etain, B Fanous, A Farmer, AE Ferrier, IN Flickinger, M Fombonne, E Foroud, T Frank, J Franke, B Fraser, C Freedman, R Freimer, NB Freitag, CM Friedl, M Frisen, L Gallagher, L Gejman, PV Georgieva, L Gershon, ES Geschwind, DH Giegling, I Gill, M Gordon, SD Gordon-Smith, K Green, EK Greenwood, TA Grice, DE Gross, M Grozeva, D Guan, WH Gurling, H De Haan, L Haines, JL Hakonarson, H Hallmayer, J Hamilton, SP Hamshere, ML Hansen, TF Hartmann, AM Hautzinger, M Heath, AC Henders, AK Herms, S Hickie, IB Hipolito, M Hoefels, S Holmans, PA Holsboer, F Hoogendijk, WJ Hottenga, JJ Hultman, CM Hus, V Ingason, A Ising, M Jamain, S Jones, EG Jones, I Jones, L Tzeng, JY Kahler, AK Kahn, RS Kandaswamy, R Keller, MC Kennedy, JL Kenny, E Kent, L Kim, Y Kirov, GK Klauck, SM Klei, L Knowles, JA Kohli, MA Koller, DL Konte, B Korszun, A Krabbendam, L Krasucki, R Kuntsi, J Kwan, P Landen, M Langstrom, N Lathrop, M Lawrence, J Lawson, WB Leboyer, M Ledbetter, DH Lee, PH Lencz, T Lesch, KP Levinson, DF Lewis, CM Li, J Lichtenstein, P Lieberman, JA Lin, DY Linszen, DH Liu, CY Lohoff, FW Loo, SK Lord, C Lowe, JK Lucae, S MacIntyre, DJ Madden, PAF Maestrini, E Magnusson, PKE Mahon, PB Maier, W Malhotra, AK Mane, SM Martin, CL Martin, NG Mattheisen, M Matthews, K Mattingsdal, M McCarroll, SA McGhee, KA McGough, JJ McGrath, PJ McGuffin, P McInnis, MG McIntosh, A McKinney, R McLean, AW McMahon, FJ McMahon, WM McQuillin, A Medeiros, H Medland, SE Meier, S Melle, I Meng, F Meyer, J Middeldorp, CM Middleton, L Milanova, V Miranda, A Monaco, AP Montgomery, GW Moran, JL Moreno-De-Luca, D Morken, G Morris, DW Morrow, EM Moskvina, V Muglia, P Muhleisen, TW Muir, WJ Muller-Myhsok, B Murtha, M Myers, RM Myin-Germeys, I Neale, MC Nelson, SF Nievergelt, CM Nikolov, I Nimgaonkar, V Nolen, WA Nothen, MM Nurnberger, JI Nwulia, EA Nyholt, DR O'Dushlaine, C Oades, RD Olincy, A Oliveira, G Olsen, L Ophoff, RA Osby, U Owen, MJ Palotie, A Parr, JR Paterson, AD Pato, CN Pato, MT Penninx, BW Pergadia, ML Pericak-Vance, MA Pickard, BS Pimm, J Piven, J Posthuma, D Potash, JB Poustka, F Propping, P Puri, V Quested, DJ Quinn, EM Ramos-Quiroga, JA Rasmussen, HB Raychaudhuri, S Rehnstrom, K Reif, A Ribases, M Rice, JP Rietschel, M Roeder, K Roeyers, H Rossin, L Rothenberger, A Rouleau, G Ruderfer, D Rujescu, D Sanders, AR Sanders, SJ Santangelo, SL Sergeant, JA Schachar, R Schalling, M Schatzberg, AF Scheftner, WA Schellenberg, GD Scherer, SW Schork, NJ Schulze, TG Schumacher, J Schwarz, M Scolnick, E Scott, LJ Shi, JX Shilling, PD Shyn, SI Silverman, JM Slager, SL Smalley, SL Smit, JH Smith, EN Sonuga-Barke, EJS St Clair, D State, M Steffens, M Steinhausen, HC Strauss, JS Strohmaier, J Stroup, TS Sutcliffe, JS Szatmari, P Szelinger, S Thirumalai, S Thompson, RC Todorov, AA Tozzi, F Treutlein, J Uhr, M van den Oord, EJCG Van Grootheest, G Van Os, J Vicente, AM Vieland, VJ Vincent, JB Visscher, PM Walsh, CA Wassink, TH Watson, SJ Weissman, MM Werge, T Wienker, TF Wijsman, EM Willemsen, G Williams, N Willsey, AJ Witt, SH Xu, W Young, AH Yu, TW Zammit, S Zandi, PP Zhang, P Zitman, FG Zollner, S Devlin, B Kelsoe, JR Sklar, P Daly, MJ O'Donovan, MC Craddock, N Sullivan, PF Smoller, JW Kendler, KS Wray, NR AF Lee, S. Hong Ripke, Stephan Neale, Benjamin M. Faraone, Stephen V. Purcell, Shaun M. Perlis, Roy H. Mowry, Bryan J. Thapar, Anita Goddard, Michael E. Witte, John S. Absher, Devin Agartz, Ingrid Akil, Huda Amin, Farooq Andreassen, Ole A. Anjorin, Adebayo Anney, Richard Anttila, Verneri Arking, Dan E. Asherson, Philip Azevedo, Maria H. Backlund, Lena Badner, Judith A. Bailey, Anthony J. Banaschewski, Tobias Barchas, Jack D. Barnes, Michael R. Barrett, Thomas B. Bass, Nicholas Battaglia, Agatino Bauer, Michael Bayes, Monica Bellivier, Frank Bergen, Sarah E. Berrettini, Wade Betancur, Catalina Bettecken, Thomas Biederman, Joseph Binder, Elisabeth B. Black, Donald W. Blackwood, Douglas H. R. Bloss, Cinnamon S. Boehnke, Michael Boomsma, Dorret I. Breen, Gerome Breuer, Rene Bruggeman, Richard Cormican, Paul Buccola, Nancy G. Buitelaar, Jan K. Bunney, William E. Buxbaum, Joseph D. Byerley, William F. Byrne, Enda M. Caesar, Sian Cahn, Wiepke Cantor, Rita M. Casas, Miguel Chakravarti, Aravinda Chambert, Kimberly Choudhury, Khalid Cichon, Sven Cloninger, C. Robert Collier, David A. Cook, Edwin H. Coon, Hilary Cormand, Bru Corvin, Aiden Coryell, William H. Craig, David W. Craig, Ian W. Crosbie, Jennifer Cuccaro, Michael L. Curtis, David Czamara, Darina Datta, Susmita Dawson, Geraldine Day, Richard De Geus, Eco J. Degenhardt, Franziska Djurovic, Srdjan Donohoe, Gary J. Doyle, Alysa E. Duan, Jubao Dudbridge, Frank Duketis, Eftichia Ebstein, Richard P. Edenberg, Howard J. Elia, Josephine Ennis, Sean Etain, Bruno Fanous, Ayman Farmer, Anne E. Ferrier, I. Nicol Flickinger, Matthew Fombonne, Eric Foroud, Tatiana Frank, Josef Franke, Barbara Fraser, Christine Freedman, Robert Freimer, Nelson B. Freitag, Christine M. Friedl, Marion Frisen, Louise Gallagher, Louise Gejman, Pablo V. Georgieva, Lyudmila Gershon, Elliot S. Geschwind, Daniel H. Giegling, Ina Gill, Michael Gordon, Scott D. Gordon-Smith, Katherine Green, Elaine K. Greenwood, Tiffany A. Grice, Dorothy E. Gross, Magdalena Grozeva, Detelina Guan, Weihua Gurling, Hugh De Haan, Lieuwe Haines, Jonathan L. Hakonarson, Hakon Hallmayer, Joachim Hamilton, Steven P. Hamshere, Marian L. Hansen, Thomas F. Hartmann, Annette M. Hautzinger, Martin Heath, Andrew C. Henders, Anjali K. Herms, Stefan Hickie, Ian B. Hipolito, Maria Hoefels, Susanne Holmans, Peter A. Holsboer, Florian Hoogendijk, Witte J. Hottenga, Jouke-Jan Hultman, Christina M. Hus, Vanessa Ingason, Andres Ising, Marcus Jamain, Stephane Jones, Edward G. Jones, Ian Jones, Lisa Tzeng, Jung-Ying Kaehler, Anna K. Kahn, Rene S. Kandaswamy, Radhika Keller, Matthew C. Kennedy, James L. Kenny, Elaine Kent, Lindsey Kim, Yunjung Kirov, George K. Klauck, Sabine M. Klei, Lambertus Knowles, James A. Kohli, Martin A. Koller, Daniel L. Konte, Bettina Korszun, Ania Krabbendam, Lydia Krasucki, Robert Kuntsi, Jonna Kwan, Phoenix Landen, Mikael Langstrom, Niklas Lathrop, Mark Lawrence, Jacob Lawson, William B. Leboyer, Marion Ledbetter, David H. Lee, Phil H. Lencz, Todd Lesch, Klaus-Peter Levinson, Douglas F. Lewis, Cathryn M. Li, Jun Lichtenstein, Paul Lieberman, Jeffrey A. Lin, Dan-Yu Linszen, Don H. Liu, Chunyu Lohoff, Falk W. Loo, Sandra K. Lord, Catherine Lowe, Jennifer K. Lucae, Susanne MacIntyre, Donald J. Madden, Pamela A. F. Maestrini, Elena Magnusson, Patrik K. E. Mahon, Pamela B. Maier, Wolfgang Malhotra, Anil K. Mane, Shrikant M. Martin, Christa L. Martin, Nicholas G. Mattheisen, Manuel Matthews, Keith Mattingsdal, Morten McCarroll, Steven A. McGhee, Kevin A. McGough, James J. McGrath, Patrick J. McGuffin, Peter McInnis, Melvin G. McIntosh, Andrew McKinney, Rebecca McLean, Alan W. McMahon, Francis J. McMahon, William M. McQuillin, Andrew Medeiros, Helena Medland, Sarah E. Meier, Sandra Melle, Ingrid Meng, Fan Meyer, Jobst Middeldorp, Christel M. Middleton, Lefkos Milanova, Vihra Miranda, Ana Monaco, Anthony P. Montgomery, Grant W. Moran, Jennifer L. Moreno-De-Luca, Daniel Morken, Gunnar Morris, Derek W. Morrow, Eric M. Moskvina, Valentina Muglia, Pierandrea Muehleisen, Thomas W. Muir, Walter J. Mueller-Myhsok, Bertram Murtha, Michael Myers, Richard M. Myin-Germeys, Inez Neale, Michael C. Nelson, Stan F. Nievergelt, Caroline M. Nikolov, Ivan Nimgaonkar, Vishwajit Nolen, Willem A. Noethen, Markus M. Nurnberger, John I. Nwulia, Evaristus A. Nyholt, Dale R. O'Dushlaine, Colm Oades, Robert D. Olincy, Ann Oliveira, Guiomar Olsen, Line Ophoff, Roel A. Osby, Urban Owen, Michael J. Palotie, Aarno Parr, Jeremy R. Paterson, Andrew D. Pato, Carlos N. Pato, Michele T. Penninx, Brenda W. Pergadia, Michele L. Pericak-Vance, Margaret A. Pickard, Benjamin S. Pimm, Jonathan Piven, Joseph Posthuma, Danielle Potash, James B. Poustka, Fritz Propping, Peter Puri, Vinay Quested, Digby J. Quinn, Emma M. Antoni Ramos-Quiroga, Josep Rasmussen, Henrik B. Raychaudhuri, Soumya Rehnstroem, Karola Reif, Andreas Ribases, Marta Rice, John P. Rietschel, Marcella Roeder, Kathryn Roeyers, Herbert Rossin, Lizzy Rothenberger, Aribert Rouleau, Guy Ruderfer, Douglas Rujescu, Dan Sanders, Alan R. Sanders, Stephan J. Santangelo, Susan L. Sergeant, Joseph A. Schachar, Russell Schalling, Martin Schatzberg, Alan F. Scheftner, William A. Schellenberg, Gerard D. Scherer, Stephen W. Schork, Nicholas J. Schulze, Thomas G. Schumacher, Johannes Schwarz, Markus Scolnick, Edward Scott, Laura J. Shi, Jianxin Shilling, Paul D. Shyn, Stanley I. Silverman, Jeremy M. Slager, Susan L. Smalley, Susan L. Smit, Johannes H. Smith, Erin N. Sonuga-Barke, Edmund J. S. St Clair, David State, Matthew Steffens, Michael Steinhausen, Hans-Christoph Strauss, John S. Strohmaier, Jana Stroup, T. Scott Sutcliffe, James S. Szatmari, Peter Szelinger, Szabocls Thirumalai, Srinivasa Thompson, Robert C. Todorov, Alexandre A. Tozzi, Federica Treutlein, Jens Uhr, Manfred van den Oord, Edwin J. C. G. Van Grootheest, Gerard Van Os, Jim Vicente, Astrid M. Vieland, Veronica J. Vincent, John B. Visscher, Peter M. Walsh, Christopher A. Wassink, Thomas H. Watson, Stanley J. Weissman, Myrna M. Werge, Thomas Wienker, Thomas F. Wijsman, Ellen M. Willemsen, Gonneke Williams, Nigel Willsey, A. Jeremy Witt, Stephanie H. Xu, Wei Young, Allan H. Yu, Timothy W. Zammit, Stanley Zandi, Peter P. Zhang, Peng Zitman, Frans G. Zoellner, Sebastian Devlin, Bernie Kelsoe, John R. Sklar, Pamela Daly, Mark J. O'Donovan, Michael C. Craddock, Nicholas Sullivan, Patrick F. Smoller, Jordan W. Kendler, Kenneth S. Wray, Naomi R. CA Cross-Disorder Grp Psychiat Genomi Int Inflammatory Bowel Dis Genetic TI Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs SO NATURE GENETICS LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; AUTISM SPECTRUM DISORDERS; MAJOR DEPRESSIVE DISORDER; BIPOLAR DISORDER; COMMON SNPS; CROHNS-DISEASE; SCHIZOPHRENIA; RISK; ASSOCIATION AB Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 +/- 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 +/- 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 +/- 0.06 s.e.), and ADHD and major depressive disorder (0.32 +/- 0.07 s.e.), low between schizophrenia and ASD (0.16 +/- 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders. C1 [Lee, S. 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[Friedl, Marion; Giegling, Ina; Hartmann, Annette M.; Konte, Bettina; Rujescu, Dan] Univ Halle, Dept Psychiat, Halle, Germany. [Geschwind, Daniel H.; Lowe, Jennifer K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Geschwind, Daniel H.; Lowe, Jennifer K.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Ctr Autism Res & Treatment, Los Angeles, CA 90095 USA. [Gordon, Scott D.; Henders, Anjali K.; Martin, Nicholas G.; Medland, Sarah E.; Montgomery, Grant W.; Nyholt, Dale R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Green, Elaine K.] Univ Plymouth, Dept Biomed & Biol Sci, Plymouth PL4 8AA, Devon, England. [Greenwood, Tiffany A.; McKinney, Rebecca; Nievergelt, Caroline M.; Shilling, Paul D.; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Grice, Dorothy E.] Icahn Sch Med Mt Sinai, Div Tics OCD & Related Disorders, New York, NY USA. [Grice, Dorothy E.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA. [Gross, Magdalena; Hoefels, Susanne; Maier, Wolfgang] Univ Bonn, Dept Psychiat, Bonn, Germany. [Guan, Weihua] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [De Haan, Lieuwe] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1012 WX Amsterdam, Netherlands. [Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet, Philadelphia, PA 19104 USA. [Hakonarson, Hakon] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Hallmayer, Joachim] Stanford Univ, Sch Med, Dept Psychiat, Stanford, CA 94305 USA. [Hamshere, Marian L.; Holmans, Peter A.; Moskvina, Valentina] Cardiff Univ, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales. [Hansen, Thomas F.; Ingason, Andres; Olsen, Line; Rasmussen, Henrik B.; Werge, Thomas] Copenhagen Univ Hosp, Inst Biol Psychiat, Roskilde, Denmark. 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EM naomi.wray@uq.edu.au RI van Grootheest, Gerard/C-6942-2014; Kahler, Anna/J-2874-2012; Franke, Barbara/D-4836-2009; Nolen, Willem/E-9006-2014; Morrow, Eric/J-2767-2013; McGuffin, Peter/A-1565-2012; Sonuga-Barke, Edmund/D-9137-2011; McIntosh, Andrew/B-9379-2008; Kuntsi, Jonna/G-9750-2011; Scherer, Stephen /B-3785-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Herms, Stefan/J-1949-2014; Stroup, Thomas/F-9188-2014; Magnusson, Patrik/C-4458-2017; Lesch, Klaus-Peter/J-4906-2013; Vicente, Astrid/F-8692-2014; Miranda, Ana/G-8619-2015; Cormand, Bru/H-5338-2015; Montgomery, Grant/B-7148-2008; Zhang, Peng/N-2920-2014; Mattheisen, Manuel/B-4949-2012; Paterson, Andrew/A-4088-2011; Melle, Ingrid /B-4858-2011; Schumacher, Johannes/F-4970-2015; Ruderfer, Douglas/M-5795-2016; Lohoff, Falk/M-7951-2016; Lencz, Todd/J-3418-2014; BELLIVIER, FRANK/H-5197-2012; McQuillin, Andrew/C-1623-2008; Franke, Andre/B-2151-2010; Nyholt, Dale/C-8384-2013; Monaco, Anthony/A-4495-2010; Bailey, Anthony/J-2860-2014; Liu, Chang/B-7249-2009; Thompson, Richard/J-8879-2014; Binder, Elisabeth/K-8905-2014; Myin-Germeys, Inez /L-5106-2014; Lee, Sang Hong/A-2569-2011; Breen, Gerome/A-5540-2010; Hansen, Thomas/O-5965-2014; Wray, Naomi/C-8639-2015; Holmans, Peter/F-4518-2015; Sutcliffe, James/C-1348-2012 OI van Grootheest, Gerard/0000-0003-4350-6661; Franke, Barbara/0000-0003-4375-6572; McGuffin, Peter/0000-0002-9888-2907; McIntosh, Andrew/0000-0002-0198-4588; Scherer, Stephen /0000-0002-8326-1999; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Andreassen, Ole A./0000-0002-4461-3568; Oliveira, Guiomar/0000-0002-7049-1277; Thapar, Anita/0000-0002-3689-737X; Etain, Bruno/0000-0002-5377-1488; Visscher, Peter/0000-0002-2143-8760; Gearry, Richard/0000-0002-2298-5141; Faraone, Stephen/0000-0002-9217-3982; Edenberg, Howard/0000-0003-0344-9690; Medland, Sarah/0000-0003-1382-380X; Pickard, Benjamin/0000-0002-2374-6329; Steffens, Michael/0000-0002-6445-8593; de Geus, Eco/0000-0001-6022-2666; Martin, Nicholas/0000-0003-4069-8020; Betancur, Catalina/0000-0002-3327-4804; Yu, Timothy/0000-0003-2988-7701; Buxbaum, Joseph/0000-0001-8898-8313; Bruggeman, Richard/0000-0002-3238-8471; Weissman, Myrna/0000-0003-3490-3075; Palmieri, Orazio/0000-0002-0019-7929; Anney, Richard/0000-0002-6083-407X; Agartz, Ingrid/0000-0002-9839-5391; Nothen, Markus/0000-0002-8770-2464; Ribases, Marta/0000-0003-1039-1116; Donohoe, Gary/0000-0003-3037-7426; Sanders, Stephan/0000-0001-9112-5148; Buccola, Nancy/0000-0003-1378-4636; Ramos-Quiroga, Josep Antoni/0000-0003-1622-0350; Escott-Price, Valentina/0000-0003-1784-5483; lichtenstein, paul/0000-0003-3037-5287; Kent, Lindsey/0000-0002-5315-3399; Moran, Jennifer/0000-0002-5664-4716; Nievergelt, Caroline/0000-0001-5766-8923; Goddard, Michael/0000-0001-9917-7946; Schachar, Russell/0000-0002-2015-4395; Zammit, Stanley/0000-0002-2647-9211; Herms, Stefan/0000-0002-2786-8200; Stroup, Thomas/0000-0002-3123-0672; Morris, Derek/0000-0002-3413-570X; Myin-Germeys, Inez/0000-0002-3731-4930; Jamain, Stephane/0000-0002-4321-4100; Greenwood, Tiffany/0000-0002-6080-6503; KELLER, MATTHEW/0000-0002-6075-9882; Nurnberger, John/0000-0002-7674-1767; Gill, Michael/0000-0003-0206-5337; McMahon, Francis/0000-0002-9469-305X; Corvin, Aiden/0000-0001-6717-4089; MacIntyre, Donald J/0000-0001-6963-1335; O'Donovan, Michael/0000-0001-7073-2379; Hamilton, Steven/0000-0001-8106-6260; Barnes, Michael/0000-0001-9097-7381; Backlund, Lena/0000-0001-9399-5024; Gallagher, Louise/0000-0001-9462-2836; Lesch, Klaus-Peter/0000-0001-8348-153X; Willsey, Arthur/0000-0002-9922-3612; Vicente, Astrid/0000-0001-7134-8037; Craig, Ian/0000-0002-4063-1005; Bergen, Sarah/0000-0002-5888-0034; Anttila, Verneri/0000-0002-0073-4675; Laukens, Debby/0000-0002-1984-5850; Wijsman, Ellen/0000-0002-2725-6669; Matthews, Keith/0000-0002-4478-5888; Miranda, Ana/0000-0001-6998-5686; Cormand, Bru/0000-0001-5318-4382; Montgomery, Grant/0000-0002-4140-8139; Zhang, Peng/0000-0003-1182-1392; Mattheisen, Manuel/0000-0002-8442-493X; Paterson, Andrew/0000-0002-9169-118X; Melle, Ingrid /0000-0002-9783-548X; Schumacher, Johannes/0000-0001-9217-6457; Ruderfer, Douglas/0000-0002-2365-386X; Lencz, Todd/0000-0001-8586-338X; McQuillin, Andrew/0000-0003-1567-2240; Franke, Andre/0000-0003-1530-5811; Monaco, Anthony/0000-0001-7480-3197; Bailey, Anthony/0000-0003-4257-972X; Lee, Sang Hong/0000-0001-9701-2718; Breen, Gerome/0000-0003-2053-1792; Hansen, Thomas/0000-0001-6703-7762; Wray, Naomi/0000-0001-7421-3357; Holmans, Peter/0000-0003-0870-9412; Sutcliffe, James/0000-0001-5200-6007 FU Australian Research Council [FT0991360, DE130100614]; Australian National Health and Medical Research Council [613608, 1011506, 1047956]; National Institute of Mental Health (NIMH) [U01 MH085520]; Netherlands Scientific Organization (NOW) [480-05-003]; Dutch Brain Foundation; VU University FX This research was directly supported by the Australian Research Council (FT0991360 and DE130100614) and the Australian National Health and Medical Research Council (613608, 1011506 and 1047956). The PGC Cross-Disorder Group is supported by National Institute of Mental Health (NIMH) grant U01 MH085520. Statistical analyses were carried out on the Genetic Cluster Computer (see URLs), which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003; principal investigator D.P.) along with a supplement from the Dutch Brain Foundation and VU University. Numerous (> 100) grants from government agencies along with substantial private and foundation support worldwide enabled the collection of phenotype and genotype data, without which this research would not be possible; grant numbers are listed in primary PGC publications or in the Supplementary Note. NR 64 TC 407 Z9 409 U1 27 U2 235 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2013 VL 45 IS 9 BP 984 EP + DI 10.1038/ng.2711 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 209ID UT WOS:000323748200007 ER PT J AU Smith, RP Taher, L Patwardhan, RP Kim, MJ Inoue, F Shendure, J Ovcharenko, I Ahituv, N AF Smith, Robin P. Taher, Leila Patwardhan, Rupali P. Kim, Mee J. Inoue, Fumitaka Shendure, Jay Ovcharenko, Ivan Ahituv, Nadav TI Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model SO NATURE GENETICS LA English DT Article ID TRANSCRIPTION FACTORS; GENE-EXPRESSION; HEART ENHANCERS; IN-VIVO; DNA; LIVER; ELEMENTS; BINDING; GENOME; DISSECTION AB Despite continual progress in the cataloging of vertebrate regulatory elements, little is known about their organization and regulatory architecture. Here we describe a massively parallel experiment to systematically test the impact of copy number, spacing, combination and order of transcription factor binding sites on gene expression. A complex library of similar to 5,000 synthetic regulatory elements containing patterns from 12 liver-specific transcription factor binding sites was assayed in mice and in HepG2 cells. We find that certain transcription factors act as direct drivers of gene expression in homotypic clusters of binding sites, independent of spacing between sites, whereas others function only synergistically. Heterotypic enhancers are stronger than their homotypic analogs and favor specific transcription factor binding site combinations, mimicking putative native enhancers. Exhaustive testing of binding site permutations suggests that there is flexibility in binding site order. Our findings provide quantitative support for a flexible model of regulatory element activity and suggest a framework for the design of synthetic tissue-specific enhancers. C1 [Smith, Robin P.; Kim, Mee J.; Inoue, Fumitaka; Ahituv, Nadav] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Smith, Robin P.; Kim, Mee J.; Inoue, Fumitaka; Ahituv, Nadav] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Taher, Leila; Ovcharenko, Ivan] NIH, Natl Ctr Biotechnol Informat, Computat Biol Branch, Natl Lib Med, Bethesda, MD USA. [Taher, Leila] Univ Rostock, Inst Biostat & Informat Med & Ageing Res, D-18055 Rostock, Germany. [Patwardhan, Rupali P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Shendure, J (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM shendure@u.washington.edu; ovcharen@nih.gov; nadav.ahituv@ucsf.edu OI Ahituv, Nadav/0000-0002-7434-8144; Shendure, Jay/0000-0002-1516-1865 FU National Human Genome Research Institute (NHGRI) [1R01HG006768]; University of California, San Francisco (UCSF) Liver Center [P30 DK026743]; National Institute of Child and Human Development [R01HD059862]; NHGRI [R01HG005058]; National Institute of General Medical Sciences [GM61390]; National Institute of Neurological Disorders and Stroke [1R01NS079231]; National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK090382]; Simons Foundation [SFARI 256769]; Canadian Institutes of Health Research (CIHR); US National Institutes of Health [T32 GM007175]; UCSF Quantitative Biosciences Consortium fellowship for Interdisciplinary Research; Amgen Research Excellence in Bioengineering and Therapeutic Sciences fellowship; US National Institutes of Health, National Library of Medicine FX This work was supported by National Human Genome Research Institute (NHGRI) grant 1R01HG006768 (N.A. and J.S.) and the Pilot/Feasibility grant from the University of California, San Francisco (UCSF) Liver Center (P30 DK026743). N.A. is also supported by National Institute of Child and Human Development grant R01HD059862, NHGRI grant R01HG005058, National Institute of General Medical Sciences grant GM61390, National Institute of Neurological Disorders and Stroke grant 1R01NS079231, National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK090382 and the Simons Foundation (SFARI 256769). R. P. S. was supported in part by a Canadian Institutes of Health Research (CIHR) fellowship in hepatology. M.J.K. was supported in part by US National Institutes of Health training grant T32 GM007175, the UCSF Quantitative Biosciences Consortium fellowship for Interdisciplinary Research and the Amgen Research Excellence in Bioengineering and Therapeutic Sciences fellowship. This work was funded in part by the Intramural Research Program of the US National Institutes of Health, National Library of Medicine (I.O.). NR 47 TC 50 Z9 50 U1 4 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2013 VL 45 IS 9 BP 1021 EP + DI 10.1038/ng.2713 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 209ID UT WOS:000323748200011 PM 23892608 ER PT J AU Xu, DY Shen, WP Guo, R Xue, YT Peng, W Sima, J Yang, J Sharov, A Srikantan, S Yang, JD Fox, D Qian, Y Martindale, JL Piao, YL Machamer, J Joshi, SR Mohanty, S Shaw, AC Lloyd, TE Brown, GW Ko, MSH Gorospe, M Zou, SG Wang, WD AF Xu, Dongyi Shen, Weiping Guo, Rong Xue, Yutong Peng, Wei Sima, Jian Yang, Jay Sharov, Alexei Srikantan, Subramanya Yang, Jiandong Fox, David, III Qian, Yong Martindale, Jennifer L. Piao, Yulan Machamer, James Joshi, Samit R. Mohanty, Subhasis Shaw, Albert C. Lloyd, Thomas E. Brown, Grant W. Ko, Minoru S. H. Gorospe, Myriam Zou, Sige Wang, Weidong TI Top3 beta is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation SO NATURE NEUROSCIENCE LA English DT Article ID MENTAL-RETARDATION PROTEIN; FOCAL ADHESION KINASE; MESSENGER-RNA; III-ALPHA; DNA-DAMAGE; STRESS GRANULES; DROSOPHILA; FMRP; SCHIZOPHRENIA; TRANSLATION AB Topoisomerases are crucial for solving DNA topological problems, but they have not been linked to RNA metabolism. Here we show that human topoisomerase 3 beta (Top3 beta) is an RNA topoisomerase that biochemically and genetically interacts with FMRP, a protein that is deficient in fragile X syndrome and is known to regulate the translation of mRNAs that are important for neuronal function, abnormalities of which are linked to autism. Notably, the FMRP-Top3 beta interaction is abolished by a disease-associated mutation of FMRP, suggesting that Top3 beta may contribute to the pathogenesis of mental disorders. Top3 beta binds multiple mRNAs encoded by genes with neuronal functions linked to schizophrenia and autism. Expression of one such gene, that encoding protein tyrosine kinase 2 (ptk2, also known as focal adhesion kinase or FAK), is reduced in the neuromuscular junctions of Top3 beta mutant flies. Synapse formation is defective in Top3 beta mutant flies and mice, as well as in FMRP mutant flies and mice. Our findings suggest that Top3 beta acts as an RNA topoisomerase and works with FMRP to promote the expression of mRNAs that are crucial for neurodevelopment and mental health. C1 [Xu, Dongyi; Shen, Weiping; Guo, Rong; Xue, Yutong; Peng, Wei; Yang, Jiandong; Fox, David, III; Wang, Weidong] NIA, Genome Instabil & Chromatin Remodeling Sect, NIH, Baltimore, MD 21224 USA. [Xu, Dongyi] Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China. [Sima, Jian] NIA, Human Genet Sect, NIH, Baltimore, MD 21224 USA. [Yang, Jay; Brown, Grant W.] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Sharov, Alexei; Qian, Yong; Piao, Yulan; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, NIH, Baltimore, MD 21224 USA. [Srikantan, Subramanya; Martindale, Jennifer L.; Gorospe, Myriam] NIA, RNA Regulat Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. [Machamer, James; Lloyd, Thomas E.] Johns Hopkins Univ, Sch Med, Dept Neurol & Neurosci, Baltimore, MD USA. [Joshi, Samit R.; Mohanty, Subhasis; Shaw, Albert C.] Yale Univ, Sch Med, Dept Internal Med, Infect Dis Sect, New Haven, CT 06510 USA. [Zou, Sige] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Zou, SG (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM zous@mail.nih.gov; wangw@grc.nia.nih.gov OI srikantan, subramanya/0000-0003-1810-6519; Xu, Dongyi/0000-0001-5711-2618 FU Intramural Research Program of the NIA [Z01 AG000657-08]; NIH; Johns Hopkins Center for Neuroscience Research [NS050274]; Canadian Institutes of Health research grant [MOP-79368]; National Basic Research Program of China [2013CB911002]; National Natural Science Foundation of China [31271435] FX We thank T. Hsieh (Duke University) for Drosophila Top3 beta reagents; J.C. Wang (Harvard University) for Top3 beta knockout mice; D. Zarnescu (University of Illinois), T. Jongens (University of Pennsylvania) and G. Dreyfuss (University of Pennsylvania) for dfmr1 fly strains and antibodies; S. Warren (Emory University), S. Ceman (University of Illinois) and Y. Feng (Emory University) for vectors of FMR1 variants; U. Fischer (University of Wuerzburg) for vectors of TDRD3 and FMR1 orthologs; A. Hoogeveen (Erasmus University) for FXR1 and FXR2 antibodies; R. Hynes (Massachusetts Institute of Technology) and R. Palmer (Umea University) for FAK reagents; T. Enomoto (Tohoku University) for Top3b-/-DT40 cells; and R. Hanai (Rikkyo University) for the Top3 beta vector. We thank E. Chen, D.J. Pan and Y. Feng for advice and assistance, S. K. Lee for assistance and D. Schlessinger for support and critical reading of the manuscript. This work is supported in part by the Intramural Research Program of the NIA (Z01 AG000657-08), the NIH, the Johns Hopkins Center for Neuroscience Research (NS050274), Canadian Institutes of Health research grant MOP-79368 (to G. W. B.), the National Basic Research Program of China (2013CB911002) and the National Natural Science Foundation of China (31271435). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, Maryland, USA (http://biowulf.nih.gov). NR 63 TC 36 Z9 36 U1 0 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2013 VL 16 IS 9 BP 1238 EP U112 DI 10.1038/nn.3479 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 207KN UT WOS:000323597500015 PM 23912945 ER PT J AU Mathur, BN Tanahira, C Tamamaki, N Lovinger, DM AF Mathur, Brian N. Tanahira, Chiyoko Tamamaki, Nobuaki Lovinger, David M. TI Voltage drives diverse endocannabinoid signals to mediate striatal microcircuit-specific plasticity SO NATURE NEUROSCIENCE LA English DT Article ID ACID AMIDE HYDROLASE; MEDIUM SPINY NEURONS; PARVALBUMIN-IMMUNOREACTIVE NEURONS; DIACYLGLYCEROL LIPASE-ALPHA; FAST-SPIKING INTERNEURONS; LONG-TERM DEPRESSION; PROJECTION NEURONS; BASAL GANGLIA; MICE LACKING; SYNAPTIC-TRANSMISSION AB The dorsolateral striatum and cannabinoid type 1 receptor (CB1) signaling mediate habitual action learning, which is thought to require a balance of activity in the direct and indirect striatal output pathways. However, very little is known about how the high CB1-expressing striatal inhibitory microcircuitry might contribute to long-term plasticity capable of sculpting direct and indirect pathway output. Using optogenetic and molecular interrogation of striatal GABAergic microcircuits, we examined voltage-dependent long-term depression of inhibitory synapses (iLTD) onto mouse and rat medium spiny projection neurons (MSNs). The observed iLTD involved recruitment of different endocannabinoid types and showed both presynaptic and postsynaptic selectivity for MSN subtypes, ultimately resulting in a powerful disinhibition of direct pathway MSNs. These results suggest a new role for voltage states in gating circuit-specific forms of synaptic plasticity and illuminate possible circuit dynamics underlying action control. C1 [Mathur, Brian N.; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, US Natl Inst Hlth, Bethesda, MD USA. [Tanahira, Chiyoko; Tamamaki, Nobuaki] Kumamoto Univ, Grad Sch Med, Dept Morphol Neural Sci, Honjo, Kumamoto, Japan. RP Lovinger, DM (reprint author), NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, US Natl Inst Hlth, Bethesda, MD USA. EM lovindav@mail.nih.gov FU Intramural NIH HHS [Z99 AA999999] NR 50 TC 11 Z9 11 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2013 VL 16 IS 9 BP 1275 EP U157 DI 10.1038/nn.3478 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 207KN UT WOS:000323597500019 PM 23892554 ER PT J AU Cole, MW Reynolds, JR Power, JD Repovs, G Anticevic, A Braver, TS AF Cole, Michael W. Reynolds, Jeremy R. Power, Jonathan D. Repovs, Grega Anticevic, Alan Braver, Todd S. TI Multi-task connectivity reveals flexible hubs for adaptive task control SO NATURE NEUROSCIENCE LA English DT Article ID HUMAN CEREBRAL-CORTEX; INTRINSIC FUNCTIONAL CONNECTIVITY; PREFRONTAL CORTEX; COGNITIVE CONTROL; HUMAN BRAIN; PSYCHOPHYSIOLOGICAL INTERACTIONS; FRONTOPARIETAL CORTEX; VISUAL-ATTENTION; NETWORKS; REGIONS AB Extensive evidence suggests that the human ability to adaptively implement a wide variety of tasks is preferentially a result of the operation of a fronto-parietal brain network (FPN). We hypothesized that this network's adaptability is made possible by flexible hubs: brain regions that rapidly update their pattern of global functional connectivity according to task demands. Using recent advances in characterizing brain network organization and dynamics, we identified mechanisms consistent with the flexible hub theory. We found that the FPN's brain-wide functional connectivity pattern shifted more than those of other networks across a variety of task states and that these connectivity patterns could be used to identify the current task. Furthermore, these patterns were consistent across practiced and novel tasks, suggesting that reuse of flexible hub connectivity patterns facilitates adaptive (novel) task performance. Together, these findings support a central role for fronto-parietal flexible hubs in cognitive control and adaptive implementation of task demands. C1 [Cole, Michael W.; Braver, Todd S.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Reynolds, Jeremy R.] Univ Denver, Dept Psychol, Denver, CO 80208 USA. [Power, Jonathan D.] Washington Univ, Dept Psychol, St Louis, MO USA. [Repovs, Grega] Univ Ljubljana, Dept Psychol, Ljubljana 61000, Slovenia. [Anticevic, Alan] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Anticevic, Alan] Yale Univ, Abraham Ribicoff Res Facil, New Haven, CT USA. [Anticevic, Alan] Natl Inst Alcohol Abuse, New Haven, CT USA. [Anticevic, Alan] Alcoholism Ctr Translat Neurosci Alcoholism, New Haven, CT USA. RP Cole, MW (reprint author), Washington Univ, Dept Psychol, St Louis, MO 63130 USA. EM mwcole@mwcole.net RI Cole, Michael/G-1056-2010; OI Cole, Michael/0000-0003-4329-438X; Repovs, Grega/0000-0003-1837-3879; Braver, Todd/0000-0002-2631-3393 FU US National Institutes of Health [K99MH096801, DP5OD012109-01]; Brain and Behavior Research Foundation (NARSAD) Young Investigator Award FX We thank S. Petersen, D. Bassett and J. Etzel for helpful feedback and suggestions during preparation of this manuscript. We also thank W. Schneider for access to data from his laboratory. Our work was supported by the US National Institutes of Health under awards K99MH096801 (M.W.C.), DP5OD012109-01 (A.A.) and a Brain and Behavior Research Foundation (NARSAD) Young Investigator Award (A.A.). NR 58 TC 222 Z9 223 U1 11 U2 87 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2013 VL 16 IS 9 BP 1348 EP U247 DI 10.1038/nn.3470 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 207KN UT WOS:000323597500028 PM 23892552 ER PT J AU Milner, JD Holland, SM AF Milner, Joshua D. Holland, Steven M. TI The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID HYPER-IGE SYNDROME; CHRONIC MUCOCUTANEOUS CANDIDIASIS; HERPES-SIMPLEX ENCEPHALITIS; ACUTE MYELOID-LEUKEMIA; T-CELL SURVIVAL; IMMUNOGLOBULIN-SECRETING CELLS; HYPOMORPHIC RAG1 MUTATIONS; FUNCTION STAT1 MUTATIONS; OF-FUNCTION MUTATIONS; B-CELL AB A recent surge in newly described primary immunodeficiencies (PIDs) has highlighted new physiological and pathophysiological pathways that affect the immune system. Furthermore, the study of individuals with PIDs has substantially improved our understanding of basic cellular and signalling pathways in host defence and immune regulation. Single-gene defects can lead to disease manifestations that range from extremely narrow infectious phenotypes to remarkably broad multisystem effects. Hypomorphic or hypermorphic gene mutations often occur in human diseases; when coupled with the fact that humans are exposed to naturally encountered antigens and pathogens, this helps to make the case that the study of immunological diseases in humans should be at the forefront of basic immunological research. C1 [Milner, Joshua D.] NIAID, Allerg Inflammat Unit, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, Clin Res Ctr B34141, NIH, Bethesda, MD 20892 USA. RP Milner, JD (reprint author), NIAID, Allerg Inflammat Unit, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.go; smh@nih.gov FU Division of Intramural Research, US National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work has been supported by the Division of Intramural Research, US National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 122 TC 38 Z9 38 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD SEP PY 2013 VL 13 IS 9 BP 635 EP 648 DI 10.1038/nri3493 PG 14 WC Immunology SC Immunology GA 208BA UT WOS:000323648900009 PM 23887241 ER PT J AU Kwong, PD Mascola, JR Nabel, GJ AF Kwong, Peter D. Mascola, John R. Nabel, Gary J. TI Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning SO NATURE REVIEWS IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; CROSS-CLADE NEUTRALIZATION; MUCOSAL SHIV CHALLENGE; B-CELL RESPONSES; STRUCTURAL BASIS; POTENT NEUTRALIZATION; ENVELOPE GLYCOPROTEIN; HIV-1-INFECTED INDIVIDUALS; CRYSTAL-STRUCTURE AB The field of HIV-1 vaccine research has seen a renaissance with the identification of antibodies that neutralize most circulating HIV-1 strains. An understanding of the structural mode of target recognition that these antibodies use and the immune pathways that lead to their development is emerging. This knowledge has provided fundamental insights into the pathways that elicit broadly neutralizing antibodies and provides a foundation for active and passive immunization strategies to prevent HIV-1 infection. C1 [Kwong, Peter D.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), Sanofi, 640 Mem Dr, Cambridge, MA 02139 USA. EM Gary.Nabel@sanofi.com RI Cheng, Yushao/E-6256-2011 FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX We thank B. Hartman and J. Stuckey for assistance with display items, J. Gorman for modelling for Figure 1, A. Tislerics for manuscript preparation, N. Michael for helpful discussions, and members of the Virology Laboratory, the Structural Biology Section, the Structural Bioinformatics Core, and the Humoral Immunology Section, Vaccine Research Center, for discussions and comments on the manuscript. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 104 TC 128 Z9 130 U1 5 U2 73 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD SEP PY 2013 VL 13 IS 9 BP 693 EP 701 DI 10.1038/nri3516 PG 9 WC Immunology SC Immunology GA 208BA UT WOS:000323648900013 PM 23969737 ER PT J AU Zhong, L Wang, JTL Wen, DR Aris, V Soteropoulos, P Shapiro, BA AF Zhong, Ling Wang, Jason T. L. Wen, Dongrong Aris, Virginie Soteropoulos, Patricia Shapiro, Bruce A. TI Effective Classification of MicroRNA Precursors Using Feature Mining and AdaBoost Algorithms SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID SUPPORT VECTOR MACHINES; SEQUENCING DATA; CIRCULATING MICRORNAS; EXPRESSION; IDENTIFICATION; PREDICTION; CELLS; GENES; RNAS; DROSOPHILA AB MicroRNAs play important roles in most biological processes, including cell proliferation, tissue differentiation, and embryonic development, among others. They originate from precursor transcripts (pre-miRNAs), which contain phylogenetically conserved stem-loop structures. An important bioinformatics problem is to distinguish the pre-miRNAs from pseudo pre-miRNAs that have similar stem-loop structures. We present here a novel method for tackling this bioinformatics problem. Our method, named MirID, accepts an RNA sequence as input, and classifies the RNA sequence either as positive (i.e., a real pre-miRNA) or as negative (i.e., a pseudo pre-miRNA). MirID employs a feature mining algorithm for finding combinations of features suitable for building pre-miRNA classification models. These models are implemented using support vector machines, which are combined to construct a classifier ensemble. The accuracy of the classifier ensemble is further enhanced by the utilization of an AdaBoost algorithm. When compared with two closely related tools on twelve species analyzed with these tools, MirID outperforms the existing tools on the majority of the twelve species. MirID was also tested on nine additional species, and the results showed high accuracies on the nine species. The MirID web server is fully operational and freely accessible at http://bioinformatics.njit.edu/MirID/. Potential applications of this software in genomics and medicine are also discussed. C1 [Zhong, Ling; Wang, Jason T. L.; Wen, Dongrong] New Jersey Inst Technol, Bioinformat Program, Newark, NJ 07102 USA. [Zhong, Ling; Wang, Jason T. L.; Wen, Dongrong] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Aris, Virginie; Soteropoulos, Patricia] Univ Med & Dent New Jersey, New Jersey Med Sch, Publ Hlth Res Inst, Ctr Appl Genom, Newark, NJ 07103 USA. [Shapiro, Bruce A.] NCI, Computat RNA Struct Grp, Ctr Canc Res, Nanobiol Program, Frederick, MD 21701 USA. RP Wang, JTL (reprint author), New Jersey Inst Technol, Bioinformat Program, GITC Bldg,Room 4211,218 Cent Ave, Newark, NJ 07102 USA. EM wangj@njit.edu FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank the reviewers for their thoughtful comments and constructive suggestions. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The current findings were presented in part in preliminary form in the Proceedings of the 2012 IEEE International Conference on Bioinformatics and Biomedicine (Zhong et al., 2012). NR 57 TC 4 Z9 4 U1 0 U2 16 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD SEP 1 PY 2013 VL 17 IS 9 BP 486 EP 493 DI 10.1089/omi.2013.0011 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 210HD UT WOS:000323820700004 PM 23808606 ER PT J AU McGowen, MR Weckle, A Agnew, D Benirschke, K Savage-Rumbaugh, S Kim, CJ Wagner, GP Romero, R Wildman, DE AF McGowen, Michael R. Weckle, Amy Agnew, Dalen Benirschke, Kurt Savage-Rumbaugh, Sue Kim, Chong Jai Wagner, Guenter P. Romero, Robert Wildman, Derek E. TI GENE EXPRESSION IN THE TERM PLACENTA OF THE OPOSSUM MONODELPHIS DOMESTICA AND THE EVOLUTION OF THE THERIAN PLACENTA SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) CY SEP 11-14, 2013 CL Whistler, CANADA SP Int Federat Placenta Assoc (IFPA) C1 [McGowen, Michael R.; Weckle, Amy; Wildman, Derek E.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Agnew, Dalen] Michigan State Univ, Coll Vet Med, Diagnost Ctr Populat & Anim Hlth, E Lansing, MI 48824 USA. [Benirschke, Kurt] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Savage-Rumbaugh, Sue] Great Ape Trust Bonobo Hope Sanctuary, Des Moines, IA USA. [Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Wagner, Guenter P.] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT USA. [Wagner, Guenter P.] Yale Univ, Yale Syst Biol Inst, New Haven, CT USA. [Kim, Chong Jai; Romero, Robert] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. [Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. NR 0 TC 0 Z9 0 U1 2 U2 5 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2013 VL 34 IS 9 BP A24 EP A25 DI 10.1016/j.placenta.2013.06.075 PG 2 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 207GW UT WOS:000323587900084 ER PT J AU Salafia, C Yampolsky, M Vulk, D Stodgell, CJ Katzman, PJ Culhane, J Landrigan, P Szabo, S Thieux, N Swanson, J Dole, N Varner, MW Moye, J Miller, R AF Salafia, Carolyn Yampolsky, Michael Vulk, Denis Stodgell, C. J. Katzman, P. J. Culhane, J. Landrigan, P. Szabo, S. Thieux, N. Swanson, J. Dole, N. Varner, M. W. Moye, John Miller, Richard TI MAPPING PLACENTAL TOPOLOGY FROM 3D SCANS, THE GRAPHIC DISPLAY OF VARIATION IN ARBORISATION ACROSS GESTATION SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) CY SEP 11-14, 2013 CL Whistler, CANADA SP Int Federat Placenta Assoc (IFPA) C1 [Salafia, Carolyn] Placental Analyt LLC, Larchmont, NY USA. [Salafia, Carolyn] New York State Inst Basic Res Dev Disabil, Staten Isl, NY 10314 USA. [Yampolsky, Michael] Univ Toronto, Toronto, ON, Canada. [Vulk, Denis] Royal Inst Technol, Kungliga Tekniska Hogskolan, Stockholm, Sweden. [Stodgell, C. J.; Katzman, P. J.; Culhane, J.; Landrigan, P.; Szabo, S.; Thieux, N.; Swanson, J.; Dole, N.; Varner, M. W.; Moye, John; Miller, Richard] Natl Childrens Study Placenta Consortium, Bethesda, MD USA. [Stodgell, C. J.; Katzman, P. J.; Miller, Richard] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Culhane, J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Landrigan, P.] Mt Sinai Sch Med, New York, NY USA. [Szabo, S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Thieux, N.] S Dakota State Univ, Brookings, SD USA. [Swanson, J.] Univ Calif Irvine, Irvine, CA USA. [Dole, N.] Univ N Carolina, Chapel Hill, NC USA. [Varner, M. W.] Univ Utah, Salt Lake City, UT USA. [Moye, John] NIH, Natl Childrens Study, Bethesda, MD 20892 USA. OI Stodgell, Christopher/0000-0002-1666-5299 NR 0 TC 1 Z9 1 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2013 VL 34 IS 9 BP A73 EP A74 DI 10.1016/j.placenta.2013.06.219 PG 2 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 207GW UT WOS:000323587900227 ER PT J AU Salafia, C Girardi, T Yampolsky, M Shlakhter, O Newschaffer, C Fallin, D Walker, C Stodgell, CJ Katzman, PJ Culhane, J Landrigan, P Szabo, S Thieux, N Swanson, J Dole, N Varner, MW Moye, J Miller, R AF Salafia, Carolyn Girardi, Theresa Yampolsky, Michael Shlakhter, Oleksandr Newschaffer, Craig Fallin, Danielle Walker, Cheryl Stodgell, C. J. Katzman, P. J. Culhane, J. Landrigan, P. Szabo, S. Thieux, N. Swanson, J. Dole, N. Varner, M. W. Moye, John Miller, Richard TI CHORIONIC VASCULAR STRUCTURE AND PLACENTAL FUNCTIONAL EFFICIENCY (BETA) DIFFER IN HIGH AND LOW AUTISM RISK PLACENTAL COHORTS SO PLACENTA LA English DT Meeting Abstract CT Annual Meeting of the International-Federation-of-Placenta-Associations (IFPA) CY SEP 11-14, 2013 CL Whistler, CANADA SP Int Federat Placenta Assoc (IFPA) C1 [Salafia, Carolyn; Girardi, Theresa; Yampolsky, Michael] Placental Analyt LLC, Larchmont, NY USA. [Salafia, Carolyn; Girardi, Theresa] New York State Off Mental Retardat & Dev Disabil, Inst Basic Res, Staten Isl, NY USA. [Yampolsky, Michael; Shlakhter, Oleksandr] Univ Toronto, Toronto, ON, Canada. [Shlakhter, Oleksandr] Alberta Hlth Serv, Edmonton, AB, Canada. [Newschaffer, Craig] Drexel Univ, Philadelphia, PA 19104 USA. [Fallin, Danielle] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Walker, Cheryl] Univ Calif Davis, Davis, CA 95616 USA. [Stodgell, C. J.; Katzman, P. J.; Culhane, J.; Landrigan, P.; Szabo, S.; Thieux, N.; Swanson, J.; Dole, N.; Varner, M. W.; Moye, John; Miller, Richard] Natl Childrens Study Placenta Consortium, Bethesda, MD USA. [Stodgell, C. J.; Katzman, P. J.; Miller, Richard] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Culhane, J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Landrigan, P.] Mt Sinai Sch Med, New York, NY USA. [Szabo, S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Thieux, N.] S Dakota State Univ, Brookings, SD 57007 USA. [Swanson, J.] Univ Calif Irvine, Irvine, CA USA. [Dole, N.] Univ N Carolina, Chapel Hill, NC USA. [Varner, M. W.] Univ Utah, Salt Lake City, UT USA. [Moye, John] NIH, Natl Childrens Study, Bethesda, MD 20892 USA. OI Stodgell, Christopher/0000-0002-1666-5299 NR 0 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2013 VL 34 IS 9 BP A72 EP A72 DI 10.1016/j.placenta.2013.06.217 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 207GW UT WOS:000323587900225 ER PT J AU Salafia, C Misra, D Stodgell, C Katzman, P Ruffolo, L Culhane, J Wadlinger, S Wapner, R Torres, C Landrigan, P Littman, L Sheffield, P Leuthner, S Szabo, S Thieux, N Specker, B Swanson, J Miller, RK Moye, J Durkin, M AF Salafia, Carolyn Misra, Dawn Stodgell, C. Katzman, P. Ruffolo, L. Culhane, J. Wadlinger, S. Wapner, R. Torres, C. Landrigan, P. Littman, L. Sheffield, P. Leuthner, S. Szabo, S. Thieux, N. Specker, B. Swanson, J. Miller, R. K. Moye, John Durkin, M. TI THE MAJORTIY OF VARIANCE IN BIRTHWEIGHT RELATIVE TO PLACENTAL WEIGHT (AS BETA = LN(PW)/LN(BW) IS ACCOUNTED FOR BY DETAILED NOVEL PLACENTAL MEASURES: IMPLICATIONS FOR FETAL ORIGINS WORK SO PLACENTA LA English DT Meeting Abstract CT Meeting of the International-Federation-of-Placenta-Associations (IFPA) CY SEP 11-14, 2013 CL Whistler, CANADA SP Int Federat Placenta Assoc (IFPA) C1 [Salafia, Carolyn; Misra, Dawn] Placental Analyt LLC, Larchmont, NY USA. [Salafia, Carolyn; Misra, Dawn; Stodgell, C.; Katzman, P.; Ruffolo, L.; Culhane, J.; Wadlinger, S.; Wapner, R.; Torres, C.; Landrigan, P.; Littman, L.; Sheffield, P.; Leuthner, S.; Szabo, S.; Thieux, N.; Specker, B.; Swanson, J.; Miller, R. K.; Moye, John; Durkin, M.] Natl Childrens Study Placenta Consortium, Bethesda, MD USA. [Stodgell, C.; Katzman, P.; Ruffolo, L.; Miller, R. K.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Culhane, J.; Wadlinger, S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wapner, R.; Torres, C.] Columbia Univ, New York, NY USA. [Landrigan, P.; Littman, L.; Sheffield, P.] Icahn Schhol Med, New York, NY USA. [Leuthner, S.; Szabo, S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Thieux, N.; Specker, B.] S Dakota State Univ, Brookings, SD 57007 USA. [Swanson, J.] Univ Calif Irvine, Irvine, CA USA. [Salafia, Carolyn; Misra, Dawn; Stodgell, C.; Katzman, P.; Ruffolo, L.; Culhane, J.; Wadlinger, S.; Wapner, R.; Torres, C.; Landrigan, P.; Littman, L.; Sheffield, P.; Leuthner, S.; Szabo, S.; Thieux, N.; Specker, B.; Swanson, J.; Miller, R. K.; Moye, John; Durkin, M.] Univ N Carolina, Chapel Hill, NC USA. [Salafia, Carolyn; Misra, Dawn; Stodgell, C.; Katzman, P.; Ruffolo, L.; Culhane, J.; Wadlinger, S.; Wapner, R.; Torres, C.; Landrigan, P.; Littman, L.; Sheffield, P.; Leuthner, S.; Szabo, S.; Thieux, N.; Specker, B.; Swanson, J.; Miller, R. K.; Moye, John; Durkin, M.] Univ Utah, Salt Lake City, UT USA. [Durkin, M.] Univ Wisconsin, Madison, WI USA. [Moye, John] NIH, Natl Childrens Study, Bethesda, MD 20892 USA. RI Durkin, Maureen/B-7834-2015 NR 0 TC 0 Z9 0 U1 0 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2013 VL 34 IS 9 BP A14 EP A15 DI 10.1016/j.placenta.2013.06.044 PG 2 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 207GW UT WOS:000323587900053 ER PT J AU Koscso, B Trepakov, A Csoka, B Nemeth, ZH Pacher, P Eltzschig, HK Hasko, G AF Koscso, Balazs Trepakov, Alexey Csoka, Balazs Nemeth, Zoltan H. Pacher, Pal Eltzschig, Holger K. Hasko, Gyoergy TI Stimulation of A(2B) adenosine receptors protects against trauma-hemorrhagic shock-induced lung injury SO PURINERGIC SIGNALLING LA English DT Article DE Trauma; Hemorrhagic shock; A(2B) adenosine receptor; BAY 60-6583 ID MULTIPLE ORGAN FAILURE; CARDIAC DYSFUNCTION; MACROPHAGE FUNCTION; TNF-ALPHA; INFLAMMATION; IL-10; MICE; RESUSCITATION; ACTIVATION; MECHANISMS AB Inflammation is responsible for secondary organ failure after trauma and hemorrhagic shock (T/HS). Adenosine, acting through four G protein-coupled cell surface receptors, A(1), A(2A), A(2B), and A(3), exerts a number of tissue protective and anti-inflammatory effects. The goal of the present study was to test the effect of A(2B) adenosine receptor stimulation on T/HS-induced organ injury and inflammation in rats. Rats after T/HS were resuscitated with Ringer's lactate containing the A(2B) receptor agonist BAY 60-6583 or its vehicle. We found that BAY 60-6583 decreased T/HS-induced lung permeability and plasma creatine kinase levels but failed to affect T/HS-induced lung neutrophil infiltration and I kappa B alpha expression and plasma alanine aminotransferase levels. Thus, we conclude that stimulation of A(2B) receptors protects against T/HS-induced lung and muscle injury. C1 [Koscso, Balazs; Trepakov, Alexey; Csoka, Balazs; Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Eltzschig, Holger K.] Univ Colorado, Sch Med, Dept Anesthesiol, Mucosal Inflammat Program, Aurora, CO USA. [Nemeth, Zoltan H.] Morristown Med Ctr, Dept Surg, Morristown, NJ USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, Bethesda, MD USA. [Hasko, Gyoergy] Univ Debrecen, Med & Hlth Sci Ctr, Dept Med Chem, H-4012 Debrecen, Hungary. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU National Institutes of Health [R01GM066189]; USAMRMC [09065004, W81XWH-10-1-1015]; Hungarian Scientific Research Fund (OTKA) [CK 78275]; National Heart Institute [R01-HL0921, R01-DK083385, R01-HL098294]; Crohn's and Colitis Foundation of America FX This work was supported by National Institutes of Health grants R01GM066189; USAMRMC grant log# 09065004 (contract W81XWH-10-1-1015); Hungarian Scientific Research Fund (OTKA) grant CK 78275 to GH; National Heart Institute Grants R01-HL0921, R01-DK083385, and R01-HL098294; and a grant by the Crohn's and Colitis Foundation of America to HKE. NR 30 TC 2 Z9 2 U1 0 U2 10 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 2013 VL 9 IS 3 BP 427 EP 432 DI 10.1007/s11302-013-9362-7 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 209HQ UT WOS:000323746700011 PM 23584760 ER PT J AU Choyke, PL AF Choyke, Peter L. TI Science to Practice: Imaging Cancer-associated Fibroblasts: No Innocent Bystanders SO RADIOLOGY LA English DT Editorial Material ID TUMOR STROMA AB The era of stromal-based therapies is coming, and methods to image the stroma are likely to become vital to improved understanding of the intricate interrelationships of these cells. Because fibroblasts are so important for the initiation of cancer, stromal-based therapies may serve as preventive regimens in patients who are at high risk for recurrent disease. The method described by Vandsburger et al uses a reporter-gene magnetic resonance (MR) imaging- agent paradigm that withstands dilution from cell division while allowing imaging without ionizing radiation. The requirement for gene transfection makes near-term clinical translation unlikely, but the opportunities for studying cancer-associated fibroblast activity in tumor models and observing and modulating their migratory behavior is an exciting prospect, one that is hoped to bring tangible benefits to patients with cancer. C1 NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, Bldg 10,Room B3B69F, Bethesda, MD 20892 USA. EM pchoyke@nih.gov NR 7 TC 1 Z9 1 U1 0 U2 6 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2013 VL 268 IS 3 BP 617 EP 618 DI 10.1148/radiol.13131447 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 205CR UT WOS:000323419300001 PM 23970505 ER PT J AU Pinsky, PF Gierada, DS Nath, PH Kazerooni, E Amorosa, J AF Pinsky, Paul F. Gierada, David S. Nath, P. Hrudaya Kazerooni, Ella Amorosa, Judith TI National Lung Screening Trial: Variability in Nodule Detection Rates in Chest CT Studies SO RADIOLOGY LA English DT Article ID SEMIAUTOMATED VOLUME MEASUREMENTS; LOW-DOSE CT; CANCER; RADIOLOGISTS; AGREEMENT; ACCURACY AB Purpose: To characterize the variability in radiologists' interpretations of computed tomography (CT) studies in the National Lung Screening Trial (NLST) (including assessment of false-positive rates [FPRs] and sensitivity), to examine factors that contribute to variability, and to evaluate trade-offs between FPRs and sensitivity among different groups of radiologists. Materials and Methods: The HIPAA-compliant NLST was approved by the institutional review board at each screening center; all participants provided informed consent. NLST radiologists reported overall screening results, nodule-specific findings, and recommendations for diagnostic follow-up. A noncalcified nodule of 4 mm or larger constituted a positive screening result. The FPR was defined as the rate of positive screening examinations in participants without a cancer diagnosis within 1 year. Descriptive analyses and mixed-effects models were utilized. The average odds ratio (OR) for a false-positive result across all pairs of radiologists was used as a measure of variability. Results: One hundred twelve radiologists at 32 screening centers each interpreted 100 or more NLST CT studies, interpreting 72 160 of 75 126 total NLST CT studies in aggregate. The mean FPR for radiologists was 28.7% +/- 13.7 (standard deviation), with a range of 3.8%-69.0%. The model yielded an average OR of 2.49 across all pairs of radiologists and an OR of 1.83 for pairs within the same screening center. Mean FPRs were similar for academic versus nonacademic centers (27.9% and 26.7%, respectively) and for centers inside (25.0%) versus outside (28.7%) the U. S. "histoplasmosis belt." Aggregate sensitivity was 96.5% for radiologists with FPRs higher than the median (27.1%), compared with 91.9% for those with FPRs lower than the median (P = .02). Conclusion: There was substantial variability in radiologists' FPRs. Higher FPRs were associated with modestly higher sensitivity. (C)RSNA, 2013 C1 [Pinsky, Paul F.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Gierada, David S.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Nath, P. Hrudaya] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. [Kazerooni, Ella] Univ Michigan, Dept Radiol, Sch Med, Ann Arbor, MI 48109 USA. [Amorosa, Judith] New Jersey Med Coll, Canc Inst New Jersey, New Brunswick, NJ USA. RP Pinsky, PF (reprint author), NCI, Canc Prevent Div, NIH, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM pp4f@nih.gov FU National Institutes of Health [U01-CA-80098, U01-CA-79778, N01-CN-25514, N01-CN-25522, N01-CN-25515, N01-CN-25512, N01-CN-25513, N01-CN-25516, N01-CN-25511, N01-CN-25524, N01-CN-25518, N01-CN-75022] FX This research was supported by the National Institutes of Health (grants U01-CA-80098 and U01-CA-79778 and contracts N01-CN-25514, N01-CN-25522, N01-CN-25515, N01-CN-25512, N01-CN-25513, N01-CN-25516, N01-CN-25511, N01-CN-25524, N01-CN-25518, and N01-CN-75022). NR 16 TC 16 Z9 16 U1 0 U2 10 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2013 VL 268 IS 3 BP 865 EP 873 DI 10.1148/radiol.13121530 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 205CR UT WOS:000323419300028 PM 23592767 ER PT J AU Chen, MY Shanbhag, SM Arai, AE AF Chen, Marcus Y. Shanbhag, Sujata M. Arai, Andrew E. TI Radiation Dose of Second-Generation 320-Detector Row CT Response SO RADIOLOGY LA English DT Letter C1 [Chen, Marcus Y.; Shanbhag, Sujata M.; Arai, Andrew E.] NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Chen, MY (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM marcus.chen@nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2013 VL 268 IS 3 BP 928 EP 928 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 205CR UT WOS:000323419300043 PM 24137710 ER PT J AU Cheng, J Chen, C Kristopher, KW Manna, SK Scerba, M Friedman, FK Luecke, H Idle, JR Gonzalez, FJ AF Cheng, Jie Chen, Chi Kristopher, Krausz W. Manna, Soumen K. Scerba, Mike Friedman, Fred K. Luecke, Hans Idle, Jeffrey R. Gonzalez, Frank J. TI Identification of 2-Piperidone as a Biomarker of CYP2E1 Activity Through Metabolomic Phenotyping SO TOXICOLOGICAL SCIENCES LA English DT Article DE CYP2E1; biomarker; metabolomics; 2-piperidone; cadaverine ID CYTOCHROME-P450 2E1; OXIDATIVE STRESS; IN-VIVO; HEPATOTOXICITY; ACETAMINOPHEN; MOUSE; PHARMACOLOGY; INHIBITION; CATABOLISM; EXPRESSION AB Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of many low molecular weight toxicants and also an important contributor to oxidative stress. A noninvasive method to monitor CYP2E1 activity in vivo would be of great value for studying the role of CYP2E1 in chemical-induced toxicities and stress-related diseases. In this study, a mass spectrometrybased metabolomic approach was used to identify a metabolite biomarker of CYP2E1 through comparing the urine metabolomes of wild-type (WT), Cyp2e1-null, and CYP2E1-humanized mice. Metabolomic analysis with multivariate models of urine metabolites revealed a clear separation of Cyp2e1-null mice from WT and CYP2E1-humanized mice in the multivariate models of urine metabolomes. Subsequently, 2-piperidone was identified as a urinary metabolite that inversely correlated to the CYP2E1 activity in the three mouse lines. Backcrossing of WT and Cyp2e1-null mice, together with targeted analysis of 2-piperidone in mouse serum, confirmed the genotype dependency of 2-piperidone. The accumulation of 2-piperidone in the Cyp2e1-null mice was mainly caused by the changes in the biosynthesis and degradation of 2-piperidone because compared with the WT mice, the conversion of cadaverine to 2-piperidone was higher, whereas the metabolism of 2-piperidone to 6-hydroxy-2-piperidone was lower in the Cyp2e1-null mice. Overall, untargeted metabolomic analysis identified a correlation between 2-piperidone concentrations in urine and the expression and activity of CYP2E1, thus providing a noninvasive metabolite biomarker that can be potentially used in to monitor CYP2E1 activity. C1 [Cheng, Jie; Chen, Chi; Kristopher, Krausz W.; Manna, Soumen K.; Friedman, Fred K.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Chi] Univ Minnesota, Dept Food Sci & Nutr, St Paul, MN 55108 USA. [Scerba, Mike; Luecke, Hans] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Idle, Jeffrey R.] Univ Bern, Dept Clin Res, Hepatol Res Grp, CH-3010 Bern, Switzerland. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Friedman, Fred/D-4208-2016; OI Idle, Jeff/0000-0002-6143-1520 FU National Cancer Institute Intramural Research Program FX National Cancer Institute Intramural Research Program. NR 35 TC 3 Z9 3 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2013 VL 135 IS 1 BP 37 EP 47 DI 10.1093/toxsci/kft143 PG 11 WC Toxicology SC Toxicology GA 207SQ UT WOS:000323624500004 PM 23811823 ER PT J AU Yeo, L Romero, R AF Yeo, Lami Romero, Roberto TI Fetal Intelligent Navigation Echocardiography (FINE): a novel method for rapid, simple, and automatic examination of the fetal heart SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE 4D; cardiac; congenital heart disease; fetal heart; prenatal diagnosis; spatiotemporal image correlation; STIC; ultrasound; Virtual Intelligent Sonographer Assistance; VIS-Assistance (R) ID SPATIOTEMPORAL IMAGE CORRELATION; STANDARD CARDIAC VIEWS; PRENATAL-DIAGNOSIS; 4-DIMENSIONAL ULTRASOUND; OUTFLOW TRACTS; GREAT-ARTERIES; 3-DIMENSIONAL ULTRASOUND; INVERSION MODE; 4-CHAMBER VIEW; INTERNET LINK AB Objective To describe a novel method (Fetal Intelligent Navigation Echocardiography (FINE)) for visualization of standard fetal echocardiography views from volume datasets obtained with spatiotemporal image correlation (STIC) and application of intelligent navigation' technology. Methods We developed a method to: 1) demonstrate nine cardiac diagnostic planes; and 2) spontaneously navigate the anatomy surrounding each of the nine cardiac diagnostic planes (Virtual Intelligent Sonographer Assistance (VIS-Assistance (R))). The method consists of marking seven anatomical structures of the fetal heart. The following echocardiography views are then automatically generated: 1) four chamber; 2) five chamber; 3) left ventricular outflow tract; 4) short-axis view of great vessels/right ventricular outflow tract; 5) three vessels and trachea; 6) abdomen/stomach; 7) ductal arch; 8) aortic arch; and 9) superior and inferior vena cava. The FINE method was tested in a separate set of 50 STIC volumes of normal hearts (18.6-37.2weeks of gestation), and visualization rates for fetal echocardiography views using diagnostic planes and/or VIS-Assistance (R) were calculated. To examine the feasibility of identifying abnormal cardiac anatomy, we tested the method in four cases with proven congenital heart defects (coarctation of aorta, tetralogy of Fallot, transposition of great vessels and pulmonary atresia with intact ventricular septum). Results In normal cases, the FINE method was able to generate nine fetal echocardiography views using: 1) diagnostic planes in 78-100% of cases; 2) VIS-Assistance (R) in 98-100% of cases; and 3) a combination of diagnostic planes and/or VIS-Assistance (R) in 98-100% of cases. In all four abnormal cases, the FINE method demonstrated evidence of abnormal fetal cardiac anatomy. Conclusions The FINE method can be used to visualize nine standard fetal echocardiography views in normal hearts by applying intelligent navigation' technology to STIC volume datasets. This method can simplify examination of the fetal heart and reduce operator dependency. The observation of abnormal echocardiography views in the diagnostic planes and/or VIS-Assistance (R) should raise the index of suspicion for congenital heart disease. Published 2013. This article is a U.S. Government work and is in the public domain in the USA C1 [Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Yeo, Lami; Romero, Roberto] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI 48201 USA. RP Yeo, L (reprint author), Hutzel Womens Hosp, Perinatol Res Branch, NICHD, NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM lyeo@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; Medge Platforms, Inc., New York, NY, USA; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); Federal funds from NICHD, NIH [HHSN275201300006C] FX The work of Dr Roberto Romero was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. Dr Roberto Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government. Dr Lami Yeo was funded by Wayne State University through a service contract in support of the Perinatology Research Branch. The contributions of Mr Abella and Mr Gayoso were funded by Medge Platforms, Inc., New York, NY, USA.; This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. NR 106 TC 16 Z9 22 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD SEP PY 2013 VL 42 IS 3 BP 268 EP 284 DI 10.1002/uog.12563 PG 17 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 209HJ UT WOS:000323746000005 PM 24000158 ER PT J AU Funk, EK Shaffer, A Shivakumar, B Sneller, M Polis, MA Masur, H Heytens, L Nelson, A Kwan, R Kottilil, S Kohli, A AF Funk, Emily K. Shaffer, Ashton Shivakumar, Bhavana Sneller, Michael Polis, Michael A. Masur, Henry Heytens, Laura Nelson, Amy Kwan, Richard Kottilil, Shyam Kohli, Anita TI Short Communication: Interferon/Ribavirin Treatment for HCV Is Associated with the Development of Hypophosphatemia in HIV/Hepatitis C Virus-Coinfected Patients SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TENOFOVIR DISOPROXIL FUMARATE; HIV-INFECTED PATIENTS; CHRONIC HEPATITIS-C; PLUS RIBAVIRIN; NATURAL-HISTORY; LIVER FIBROSIS; THERAPY; PROGRESSION; PREVALENCE AB One-third of all HIV-infected individuals in the United States are estimated to be coinfected with the hepatitis C virus (HCV). Treatment of chronic hepatitis C in patients coinfected with HIV is a complex problem associated with toxicities and drug interactions between HIV antiretrovirals and interferon and ribavirin. In recent HCV treatment studies, we observed a previously unreported development of hypophosphatemia in HIV/HCV-coinfected patients treated with interferon/ribavirin (IFN/RBV). To further investigate this observation, we retrospectively reviewed 61 HIV/HCV-coinfected patients on antiretrovirals (ARVs) during treatment with IFN/RBV as well as 154 HIV-infected patients treated with ARVs alone. We found that HIV/HCV-coinfected patients on IFN/RBV therapy were more likely to develop frequent (57% vs. 13%, IFN/RBV-treated patients vs. no IFN/RBV; chi(2) = 0.001) and higher-grade hypophosphatemia (67.0% Grade 2, 33.3% Grade 3 vs. 94.7% Grade 2, 5.3% Grade 3, IFN/RBV-treated patients vs. no IFN/RBV; chi(2) < 0.001) than untreated patients. In addition, we found that the new onset of hypophosphatemia after IFN/RBV treatment initiation was followed by a diminished frequency of this toxicity upon cessation of IFN/RBV, supporting the idea that a drug-drug interaction may increase the risk of this toxicity. To understand the risks of developing this toxicity, we evaluated the association between individual ARV use and hypophosphatemia incidence. Our data suggest that concomitant tenofovir (TDF) use may be a risk factor for the development of hypophosphatemia in HIV/HCV-coinfected patients treated with IFN/RBV. Although the etiology of this abnormality is likely multifactorial, clinicians should be aware of hypophosphatemia as a potential marker of renal toxicity in HIV/HCV-coinfected patients being treated with IFN/RBV regimens. C1 [Funk, Emily K.; Shaffer, Ashton; Shivakumar, Bhavana; Sneller, Michael; Polis, Michael A.; Heytens, Laura; Nelson, Amy; Kwan, Richard; Kottilil, Shyam; Kohli, Anita] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kohli, Anita] SAIC Frederick Inc, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kohli, A (reprint author), NIAID, NIH, 10 Ctr Dr,Bldg 10-11C442, Bethesda, MD 20892 USA. EM kohlia@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The data were presented in part at CROI 2012 in Seattle, WA. NR 26 TC 7 Z9 7 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2013 VL 29 IS 9 BP 1190 EP 1194 DI 10.1089/aid.2013.0035 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 204NL UT WOS:000323372600002 PM 23701022 ER PT J AU Manuel, SL Sehgal, M Khan, ZK Goedert, JJ Betts, MR Jain, P AF Manuel, Sharron L. Sehgal, Mohit Khan, Zafar K. Goedert, James J. Betts, Michael R. Jain, Pooja TI An Altered Maturation and Adhesion Phenotype of Dendritic Cells in Diseased Individuals Compared to Asymptomatic Carriers of Human T Cell Leukemia Virus Type 1 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HTLV-I INFECTION; FLOW-CYTOMETRY; PD-1 BLOCKADE; RHESUS MACAQUES; TAX PROTEIN; EXPRESSION; HIV; BLOOD; LYMPHOCYTES; ACTIVATION AB The immunopathogenic mechanisms underlying human T cell leukemia virus type 1 (HTLV-1)-mediated diseases such as adult T cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are not clearly understood. As critical effectors of antiviral immune response, dendritic cells (DCs) are implicated to play an important role in determining the outcome of HTLV-1 infection. However, a complete understanding of their role in any disease pathogenesis requires extensive assessment of the phenotypic and functional state of DCs. To enable this, we developed a polychromatic antibody cocktail comprising key phenotypic and functional markers of DCs and applied it in a patient cohort from the HTLV-1 endemic region, Jamaica, consisted of seronegative controls, asymptomatic carriers (ACs), ATL, and HAM/TSP patients. This ex vivo analyses included two major subsets of blood DCs, myeloid and plasmacytoid (mDCs and pDCs, respectively). The comparative analyses of results demonstrated a decreased pDC frequency in both ATL and HAM/TSP patients as compared to ACs and seronegative controls. Similarly, CD86 expression on both mDCs and pDCs was significantly higher in HAM/TSP (but not ATL) patients compared to ACs. Interestingly, HLA-DR expression was significantly lower on pDCs of patients as compared to carriers; however, for mDCs, only the HAM/TSP group had significantly lower expression of HLA-DR. Unlike HAM/TSP individuals, ATL individuals had higher HLA-ABC expression on mDCs compared to ACs. Finally, both mDCs and pDCs of HAM/ TSP patients had significantly higher expression of the programmed death ligand 1 (PD-L1) compared to ACs. Overall, this study suggests that DCs exhibit a differential phenotypic and functional profile between patients (ATL and HAM/TSP) and carriers of HTLV-1 and could provide an important tool for understanding HTLV-1 immunopathogenesis during infection and disease. C1 [Manuel, Sharron L.; Sehgal, Mohit; Khan, Zafar K.; Jain, Pooja] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA. [Manuel, Sharron L.; Sehgal, Mohit; Khan, Zafar K.; Jain, Pooja] Drexel Univ, Coll Med, Drexel Inst Biotechnol & Virol, Philadelphia, PA 19104 USA. [Goedert, James J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Betts, Michael R.] Univ Penn, Sch Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA. RP Jain, P (reprint author), Drexel Univ, Coll Med, Dept Microbiol & Immunol, 3805 Old Easton Rd, Doylestown, PA 18902 USA. EM pjain@drexelmed.edu FU Public Health Service, National Institutes of Health; NIAID [R01 AI077414, R21 AI 093172-01]; NCI [R01 CA054559]; Philadelphia NeuroAIDS Training Grant [T32 MH079785] FX This work was supported by the Public Health Service, National Institutes of Health, wherein P.J. was funded through NIAID R01 AI077414 and NCI R01 CA054559 while Z.K.K. was funded through NIAID R21 AI 093172-01. In addition, we thank the Philadelphia NeuroAIDS Training Grant T32 MH079785 that has supported the efforts of S. Manuel. NR 53 TC 4 Z9 4 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2013 VL 29 IS 9 BP 1273 EP 1285 DI 10.1089/aid.2013.0054 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 204NL UT WOS:000323372600015 PM 23750452 ER PT J AU White, CL Pergola, PE Szychowski, JM Talbert, R Cervantes-Arriaga, A Clark, HD Del Brutto, OH Godoy, IE Hill, MD Pelegri, A Sussman, CR Taylor, AA Valdivia, J Anderson, DC Conwit, R Benavente, OR AF White, Carole L. Pergola, Pablo E. Szychowski, Jeff M. Talbert, Robert Cervantes-Arriaga, Amin Clark, Heather D. Del Brutto, Oscar H. Esteban Godoy, Ivan Hill, Michael D. Pelegri, Antoni Sussman, Craig R. Taylor, Addison A. Valdivia, Jose Anderson, Dave C. Conwit, Robin Benavente, Oscar R. CA SPS3 Investigators TI Blood Pressure After Recent Stroke: Baseline Findings From the Secondary Prevention of Small Subcortical Strokes Trial SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure control; blood pressure; ethnicity; hypertension; ischemic stroke; lacunar stroke; risk factors; stroke prevention; white matter disease ID CONVERTING-ENZYME-INHIBITOR; TRANSIENT ISCHEMIC ATTACK; RECURRENT STROKE; RANDOMIZED TRIAL; LOWERING REGIMEN; UNITED-STATES; HYPERTENSION; RISK; MANAGEMENT; GUIDELINES AB BACKGROUND Hypertension is the most powerful risk factor for stroke. The aim of this study was to characterize baseline blood pressure in participants in the Secondary Prevention of Small Subcortical Strokes trial. METHODS For this cross-sectional analysis, participants were categorized by baseline systolic blood pressure (SBP) < 120, 120-139, 140-159, 160-179, and 180 mm Hg and compared on demographic and clinical characteristics. Predictors of SBP < 140 mm Hg were examined. RESULTS Mean SBP was 143 +/- 19 mm Hg while receiving an average of 1.7 antihypertensive medications; SBP >= 140 mm Hg for 53% and >= 160 mm Hg for 18% of the 3,020 participants. Higher SBP was associated with a history of hypertension and hypertension for longer duration (both P < 0.0001). Higher SBPs were associated with more extensive white matter disease on magnetic resonance imaging (P < 0.0001). There were significant differences in entry-level SBP when participants were categorized by race and region (both P < 0.0001). Black participants were more likely to have SBP >= 140 mm Hg. Multivariable logistic regression showed an independent effect for region with those from Canada more likely (odds ratio = 1.7; 95% confidence interval, 1.29, 2.32) to have SBP < 140 mm Hg compared with participants from United States. CONCLUSIONS In this cohort with symptomatic lacunar stroke, more than half had uncontrolled hypertension at approximately 2.5 months after stroke. Regional, racial, and clinical differences should be considered to improve control and prevent recurrent stroke. C1 [White, Carole L.] Univ Texas Hlth Sci Ctr San Antonio, Sch Nursing, San Antonio, TX 78229 USA. [Pergola, Pablo E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Pergola, Pablo E.] Renal Associates PA, San Antonio, TX USA. [Szychowski, Jeff M.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Talbert, Robert] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Cervantes-Arriaga, Amin] Natl Inst Neurol & Neurosurg, Neurodegenerat Res Unit, Mexico City, DF, Mexico. [Clark, Heather D.] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [Clark, Heather D.] Ottawa Hosp, Ottawa, ON, Canada. [Del Brutto, Oscar H.] Hosp Clin Kennedy, Dept Neurol Sci, Guayaquil, Ecuador. [Esteban Godoy, Ivan] Pontificia Univ Catolica Chile, Dept Med, Santiago, Chile. [Hill, Michael D.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Pelegri, Antoni] Hosp Sagrat Cor, Dept Nephrol, Barcelona, Spain. [Sussman, Craig R.] Vanderbilt Univ, Med Ctr, Div Gen Internal Med, Nashville, TN USA. [Sussman, Craig R.] Vanderbilt Univ, Med Ctr, Div Endocrinol Metab, Nashville, TN USA. [Taylor, Addison A.] Baylor Coll Med, Dept Med, Div Hypertens & Clin Pharmacol, Sect Cardiovasc Res, Houston, TX 77030 USA. [Valdivia, Jose] Hosp Alberto Sabogal, Dept Med, Lima, Peru. [Anderson, Dave C.] Univ Minnesota, Sch Med, Hennepin Cty Med Ctr, Minneapolis, MN 55455 USA. [Conwit, Robin] NINDS, Off Clin Res, Bethesda, MD 20892 USA. [Benavente, Oscar R.] Univ British Columbia, Dept Med, Div Neurol, Brain Res Ctr, Vancouver, BC V6T 1W5, Canada. RP Pergola, PE (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM ppergola@raparesearch.com RI Hill, Michael/C-9073-2012 OI Hill, Michael/0000-0002-6269-1543 FU National Institute of Neurological Disorders and Stroke [2 U01 NS38529-04A1] FX The SPS3 study was funded by the National Institute of Neurological Disorders and Stroke (2 U01 NS38529-04A1). We gratefully acknowledge the contributions of the SPS3 investigators and coordinators. NR 38 TC 11 Z9 11 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD SEP PY 2013 VL 26 IS 9 BP 1114 EP 1122 DI 10.1093/ajh/hpt076 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 203NB UT WOS:000323298800009 PM 23736109 ER PT J AU Yabroff, KR Short, PF Machlin, S Dowling, E Rozjabek, H Li, CY McNeel, T Ekwueme, DU Virgo, KS AF Yabroff, K. Robin Short, Pamela F. Machlin, Steven Dowling, Emily Rozjabek, Heather Li, Chunyu McNeel, Timothy Ekwueme, Donatus U. Virgo, Katherine S. TI Access to Preventive Health Care for Cancer Survivors SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID 2ND PRIMARY CANCERS; UNITED-STATES; MEDICAL-CARE; BREAST; MAINTENANCE AB Background: Access to health care, particularly effective primary and secondary preventive care, is critical for cancer survivors, in order to minimize the adverse sequelae of cancer and its treatment. Purpose: The goal of the study was to evaluate the association between cancer survivorship and access to primary and preventive health care. Methods: Cancer survivors (n=4960) and individuals without a cancer history (n=64,431) aged >= 18 years, from the 2008-2010 Medical Expenditure Panel Survey (MEPS), were evaluated. Multiple measures of access and preventive services use were compared. The association between cancer survivorship and access and preventive services was evaluated with multivariate logistic regression models, stratified by age group (18-64 years and >= 65 years), controlling for the effects of age, gender, race/ethnicity, education, marital status, and comorbidities. Data were analyzed in 2013. Results: Cancer survivors aged >= 65 years had equivalent or greater access and preventive services use than individuals without a cancer history, in adjusted analyses. However, among those aged 18-64 years with private health insurance, cancer survivors were more likely than other individuals to have a usual source of care and to use preventive services, whereas uninsured or publicly insured cancer survivors were generally less likely to have a usual source of care and to use preventive services than were uninsured or publicly insured adults without a cancer history. Conclusions: Although access and preventive care use in cancer survivors is generally equivalent or greater compared to that of other individuals, disparities for uninsured and publicly insured cancer survivors aged 18-64 years suggest that improvements in survivor care are needed. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Yabroff, K. Robin; Rozjabek, Heather] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Machlin, Steven] Agcy Healthcare Res & Qual, Ctr Financing Access & Cost Trends, Rockville, MD USA. [McNeel, Timothy] Informat Management Serv Inc, Calverton, MD USA. [Short, Pamela F.] Penn State Univ, Ctr Hlth Care & Policy Res, University Pk, PA 16802 USA. [Dowling, Emily] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Li, Chunyu; Ekwueme, Donatus U.] CDC, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Virgo, Katherine S.] Intramural Res Dept, Hlth Serv Res Program, Amer Canc Soc, Natl Home Off, Atlanta, GA USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, 9609 Med Ctr Dr,3E436, Rockville, MD 20850 USA. EM yabroffr@mail.nih.gov NR 28 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2013 VL 45 IS 3 BP 304 EP 312 DI 10.1016/j.amepre.2013.04.021 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 202CU UT WOS:000323191900008 ER PT J AU Gorelick, DA Goodwin, RS Schwilke, E Schroeder, JR Schwope, DM Kelly, DL Ortemann-Renon, C Bonnet, D Huestis, MA AF Gorelick, David A. Goodwin, Robert S. Schwilke, Eugene Schroeder, Jennifer R. Schwope, David M. Kelly, Deanna L. Ortemann-Renon, Catherine Bonnet, Denis Huestis, Marilyn A. TI Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID ADMINISTERED DELTA-9-TETRAHYDROCANNABINOL; MARIJUANA; HUMANS; ADULTS AB Background and Objectives: Delta 9-tetrahydrocannabinol (THC) promotes sleep in animals; clinical use of THC is associated with somnolence. Human laboratory studies of oral THC have not shown consistent effects on sleep. We prospectively evaluated self-reported sleep parameters during controlled oral THC administration to research volunteers. Methods: Thirteen male chronic daily cannabis smokers (mean +/- SD age 24.6 +/- 3.7 years, self-reported smoking frequency of 5.5 +/- 5.9 (range 1-24) joint-equivalents daily at study entry) were administered oral THC doses (20 mg) around-the-clock for 7 days (40-120 mg daily) starting the afternoon after admission. The St. Mary's Hospital Sleep Questionnaire was completed every morning. Plasma THC and 11-OH-THC (active metabolite) concentrations were measured in venous blood samples collected every evening. Changes in sleep characteristics over time and associations between sleep characteristics and plasma cannabinoid concentrations were evaluated with repeated measures mixed linear regression. Results: Higher evening THC and 11-OH-THC concentrations were significantly associated with shorter sleep latency, less difficulty falling asleep, and more daytime sleep the following day. In contrast, the duration of calculated and self-reported nighttime sleep decreased slightly (3.54 and 5.34 minutes per night, respectively) but significantly during the study. Conclusions: These findings suggest that tolerance to the somnolent effects of THC may have occurred, but results should be considered preliminary due to design limitations. Scientific Significance: Somnolence from oral THC may dissipate with chronic, high-dose use. This has implications for patients who may take chronic oral THC for medicinal purposes, including cannabis dependence treatment. C1 [Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, NIH, Baltimore, MD 21224 USA. [Schroeder, Jennifer R.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kelly, Deanna L.] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Ortemann-Renon, Catherine; Bonnet, Denis] Sanofi Aventis Rech, Montpellier, France. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, IRP, NIH, 251 Bayview Blvd,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000414-10, Z01 DA000414-11, Z01 DA000415-10, Z01 DA000415-11] NR 19 TC 7 Z9 7 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SEP PY 2013 VL 22 IS 5 BP 510 EP 514 DI 10.1111/j.1521-0391.2013.12003.x PG 5 WC Substance Abuse SC Substance Abuse GA 202DV UT WOS:000323194600014 PM 23952899 ER PT J AU Liu, W Harman, MP Hancock, C Phang, JM AF Liu, Wei Harman, Meredith P. Hancock, Chad Phang, James M. TI The control of proline metabolism in cancers by oncogenic and tumor suppressor signalings SO AMINO ACIDS LA English DT Meeting Abstract C1 [Liu, Wei; Harman, Meredith P.; Hancock, Chad; Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD SEP PY 2013 VL 45 IS 3 BP 585 EP 585 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202JZ UT WOS:000323212600086 ER PT J AU Hancock, CN Phang, JM AF Hancock, Chad N. Phang, James M. TI Effects of co-regulation of proline oxidase and succinate dehydrogenase on mitochondrial respiration SO AMINO ACIDS LA English DT Meeting Abstract C1 [Hancock, Chad N.; Phang, James M.] Frederick Natl Lab Canc Res, Basic Res Lab, Metab & Canc Susceptibil Sect, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD SEP PY 2013 VL 45 IS 3 BP 593 EP 593 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202JZ UT WOS:000323212600112 ER PT J AU Louis, JF Thoma, ME Sorensen, DN McLain, AC King, RB Sundaram, R Keiding, N Louis, GMB AF Louis, J. F. Thoma, M. E. Sorensen, D. N. McLain, A. C. King, R. B. Sundaram, R. Keiding, N. Louis, G. M. Buck TI The prevalence of couple infertility in the United States from a male perspective: evidence from a nationally representative sample SO ANDROLOGY LA English DT Article ID CURRENT-DURATION APPROACH; TIME-TO-PREGNANCY; SEMEN QUALITY; TESTICULAR CANCER; OLDER MEN; FERTILITY; AGE; POPULATION; FECUNDITY; HEALTH AB Infertility is a couple-based fecundity impairment, although population level research is largely based upon information reported by female partners. Of the few studies focusing on male partners, most focus on the utilization of infertility services rather than efforts to estimate the prevalence and determinants of infertility as reported by male partners. Data from a nationally representative sample of men aged 15-44 years who participated in the 2002 National Survey of Family Growth (NSFG) were used to estimate the prevalence of infertility and determinants of longer time-to-pregnancy (TTP) using the novel current duration (CD) approach. Using backward recurrence time parametric survival methods, we estimated infertility prevalence (TTP > 12 months) and time ratios (TR) associated with TTP as derived from males' reported CD of their pregnancy attempt. The estimated prevalence of infertility was 12.0% (95% CI: 7.0, 23.2). Longer TTP was associated with older male age (35-45 vs. 17-24 years) (TR: 2.49; 95% CI: 1.03, 6.03), biological childlessness (TR: 1.53; 95% CI: 1.07, 2.19) and lack of health insurance (TR: 1.73; 95% CI: 1.02, 2.94) after controlling for the differences in couples' age and other socioeconomic factors. The prevalence of infertility based on male reporting is consistent with estimates of infertility in the US found in prospective cohort studies and CD studies based on female reporting. Our findings suggest that male partners can reliably inform about couple infertility. Interventions and services aimed at reducing couple infertility should include attention to male factors associated with longer TTP identified in this study. C1 [Louis, J. F.; Thoma, M. E.; Sundaram, R.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Sorensen, D. N.; Keiding, N.] Univ Copenhagen, Dept Biostat, Copenhagen, Denmark. [McLain, A. C.] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [King, R. B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Populat Dynam Branch, NIH, Rockville, MD USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM louisg@mail.nih.gov OI Louis, Jean F/0000-0003-0339-647X; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU U.S. Department of Health and Human Services: Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD); National Institutes of Health (NIH); Office of Population Affairs; CDC's National Center for Health Statistics (CDC/NCHS); CDC's Division of HIV/AIDS Prevention (CDC/DHAP); CDC's Division of Sexually Transmitted Disease Prevention (CDC/DSTDP); CDC's Division of Reproductive Health (CDC/DRH); Office of the Assistant Secretary for Planning and Evaluation (OASPE); Children's Bureau of the Administration for Children and Families; Intramural Research Program, NICHD, NIH FX The 2002 NSFG was conducted by the Centers for Disease Control and Prevention's (CDC) National Center for Health Statistics (NCHS) with the support and assistance of a number of other organizations and individuals, with the participation and funding support of the following programs of the U.S. Department of Health and Human Services: Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), National Institutes of Health (NIH), Office of Population Affairs, CDC's National Center for Health Statistics (CDC/NCHS), CDC's Division of HIV/AIDS Prevention (CDC/DHAP), CDC's Division of Sexually Transmitted Disease Prevention (CDC/DSTDP), CDC's Division of Reproductive Health (CDC/DRH), Office of the Assistant Secretary for Planning and Evaluation (OASPE), Children's Bureau of the Administration for Children and Families. The analysis and writing of this paper was supported by the Intramural Research Program, NICHD, NIH. NR 47 TC 40 Z9 40 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 J9 ANDROLOGY-US JI Andrology PD SEP PY 2013 VL 1 IS 5 BP 741 EP 748 DI 10.1111/j.2047-2927.2013.00110.x PG 8 WC Andrology SC Endocrinology & Metabolism GA 204RJ UT WOS:000323385700011 PM 23843214 ER PT J AU Moayeri, M Crown, D Jiao, GS Kim, S Johnson, A Leysath, C Leppla, SH AF Moayeri, Mahtab Crown, Devorah Jiao, Guan-Sheng Kim, Seongjin Johnson, Alan Leysath, Clinton Leppla, Stephen H. TI Small-Molecule Inhibitors of Lethal Factor Protease Activity Protect against Anthrax Infection SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID EDEMA TOXIN; KINASE-KINASE; IDENTIFICATION; DYSFUNCTION; ANTIBODIES; ANTIDOTES; BARRIER; MODEL; SHOCK; RATS AB Bacillus anthracis, the causative agent of anthrax, manifests its pathogenesis through the action of two secreted toxins. The bipartite lethal and edema toxins, a combination of lethal factor or edema factor with the protein protective antigen, are important virulence factors for this bacterium. We previously developed small-molecule inhibitors of lethal factor proteolytic activity (LFIs) and demonstrated their in vivo efficacy in a rat lethal toxin challenge model. In this work, we show that these LFIs protect against lethality caused by anthrax infection in mice when combined with subprotective doses of either antibiotics or neutralizing monoclonal antibodies that target edema factor. Significantly, these inhibitors provided protection against lethal infection when administered as a monotherapy. As little as two doses (10 mg/kg) administered at 2 h and 8 h after spore infection was sufficient to provide a significant survival benefit in infected mice. Administration of LFIs early in the infection was found to inhibit dissemination of vegetative bacteria to the organs in the first 32 h following infection. In addition, neutralizing antibodies against edema factor also inhibited bacterial dissemination with similar efficacy. Together, our findings confirm the important roles that both anthrax toxins play in establishing anthrax infection and demonstrate the potential for small-molecule therapeutics targeting these proteins. C1 [Moayeri, Mahtab; Crown, Devorah; Leysath, Clinton; Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Jiao, Guan-Sheng; Kim, Seongjin; Johnson, Alan] PanTheraBiopharma LLC, Aiea, HI USA. RP Moayeri, M (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. EM mmoayeri@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; NIH [U01 AI078067] FX This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases. A.J., G.-S.J., and S. K. are supported by NIH grant U01 AI078067. NR 38 TC 13 Z9 13 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2013 VL 57 IS 9 BP 4139 EP 4145 DI 10.1128/AAC.00941-13 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 203IL UT WOS:000323285500006 PM 23774434 ER PT J AU Lin, PL Coleman, T Carney, JPJ Lopresti, BJ Tomko, J Fillmore, D Dartois, V Scanga, C Frye, LJ Janssen, C Klein, E Barry, CE Flynn, JL AF Lin, Philana Ling Coleman, Teresa Carney, Jonathan P. J. Lopresti, Brian J. Tomko, Jaime Fillmore, Dan Dartois, Veronique Scanga, Charles Frye, L. James Janssen, Christopher Klein, Edwin Barry, Clifton E., III Flynn, JoAnne L. TI Radiologic Responses in Cynomolgus Macaques for Assessing Tuberculosis Chemotherapy Regimens SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; GAMMA RELEASE ASSAYS; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; THERAPEUTIC RESPONSE; LATENT TUBERCULOSIS; F-18-FDG PET/CT; ENDEMIC COUNTRY; MURINE MODEL; FDG PET AB Trials to test new drugs currently in development against tuberculosis in humans are impractical. All animal models to prioritize new regimens are imperfect, but nonhuman primates (NHPs) infected with Mycobacterium tuberculosis develop active tuberculosis (TB) disease with a full spectrum of lesion types seen in humans. Serial 2-deoxy-2-[F-18]-fluoro-D-glucose (FDG) positron emission tomography (PET) with computed tomography (CT) imaging was performed on cynomolgus macaques during infection and chemotherapy with individual agents or the four-drug combination therapy most widely used globally. The size and metabolic activity of lung granulomas varied among animals and even within a single animal during development of disease. Individual granulomas within untreated animals had highly local and independent outcomes, some progressing in size and FDG uptake, while others waned, illustrating the highly dynamic nature of active TB. At necropsy, even untreated animals were found to have a proportion of sterile lesions consistent with the dynamics of this infection. A more marked reduction in overall metabolic activity in the lungs (decreased FDG uptake) was associated with effective treatment. A reduction in the size of individual lesions correlated with a lower bacterial burden at necropsy. Isoniazid treatment was associated with a transient increase in metabolic activity in individual lesions, whereas a net reduction occurred in most lesions from rifampin-treated animals. Quadruple-drug therapy resulted in the highest decrease in FDG uptake. The findings of PET-CT imaging may provide an important early correlate of the efficacy of novel combinations of new drugs that can be directly translated to human clinical trials. C1 [Lin, Philana Ling] Univ Pittsburgh, Dept Pediat, Childrens Hosp Pittsburgh, Med Ctr,Sch Med, Pittsburgh, PA 15260 USA. [Coleman, Teresa; Carney, Jonathan P. J.; Lopresti, Brian J.] Univ Pittsburgh, Dept Radiol, Med Ctr, Pittsburgh, PA 15260 USA. [Tomko, Jaime; Fillmore, Dan; Scanga, Charles; Flynn, JoAnne L.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15260 USA. [Dartois, Veronique] Univ Med & Dent New Jersey, Dept Med, Newark, NJ 07103 USA. [Scanga, Charles; Frye, L. James; Flynn, JoAnne L.] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA USA. [Janssen, Christopher; Klein, Edwin] Univ Pittsburgh, Div Lab Anim Res, Pittsburgh, PA USA. [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 15260 USA. EM joanne@pitt.edu RI Barry, III, Clifton/H-3839-2012; Lopresti, Brian/O-2465-2016 OI Lopresti, Brian/0000-0002-0595-0203 FU Bill and Melinda Gates Foundation TB Drug Accelerator; Intramural Research Program of the NIAID, NIH FX These studies were supported by the Bill and Melinda Gates Foundation TB Drug Accelerator and (in part) by the Intramural Research Program of the NIAID, NIH. NR 35 TC 53 Z9 54 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2013 VL 57 IS 9 BP 4237 EP 4244 DI 10.1128/AAC.00277-13 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 203IL UT WOS:000323285500018 PM 23796926 ER PT J AU Thanassoulis, G Peloso, GM O'Donnell, CJ AF Thanassoulis, George Peloso, Gina M. O'Donnell, Christopher J. TI Genomic Medicine for Improved Prediction and Primordial Prevention of Cardiovascular Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Editorial Material DE atherosclerosis; cholesterol; genetics; genomics; myocardial infarction; prediction; prevention; risk ID CORONARY-HEART-DISEASE; GENETIC RISK SCORE; MENDELIAN RANDOMIZATION; TRIAL; ASSOCIATION C1 [Thanassoulis, George] McGill Univ, Ctr Hlth, Montreal, PQ H3A 2T5, Canada. [Peloso, Gina M.; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst, Framingham, MA USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999, ZIA HL006002-06] NR 21 TC 5 Z9 5 U1 0 U2 7 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 2013 VL 33 IS 9 BP 2049 EP 2050 DI 10.1161/ATVBAHA.113.301814 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 203UY UT WOS:000323320700002 PM 23946465 ER PT J AU Altarifi, AA Rice, KC Negus, SS AF Altarifi, Ahmad A. Rice, Kenner C. Negus, S. Stevens TI Abuse-related effects of mu-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE chronic morphine; drug abuse; fentanyl; intracranial self-stimulation; methadone; nalbuphine; rat; tolerance ID MIXED-ACTION OPIOIDS; CROSS-TOLERANCE; HEALTHY-VOLUNTEERS; FOOD PRESENTATION; SQUIRREL-MONKEYS; RHESUS-MONKEYS; RECEPTOR; AGONISTS; SENSITIZATION; WITHDRAWAL AB Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be varied rapidly to maintain a wide range of baseline response rates, and drugs' effects can be evaluated simultaneously on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS facilitation' indicates drug-induced increases in low ICSS rates and is often considered an abuse-related effect, whereas ICSS depression' indicates decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of mu-agonist efficacy and of previous mu-agonist exposure as determinants of mu-agonist effects on ICSS in rats with electrodes implanted into the medial forebrain bundle. The high-efficacy, intermediate-efficacy, and low-efficacy mu agonists methadone, fentanyl, and nalbuphine were tested during escalating regimens of morphine exposure (vehicle, 3.2, and 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that mu-agonist exposure increases the expression of abuse-related ICSS facilitation by mu agonists with a broad range of efficacies at mu receptors. C1 [Altarifi, Ahmad A.; Negus, S. Stevens] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Rice, Kenner C.] NIAAA, Chem Biol Res Branch, NIDA, Bethesda, MD USA. [Altarifi, Ahmad A.] Jordan Univ Sci & Technol, Fac Med, Irbid, Jordan. RP Negus, SS (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 North 12th St,POB 980613, Richmond, VA 23298 USA. EM ssnegus@vcu.edu FU NIH [R01-NS070715, T32-DA007027]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This research was supported by NIH grants R01-NS070715 and T32-DA007027 and by training support from the Jordan University of Science and Technology. A portion of this work was also supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. NR 43 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2013 VL 24 IS 5-6 BP 459 EP 470 DI 10.1097/FBP.0b013e328364c0bd PG 12 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 202NX UT WOS:000323225500013 PM 23881045 ER PT J AU Comer, SD Metz, VE Cooper, ZD Kowalczyk, WJ Jones, JD Sullivan, MA Manubay, JM Vosburg, SK Smith, ME Peyser, D Saccone, PA AF Comer, Sandra D. Metz, Verena E. Cooper, Ziva D. Kowalczyk, William J. Jones, Jermaine D. Sullivan, Maria A. Manubay, Jeanne M. Vosburg, Suzanne K. Smith, Mary E. Peyser, Deena Saccone, Phillip A. TI Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE abuse liability; buprenorphine maintenance; human; morphine : oxycodone ratio; opioid dependence; physiological and subjective effects; self-administration procedure ID BUPRENORPHINE-NALOXONE; INTRANASAL HEROIN; MAINTAINED HUMANS; PAIN MANAGEMENT; DEPENDENCE; ABUSE; ANALGESICS AB This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3 : 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures - that is, a drug versus money and a drug versus drug procedure - were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3 : 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. C1 [Comer, Sandra D.; Metz, Verena E.; Cooper, Ziva D.; Jones, Jermaine D.; Sullivan, Maria A.; Manubay, Jeanne M.; Vosburg, Suzanne K.; Smith, Mary E.; Peyser, Deena] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, Div Substance Abuse, New York, NY 10032 USA. [Kowalczyk, William J.] NIDA, NIH, IRP,Clin Pharmacol & Therapeut Branch, Nicotine Pharmacol Sect, Baltimore, MD USA. [Saccone, Phillip A.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. RP Comer, SD (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, Div Substance Abuse, 1051 Riverside Dr,Unit 120, New York, NY 10032 USA. EM sdc10@columbia.edu RI Cooper, Ziva/L-2009-2014; OI Kowalczyk, William/0000-0001-8026-285X FU NIDA [DA09236] FX The authors gratefully acknowledge NIDA for providing funding for this study (DA09236). NIDA had no role in study design or in the decision to submit the paper for publication. NIDA also had no role in the collection, analysis, and interpretation of data or in the writing of the report. The authors thank Drs Jennifer Hanner, Benjamin Nordstrom, Shabnam Shakibaie, and Soteri Polydorou for providing medical coverage during laboratory sessions and participant screening. In addition, they thank Janet Murray, RN, and Claudia Tindall, NP, for providing nursing support during the study. Portions of these data were presented at the 2007 and 2009 meetings of the College on Problems of Drug Dependence. NR 21 TC 4 Z9 4 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2013 VL 24 IS 5-6 BP 504 EP 516 DI 10.1097/FBP.0b013e328363d1c4 PG 13 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 202NX UT WOS:000323225500019 PM 23839029 ER PT J AU Galski, H Oved-Gelber, T Simanovsky, M Lazarovici, P Gottesman, MM Nagler, A AF Galski, Hanan Oved-Gelber, Tamar Simanovsky, Masha Lazarovici, Philip Gottesman, Michael M. Nagler, Arnon TI P-glycoprotein-dependent resistance of cancer cells toward the extrinsic TRAIL apoptosis signaling pathway SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Apoptosis; P-glycoprotein; TRAIL; Resistance; Modulators ID MULTIDRUG-RESISTANCE; IMMUNE-SYSTEM; HEMATOLOGICAL MALIGNANCIES; DEATH RECEPTOR; THERAPEUTICS; CYTOTOXICITY; ACTIVATION; EXPRESSION; REVERSAL; ANTIBODY AB The TNF-related apoptosis-inducing ligand (TRAIL or Apo2L) preferentially cause apoptosis of malignant cells in vitro and in vivo without severe toxicity. Therefore, TRAIL or agonist antibodies to the TRAIL DR4 and DR5 receptors are used in cancer therapy. However, many malignant cells are intrinsically-resistant or acquire resistance to TRAIL. It has been previously proposed that the multidrug transporter P-glycoprotein (Pgp) might play a role in resistance of cells to intrinsic apoptotic pathways by interfering with components of ceramide metabolism or by modulating the electrochemical gradient across the plasma membrane. In this study we investigated whether Pgp also confers resistance toward extrinsic death ligands of the TNF family. To this end we focused our study on HeLa cells carrying a tetracycline-repressible plasmid system which shuts down Pgp expression in the presence of tetracycline. Our findings demonstrate that expression of Pgp is a significant factor conferring resistance to TRAIL administration, but not to other death ligands such as TNF-alpha. and Fas ligand. Moreover, blocking Pgp transport activity sensitizes the malignant cells toward TRAIL. Therefore, Pgp transport function is required to confer resistance to TRAIL. Although the resistance to TRAIL-induced apoptosis is Pgp specific, TRAIL itself is not a direct substrate of Pgp. Pgp expression has no effect on the level of the TRAIL receptors DR4 and DR5. These findings might have clinical implications since the combination of TRAIL therapy with administration of Pgp modulators might sensitize TRAIL resistant tumors. (C) 2013 Elsevier Inc. All rights reserved. C1 [Galski, Hanan; Oved-Gelber, Tamar; Simanovsky, Masha; Nagler, Arnon] Chaim Sheba Med Ctr, Div Hematol, Lab Mol Immunol, IL-52621 Tel Hashomer, Ramat Gan, Israel. [Lazarovici, Philip] Hebrew Univ Jerusalem, Sch Pharm, Inst Drug Sci, IL-91905 Jerusalem, Israel. [Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Galski, H (reprint author), Chaim Sheba Med Ctr, Lab Mol Immunobiol, IL-52621 Tel Hashomer, Ramat Gan, Israel. EM hgalski@sheba.health.gov.il FU Israel Science Foundation [ISF494/04-08]; Israel Cancer Association (ICA) [20052008] FX This study has been performed as part of T. O-G Ph.D. thesis. This study supported in part by grants from The Israel Science Foundation (ISF494/04-08) and Israel Cancer Association (ICA # 20052008) granted to H.G & A.N. NR 36 TC 7 Z9 8 U1 2 U2 20 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 SEP 1 PY 2013 VL 86 IS 5 BP 584 EP 596 DI 10.1016/j.bcp.2013.06.004 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 204XL UT WOS:000323404500003 PM 23774624 ER PT J AU Dartois, V Barry, CE AF Dartois, Veronique Barry, Clifton E., III TI A medicinal chemists' guide to the unique difficulties of lead optimization for tuberculosis SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Tuberculosis; Drug discovery ID INTENSIVE PHASE TREATMENT; IN-VITRO MODEL; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; LATENT TUBERCULOSIS; GUINEA-PIG; RABBIT MODEL; NONREPLICATING PERSISTENCE; TREATMENT STRATEGIES; MURINE TUBERCULOSIS AB Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium resides, often under conditions where replication is limited and intrinsic drug susceptibility is low. This consolidated pathology also results in impaired vascularization that limits access of potential lead molecules to the site of infection. Translating these considerations into a target-product profile to guide lead optimization programs involves implementing unique in vitro and in vivo assays to maximize the likelihood of developing clinically meaningful candidates. (C) 2013 Published by Elsevier Ltd. C1 [Dartois, Veronique] Univ Med & Dent New Jersey, New Jersey Med Sch, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 FU NIAID, NIH; Bill and Melinda Gates Foundation FX This work was funded (in part) by the Intramural Research Program of the NIAID, NIH (CEB) and by the TB Drug Accelerator program of the Bill and Melinda Gates Foundation (VD). NR 108 TC 46 Z9 46 U1 2 U2 19 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 SEP 1 PY 2013 VL 23 IS 17 BP 4741 EP 4750 DI 10.1016/j.bmcl.2013.07.006 PG 10 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 202AX UT WOS:000323187000001 PM 23910985 ER PT J AU Li, XP Qi, J Yamaguchi, T Wang, HL Morales, M AF Li, Xueping Qi, Jia Yamaguchi, Tsuyoshi Wang, Hui-Ling Morales, Marisela TI Heterogeneous composition of dopamine neurons of the rat A10 region: molecular evidence for diverse signaling properties SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Ventral tegmental area; Substantia nigra; Reward; Corelease of dopamine and glutamate; VGluT2 ID VENTRAL TEGMENTAL AREA; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; INTERFASCICULAR NUCLEUS; GLUTAMATERGIC NEURONS; SUBSTANTIA-NIGRA; BINDING-PROTEIN; MESSENGER-RNAS; IN-VITRO; MIDBRAIN AB The A10 region contains different neurons: dopamine (expressing tyrosine hydroxylase; TH), GABA, glutamate-only (expressing the vesicular glutamate transporter 2; VGluT2), and TH-VGluT2 (coexpressing TH and VGluT2). We used three methods to investigate proteins necessary for the synthesis (aromatic l-amino acid decarboxylase, AADC) or transport (vesicular monoamine transporter; VMAT2 or dopamine transporter; DAT) of dopamine within TH neurons in the A10 region. By in situ hybridization-immunohistochemistry, we found that all TH neurons in the A10 region had AADC, but not all had VMAT2, DAT or D2 receptors (D2R). To determine whether TH-VGluT2 neurons account for TH neurons lacking these dopamine markers, we implemented an anatomical "mirror technique", and found that not all TH-VGluT2 neurons lacked VMAT2, DAT or D2R. Next, by quantitative RT-PCR of individual micro-dissected TH neurons, we discovered two classes of TH-VGluT2 and three classes of TH-only neurons with different latero-medial distribution. Some of the TH-VGluT2 neurons had both VMAT2 and DAT (TH-VGluT2 Class 1); others lacked detectable levels of both transporters (TH-VGluT2 Class 2). Most of the TH-only neurons contained VMAT2 and DAT (TH-only Class 1), a few had DAT without detectable VMAT2 (TH-only Class 2), and others lacked detectable levels of both transporters (TH-only Class 3). We concluded that (a) the majority of TH neurons lacking DAT are TH-VGluT2 neurons, (b) very few TH-only neurons express DAT without VMAT2, and (c) TH-VGluT2 neurons lacking DAT also lack VMAT2. Thus, the A10 region contains dopamine neurons with differential compartmentalization and unique signaling properties. C1 [Li, Xueping; Qi, Jia; Yamaguchi, Tsuyoshi; Wang, Hui-Ling; Morales, Marisela] NIDA, Intramural Res Program, Neuronal Networks Sect, Baltimore, MD 21224 USA. [Li, Xueping] Xian Med Univ, Xian, Peoples R China. RP Morales, M (reprint author), NIDA, Intramural Res Program, Neuronal Networks Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov RI QI, JIA/A-6337-2014 FU National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. We thank Bing Liu for her help in processing brain tissue. NR 43 TC 43 Z9 43 U1 1 U2 13 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD SEP PY 2013 VL 218 IS 5 BP 1159 EP 1176 DI 10.1007/s00429-012-0452-z PG 18 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA 206CT UT WOS:000323495100006 PM 22926514 ER PT J AU Faranesh, AZ Lederman, RJ AF Faranesh, Anthony Z. Lederman, Robert J. TI Roadmaps show the way: Coregistration to enhance structural heart interventions SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material ID MAGNETIC-RESONANCE C1 [Faranesh, Anthony Z.; Lederman, Robert J.] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2C713 MSC1538, Bethesda, MD 20892 USA. EM lederman@nih.gov OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [ZID HL006061-04, ZIA HL006039-04]; NHLBI NIH HHS [ZIA HL005062] NR 5 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD SEP 1 PY 2013 VL 82 IS 3 BP 443 EP 444 DI 10.1002/ccd.25115 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 205OP UT WOS:000323454100043 PM 24038978 ER PT J AU Palys, KE Berger, VW Alperson, S AF Palys, Kaitlin E. Berger, Vance W. Alperson, Sunny TI Trial quality checklists: on the need to multiply (not add) scores SO CLINICAL ORAL INVESTIGATIONS LA English DT Letter C1 [Palys, Kaitlin E.] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. [Alperson, Sunny] Montgomery Coll, Takoma Pk, MD USA. RP Palys, KE (reprint author), Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. EM palysk@vt.edu; vb78c@nih.gov; sunny.alperson@montgomerycollege.edu NR 5 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1432-6981 J9 CLIN ORAL INVEST JI Clin. Oral Investig. PD SEP PY 2013 VL 17 IS 7 BP 1789 EP 1790 DI 10.1007/s00784-013-1020-5 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 203EP UT WOS:000323274000020 PM 23793406 ER PT J AU Mercado-Feliciano, M Herbert, RA Wyde, ME Gerken, DK Hejtmancik, MR Hooth, MJ AF Mercado-Feliciano, Minerva Herbert, Ronald A. Wyde, Michael E. Gerken, Diane K. Hejtmancik, Milton R. Hooth, Michelle J. TI Pyrogallol-associated dermal toxicity and carcinogenicity in F344/N rats and B6C3F1/N mice SO CUTANEOUS AND OCULAR TOXICOLOGY LA English DT Article DE Hyperkeratosis; hyperplasia; pyrogallol; squamous cell carcinoma; squamous papilloma ID ZERO DOSE CONTROL; CONTACT-DERMATITIS; HAIR-DYES; HAIRDRESSERS; MUTAGENICITY; POLYPHENOLS; AGENTS AB Pyrogallol (CAS No. 87-66-1), a benzenetriol used historically as a hair dye and currently in a number of industrial applications, was nominated to the National Toxicology Program (NTP) for testing based on the lack of toxicity and carcinogenicity data. Three-month and two-year toxicity studies to determine the toxicity and carcinogenicity of pyrogallol when applied to naive skin (i.e. dermal administration) were conducted in both sexes of F344/N rats and B6C3F1/N mice. In the three-month studies, adult rodents were administered pyrogallol in 95% ethanol five days per week for 3 months at doses of up to 150 mg/kg body weight (rats) or 600 mg/kg (mice). Based on the subchronic studies, the doses for the two-year studies in rats and mice were 5, 20 and 75 mg/kg of pyrogallol. All mice and most rats survived until the end of the three-month study and body weights were comparable to controls. During the two-year study, survival of dosed rats and male mice was comparable to controls; however survival of 75 mg/kg female mice significantly decreased compared to controls. The incidences of microscopic non-neoplastic lesions at the site of application were significantly higher in all dosed groups of rats and mice and in both the 3-months and two-year studies. In the two-year study, hyperplasia, hyperkeratosis and inflammation tended to be more severe in mice than in rats, and in the mice they tended to be more severe in females than in males. The incidence of squamous cell carcinoma at the site of application (SOA) in 75 mg/kg female mice and SOA squamous cell papillomas in 75 mg/kg male mice were greater than controls. Pyrogallol was carcinogenic in female mice and may have caused tumors in male mice. C1 [Mercado-Feliciano, Minerva; Herbert, Ronald A.; Wyde, Michael E.; Hooth, Michelle J.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Gerken, Diane K.; Hejtmancik, Milton R.] Battelle Mem Inst, Columbus, OH 43201 USA. RP Hooth, MJ (reprint author), NIEHS, 111 Alexander Dr,Mail Drop K2-13, Res Triangle Pk, NC 27709 USA. EM hooth@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 32 TC 2 Z9 2 U1 3 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1556-9527 EI 1556-9535 J9 CUTAN OCUL TOXICOL JI Cutan. Ocul. Toxicol. PD SEP PY 2013 VL 32 IS 3 BP 234 EP 240 DI 10.3109/15569527.2012.746358 PG 7 WC Ophthalmology; Toxicology SC Ophthalmology; Toxicology GA 206BH UT WOS:000323490400008 PM 23231012 ER PT J AU Laronda, MM Unno, K Ishi, K Serna, VA Butler, LM Mills, AA Orvis, GD Behringer, RR Deng, CX Sinha, S Kurita, T AF Laronda, Monica M. Unno, Kenji Ishi, Kazutomo Serna, Vanida A. Butler, Lindsey M. Mills, Alea A. Orvis, Grant D. Behringer, Richard R. Deng, Chuxia Sinha, Satrajit Kurita, Takeshi TI Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Mallerian duct epithelium SO DEVELOPMENTAL BIOLOGY LA English DT Article DE DES daughter; Vaginal clear cell adenocarcinoma; Endocrine disruptor; p63 ID ESTROGEN-RECEPTOR-ALPHA; KNOCKOUT MICE; P53 HOMOLOG; IN-UTERO; P63; FEMALE; EXPOSURE; MOUSE; DIFFERENTIATION; PROLIFERATION AB Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of Delta Np63, thus deciding vaginal epithelial cell fate in the Mullerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5' sequence of Delta Np63. Therefore, mice in which Smad4 was deleted in MDECs failed to express Delta Np63 in vaginal epithelium and developed adenosis. This SMAD-dependent Delta Np63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of Delta Np63 expression in vaginal epithelium. Instead, the activity of the Delta Np63 locus in vaginal epithelium was maintained by a Delta Np63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate. (C) 2013 Elsevier Inc. All rights reserved. C1 [Laronda, Monica M.; Unno, Kenji; Ishi, Kazutomo; Serna, Vanida A.; Butler, Lindsey M.; Kurita, Takeshi] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Reprod Biol, Chicago, IL 60611 USA. [Mills, Alea A.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Orvis, Grant D.; Behringer, Richard R.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20817 USA. [Sinha, Satrajit] SUNY Buffalo, Dept Biochem, Ctr Excellence Bioinformat & Life Sci, Buffalo, NY 14203 USA. RP Kurita, T (reprint author), 303 E Super St,Lurie 7-117, Chicago, IL 60611 USA. EM t-kurita@northwestern.edu RI Laronda, Monica/F-9136-2014; Kurita, Takeshi/A-2236-2013; deng, chuxia/N-6713-2016 OI Kurita, Takeshi/0000-0003-4281-5884; FU National Institutes of Health [HD30284, RO1CA154358, RO1HD064402] FX The authors thank Dr. So-Youn Kim for technical help and Stacy A. Druschitz, Drs. So-Youn Kim, Tsutomu Kume and Gerald R. Cunha for editorial suggestions. This work was supported by the National Institutes of Health [HD30284 to R.R.B, RO1CA154358 and RO1HD064402 to T.K.]. NR 48 TC 7 Z9 7 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 1 PY 2013 VL 381 IS 1 BP 5 EP 16 DI 10.1016/j.ydbio.2013.06.024 PG 12 WC Developmental Biology SC Developmental Biology GA 204WL UT WOS:000323401900003 PM 23830984 ER PT J AU Rothschild, SC Lahvic, J Francescatto, L McLeod, JJA Burgess, SM Tombes, RM AF Rothschild, Sarah C. Lahvic, Jamie Francescatto, Ludmila McLeod, Jamie J. A. Burgess, Shawn M. Tombes, Robert M. TI CaMK-II activation is essential for zebrafish inner ear development and acts through Delta-Notch signaling SO DEVELOPMENTAL BIOLOGY LA English DT Article DE CaMK-II; Cilia; Otolith; Inner ear; Delta-notch ID PROTEIN-KINASE-II; DRIVEN FLUID-FLOW; MIND-BOMB MUTANT; HAIR-CELLS; OTOLITH FORMATION; CILIARY MOTILITY; SYNAPTIC VESICLES; EPITHELIAL-CELLS; KUPFFERS VESICLE; OTIC VESICLE AB Zebrafish inner ear development is characterized by the crystallization of otoliths onto immotile kinocilia that protrude from sensory "hair" cells. The stereotypical formation of these sensory structures is dependent on the expression of key patterning genes and on Ca2+ signals. One potential target of Ca2+ signaling in the inner ear is the type II Ca2+/calmodulin-dependent protein kinase (CaMK-II), which is preferentially activated in hair cells, with intense activation at the base of kinocilia. In zebrafish, CaMK-II is encoded by seven genes; the expression of one of these genes (camk2g1) is enriched in hair cells. The suppression of camk2g1 expression by antisense morpholino oligonucleotides or inhibition of CaMK-II activation by the pharmacological antagonist, KN-93, results in aberrant otolith formation without preventing cilia formation. In fact, CaMK-II suppression results in additional ciliated hair cells and altered levels of Delta Notch signaling members. DeltaA and deltaD transcripts are increased and DeltaD protein accumulates in hair cells of CaMK-II morphants, indicative of defective recycling and/or exocytosis. Our findings indicate that CaMK-II plays a critical role in the developing ear, influencing cell differentiation through extranuclear effects on Delta Notch signaling. Continued expression and activation of CaMK-II in maculae and cristae in older embryos suggests continued roles in auditory sensory maturation and transduction. (C) 2013 Elsevier Inc. All rights reserved. C1 [Rothschild, Sarah C.; Lahvic, Jamie; Francescatto, Ludmila; McLeod, Jamie J. A.; Tombes, Robert M.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Burgess, Shawn M.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RP Tombes, RM (reprint author), Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. EM rtombes@vcu.edu OI Burgess, Shawn/0000-0003-1147-0596 FU National Science Foundation [IOS-0817658] FX The authors gratefully acknowledge Paul Vorster, Minh Nguyen, Bennett Childs, Rachel Troch, and Amritha Yelamilli for their assistance with this study and Amanda Dickinson, Greg Walsh, James Lister, Bruce Riley, Bernard Thisse, Alan Davidson, Lila Solnica-Krezel, and lain Drummond for sharing useful reagents and advice. Supported by National Science Foundation Grant IOS-0817658. NR 63 TC 2 Z9 2 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 1 PY 2013 VL 381 IS 1 BP 179 EP 188 DI 10.1016/j.ydbio.2013.05.028 PG 10 WC Developmental Biology SC Developmental Biology GA 204WL UT WOS:000323401900018 PM 23747599 ER PT J AU Toyama, R Kim, MH Rebbert, ML Gonzales, J Burgess, H Dawid, IB AF Toyama, Reiko Kim, Mi Ha Rebbert, Martha L. Gonzales, John Burgess, Harold Dawid, Igor B. TI Habenular commissure formation in zebrafish is regulated by the pineal gland-specific gene unc119c SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Zebrafish; pineal gland; epiphysis; habenular commissure; unc119; wnt4 ID RETINAL DEGENERATION; WNT PROTEINS; TRANSMEMBRANE PROTEIN; NERVOUS-SYSTEM; PHOTORECEPTOR; TRAFFICKING; SECRETION; ABLATION; ELEGANS; NITROREDUCTASE AB Background: The zebrafish pineal gland (epiphysis) is a site of melatonin production, contains photoreceptor cells, and functions as a circadian clock pacemaker. Since it is located on the surface of the forebrain, it is accessible for manipulation and, therefore, is a useful model system to analyze pineal gland function and development. We previously analyzed the pineal transcriptome during development and showed that many genes exhibit a highly dynamic expression pattern in the pineal gland. Results: Among genes preferentially expressed in the zebrafish pineal gland, we identified a tissue-specific form of the unc119 gene family, unc119c, which is highly preferentially expressed in the pineal gland during day and night at all stages examined from embryo to adult. When expression of unc119c was inhibited, the formation of the habenular commissure (HC) was specifically compromised. The Unc119c interacting factors Arl3l1 and Arl3l2 as well as Wnt4a also proved indispensible for HC formation. Conclusions: We suggest that Unc119c, together with Arl3l1/2, plays an important role in modulating Wnt4a production and secretion during HC formation in the forebrain of the zebrafish embryo. Developmental Dynamics 242: 10331042, 2013. (C) 2013 Wiley Periodicals, Inc. C1 [Toyama, Reiko; Kim, Mi Ha; Rebbert, Martha L.; Burgess, Harold; Dawid, Igor B.] NICHD, Program Genom Dev, NIH, Bethesda, MD USA. [Gonzales, John] NICHD, Charles River, NIH, Bethesda, MD USA. RP Dawid, IB (reprint author), Bldg 6B,Room 420,9000 Rockville Pike, Bethesda, MD 20892 USA. EM idawid@nih.gov RI Burgess, Harold/B-8474-2015 OI Burgess, Harold/0000-0003-1966-7801 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Grant sponsor: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 46 TC 4 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD SEP PY 2013 VL 242 IS 9 BP 1033 EP 1042 DI 10.1002/dvdy.23994 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 203TB UT WOS:000323315200004 PM 23749482 ER PT J AU Hsu, JC Koo, H Harunaga, JS Matsumoto, K Doyle, AD Yamada, KM AF Hsu, Jeff C. Koo, Hyun Harunaga, Jill S. Matsumoto, Kazue Doyle, Andrew D. Yamada, Kenneth M. TI Region-specific epithelial cell dynamics during branching morphogenesis SO DEVELOPMENTAL DYNAMICS LA English DT Article DE organ morphogenesis; salivary gland; cell migration; basement membrane; integrin; myosin II; E-cadherin; KikGR ID MOUSE SUBMANDIBULAR-GLAND; EXTRACELLULAR-MATRIX; LUNG DEVELOPMENT; MYOSIN-IIA; MIGRATION; PHOSPHORYLATION; MECHANISMS; MORPHOLOGY; INVASION; INSIGHTS AB Background: Epithelial cells of developing embryonic organs, such as salivary glands, can display substantial motility during branching morphogenesis. Their dynamic movements and molecules involved in their migration are not fully characterized. Results: We generated transgenic mice expressing photoconvertible KikGR and tracked the movements of individual cells highlighted by red fluorescence in different regions of developing salivary glands. Motility was highest for outer bud epithelial cells adjacent to the basement membrane, lower in inner bud cells, and lowest in duct cells. The highly motile outer cells contacting the basement membrane were pleomorphic, whereas inner cells were rounded. Peripheral cell motility was disrupted by antibodies inhibiting alpha 6+beta 1 integrins and the nonmuscle myosin II inhibitor blebbistatin. Inner bud cell migration was unaffected by these inhibitors, but their rate of migration was stimulated by inhibiting E-cadherin. Conclusions: Cell motility in developing salivary glands was highest in cells in contact with the basement membrane. The basement membrane-associated motility of these outer bud cells depended on integrins and myosin II, but not E-cadherin. In contrast, motility of inner bud cells was restrained by E-cadherin. These findings identify the importance of integrin-dependent basement membrane association for the morphology, tissue organization, and lateral motility of morphogenetic epithelial cells. Developmental Dynamics 242: 1066-1077, 2013. (C) 2013 Wiley Periodicals, Inc. C1 [Hsu, Jeff C.; Koo, Hyun; Harunaga, Jill S.; Matsumoto, Kazue; Doyle, Andrew D.; Yamada, Kenneth M.] NIDCR, Cell Biol Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Koo, Hyun] Univ Rochester, Med Ctr, Ctr Oral Biol, Rochester, NY 14642 USA. RP Doyle, AD (reprint author), NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM kenneth.yamada@nih.gov FU National Institute of Dental and Craniofacial Research, National Institutes of Health FX We thank Dr. Atsushi Miyawaki for the KikGR photo-convertible fluorescence probe and for advice, Dr. Kenn Holmbeck for advice on recombineering, Dr. Andrzej Dlugosz for the pCLE GFP plasmid, and Andrew Cho, Bradford Hall, Ashok Kulkarni, and the NIDCR Gene Targeting Core for generating KikGR transgenic mouse lines. Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 49 TC 16 Z9 16 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD SEP PY 2013 VL 242 IS 9 BP 1066 EP 1077 DI 10.1002/dvdy.24000 PG 12 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 203TB UT WOS:000323315200007 PM 23780688 ER PT J AU Lizunov, VA Lee, JP Skarulis, MC Zimmerberg, J Cushman, SW Stenkula, KG AF Lizunov, Vladimir A. Lee, Jo-Ping Skarulis, Monica C. Zimmerberg, Joshua Cushman, Samuel W. Stenkula, Karin G. TI Impaired Tethering and Fusion of GLUT4 Vesicles in Insulin-Resistant Human Adipose Cells SO DIABETES LA English DT Article ID FAT-CELLS; DIABETES-MELLITUS; PLASMA-MEMBRANE; PHOSPHORYLATION; TRANSLOCATION; ADIPOCYTES; OBESITY; SURFACE; TRAFFICKING; DISEASE AB Systemic glucose homeostasis is profoundly influenced by adipose cell function. Here we investigated GLUT4 dynamics in living adipose cells from human subjects with varying BMI and insulin sensitivity index (S-i) values. Cells were transfected with hemagglutinin (HA)-GLUT4-green fluorescent protein (GFP)/mCherry (red fluorescence), and were imaged live using total internal reflection fluorescence and confocal microscopy. HA-GLUT4-GFP redistribution to the plasma membrane (PM) was quantified by surface-exposed HA epitope. In the basal state, GLUT4 storage vesicle (GSV) trafficking to and fusion with the PM were invariant with donor subject S-i, as was total cell-surface GLUT4. In cells from insulin-sensitive subjects, insulin augmented GSV tethering and fusion approximately threefold, resulting in a corresponding increase in total PM GLUT4. However, with decreasing S-i, these effects diminished progressively. All insulin-induced effects on GLUT4 redistribution and trafficking correlated strongly with S-i and only weakly with BMI. Thus, while basal GLUT4 dynamics and total cell-surface GLUT4 are intact in human adipose cells, independent of donor S-i, cells from insulin-resistant donors show markedly impaired GSV tethering and fusion responses to insulin, even after overnight culture. This altered insulin responsiveness is consistent with the hypothesis that adipose cellular dysfunction is a primary contributor to systemic metabolic dysfunction. C1 [Lizunov, Vladimir A.; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Lee, Jo-Ping; Cushman, Samuel W.; Stenkula, Karin G.] NIH, Expt Diabet Metab & Nutr Sect, Bethesda, MD 20892 USA. [Skarulis, Monica C.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Stenkula, Karin G.] Lund Univ, Lund, Sweden. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM joshz@mail.nih.gov RI Bai, Li/N-8311-2013 FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 25 TC 7 Z9 7 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2013 VL 62 IS 9 BP 3114 EP 3119 DI 10.2337/db12-1741 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205DG UT WOS:000323421000018 PM 23801575 ER PT J AU Deshpande, SD Putta, S Wang, M Lai, JY Bitzer, M Nelson, RG Lanting, LL Kato, M Natarajan, R AF Deshpande, Supriya D. Putta, Sumanth Wang, Mei Lai, Jennifer Y. Bitzer, Markus Nelson, Robert G. Lanting, Linda L. Kato, Mitsuo Natarajan, Rama TI Transforming Growth Factor-beta-Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy SO DIABETES LA English DT Article ID KIDNEY-DISEASE; RENAL FIBROSIS; EXPRESSION; MECHANISM; PATHWAY; INJURY; GENE; CONTRIBUTES; ACTIVATION; GLOMERULI AB Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-beta 1 (TGF-beta), p53, and microRNA-192 (miR-192) are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to nondiabetic mice. Targeting miR-192 with locked nucleic acid-modified inhibitors in vivo decreases expression of p53 in the renal cortex of control and streptozotocin-injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-beta and p53 expression when made diabetic, and have reduced renal fibrosis, hypertrophy, proteinuria, and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-beta induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN, consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-beta-induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR-192-knockout mice are protected from key features of DN. C1 [Deshpande, Supriya D.; Natarajan, Rama] City Hope Natl Med Ctr, Beckman Res Inst, Irell & Manella Grad Sch Biol Sci, Duarte, CA USA. [Deshpande, Supriya D.; Putta, Sumanth; Wang, Mei; Lanting, Linda L.; Kato, Mitsuo; Natarajan, Rama] City Hope Natl Med Ctr, Beckman Res Inst, Dept Diabet & Metab Dis Res, Div Mol Diabet Res, Duarte, CA USA. [Lai, Jennifer Y.; Bitzer, Markus] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Nelson, Robert G.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Phoenix, AZ USA. RP Natarajan, R (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Irell & Manella Grad Sch Biol Sci, Duarte, CA USA. EM mkato@coh.org; rnatarajan@coh.org RI Kato, Mitsuo/D-5411-2009 FU National Institutes of Health [R01-DK-081705, R01-DK-058191]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by grants from the National Institutes of Health (R01-DK-081705 and R01-DK-058191 to R.N.) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (to R.G.N.). NR 49 TC 53 Z9 58 U1 1 U2 27 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2013 VL 62 IS 9 BP 3151 EP 3162 DI 10.2337/db13-0305 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205DG UT WOS:000323421000022 PM 23649518 ER PT J AU Weil, EJ Fufaa, G Jones, LI Lovato, T Lemley, KV Hanson, RL Knowler, WC Bennett, PH Yee, B Myers, BD Nelson, RG AF Weil, E. Jennifer Fufaa, Gudeta Jones, Lois I. Lovato, Tracy Lemley, Kevin V. Hanson, Robert L. Knowler, William C. Bennett, Peter H. Yee, Berne Myers, Bryan D. Nelson, Robert G. TI Effect of Losartan on Prevention and Progression of Early Diabetic Nephropathy in American Indians With Type 2 Diabetes SO DIABETES LA English DT Article ID GLOMERULAR STRUCTURAL-CHANGES; CONVERTING-ENZYME-INHIBITOR; MELLITUS; MICROALBUMINURIA; DISEASE; IRBESARTAN; ENALAPRIL; YOUNG AB Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g; n = 91) or microalbuminuria (ACR 30-299 mg/g; n = 78) at baseline. The primary outcome was decline in glomerular filtration rate (GFR) to 60 mL/min or to half the baseline value in subjects who entered with GFR <120 mL/min. Another outcome was differences in glomerular structure at end of treatment. Subjects received 100 mg losartan or placebo daily. GFR was measured annually; 111 subjects underwent kidney biopsies. Only nine subjects reached the GFR outcome, and the unadjusted hazard ratio (losartan vs. placebo) was 0.50 (95% CI, 0.12-1.99). Differences in mesangial fractional volume were not estimated in the combined albuminuria groups because of an interaction with treatment assignment. In separate analyses, mesangial fractional volume was lower in subjects treated with losartan in the microalbuminuria group (18.8 vs. 25.6%; P = 0.02), but not in the normoalbuminuria group (19.6 vs. 17.8%; P = 0.86). Treatment with losartan may preserve some features of kidney structure in American Indians with type 2 diabetes and microalbuminuria. C1 [Weil, E. Jennifer; Fufaa, Gudeta; Jones, Lois I.; Lovato, Tracy; Hanson, Robert L.; Knowler, William C.; Bennett, Peter H.; Nelson, Robert G.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Phoenix, AZ USA. [Lemley, Kevin V.] Childrens Hosp Los Angeles, Div Nephrol, Los Angeles, CA 90027 USA. [Yee, Berne] Southwest Kidney Inst, Phoenix, AZ USA. [Myers, Bryan D.] Stanford Univ, Div Nephrol, Sch Med, Stanford, CA 94305 USA. RP Nelson, RG (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Phoenix, AZ USA. EM rnelson@nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association [1-08-CR-42] FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, the American Diabetes Association (Clinical Science Award 1-08-CR-42), and by Merck, which provided the study drug and placebo tablets. No other potential conflicts of interest relevant to this article were reported. NR 26 TC 24 Z9 24 U1 1 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2013 VL 62 IS 9 BP 3224 EP 3231 DI 10.2337/db12-1512 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205DG UT WOS:000323421000030 PM 23545707 ER PT J AU Bonner, JS Lantier, L Hocking, KM Kang, L Owolabi, M James, FD Bracy, DP Brophy, CM Wasserman, DH AF Bonner, Jeffrey S. Lantier, Louise Hocking, Kyle M. Kang, Li Owolabi, Mark James, Freyja D. Bracy, Deanna P. Brophy, Colleen M. Wasserman, David H. TI Relaxin Treatment Reverses Insulin Resistance in Mice Fed a High-Fat Diet SO DIABETES LA English DT Article ID MUSCLE GLUCOSE-UPTAKE; ENDOTHELIAL GROWTH-FACTOR; SKELETAL-MUSCLE; IN-VIVO; BLOOD-FLOW; POTENTIAL MECHANISM; HYPERTENSIVE-RATS; CAPILLARY DENSITY; NITRIC-OXIDE; MICROVASCULAR RECRUITMENT AB The endogenous hormone relaxin increases vascular reactivity and angiogenesis. We demonstrate that acute relaxin infusion in lean C57BL/6J mice enhances skeletal muscle perfusion and augments muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. However, an acute effect was absent in mice fed a high-fat (HF) diet for 13 weeks. In contrast, mice fed an HF diet for 13 weeks and continuously treated with relaxin for the final 3 weeks of the diet exhibited decreased fasting blood glucose. Insulin-stimulated whole-body glucose disappearance and percent suppression of hepatic glucose production are corrected by chronic relaxin. The increase in peripheral glucose utilization is a result of augmented in vivo skeletal muscle glucose uptake. Relaxin intervention improves endothelial-dependent vascular reactivity and induces a two-fold proliferation in skeletal muscle capillarity. The metabolic effects of the treatment are not attributed to changes in myocellular insulin signaling. Relaxin intervention reverses the accumulation of collagen III in the liver and collagen III and collagen IV in the heart; this is induced by HF feeding. These studies show the potential of relaxin in the treatment of diet-induced insulin resistance and vascular dysfunction. Relaxin provides a novel therapeutic approach targeting the extramyocellular barriers to insulin action, which are critical to the pathogenesis of insulin resistance. C1 [Bonner, Jeffrey S.; Lantier, Louise; Kang, Li; Owolabi, Mark; James, Freyja D.; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Kang, Li; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. [Hocking, Kyle M.; Brophy, Colleen M.] Vanderbilt Univ, Sch Med, Dept Surg, Div Vasc Surg, Nashville, TN 37212 USA. RP Bonner, JS (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. EM jeffrey.s.bonner@vanderbilt.edu FU National Institutes of Health [DK054902, DK059637]; Diabetes Research and Training Center [DK20593] FX This work was funded by National Institutes of Health grants DK054902 andDK059637 (Mouse Metabolic Phenotyping Center). The Diabetes Research and Training Center (DK20593) also provided support for this work. NR 62 TC 15 Z9 15 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2013 VL 62 IS 9 BP 3251 EP 3260 DI 10.2337/db13-0033 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205DG UT WOS:000323421000033 PM 23801576 ER PT J AU Horton, JK Stefanick, DF Gassman, NR Williams, JG Gabel, SA Cuneo, MJ Prasad, R Kedar, PS DeRose, EF Hou, EW London, RE Wilson, SH AF Horton, Julie K. Stefanick, Donna F. Gassman, Natalie R. Williams, Jason G. Gabel, Scott A. Cuneo, Matthew J. Prasad, Rajendra Kedar, Padmini S. DeRose, Eugene F. Hou, Esther W. London, Robert E. Wilson, Samuel H. TI Preventing oxidation of cellular XRCC1 affects PARP-mediated DNA damage responses SO DNA REPAIR LA English DT Article DE DNA polymerase beta; XRCC1; PARP-1; Methyl methanesulfonate; PARP inhibitor; Poly(ADP-ribose) ID STRAND-BREAK REPAIR; BASE EXCISION-REPAIR; POLYMERASE-BETA INTERACTION; LIGASE III-ALPHA; BRCT DOMAIN; NUCLEAR ANTIGEN; PROTEIN; CELLS; POLY(ADP-RIBOSE); HYPERSENSITIVITY AB Poly(ADP-ribose) polymerase-1 (PARP-1) binds intermediates of base excision repair (BER) and becomes activated for poly(ADP-ribose) (PAR) synthesis. PAR mediates recruitment and functions of the key BER factors XRCC1 and DNA polymerase beta (pol beta) that in turn regulate PAR. Yet, the molecular mechanism and implications of coordination between XRCC1 and pol beta in regulating the level of PAR are poorly understood. A complex of PARP-1, XRCC1 and pol beta is found in vivo, and it is known that pol beta and XRCC1 interact through a redox-sensitive binding interface in the N-terminal domain of XRCC1. We confirmed here that both oxidized and reduced forms of XRCC1 are present in mouse fibroblasts. To further understand the importance of the C12-C20 oxidized form of XRCC1 and the interaction with pol beta, we characterized cell lines representing stable transfectants in Xrcc1(-/-) mouse fibroblasts of wildtype XRCC1 and two mutants of XRCC1, a novel reduced form with the C12-C20 disulfide bond blocked (C12A) and a reference mutant that is unable to bind pol beta (V88R). XRCC1-deficient mouse fibroblasts are extremely hypersensitive to methyl methanesulfonate (MMS), and transfected wild-type and C12A mutant XRCC1 proteins similarly reversed MMS hypersensitivity. However, after MMS exposure the cellular PAR level was found to increase to a much greater extent in cells expressing the C12A mutant than in cells expressing wild-type XRCC1. PARP inhibition resulted in very strong MMS sensitization in cells expressing wild-type XRCC1, but this sensitization was much less in cells expressing the C12A mutant. The results suggest a role for the oxidized form of XRCC1 in the interaction with pol beta in (1) controlling the PAR level after MMS exposure and (2) enabling the extreme cytotoxicity of PARP inhibition during the MMS DNA damage response. Published by Elsevier B.V. C1 [Horton, Julie K.; Stefanick, Donna F.; Gassman, Natalie R.; Williams, Jason G.; Gabel, Scott A.; Prasad, Rajendra; Kedar, Padmini S.; DeRose, Eugene F.; Hou, Esther W.; London, Robert E.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Cuneo, Matthew J.] Oak Ridge Natl Lab, Biol & Soft Matter Div, Oak Ridge, TN 37831 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov OI Gassman, Natalie/0000-0002-8488-2332; Cuneo, Matthew/0000-0002-1475-6656 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES050158, ES050159, Z01 ES050147] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project numbers Z01 ES050158, ES050159 to S.H.W. and Z01 ES050147 to R.E.L.). NR 37 TC 12 Z9 14 U1 0 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD SEP PY 2013 VL 12 IS 9 BP 774 EP 785 DI 10.1016/j.dnarep.2013.06.004 PG 12 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 205TT UT WOS:000323468400010 PM 23871146 ER PT J AU Akers, NK Lan, Q McHale, CM Zhang, L Thomas, R Hubbard, AE Rappaport, SM Vermeulen, R Lee, G Yin, S Rothman, N Smith, MT AF Akers, N. K. Lan, Q. McHale, C. M. Zhang, L. Thomas, R. Hubbard, A. E. Rappaport, S. M. Vermeulen, R. Lee, G. Yin, S. Rothman, N. Smith, M. T. TI Application of RNA Sequencing to Detect Fusion Transcripts in Benzene-Exposed Workers. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Akers, N. K.; McHale, C. M.; Zhang, L.; Thomas, R.; Hubbard, A. E.; Rappaport, S. M.; Smith, M. T.] Univ Calif Berkeley, Sch Publ Hlth, Superfund Res Program, Berkeley, CA 94720 USA. [Lan, Q.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Vermeulen, R.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Lee, G.; Yin, S.] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 11 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 2013 VL 54 SU 1 BP S51 EP S51 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400155 ER PT J AU Balshaw, DM AF Balshaw, D. M. TI Measuring External Environmental Exposures as Part of the Exposome. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Balshaw, D. M.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 3 U2 16 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 2013 VL 54 SU 1 BP S15 EP S15 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400011 ER PT J AU Chan, K Resnick, M Gordenin, D AF Chan, K. Resnick, M. Gordenin, D. TI In Vivo Analysis of Translesion DNA Synthesis-Mediated Bypass of Abasic Sites and Sulfite-Induced Lesions in Single-Strand DNA. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Chan, K.; Resnick, M.; Gordenin, D.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2013 VL 54 SU 1 BP S51 EP S51 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400158 ER PT J AU Heindel, J AF Heindel, J. TI Prenatal Exposures to Environmental Pollutants, Epigenetics, and Children's Health. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Heindel, J.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2013 VL 54 SU 1 BP S16 EP S16 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400018 ER PT J AU Hernandez-Ramon, EE Wise, JP Si, N Wise, SS Wise, JP Poirier, MC AF Hernandez-Ramon, E. E. Wise, Sr J. P. Si, N. Wise, S. S. Wise, Jr J. P. Poirier, M. C. TI Detection of Polycyclic Aromatic Hydrocarbon (PAH)-DNA Adducts in Epidermis from Sperm Whales (Physeter macrocephalus) in the Gulf of Mexico. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Hernandez-Ramon, E. E.; Si, N.; Poirier, M. C.] NCI, Carcinogen DNA Interact Sect, LCBG, CCR,NIH, Bethesda, MD 20892 USA. [Wise, Sr J. P.; Wise, S. S.; Wise, Jr J. P.] Univ So Maine, Dept Appl Sci Med, Wise Lab Environm & Genet Toxicol, Maine Ctr Toxicol & Environm Hlth, Portland, ME 04103 USA. NR 0 TC 0 Z9 0 U1 0 U2 7 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 2013 VL 54 SU 1 BP S50 EP S50 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400154 ER PT J AU Hobbs, CA Mercado-Feliciano, M Cora, MC McIntyre, BS Stout, MD Foster, PM Shepard, KG Swartz, CD Garantziotis, S Witt, KL Smith-Roe, SL AF Hobbs, C. A. Mercado-Feliciano, M. Cora, M. C. McIntyre, B. S. Stout, M. D. Foster, P. M. Shepard, K. G. Swartz, C. D. Garantziotis, S. Witt, K. L. Smith-Roe, S. L. TI Black Cohosh Extract is Genotoxic in Rodents and Induces Hematological Changes Associated with Disruption of Folate Metabolism SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Hobbs, C. A.; Shepard, K. G.; Swartz, C. D.] ILS Inc, Genet & Mol Toxicol Div, Res Triangle Pk, NC USA. [Mercado-Feliciano, M.; Cora, M. C.; McIntyre, B. S.; Stout, M. D.; Foster, P. M.; Witt, K. L.; Smith-Roe, S. L.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Garantziotis, S.] NIEHS, Clin Res Program, Res Triangle Pk, NC 27709 USA. [Mercado-Feliciano, M.] US EPA, Div Hlth Effects, Off Pesticide Programs, Washington, DC 20460 USA. RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 1 U2 10 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 2013 VL 54 SU 1 BP S27 EP S27 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400059 ER PT J AU McHale, C Thomas, R Lan, Q Hubbard, A Zhang, L Vermeulen, R Li, G Rappaport, S Yin, S Rothman, N Smith, M AF McHale, C. Thomas, R. Lan, Q. Hubbard, A. Zhang, L. Vermeulen, R. Li, G. Rappaport, S. Yin, S. Rothman, N. Smith, M. TI Analysis of Global Gene Expression in Benzene-Exposed and Control Workers by RNA-Sequencing: A Pilot Study. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [McHale, C.; Thomas, R.; Hubbard, A.; Zhang, L.; Rappaport, S.; Smith, M.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Lan, Q.; Rothman, N.] NCI, Bethesda, MD 20892 USA. [Vermeulen, R.] Univ Utrecht, Utercht, Netherlands. [Li, G.; Yin, S.] China Ctr Dis Control, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 1 U2 6 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 2013 VL 54 SU 1 BP S40 EP S40 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400113 ER PT J AU Rivera, AV Sanchez, VC Poirier, MC Olivero, OA AF Rivera, A., V Sanchez, V. C. Poirier, M. C. Olivero, O. A. TI A Novel Mechanism of Zidovudine-Induced Cytotoxicity Involves Abnormal Polymerization of alpha and beta-Tubulin. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Rivera, A., V; Poirier, M. C.; Olivero, O. A.] NCI, Carcinogen DNA Interact, NIH, Bethesda, MD 20892 USA. [Sanchez, V. C.] In Vitro Pathogenesis, 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 2013 VL 54 SU 1 BP S39 EP S39 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400109 ER PT J AU Swartz, C Green, A Garibaldi, P Recio, L Witt, K AF Swartz, C. Green, A. Garibaldi, P. Recio, L. Witt, K. TI Results of Genotoxicity Testing of Drinking Water Contaminants Demonstrates the Importance of Using a Broad Test Battery SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Swartz, C.; Green, A.; Garibaldi, P.; Recio, L.] Integrated Syst Lab, Res Triangle Pk, NC USA. [Witt, K.] NIEHS, 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 2013 VL 54 SU 1 BP S49 EP S49 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400150 ER PT J AU Wilson, SH AF Wilson, S. H. TI Understanding Step-to-Step Coordination during Base Lesion DNA Repair. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Wilson, S. H.] NIEHS, NIH, 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 2013 VL 54 SU 1 BP S22 EP S22 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400042 ER PT J AU Suren, P Stoltenberg, C Bresnahan, M Hirtz, D Lie, KK Lipkin, WI Magnus, P Reichborn-Kjennerud, T Schjolberg, S Susser, E Oyen, AS Li, L Hornig, M AF Suren, Pal Stoltenberg, Camilla Bresnahan, Michaeline Hirtz, Deborah Lie, Kari Kveim Lipkin, W. Ian Magnus, Per Reichborn-Kjennerud, Ted Schjolberg, Synnve Susser, Ezra Oyen, Anne-Siri Li, Leah Hornig, Mady TI Early Growth Patterns in Children with Autism SO EPIDEMIOLOGY LA English DT Article AB Background: Case-control studies have found increased head growth during the first year of life in children with autism spectrum disorder. Length and weight have not been as extensively studied, and there are few studies of population-based samples. Methods: The study was conducted in a sample of 106,082 children from the population-based Norwegian Mother and Child Cohort. The children were born in 1999-2009; by the end of follow-up on 31 December 2012, the age range was 3.6 through 13.1 years (mean 7.4 years). Measures were obtained prospectively until age 12 months for head circumference and 36 months for length and weight. We compared growth trajectories in autism spectrum disorder cases and noncases using Reed first-order models. Results: Subjects included 376 children (310 boys and 66 girls) with specialist-confirmed autism spectrum disorder. In boys with autism spectrum disorder, mean head growth was similar to that of other boys, but variability was greater, and 8.7% had macrocephaly (head circumference >97th cohort percentile) by 12 months of age. Autism spectrum disorder boys also had slightly increased body growth, with mean length 1.1cm above and mean weight 300g above the cohort mean for boys at age 12 months. Throughout the first year, the head circumference of girls with autism spectrum disorder was reduced by 0.3cm at birth and 0.5cm at 12 months. Their mean length was similar to that of other girls, but their mean weight was 150-350g below at all ages from birth to 3 years. The reductions in mean head circumference and weight in girls with autism spectrum disorder appear to be driven by those with intellectual disability, genetic disorders, and epilepsy. Discussion: Growth trajectories in children with autism spectrum disorder diverge from those of other children and the differences are sex specific. Previous findings of increased mean head growth were not replicated. C1 [Suren, Pal; Li, Leah] UCL Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Suren, Pal; Stoltenberg, Camilla; Lie, Kari Kveim; Magnus, Per; Reichborn-Kjennerud, Ted; Schjolberg, Synnve; Oyen, Anne-Siri] Norwegian Inst Publ Hlth, N-0403 Oslo, Norway. [Bresnahan, Michaeline; Lipkin, W. Ian; Susser, Ezra; Hornig, Mady] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Bresnahan, Michaeline; Susser, Ezra] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hirtz, Deborah] NINDS, Bethesda, MD 20892 USA. [Reichborn-Kjennerud, Ted] Univ Oslo, Inst Psychiat, Oslo, Norway. [Oyen, Anne-Siri] Lovisenberg Hosp, Nic Waals Inst, Oslo, Norway. RP Suren, P (reprint author), Norwegian Inst Publ Hlth, POB 4404 Nydalen, N-0403 Oslo, Norway. EM pal.suren@fhi.no FU Norwegian Ministry of Health and Care Services; Norwegian Ministry of Education and Research; Research Council of Norway/FUGE [151918]; National Institute of Neurological Disorders and Stroke (NIH/NINDS), Bethesda [NS47537]; National Institute of Environmental Health Sciences (NIH/NIEHS), Research Triangle Park, NC [NO-ES-75558]; NINDS [NS47537 [Lipkin]]; Research Council of Norway [185476, 190694]; UK Medical Research Council (MRC) Career Development Award in Biostatistics; MRC FX The Norwegian Mother and Child Cohort is supported by the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research, the Research Council of Norway/FUGE (grant 151918), the National Institute of Neurological Disorders and Stroke (NIH/NINDS), Bethesda (grant NS47537), and the National Institute of Environmental Health Sciences (NIH/NIEHS), Research Triangle Park, NC (contract NO-ES-75558). The Autism Birth Cohort study is funded by the NINDS (grant NS47537 [Lipkin]). P.S. is funded by the Research Council of Norway, grant numbers 185476 and 190694. L.L. is funded by a UK Medical Research Council (MRC) Career Development Award in Biostatistics. The Centre for Paediatric Epidemiology and Biostatistics is supported by the MRC in its capacity as the MRC Centre of Epidemiology for Child Health. NR 36 TC 18 Z9 18 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2013 VL 24 IS 5 BP 660 EP 670 DI 10.1097/EDE.0b013e31829e1d45 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200YL UT WOS:000323107600006 PM 23867813 ER PT J AU Menke, A Orchard, TJ Imperatore, G Bullard, KM Mayer-Davis, E Cowie, CC AF Menke, Andy Orchard, Trevor J. Imperatore, Giuseppina Bullard, Kai McKeever Mayer-Davis, Elizabeth Cowie, Catherine C. TI The Prevalence of Type 1 Diabetes in the United States SO EPIDEMIOLOGY LA English DT Letter C1 [Menke, Andy] Social & Sci Syst Inc, Silver Spring, MD USA. [Orchard, Trevor J.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Imperatore, Giuseppina; Bullard, Kai McKeever] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, Atlanta, GA USA. [Mayer-Davis, Elizabeth] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Cowie, Catherine C.] NIDDK, NIH, Bethesda, MD USA. RP Menke, A (reprint author), Social & Sci Syst Inc, Silver Spring, MD USA. EM amenke@s-3.com OI orchard, trevor/0000-0001-9552-3215 FU Intramural CDC HHS [CC999999]; PHS HHS [GS10F0381L] NR 8 TC 15 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 2013 VL 24 IS 5 BP 773 EP 774 DI 10.1097/EDE.0b013e31829ef01a PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200YL UT WOS:000323107600019 PM 23903880 ER PT J AU Rahu, K Hakulinen, T Smailyte, G Stengrevics, A Auvinen, A Inskip, PD Boice, JD Rahu, M AF Rahu, Kaja Hakulinen, Timo Smailyte, Giedre Stengrevics, Aivars Auvinen, Anssi Inskip, Peter D. Boice, John D., Jr. Rahu, Mati TI Site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986-2007 SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Chernobyl nuclear accident; Neoplasms; Incidence; Radiation effects; Estonia; Latvia; Lithuania ID THYROID-CANCER; LIQUIDATORS; ESTONIA; CONSEQUENCES; MORTALITY; LATVIA AB Objective: To assess site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986-2007. Methods: The Baltic cohort includes 17,040 men from Estonia, Latvia and Lithuania who participated in the environmental cleanup after the accident at the Chernobyl Nuclear Power Station in 1986-1991 and who were followed up for cancer incidence until the end of 2007. Cancer cases diagnosed in the cohort and in the male population of each country were identified from the respective national cancer registers. The proportional incidence ratio (PIR) with 95% confidence interval (CI) was used to estimate the site-specific cancer risk in the cohort. For comparison and as it was possible, the site-specific standardised incidence ratio (SIR) was calculated for the Estonian sub-cohort, which was not feasible for the other countries. Results: Overall, 756 cancer cases were reported during 1986-2007. A higher proportion of thyroid cancers in relation to the male population was found (PIR = 2.76; 95% CI 1.63-4.36), especially among those who started their mission shortly after the accident, in April-May 1986 (PIR = 6.38; 95% CI 2.34-13.89). Also, an excess of oesophageal cancers was noted (PIR = 1.52; 95% CI 1.06-2.11). No increased PIRs for leukaemia or radiation-related cancer sites combined were observed. PIRs and SIRs for the Estonian sub-cohort demonstrated the same site-specific cancer risk pattern. Conclusion: Consistent evidence of an increase in radiation-related cancers in the Baltic cohort was not observed with the possible exception of thyroid cancer, where conclusions are hampered by known medical examination including thyroid screening among cleanup workers. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Rahu, Kaja; Rahu, Mati] Natl Inst Hlth Dev, Dept Epidemiol & Biostat, EE-11619 Tallinn, Estonia. [Hakulinen, Timo] Finnish Canc Registry, FIN-00170 Helsinki, Finland. [Smailyte, Giedre] Vilnius Univ, Inst Oncol, Lithuanian Canc Registry, Vilnius, Lithuania. [Stengrevics, Aivars] Latvian Canc Registry, Riga, Latvia. [Auvinen, Anssi] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Auvinen, Anssi] Radiat & Nucl Safety Author, Helsinki, Finland. [Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Boice, John D., Jr.] Natl Council Radiat Protect & Measurements, Bethesda, MD USA. [Boice, John D., Jr.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. RP Rahu, K (reprint author), Natl Inst Hlth Dev, Hiiu 42, EE-11619 Tallinn, Estonia. EM kaja.rahu@tai.ee RI Rahu, Mati/A-9981-2008; OI Auvinen, Anssi/0000-0003-1125-4818 FU Estonian Ministry of Education and Science [SF0940026s07]; Estonian Research Council [IUT5-1]; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; US National Cancer Institute [N01-CP-85638-03] FX This study was supported financially by the Estonian Ministry of Education and Science (target funding SF0940026s07), the Estonian Research Council (IUT5-1) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The initial work was financed by US National Cancer Institute Contract N01-CP-85638-03. NR 33 TC 8 Z9 10 U1 1 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 IS 13 BP 2926 EP 2933 DI 10.1016/j.ejca.2013.04.014 PG 8 WC Oncology SC Oncology GA 194JD UT WOS:000322627300019 PM 23683549 ER PT J AU Ghayee, HK Giubellino, A Click, A Kapur, P Christie, A Xie, XJ Martucci, V Shay, JW Souza, RF Pacak, K AF Ghayee, Hans K. Giubellino, Alessio Click, Arielle Kapur, Payal Christie, Alana Xie, Xian-Jin Martucci, Victoria Shay, Jerry W. Souza, Rhonda F. Pacak, Karel TI Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE Paraganglioma; pmTOR; SDHB ID NEUROENDOCRINE TUMORS; PHEOCHROMOCYTOMA; EVEROLIMUS; MUTATIONS; GROWTH; HYPOXIA; RAD001 AB Background Pheochromocytomas (PCCs)/paragangliomas (PGLs) are neuroendocrine tumours that may cause arrhythmia and death if untreated. Treatment for patients with metastatic tumours is lacking. As new PCC/PGL susceptibility genes are discovered that are associated with the mTOR pathway, treatment targets focusing on this pathway are being intensively explored. Design Twenty-one human PCC/PGLs were analysed from two tertiary care centres. Immunohistochemistry (IHC) analysis was performed for phospho-mTOR (pmTOR), phospho-S6K (pS6K), phosphoinositide 3-kinase (PI3K), phospho-4EBP1 (p4EBP1), HIF1 alpha and MIB-1 in 6 metastatic SDHB PCC/PGLs, 15 nonmetastatic PCC/PGLs, (including 1 TMEM127 PCC and 1 nonmetastatic SDHB PGL) and 6 normal adrenal medullas. The product of the intensity of stain and percentage of cells stained was calculated as an H score. Results Using a two-sample t-test and paired t-test, pmTOR and pS6K had significantly higher H scores in nonmetastatic PCC/PGLs than in metastatic SDHB PCC/PGLs. HIF1 alpha had significantly higher H scores in metastatic SDHB PCC/PGLs compared with nonmetastatic PCC/PGLs and normal adrenal medulla. No difference in H scores was seen with p4EBP1, PI3K and MIB-1 when comparing metastatic SDHB PCC/PGLs and nonmetastatic PCC/PGLs. Significantly higher difference in pS6K was seen in normal adrenal medullas compared to nonmetastatic PCC/PGLs and metastatic SDHB PCC/PGLs. Conclusion The present results suggest that the use of mTOR inhibitors alone for metastatic SDHB PCC/PGLs may not achieve good therapeutic efficacy in patients. C1 [Ghayee, Hans K.; Souza, Rhonda F.] Univ Texas SW Med Ctr Dallas, VA North Texas Hlth Care Syst, Dept Internal Med, Dallas, TX 75235 USA. [Giubellino, Alessio; Martucci, Victoria; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Click, Arielle; Shay, Jerry W.] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75235 USA. [Kapur, Payal] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75235 USA. [Christie, Alana; Xie, Xian-Jin] Univ Texas SW Med Ctr Dallas, Simmons Canc Ctr, Dallas, TX 75235 USA. [Xie, Xian-Jin] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75235 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU North American Neuroendocrine Tumor Society (NANETS); American Cancer Society University of Texas Southwestern Institutional Grant FX The authors are grateful to Amita Kathuria, MD at the University of Texas Southwestern Medical Center for helpful discussions and for reviewing this manuscript. This study was funded by the North American Neuroendocrine Tumor Society (NANETS) and the American Cancer Society University of Texas Southwestern Institutional Grant (to HKG). NR 22 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD SEP PY 2013 VL 43 IS 9 BP 970 EP 977 DI 10.1111/eci.12127 PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 201PA UT WOS:000323152800010 PM 23889685 ER PT J AU Klabunde, CN Willis, GB Casalino, LP AF Klabunde, Carrie N. Willis, Gordon B. Casalino, Lawrence P. TI Facilitators and Barriers to Survey Participation by Physicians: A Call to Action for Researchers SO EVALUATION & THE HEALTH PROFESSIONS LA English DT Article DE survey; physician; response rates; qualitative research; clinicians ID RESPONSE RATES; MEDICAL GROUPS AB Surveys of health care providers are a well-established tool for obtaining information about the organization and delivery of care as well as about provider knowledge and attitudes. However, declining response rates to provider surveys are a widely acknowledged concern. Although a number of studies have identified specific methods for increasing response rates in health care providerand particularly physiciansurveys, few have addressed the more fundamental question of what motivates or deters providers from survey participation. We briefly review theoretical perspectives concerning why providers choose to participate in surveys, and what is known about facilitators and barriers to participation. We then describe several research designs (i.e., focus groups, key informant interviews, diary and office workflow studies, surveying the surveyors, and follow-back studies of respondents/nonrespondents) for obtaining empirical data on facilitators and barriers to survey participation, particularly by physicians and medical groups. Researchers must begin to build an evidence base for understanding provider decisions concerning survey participation. C1 [Klabunde, Carrie N.; Willis, Gordon B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Casalino, Lawrence P.] Weill Cornell Med Coll, Dept Publ Hlth, Div Outcomes & Effectiveness Res, New York, NY USA. RP Klabunde, CN (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, EPN 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. EM KlabundC@mail.nih.gov NR 31 TC 16 Z9 16 U1 0 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0163-2787 J9 EVAL HEALTH PROF JI Eval. Health Prof. PD SEP PY 2013 VL 36 IS 3 SI SI BP 279 EP 295 DI 10.1177/0163278713496426 PG 17 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 205HK UT WOS:000323434100002 PM 23975758 ER PT J AU Kranick, SM Hallett, M AF Kranick, Sarah M. Hallett, Mark TI Neurology of volition SO EXPERIMENTAL BRAIN RESEARCH LA English DT Review DE Volition; Agency; Will; Movement disorders; Psychogenic; Anosognosia; Alien hand; Passivity phenomena ID LA-TOURETTE SYNDROME; MOVEMENT-RELATED POTENTIALS; MOTOR CONVERSION DISORDER; ALIEN HAND SYNDROME; HUNTINGTONS-DISEASE; UTILIZATION BEHAVIOR; VOLUNTARY MOVEMENT; SENSORY CONSEQUENCES; PSYCHOGENIC TREMOR; STRUCTURAL-CHANGES AB Neurological disorders of volition may be characterized by deficits in willing and/or agency. When we move our bodies through space, it is the sense that we intended to move (willing) and that our actions were a consequence of this intention (self-agency) that gives us the sense of voluntariness and a general feeling of being "in control." While it is possible to have movements that share executive machinery ordinarily used for voluntary movement but lack a sense of voluntariness, such as psychogenic movement disorders, it is also possible to claim volition for presumed involuntary movements (early chorea) or even when no movement is produced (anosognosia). The study of such patients should enlighten traditional models of how the percepts of volition are generated in the brain with regard to movement. We discuss volition and its components as multi-leveled processes with feedforward and feedback information flow, and dependence on prior expectations as well as external and internal cues. C1 [Kranick, Sarah M.; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Kranick, SM (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, 10-6-5700,10 Ctr Dr,MSC 1430, Bethesda, MD 20892 USA. EM sarah.kranick@nih.gov FU NINDS Intramural Program FX This research was supported by the NINDS Intramural Program. NR 83 TC 8 Z9 9 U1 8 U2 30 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD SEP PY 2013 VL 229 IS 3 BP 313 EP 327 DI 10.1007/s00221-013-3399-2 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 203IY UT WOS:000323287000004 PM 23329204 ER PT J AU Beinart, R Khurram, IM Liu, ST Yarmohammadi, H Halperin, HR Bluemke, DA Gai, N van der Geest, RJ Lima, JAC Calkins, H Zimmerman, SL Nazarian, S AF Beinart, Roy Khurram, Irfan M. Liu, Songtao Yarmohammadi, Hirad Halperin, Henry R. Bluemke, David A. Gai, Neville van der Geest, Rob J. Lima, Joao A. C. Calkins, Hugh Zimmerman, Stefan L. Nazarian, Saman TI Cardiac magnetic resonance T1 mapping of left atrial myocardium SO HEART RHYTHM LA English DT Article DE Atrial fibrillation; Cardiac magnetic resonance; T1 mapping; Left atrial fibrosis; Late gadolinium enhancement ID CATHETER ABLATION; DELAYED-ENHANCEMENT; PULMONARY VEIN; FIBRILLATION; FIBROSIS; MRI; CARDIOMYOPATHY; DISEASE; DYSFUNCTION; ASSOCIATION AB BACKGROUND Cardiac magnetic resonance (CMR) T1 mapping is an emerging tool for objective quantification of myocardial fibrosis. OBJECTIVES To (a) establish the feasibility of left atrial (LA) T1 measurements, (b) determine the range of LA T1 values in patients with atrial fibrillation (AF) vs healthy volunteers, and (c) validate T1 mapping vs LA intracardiac electrogram voltage amplitude measures. METHODS CMR imaging at 1.5 T was performed in 51 consecutive patients before AF ablation and in 16 healthy volunteers. T1 measurements were obtained from the posterior LA myocardium by using the modified Look-Locker inversion-recovery sequence. Given the established association of reduced electrogram amplitude with fibrosis, intracardiac point-by-point bipolar LA voltage measures were recorded for the validation of T1 measurements. RESULTS The median LA T1 relaxation time was shorter in patients with AF (387 [interquartile range 364-428] ms) compared to healthy volunteers (459 [interquartile range 418-532] ms; P < .001) and was shorter in patients with AF with prior ablation compared to patients without prior ablation (P = .035). In a generalized estimating equations model., adjusting for data clusters per participant, age, rhythm during CMR, prior ablation, AF type, hypertension, and diabetes, each 100-ms increase in T1 relaxation time was associated with 0.1 mV increase in intracardiac bipolar LA voltage (P = .025). CONCLUSIONS Measurement of the LA myocardium T1 relaxation time is feasible and strongly associated with invasive voltage measures. This methodology may improve the quantification of fibrotic changes in thin-walled myocardial tissues. C1 [Beinart, Roy; Khurram, Irfan M.; Yarmohammadi, Hirad; Halperin, Henry R.; Lima, Joao A. C.; Calkins, Hugh; Nazarian, Saman] Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. [Liu, Songtao; Bluemke, David A.; Gai, Neville] NIH, Bethesda, MD 20892 USA. [van der Geest, Rob J.] Leiden Univ, Dept Radiol, Leiden, Netherlands. [Zimmerman, Stefan L.] Johns Hopkins Univ Hosp, Dept Radiol, Baltimore, MD 21287 USA. RP Beinart, R (reprint author), Johns Hopkins Univ Hosp, 702 Rutland Ave,Traylor 903, Baltimore, MD 21287 USA. EM rbeiner1@jhmi.edu RI van der Geest, Rob/J-8193-2015; OI van der Geest, Rob/0000-0002-9084-5597; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [K23HL089333]; Dr Francis P. Chiaramonte Foundation; Norbert and Louise Grunwald Cardiac Arrhythmia Research Fund; Biosense Webste FX The study was funded by National Institutes of Health grant K23HL089333 (to Dr Nazarian) and by the Dr Francis P. Chiaramonte Foundation and the Norbert and Louise Grunwald Cardiac Arrhythmia Research Fund. Dr Nazarian is on the MRI Advisory Panel (unpaid) for Medtronic and is a scientific advisor to Biosense Webster; he is also the principal investigator for research funding awarded to Johns Hopkins from Biosense Webster and from the National Institutes of Health (K23HL089333). Dr van der Geest is a consultant to Medis Medical Imaging Systems. NR 34 TC 31 Z9 31 U1 3 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD SEP PY 2013 VL 10 IS 9 BP 1325 EP 1331 DI 10.1016/j.hrthm.2013.01.003 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 206CQ UT WOS:000323494600021 PM 23643513 ER PT J AU Nugent, AC Luckenbaugh, DA Wood, SE Bogers, W Zarate, CA Drevets, WC AF Nugent, Allison C. Luckenbaugh, David A. Wood, Suzanne E. Bogers, Wendy Zarate, Carlos A., Jr. Drevets, Wayne C. TI Automated subcortical segmentation using FIRST: Test-retest reliability, interscanner reliability, and comparison to manual segmentation SO HUMAN BRAIN MAPPING LA English DT Article DE brain; volume; amygdale; hippocampus; caudate; putamen; pallidum; accumbens; thalamus ID BIPOLAR DISORDER; MOOD DISORDERS; BRAIN VOLUMES; MRI AB Multiple techniques exist for the automated segmentation of magnetic resonance images (MRIs). The validity of these techniques can be assessed by evaluating test-retest reliability, interscanner reliability, and consistency with manual segmentation. We evaluate these measures for the FSL/FIRST subcortical segmentation tool. We retrospectively analyzed 190 MRI scans from 87 subjects with mood or anxiety disorders and healthy volunteers scanned multiple times on different platforms (N = 56) and/or the same platform (N = 45, groups overlap), and 146 scans from subjects who underwent both high-resolution and whole brain imaging in a single session, for comparison with manual segmentation of the hippocampus. The thalamus, caudate, putamen, hippocampus, and pallidum were reliably segmented in different sessions on the same scanner (Intraclass correlation coefficient (ICC) > 0.83 scanners and diagnostic groups pooled). In these regions, the range of between platform reliabilities were lower (0.527 < ICC < 0.953), although values below 0.7 were due to systematic differences between platforms or low reliability in the hippocampus between eight- and single-channel coil platforms. Accumbens and amygdala segmentations were generally unreliable within and between scanning platforms. ICC values for hippocampal volumes between automated and manual segmentations were acceptable (ICC > 0.7, groups pooled), and both methods detected significant differences between genders. In addition, FIRST segmentations were consistent with manual segmentations (in a subset of images; N = 20) in the left caudate and bilateral putamen. This retrospective analysis assesses realistic performance of the algorithm in conditions like those found in multisite trials or meta-analyses. In addition, the inclusion of psychiatric patients establishes reliability in subjects exhibiting volumetric abnormalities, validating patient studies. Hum Brain Mapp 34:2313-2329, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Nugent, Allison C.; Luckenbaugh, David A.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Wood, Suzanne E.] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Bogers, Wendy; Drevets, Wayne C.] Univ Oklahoma, Coll Med, Dept Psychiat, Laureate Inst Brain Res, Tulsa, OK USA. RP Nugent, AC (reprint author), NIMH, Sect Neuroimaging Mood Disorders, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr,MSC 1030, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov OI Nugent, Allison/0000-0003-2569-2480 FU NIMH (Intramural Research Program) FX Contract grant sponsor: NIMH (Intramural Research Program). NR 18 TC 33 Z9 33 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2013 VL 34 IS 9 BP 2313 EP 2329 DI 10.1002/hbm.22068 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 203UZ UT WOS:000323320800026 PM 22815187 ER PT J AU You, XZ Adjouadi, M Wang, J Guillen, MR Bernal, B Sullivan, J Donner, E Bjornson, B Berl, M Gaillard, WD AF You, Xiaozhen Adjouadi, Malek Wang, Jin Guillen, Magno R. Bernal, Byron Sullivan, Joseph Donner, Elizabeth Bjornson, Bruce Berl, Madison Gaillard, William D. TI A decisional space for fMRI pattern separation using the principal component analysisa comparative study of language networks in pediatric epilepsy SO HUMAN BRAIN MAPPING LA English DT Article DE brain activation pattern; data-driven clustering; fMRI; epilepsy; language; lateralization indices; PCA-based decisional space; visual rating ID INTRACAROTID AMOBARBITAL PROCEDURE; FUNCTIONAL MRI; WADA TEST; CEREBRAL LATERALIZATION; BRAIN INJURY; DOMINANCE; ACTIVATION; HANDEDNESS; LOCALIZATION; PEOPLE AB Atypical functional magnetic resonance imaging (fMRI) language patterns may be identified by visual inspection or by region of interest (ROI)-based laterality indices (LI) but are constrained by a priori assumptions. We compared a data-driven novel application of principal component analysis (PCA) to conventional methods. We studied 122 fMRI data sets from control and localization-related epilepsy patients provided by five children's hospitals. Each subject performed an auditory description decision task. The data sets, acquired with different scanners but similar acquisition parameters, were processed through fMRIB software library to obtain 3D activation maps in standard space. A PCA analysis was applied to generate the decisional space and the data cluster into three distinct activation patterns. The classified activation maps were interpreted by (1) blinded reader rating based on predefined language patterns and (2) by language area ROI-based LI (i.e., fixed threshold vs. bootstrap approaches). The different classification results were compared through inter-rater agreement statistics. The unique decisional space classified activation maps into three clusters (a) lower intensity typical language representation, (b) higher intensity typical, as well as (c) higher intensity atypical representation. Inter-rater agreements among the three raters were excellent (Fleiss = 0.85, P = 0.05). There was substantial to excellent agreement between the conventional visual rating and LI methods ( = 0.69-0.82, P = 0.05). The PCA-based method yielded excellent agreement with conventional methods ( = 0.82, P = 0.05). The automated and data-driven PCA decisional space segregates language-related activation patterns in excellent agreement with current clinical rating and ROI-based methods. Hum Brain Mapp 34:2330-2342, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [You, Xiaozhen] Florida Int Univ, Dept Biomed Engn, Miami, FL 33174 USA. [You, Xiaozhen] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. [Adjouadi, Malek; Wang, Jin] Florida Int Univ, Dept Elect & Comp Engn, Miami, FL 33174 USA. [Guillen, Magno R.; Bernal, Byron] Miami Childrens Hosp, Dept Radiol, Miami, FL USA. [Sullivan, Joseph] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Donner, Elizabeth] Hosp Sick Children, Dept Neurol, Toronto, ON M5G 1X8, Canada. [Bjornson, Bruce] BC Childrens Hosp, Div Neurol, Vancouver, BC, Canada. [Bjornson, Bruce] Child & Family Res Inst, Vancouver, BC, Canada. [Berl, Madison; Gaillard, William D.] George Washington Univ, Childrens Natl Med Ctr, Dept Neurosci, Washington, DC USA. [Gaillard, William D.] Georgetown Univ, Dept Neurol, Washington, DC USA. [Gaillard, William D.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Adjouadi, M (reprint author), Florida Int Univ, Coll Engn & Comp, 10555 W Flagler St,EC 2672, Miami, FL 33174 USA. EM adjouadi@fiu.edu RI Bjornson, Bruce/A-8616-2010; OI Bjornson, Bruce/0000-0002-1465-6196; Guilen, Magno/0000-0001-9649-8429 FU American Epilepsy Society [NINDS R01 NS44280]; Children's Research Institute Avery Award, Intellectual and Developmental Disabilities Research Center at Children's National Medical Center [NIH IDDRC P30HD40677]; General Clinic Research Center [NIH GCRC M01-RR13297]; National Science Foundation [HRD-0833093, CNS-0959985, CNS-1042341]; Ware Foundation; Miami Children's Hospital FX Contract grant sponsor: The American Epilepsy Society; Contract grant number: NINDS R01 NS44280; Contract grant sponsor: Children's Research Institute Avery Award, Intellectual and Developmental Disabilities Research Center at Children's National Medical Center; Contract grant number: NIH IDDRC P30HD40677; Contract grant sponsor: The General Clinic Research Center; Contract grant number: NIH GCRC M01-RR13297; Contract grant sponsor: The National Science Foundation; Contract grant numbers: HRD-0833093, CNS-0959985, CNS-1042341; Contract grant sponsor: Ware Foundation and the joint Neuro-Engineering Program with Miami Children's Hospital. NR 48 TC 8 Z9 8 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2013 VL 34 IS 9 BP 2330 EP 2342 DI 10.1002/hbm.22069 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 203UZ UT WOS:000323320800027 PM 22461299 ER PT J AU Kantor, DB Palmer, CD Young, TR Meng, Y Gajdos, ZK Lyon, H Price, AL Pollack, S London, SJ Loehr, LR Smith, LJ Kumar, R Jacobs, DR Petrini, MF O'Connor, GT White, WB Papanicolaou, G Burkart, KM Heckbert, SR Barr, RG Hirschhorn, JN AF Kantor, David B. Palmer, Cameron D. Young, Taylor R. Meng, Yan Gajdos, Zofia K. Lyon, Helen Price, Alkes L. Pollack, Samuela London, Stephanie J. Loehr, Laura R. Smith, Lewis J. Kumar, Rajesh Jacobs, David R., Jr. Petrini, Marcy F. O'Connor, George T. White, Wendy B. Papanicolaou, George Burkart, Kristin M. Heckbert, Susan R. Barr, R. Graham Hirschhorn, Joel N. TI Replication and fine mapping of asthma-associated loci in individuals of African ancestry SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; POPULATIONS; METAANALYSIS; VARIANTS; SUSCEPTIBILITY; EFFICIENT; DISEASE; SAMPLE; GENE AB Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry. C1 [Kantor, David B.] Boston Childrens Hosp, Div Crit Care Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Palmer, Cameron D.; Young, Taylor R.; Meng, Yan; Gajdos, Zofia K.; Lyon, Helen; Hirschhorn, Joel N.] Broad Inst, Program Med & Populat Genet, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Price, Alkes L.; Pollack, Samuela] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Price, Alkes L.; Pollack, Samuela] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [London, Stephanie J.] NIEHS, Div Intramural Res, DHHS, NIH, Res Triangle Pk, NC 27709 USA. [Loehr, Laura R.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Smith, Lewis J.] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60611 USA. [Kumar, Rajesh] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Jacobs, David R., Jr.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Petrini, Marcy F.] Univ Mississippi, Med Ctr, Div Pulm Crit Care & Sleep Med, Jackson, MS 39216 USA. [O'Connor, George T.] Boston Univ, Dept Med, Ctr Pulm, Sch Med, Boston, MA 02118 USA. [White, Wendy B.] Tougaloo Coll, Tougaloo, MS 39174 USA. [White, Wendy B.] Jackson Heart Study, Tougaloo, MS 39174 USA. [Papanicolaou, George] NHLBI, Div Prevent & Populat Sci, NIH, Rockledge Ctr 2, Bethesda, MD 20892 USA. [Burkart, Kristin M.] Columbia Univ, Coll Phys & Surg, Div Pulm Allergy & Crit Care, New York, NY 10032 USA. [Heckbert, Susan R.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, Dept Med,Coll Phys & Surg, New York, NY 10032 USA. [Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Hirschhorn, JN (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM david.kantor@childrens.harvard.edu; joelh@broadinstitute.org OI Smith, Lewis J/0000-0002-4728-1562; O'Connor, George/0000-0002-6476-3926; London, Stephanie/0000-0003-4911-5290 FU National Heart, Lung, and Blood Institute [HHSN26800625226C, N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Institutes of Health [T32 5T32HD040128-09]; American Asthma Foundation; American Medical Association; NIH, National Institute of Environmental Health Sciences; University of North Carolina at Chapel Hill [N01-HC-55015, N01-HC-55018]; Baylor Medical College [N01-HC-55016]; University of Mississippi Medical Center [N01-HC-55021]; University of Minnesota [N01-HC-55019, N01-HC-48048, N01-HC-95163]; Johns Hopkins University [N01-HC-55020, N01-HC-95162, N01-HC-95168]; University of Texas, Houston [N01-HC-55022]; University of Alabama at Birmingham [N01-HC-48047, N01-HC- 95095]; Northwestern University [N01-HC-48049, N01-HC-95164]; Kaiser Foundation Research Institute [N01-HC-48050]; Tufts-New England Medical Center [N01-HC- 45204]; Wake Forest University [N01-HC-45205, N01-HC-95165]; Harbor-UCLA Research and Education Institute [N01-HC-05187, N01-HC-95169]; University of California, Irvine [N01-HC-45134, N01-HC-95100]; National Institute on Minority Health and Health Disparities; National Institute on Biomedical Imaging and Bioengineering; University of Washington [N01-HC-95159]; University of California, Los Angeles [N01-HC-95160]; Columbia University [N01-HC-95161]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia [R01-HL-071205]; NIH [R01-HL077612, RC1-HL100543, R01-HL093081] FX This work is supported by Contract HHSN26800625226C from the National Heart, Lung, and Blood Institute, T32 5T32HD040128-09 from the National Institutes of Health, the American Asthma Foundation, the American Medical Association Seed Grant Research Program, and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating the CARe resource for biomedical research. The following studies, funded by the listed National Institutes of Health grants, were utilized in this study. Atherosclerosis Risk in Communities (ARIC): University of North Carolina at Chapel Hill (N01-HC-55015, N01-HC-55018), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center (N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas, Houston (N01-HC-55022). Coronary Artery Risk in Young Adults: University of Alabama at Birmingham (N01-HC-48047, N01-HC- 95095), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), Tufts-New England Medical Center (N01-HC- 45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100); Jackson Heart Study: Contracts N01-HC-95170, N01-HC-95171, N01-HC-95172 from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities, with additional support from the National Institute on Biomedical Imaging and Bioengineering. Multi-Ethnic Study of Atherosclerosis: University of Washington (N01-HC-95159), University of California, Los Angeles (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205). Pulmonary phenotyping and analyses in MESA are funded by NIH grants R01-HL077612, RC1-HL100543 and R01-HL093081. NR 38 TC 2 Z9 3 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD SEP PY 2013 VL 132 IS 9 BP 1039 EP 1047 DI 10.1007/s00439-013-1310-7 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 202UW UT WOS:000323246200006 PM 23666277 ER PT J AU Shriner, D AF Shriner, Daniel TI Impact of Hardy-Weinberg disequilibrium on post-imputation quality control SO HUMAN GENETICS LA English DT Letter C1 NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Shriner, D (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047,12 South Dr,MSC 5635, Bethesda, MD 20892 USA. EM shrinerda@mail.nih.gov FU NCRR NIH HHS [2M01RR010284]; NHGRI NIH HHS [Z01HG200362]; NIGMS NIH HHS [S06GM008016-320107, S06GM008016-380111] NR 5 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD SEP PY 2013 VL 132 IS 9 BP 1073 EP 1075 DI 10.1007/s00439-013-1336-x PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 202UW UT WOS:000323246200009 PM 23842951 ER PT J AU Nickerson, ML Im, KM Misner, KJ Tan, W Lou, H Gold, B Wells, DW Bravo, HC Fredrikson, KM Harkins, TT Milos, P Zbar, B Linehan, WM Yeager, M Andresson, T Dean, M Bova, GS AF Nickerson, Michael L. Im, Kate M. Misner, Kevin J. Tan, Wei Lou, Hong Gold, Bert Wells, David W. Bravo, Hector C. Fredrikson, Karin M. Harkins, Timothy T. Milos, Patrice Zbar, Berton Linehan, W. Marston Yeager, Meredith Andresson, Thorkell Dean, Michael Bova, G. Steven TI Somatic Alterations Contributing to Metastasis of a Castration-Resistant Prostate Cancer SO HUMAN MUTATION LA English DT Article DE tumor heterogeneity; somatic mutation; metastasis; epigenetic modifiers; BRCA1; TMPRSS2; ERG; PBRM1; TET2 AB Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease, and molecular markers that differentiate indolent from aggressive subtypes are needed. We sequenced the exomes of five metastatic tumors and healthy kidney tissue from an index case with mCRPC to identify lesions associated with disease progression and metastasis. An Ashkenazi Jewish (AJ) germline founder mutation, del185AG in BRCA1, was observed and AJ ancestry was confirmed. Sixty-two somatic variants altered proteins in tumors, including cancer-associated genes, TMPRSS2-ERG, PBRM1, and TET2. The majority (n=53) of somatic variants were present in all metastases and only a subset (n=31) was observed in the primary tumor. Integrating tumor next-generation sequencing and DNA copy number showed somatic loss of BRCA1 and TMPRSS2-ERG. We sequenced 19 genes with deleterious mutations in the index case in additional mCRPC samples and detected a frameshift, two somatic missense alterations, tumor loss of heterozygosity, and combinations of germline missense SNPs in TET2. In summary, genetic analysis of metastases from an index case permitted us to infer a chronology for the clonal spread of disease based on sequential accrual of somatic lesions. The role of TET2 in mCRPC deserves additional analysis and may define a subset of metastatic disease. Published 2013 Wiley Periodicals, Inc. C1 [Nickerson, Michael L.; Im, Kate M.; Misner, Kevin J.; Gold, Bert; Zbar, Berton; Dean, Michael] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. [Tan, Wei; Lou, Hong] NCI, Basic Sci Program, SAIC Frederick, NIH, Frederick, MD 21702 USA. [Wells, David W.] NCI, Genet Core, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Bravo, Hector C.] Univ Maryland, Dept Comp Sci, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Fredrikson, Karin M.; Harkins, Timothy T.] Roche Diagnost Corp, Indianapolis, IN USA. [Milos, Patrice] Helicos BioSci Corp, Cambridge, MA USA. [Linehan, W. Marston] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Yeager, Meredith] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Andresson, Thorkell] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick,NIH, Frederick, MD 21702 USA. [Bova, G. Steven] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Bova, G. Steven] Univ Tampere, Inst Biomed Technol, FIN-33101 Tampere, Finland. RP Nickerson, ML (reprint author), NCI, Canc & Inflammat Program, Bldg 560,Room 21-21, Frederick, MD 21702 USA. EM nickersonml@mail.nih.gov; deanm@mail.nih.gov RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Corrada Bravo, Hector/0000-0002-1255-4444 FU NIH; National Cancer Institute Center for Cancer Research; National Institutes of Health [CA92234, HHSN26120080001E]; American Cancer Society; Association for the Cure of Cancer of the Prostate FX Contract grant sponsors: NIH; The National Cancer Institute Center for Cancer Research; National Institutes of Health funding (CA92234, HHSN26120080001E); John and Kathe Dyson; The American Cancer Society; and the Association for the Cure of Cancer of the Prostate. NR 68 TC 18 Z9 18 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2013 VL 34 IS 9 BP 1231 EP 1241 DI 10.1002/humu.22346 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 200YZ UT WOS:000323109200009 PM 23636849 ER PT J AU Johnston, JJ Wen, KK Keppler-Noreuil, K McKane, M Maiers, JL Greiner, A Sapp, JC DeMali, KA Rubenstein, PA Biesecker, LG AF Johnston, Jennifer J. Wen, Kuo-Kuang Keppler-Noreuil, Kim McKane, Melissa Maiers, Jessica L. Greiner, Alexander Sapp, Julie C. DeMali, Kris A. Rubenstein, Peter A. Biesecker, Leslie G. CA NIH Intramural Sequencing Ctr TI Functional Analysis of a De Novo ACTB Mutation in a Patient with Atypical Baraitser-Winter Syndrome SO HUMAN MUTATION LA English DT Article DE actin; ACTB; Dubowitz; Baraitser-Winter syndrome AB Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser-Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser-Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein. (C) 2013 Wiley Periodicals, Inc. C1 [Johnston, Jennifer J.; Keppler-Noreuil, Kim; Sapp, Julie C.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Wen, Kuo-Kuang; McKane, Melissa; Maiers, Jessica L.; Greiner, Alexander; DeMali, Kris A.; Rubenstein, Peter A.] Univ Iowa, Iowa City, IA USA. [NIH Intramural Sequencing Ctr] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Johnston, JJ (reprint author), NHGRI, Bldg 49,Room 4C64, Bethesda, MD 20892 USA. EM jjohnsto@mail.nih.gov FU National Institutes of Health [DC8803]; National Science Foundation [1120478] FX Contract grant sponsors: National Institutes of Health (#DC8803); National Science Foundation (#1120478). NR 35 TC 8 Z9 8 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2013 VL 34 IS 9 BP 1242 EP 1249 DI 10.1002/humu.22350 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 200YZ UT WOS:000323109200010 PM 23649928 ER PT J AU Tan, XH Anzick, SL Khan, SG Ueda, T Stone, G DiGiovanna, JJ Tamura, D Wattendorf, D Busch, D Brewer, CC Zalewski, C Butman, JA Griffith, AJ Meltzer, PS Kraemer, KH AF Tan, Xiaohui Anzick, Sarah L. Khan, Sikandar G. Ueda, Takahiro Stone, Gary DiGiovanna, John J. Tamura, Deborah Wattendorf, Daniel Busch, David Brewer, Carmen C. Zalewski, Christopher Butman, John A. Griffith, Andrew J. Meltzer, Paul S. Kraemer, Kenneth H. TI Chimeric Negative Regulation of p14ARF and TBX1 by a t(9;22) Translocation Associated with Melanoma, Deafness, and DNA Repair Deficiency SO HUMAN MUTATION LA English DT Article DE melanoma; TBX1; deafness; p14ARF; PATRR22; DiGeorge syndrome AB Melanoma is the most deadly form of skin cancer and DiGeorge syndrome (DGS) is the most frequent interstitial deletion syndrome. We characterized a novel balanced t(9;22)(p21;q11.2) translocation in a patient with melanoma, DNA repair deficiency, and features of DGS including deafness and malformed inner ears. Using chromosome sorting, we located the 9p21 breakpoint in CDKN2A intron 1. This resulted in underexpression of the tumor suppressor p14 alternate reading frame (p14ARF); the reduced DNA repair was corrected by transfection with p14ARF. Ultraviolet radiation-type p14ARF mutations in his melanoma implicated p14ARF in its pathogenesis. The 22q11.2 breakpoint was located in a palindromic AT-rich repeat (PATRR22). We identified a new gene, FAM230A, that contains PATRR22 within an intron. The 22q11.2 breakpoint was located 800 kb centromeric to TBX1, which is required for inner ear development. TBX1 expression was greatly reduced. The translocation resulted in a chimeric transcript encoding portions of p14ARF and FAM230A. Inhibition of chimeric p14ARF-FAM230A expression increased p14ARF and TBX1 expression and improved DNA repair. Expression of the chimera in normal cells produced dominant negative inhibition of p14ARF. Similar chimeric mRNAs may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma. Published 2013 Wiley Periodicals, Inc. C1 [Tan, Xiaohui; Khan, Sikandar G.; Ueda, Takahiro; DiGiovanna, John J.; Tamura, Deborah; Kraemer, Kenneth H.] NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Anzick, Sarah L.; Stone, Gary; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wattendorf, Daniel] Off Air Force Surgeon Gen, Washington, DC USA. [Busch, David] Armed Forces Inst Pathol, Washington, DC 20306 USA. [Brewer, Carmen C.; Zalewski, Christopher; Griffith, Andrew J.] Natl Inst Deafness & Commun Disorders, Otolaryngol Branch, Bethesda, MD USA. [Butman, John A.] NIH, Radiol Branch, Ctr Clin, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, Bldg 37 Room 4002, Bethesda, MD 20892 USA. EM kraemerk@nih.gov RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU National Cancer Institute; National Institute of Deafness and Communication Disorders; Clinical Center, National Institutes of Health, Bethesda, Maryland FX This work was supported by the Intramural Research Program of the National Cancer Institute, the National Institute of Deafness and Communication Disorders, and the Clinical Center, National Institutes of Health, Bethesda, Maryland. We thank Drs. Paul Bergstresser and Clay Cockerell for assistance in care of the patient, Drs. Vladimir Larionov, Robert Walker, and Alexander Kovalchuk for assistance in molecular analysis, Drs. Medha Bhagwhat and Paul Khavari for bioinformatics advice, Dr. Doris Wu for expertise in mouse ear development, and Drs. Kurt Kohn and Allan Balmian for metabolic pathway analysis. NR 76 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2013 VL 34 IS 9 BP 1250 EP 1259 DI 10.1002/humu.22354 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 200YZ UT WOS:000323109200011 PM 23661601 ER PT J AU Barnes, AM Duncan, G Weis, M Paton, W Cabral, WA Mertz, EL Makareeva, E Gambello, MJ Lacbawan, FL Leikin, S Fertala, A Eyre, DR Bale, SJ Marini, JC AF Barnes, Aileen M. Duncan, Geraldine Weis, MaryAnn Paton, William Cabral, Wayne A. Mertz, Edward L. Makareeva, Elena Gambello, Michael J. Lacbawan, Felicitas L. Leikin, Sergey Fertala, Andrzej Eyre, David R. Bale, Sherri J. Marini, Joan C. TI Kuskokwim Syndrome, a Recessive Congenital Contracture Disorder, Extends the Phenotype of FKBP10 Mutations SO HUMAN MUTATION LA English DT Article DE osteogenesis imperfecta; contractures; FKBP65; FKBP10; Bruck syndrome; cross-linking AB Recessive mutations in FKBP10 at 17q21.2, encoding FKBP65, cause both osteogenesis imperfecta (OI) and Bruck syndrome (OI plus congenital contractures). Contractures are a variable manifestation of null/missense FKBP10 mutations. Kuskokwim syndrome (KS) is an autosomal recessive congenital contracture disorder found among Yup'ik Eskimos. Linkage mapping of KS to chromosome 17q21, together with contractures as a feature of FKBP10 mutations, made FKBP10 a candidate gene. We identified a homozygous three-nucleotide deletion in FKBP10 (c.877_879delTAC) in multiple Kuskokwim pedigrees; 3% of regional controls are carriers. The mutation deletes the highly conserved p.Tyr293 residue in FKBP65's third peptidyl-prolyl cis-trans isomerase domain. FKBP10 transcripts are normal, but mutant FKBP65 is destabilized to a residual 5%. Collagen synthesized by KS fibroblasts has substantially decreased hydroxylation of the telopeptide lysine crucial for collagen cross-linking, with 2%-10% hydroxylation in probands versus 60% in controls. Matrix deposited by KS fibroblasts has marked reduction in maturely cross-linked collagen. KS collagen is disorganized in matrix, and fibrils formed in vitro had subtle loosening of monomer packing. Our results imply that FKBP10 mutations affect collagen indirectly, by ablating FKBP65 support for collagen telopeptide hydroxylation by lysyl hydroxylase 2, thus decreasing collagen cross-links in tendon and bone matrix. FKBP10 mutations may also underlie other arthrogryposis syndromes. Published 2013. This article has been contributed to by US Government employees and their work is in the public domain in the USA. C1 [Barnes, Aileen M.; Cabral, Wayne A.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [Duncan, Geraldine; Bale, Sherri J.] NIAMS, Skin Biol Lab, NIH, Bethesda, MD USA. [Weis, MaryAnn; Eyre, David R.] Univ Washington, Orthopaed Res Labs, Seattle, WA 98195 USA. [Paton, William] Alaska Native Med Ctr, Dept Orthopaed, Anchorage, AK USA. [Mertz, Edward L.; Makareeva, Elena; Leikin, Sergey] NICHD, Sect Phys Biochem, NIH, Bethesda, MD 20892 USA. [Fertala, Andrzej] Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. RP Marini, JC (reprint author), NICHD, Bone & Extracellular Matrix Branch, NIH, Bldg 10,Rm 10D39,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov RI Makareeva, Elena/F-5183-2011; Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU NICHD; NIAMS; NIH [HD22657, AR37694, AR37318, AR061118, AR048544] FX Contract grant sponsors: NICHD; NIAMS; NIH (HD22657, AR37694, AR37318, AR061118, and AR048544). NR 31 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2013 VL 34 IS 9 BP 1279 EP 1288 DI 10.1002/humu.22362 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 200YZ UT WOS:000323109200014 PM 23712425 ER PT J AU Whelton, SP Blankstein, R Al-Mallah, MH Lima, JAC Bluemke, DA Hundley, WG Polak, JF Blumenthal, RS Nasir, K Blaha, MJ AF Whelton, Seamus P. Blankstein, Ron Al-Mallah, Mouaz H. Lima, Joao A. C. Bluemke, David A. Hundley, W. Gregory Polak, Joseph F. Blumenthal, Roger S. Nasir, Khurram Blaha, Michael J. TI Association of Resting Heart Rate With Carotid and Aortic Arterial Stiffness: Multi-Ethnic Study of Atherosclerosis SO HYPERTENSION LA English DT Article DE cardiovascular diseases; heart rate; magnetic resonance imaging; ultrasonography; vascular stiffness ID SYMPATHETIC-NERVE ACTIVITY; MYOCARDIAL-INFARCTION; RISK-FACTOR; CARDIOVASCULAR-DISEASE; ESSENTIAL-HYPERTENSION; INDEPENDENT PREDICTOR; DISTENSIBILITY; HUMANS; MORTALITY; PRESSURE AB Resting heart rate is an easily measured, noninvasive vital sign that is associated with cardiovascular disease events. The pathophysiology of this association is not known. We investigated the relationship between resting heart rate and stiffness of the carotid (a peripheral artery) and the aorta (a central artery) in an asymptomatic multi-ethnic population. Resting heart rate was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Distensibility was used as a measure of arterial elasticity, with a lower distensibility indicating an increase in arterial stiffness. Carotid distensibility was measured in 6484 participants (98% of participants) using B-mode ultrasound, and aortic distensibility was measured in 3512 participants (53% of participants) using cardiac MRI. Heart rate was divided into quintiles and we used progressively adjusted models that included terms for physical activity and atrioventricular nodal blocking agents. Mean resting heart rate of participants (mean age, 62 years; 47% men) was 63 bpm (SD, 9.6 bpm). In unadjusted and fully adjusted models, carotid distensibility and aortic distensibility decreased monotonically with increasing resting heart rate (P for trend <0.001 and 0.009, respectively). The relationship was stronger for carotid versus aortic distensibility. Similar results were seen using the resting heart rate taken at the time of MRI scanning. Our results suggest that a higher resting heart rate is associated with an increased arterial stiffness independent of atrioventricular nodal blocker use and physical activity level, with a stronger association for a peripheral (carotid) compared with a central (aorta) artery. C1 [Whelton, Seamus P.] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Whelton, Seamus P.; Blumenthal, Roger S.; Nasir, Khurram; Blaha, Michael J.] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA. [Blankstein, Ron] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Blankstein, Ron] Brigham & Womens Hosp, Boston, MA 02115 USA. [Al-Mallah, Mouaz H.] Natl Guard Hlth Affairs, King Abdul Aziz Med City Riyadh, King Abdul Aziz Cardiac Ctr, Cardiac Imaging, Riyadh, Saudi Arabia. [Lima, Joao A. C.; Blumenthal, Roger S.; Nasir, Khurram; Blaha, Michael J.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. [Bluemke, David A.] Ctr Clin, Bethesda, MD USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Hundley, W. Gregory] Wake Forest Univ, Dept Internal Med Cardiol, Winston Salem, NC 27109 USA. [Polak, Joseph F.] Tufts Univ, Sch Med, Dept Radiol, Tufts Med Ctr, Boston, MA 02111 USA. [Nasir, Khurram] Baptist Hlth South Florida, Ctr Prevent & Wellness, Miami, FL USA. [Nasir, Khurram] Florida Int Univ, Herbert Wertheim Coll Med, Dept Med, Miami, FL 33199 USA. [Nasir, Khurram] Florida Int Univ, Dept Epidemiol, Robert Stempel Coll Publ Hlth, Miami, FL 33199 USA. RP Blaha, MJ (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Johns Hopkins Sch Med, Div Cardiol, 1830 E Monument St,Carnegie 565A, Baltimore, MD 21287 USA. EM mblaha1@jhmi.edu OI Bluemke, David/0000-0002-8323-8086; Al-Mallah, Mouaz/0000-0003-2348-0484 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169]; NCRR [UL1-RR-024156, UL1-RR-025005] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-RR-024156 and UL1-RR-025005 from NCRR. NR 51 TC 27 Z9 30 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2013 VL 62 IS 3 BP 477 EP 484 DI 10.1161/HYPERTENSIONAHA.113.01605 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 201OA UT WOS:000323149700017 PM 23836802 ER PT J AU Cheng, S Gupta, DK Claggett, B Sharrett, AR Shah, AM Skali, H Takeuchi, M Ni, HY Solomon, SD AF Cheng, Susan Gupta, Deepak K. Claggett, Brian Sharrett, A. Richey Shah, Amil M. Skali, Hicham Takeuchi, Madoka Ni, Hanyu Solomon, Scott D. TI Differential Influence of Distinct Components of Increased Blood Pressure on Cardiovascular Outcomes: From the Atherosclerosis Risk in Communities Study SO HYPERTENSION LA English DT Article DE blood pressure; cardiovascular diseases; epidemiology; hypertension; outcomes assessment ID CORONARY-ARTERY-DISEASE; PULSE-WAVE VELOCITY; AGE-RELATED-CHANGES; MYOCARDIAL-INFARCTION; HEART-FAILURE; HYPERTENSIVE PATIENTS; MORTALITY-RATES; SEX-DIFFERENCES; UNITED-STATES; ALL-CAUSE AB Elevation in blood pressure (BP) increases risk for all cardiovascular events. Nevertheless, the extent to which different indices of BP elevation may be associated to varying degrees with different cardiovascular outcomes remains unclear. We studied 13340 participants (aged 54 +/- 6 years, 56% women and 27% black) of the Atherosclerosis Risk in Communities Study who were free of baseline cardiovascular disease. We used Cox proportional hazards models to compare the relative contributions of systolic BP, diastolic BP, pulse pressure, and mean arterial pressure to risk for coronary heart disease, heart failure, stroke, and all-cause mortality. For each multivariable-adjusted model, the largest area under the receiver-operating curve (AUC) and smallest -2 log-likelihood values were used to identify BP measures with the greatest contribution to risk prediction for each outcome. A total of 2095 coronary heart disease events, 1669 heart failure events, 771 stroke events, and 3016 deaths occurred during 18 +/- 5 years of follow-up. In multivariable analyses adjusting for traditional cardiovascular risk factors, the BP measures with the greatest risk contributions were the following: systolic BP for coronary heart disease (AUC=0.74); pulse pressure for heart failure (AUC=0.79); systolic BP for stroke (AUC=0.74); and pulse pressure for all-cause mortality (AUC=0.74). With few exceptions, results were similar in analyses stratified by age, sex, and race. Our data indicate that distinct BP components contribute variably to risk for different cardiovascular outcomes. C1 [Cheng, Susan; Gupta, Deepak K.; Claggett, Brian; Shah, Amil M.; Skali, Hicham; Takeuchi, Madoka; Solomon, Scott D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Sharrett, A. Richey] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Ni, Hanyu] NHLBI, NIH, Bethesda, MD 20892 USA. RP Cheng, S (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM scheng3@partners.org OI Skali, Hicham/0000-0002-5629-4138 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN2682011000 09C, HHSN268201100010C, HHSN268201100011C, HHSN268 201100012C]; Ellison Foundation; [K99-HL-107642] FX The Atherosclerosis Risk in Communities (ARIC) Study is a collaborative study supported by the following National Heart, Lung, and Blood Institute contracts: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN2682011000 09C, HHSN268201100010C, HHSN268201100011C, and HHSN268 201100012C. Dr Cheng is supported in part by K99-HL-107642 and a grant from the Ellison Foundation. NR 43 TC 8 Z9 8 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2013 VL 62 IS 3 BP 492 EP 498 DI 10.1161/HYPERTENSIONAHA.113.01561 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 201OA UT WOS:000323149700019 PM 23876475 ER PT J AU Goldenberg, RL McClure, EM Kodkany, B Wembodinga, G Pasha, O Esamai, F Tshefu, A Patel, A Mabaye, H Goudar, S Saleem, S Waikar, M Langer, A Bose, CL Rubens, CE Wright, LL Moore, J Blanc, A AF Goldenberg, Robert L. McClure, Elizabeth M. Kodkany, Bhala Wembodinga, Gilbert Pasha, Omrana Esamai, Fabian Tshefu, Antoinette Patel, Archana Mabaye, Hillary Goudar, Shivaparasad Saleem, Sarah Waikar, Manjushri Langer, Ana Bose, Carl L. Rubens, Craig E. Wright, Linda L. Moore, Janet Blanc, Ann TI A multi-country study of the "intrapartum stillbirth and early neonatal death indicator" in hospitals in low-resource settings SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Doptone; Fetal heart tones; Hospital-based perinatal mortality; Neonatal mortality; Perinatal mortality; Stillbirth ID NEWBORN; BIRTHS AB Objective: To determine the feasibility of introducing a simple indicator of quality of obstetric and neonatal care and to determine the proportion of potentially avoidable perinatal deaths in hospitals in low-income countries. Methods: Between September 1, 2011, and February 29, 2012, data were collected from consecutive women who were admitted to the labor ward of 1 of 6 hospitals in 4 low-income countries. Fetal heart tones on admission were monitored, and demographic and birth data were recorded. Results: Data were obtained for 3555 women and 3593 neonates (including twins). The doptone was used on 97% of women admitted. The overall perinatal mortality rate was 34 deaths per 1000 deliveries. Of the perinatal deaths, 40%-45% occurred in the hospital and were potentially preventable by better hospital care. Conclusion: The results demonstrated that it is possible to accurately determine fetal viability on admission via a doptone. Implementation of doptone use, coupled with a concise data record, might form the basis of a low-cost and sustainable program to monitor and evaluate efforts to improve quality of care and ultimately might help to reduce the in-hospital component of perinatal mortality in low-income countries. (C) 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY 10032 USA. [McClure, Elizabeth M.; Moore, Janet] Res Triangle Inst, Dept Social Stat & Environm Sci, Durham, NC USA. [Kodkany, Bhala; Goudar, Shivaparasad] Jawaharlal Nehru Med Coll, Karnataka Lingayat Educ Soc, Dept Obstet, Belgaum, India. [Wembodinga, Gilbert; Tshefu, Antoinette] Sch Publ Hlth, Kinshasa, Zaire. [Pasha, Omrana; Saleem, Sarah] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Esamai, Fabian; Mabaye, Hillary] Moi Univ, Dept Pediat, Eldoret, Kenya. [Patel, Archana; Waikar, Manjushri] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Langer, Ana] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Bose, Carl L.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Rubens, Craig E.] Seattle Childrens Hosp, Global Alliance Prevent Preterm Birth & Stillbirt, Seattle, WA USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Goldenberg, RL (reprint author), Columbia Univ, Coll Med, Dept Obstet & Gynecol, New York, NY 10032 USA. EM rlg88@columbia.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Bill & Melinda Gates Foundation; Eunice Kennedy Shriver NICHD Global Network for Women's and Children's Health Research grants [U01 HD042372, U01 HD040607, U01 HD040636, U01 HD058322, U01 HD058326] FX Support for the study design meeting and study were provided by the Bill & Melinda Gates Foundation-funded Maternal Health Task Force at EngenderHealth, GAPPS and by the Eunice Kennedy Shriver NICHD Global Network for Women's and Children's Health Research grants (U01 HD042372, U01 HD040607, U01 HD040636, U01 HD058322, U01 HD058326). GAPPS (C.E.R.), MHTF (A.L., A.B.), and NICHD (L.L.W.) contributed to development of the study protocol and review of the manuscript. NR 10 TC 12 Z9 12 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD SEP PY 2013 VL 122 IS 3 BP 230 EP 233 DI 10.1016/j.ijgo.2013.04.008 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 204XS UT WOS:000323405200012 PM 23796259 ER PT J AU Preuss, N Salehi, B van der Veen, JW Shen, J Drevets, WC Hodgkinson, C Goldman, D Hasler, G AF Preuss, Nora Salehi, Basira van der Veen, Jan Willem Shen, Jun Drevets, Wayne C. Hodgkinson, Colin Goldman, David Hasler, Gregor TI Associations between prefrontal gamma-aminobutyric acid concentration and the tryptophan hydroxylase isoform 2 gene, a panic disorder risk allele in women SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE GABA; genetics; magnetic resonance spectroscopy; single nucleotide polymorphisms; tryptophan hydroxylase 2 ID MAGNETIC-RESONANCE SPECTROSCOPY; MAJOR DEPRESSION; TRYPTOPHAN-HYDROXYLASE-2 GENE; TRANSMISSION DISEQUILIBRIUM; POLYMORPHIC VARIANTS; GABA CONCENTRATIONS; BIPOLAR DISORDER; SEX-DIFFERENCES; TPH2 GENE; IN-VIVO AB Associations between the central serotonergic and gamma-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (-703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder. Our results revealed a significant association between increased GABA concentration in the PFC and the T-allele frequencies of two TPH2 SNPs, namely rs4570625 (-703 G/T) and rs2129575 (p <= 0.0004) and the C-allele frequency of one TPH2 SNP, namely rs1386491 (p=0.0003) in female subjects. We concluded that rs4570625 (-703 G/T), rs2129575 and rs1386491 play a significant role in GABAergic neurotransmission and may contribute to the sex-specific dysfunction of the GABAergic system in the PFC. C1 [Preuss, Nora] Univ Bern, Dept Psychol, CH-3012 Bern, Switzerland. [Salehi, Basira; Hasler, Gregor] Univ Bern, Psychiat Univ Hosp, CH-3012 Bern, Switzerland. [van der Veen, Jan Willem] NIMH, Magnet Resonance Spect Core, Bethesda, MD 20892 USA. [Shen, Jun] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Tulsa, OK USA. [Drevets, Wayne C.] Johnson & Johnson Inc, Janssen Res & Dev LLC, Titusville, NJ USA. [Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, Bethesda, MD USA. RP Hasler, G (reprint author), Psychiat Univ Hosp, Bolligenstr 111, CH-3000 Bern 60, Switzerland. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012; Goldman, David/F-9772-2010 OI Hasler, Gregor/0000-0002-8311-0138; Goldman, David/0000-0002-1724-5405 FU Intramural Research Program of the National Institutes of Mental Health; Lundebck; Servier; Lilly; Bistol-Myers Squibb; GlaxoSmithKline; Astra Zeneca FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. We thank Qiaoping Yuan and Pei-Hong Shen for their support in data management and bioinformatics. Gregor Hasler received honoraria or consulting fees from Lundebck, Servier, Lilly, Bistol-Myers Squibb, GlaxoSmithKline and Astra Zeneca for projects unrelated to this study. Wayne Drevets, M. D. is an employee of Johnson & Johnson, Inc. and has consulted for Myriad/Rules Based Medicine and Eisai, Inc. for projects unrelated to this study. NR 62 TC 4 Z9 4 U1 1 U2 14 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 2013 VL 16 IS 8 BP 1707 EP 1717 DI 10.1017/S1461145713000254 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 201TQ UT WOS:000323166300002 PM 23552096 ER PT J AU Cheung, WY Aziz, N Noone, AM Rowland, JH Potosky, AL Ayanian, JZ Virgo, KS Ganz, PA Stefanek, M Earle, CC AF Cheung, Winson Y. Aziz, Noreen Noone, Anne-Michelle Rowland, Julia H. Potosky, Arnold L. Ayanian, John Z. Virgo, Katherine S. Ganz, Patricia A. Stefanek, Michael Earle, Craig C. TI Physician preferences and attitudes regarding different models of cancer survivorship care: a comparison of primary care providers and oncologists SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Cancer; Survivorship; Care models; Physician; Preferences ID FOLLOW-UP; BREAST-CANCER; COLORECTAL-CANCER; PREVENTIVE CARE; SPECIALTY CARE; DIAGNOSIS; INTERFACE; TRENDS; VIEWS AB New strategies for delivering cancer follow-up care are needed. We surveyed primary care providers (PCPs) and oncologists to assess how physician attitudes toward and self-efficacy with cancer follow-up affect preferences for different cancer survivorship models. The survey of physician attitudes regarding the care of cancer survivors was mailed to a randomly selected national sample of PCPs and oncologists to evaluate their perspectives regarding physician roles, knowledge about survivorship care processes, and views on cancer surveillance. Multinomial logistic regression models were constructed to examine how physician attitudes towards, and self-efficacy with, their own skills affected preferences for different cancer survivorship care models. Of 3,434 physicians identified, a total of 2,026 participants provided eligible responses: 938 PCPs and 1,088 oncologists. Most PCPs (51 %) supported a PCP/shared care model; whereas, the majority of specialists (59 %) strongly endorsed an oncologist-based model (p < 0.001). Less than a quarter of PCPs and oncologists preferred specialized survivor clinics. A significant proportion of oncologists (87 %) did not feel that PCPs should take on the primary role of cancer follow-up. Most PCPs believed that they were better able to perform breast and colorectal cancer follow-up (57 %), detect recurrent cancers (74 %), and offer psychosocial support (50 %), but only a minority (32 %) was willing to assume primary responsibility. PCPs already involved with cancer surveillance (43 %) were more likely to prefer a PCP/shared care than oncologist-based survivorship model (OR, 2.08; 95 % CI, 1.34-3.23). PCPs and oncologists have different preferences for models of cancer survivorship care. Prior involvement with cancer surveillance was one of the strongest predictors of PCPs' willingness to assume this responsibility. C1 [Cheung, Winson Y.] British Columbia Canc Agcy, Div Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Aziz, Noreen] NINR, Off Extramural Programs, Div Extramural Act, NIH, Bethesda, MD 20892 USA. [Noone, Anne-Michelle] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Virgo, Katherine S.] Amer Canc Soc, Hlth Serv Res Program, Intramural Res Dept, Atlanta, GA 30329 USA. [Virgo, Katherine S.; Stefanek, Michael] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Publ Hlth, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. [Earle, Craig C.] Ontario Inst Canc Res, Toronto, ON, Canada. [Earle, Craig C.] Inst Clin Evaluat Sci, Toronto, ON M4N 3M5, Canada. RP Earle, CC (reprint author), Inst Clin Evaluat Sci, 2075 Bayview Ave,G Wing 106, Toronto, ON M4N 3M5, Canada. EM craig.earle@ices.on.ca RI chen, zhu/K-5923-2013 FU National Cancer Institute [HHSN261201000316C] FX National Cancer Institute HHSN261201000316C and intramural support from the American Cancer Society NR 34 TC 25 Z9 25 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD SEP PY 2013 VL 7 IS 3 BP 343 EP 354 DI 10.1007/s11764-013-0281-y PG 12 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 197WM UT WOS:000322883100007 PM 23526165 ER PT J AU Stanton, AL Morra, ME Diefenbach, MA Miller, SM Perocchia, RS Raich, PC Fleisher, L Wen, KY Tran, ZV Mohamed, NE George, R Bright, MA Marcus, AC AF Stanton, Annette L. Morra, Marion E. Diefenbach, Michael A. Miller, Suzanne M. Perocchia, Rosemarie Slevin Raich, Peter C. Fleisher, Linda Wen, Kuang-Yi Zung Vu Tran Mohamed, Nihal E. George, Roshini Bright, Mary Anne Marcus, Alfred C. TI Responding to a significant recruitment challenge within three nationwide psychoeducational trials for cancer patients SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Cancer; Accrual; Recruitment; Randomized controlled trial; Psychoeducational; Survivorship ID RANDOMIZED CONTROLLED-TRIAL; SPANISH-SPEAKING SMOKERS; STAGE BREAST-CANCER; INFORMATION-SERVICE; MINORITY WOMEN; STRATEGIES; RETENTION; INTERVENTION; PREVENTION; SURVIVORS AB When faced with a significant recruitment challenge for three nationwide psychoeducational trials targeting prostate and breast cancer patients, the Cancer Information Service Research Consortium initiated outreach efforts to increase accrual. Recruitment is reported by major outreach strategy to inform the use of similar campaigns, either as primary recruitment efforts or to supplement "in-reach" recruitment within oncology settings. During a 33-month period, recruitment was tracked from the National Cancer Institute's Cancer Information Service (CIS), the American Cancer Society (ACS), Dr. Susan Love Research Foundation's Love/Avon Army of Women (AOW), Internet advertising, press releases, radio/television interviews, recruitment materials in community venues, and outreach to churches and cancer support organizations. Across projects, the majority (89 %) of recruited participants (N = 2,134) was obtained from the CIS (n = 901, 19 months of recruitment), AOW (n = 869, 18 months), and ACS (n = 123, 12 months). Other efforts showed minimal gain in recruitment. Cancer information programs (e.g., CIS and ACS) and registries of individuals willing to participate in cancer-related research (e.g., AOW) can represent exceptional resources for outreach recruitment of cancer patients, especially when the eligibility criteria are highly restrictive. However, these resources do not yield samples representative of the larger population of adults diagnosed with cancer, and conclusions from such trials must be tempered accordingly. Inadequate recruitment to randomized controlled trials limits the creation of useful interventions for cancer survivors. By enrolling in cancer registries and taking part in research, cancer survivors can contribute to the development of effective resources for the survivor population. C1 [Stanton, Annette L.] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Dept Psychol, Los Angeles, CA 90095 USA. [Stanton, Annette L.] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Dept Psychiat Biobehav Sci, Los Angeles, CA 90095 USA. [Morra, Marion E.] Morra Commun, Milford, CT USA. [Miller, Suzanne M.; Fleisher, Linda; Wen, Kuang-Yi] Fox Chase Temple Hlth, Philadelphia, PA USA. [Mohamed, Nihal E.; Bright, Mary Anne] Icahn Sch Med Mt Sinai, New York, NY USA. [Perocchia, Rosemarie Slevin] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Raich, Peter C.] Denver Hlth & Hosp Author, Denver, CO USA. [Zung Vu Tran; Marcus, Alfred C.] Univ Colorado, Ctr Canc, Denver, CO 80262 USA. [George, Roshini] Amer Canc Soc, Atlanta, GA 30329 USA. [Bright, Mary Anne] NCI, Off Publ Informat & Resource Management, Off Commun & Educ, Bethesda, MD 20892 USA. RP Stanton, AL (reprint author), Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. EM astanton@ucla.edu OI Tran, Zung/0000-0002-9322-9562 FU NCI of the National Institutes of Health [5P01CA057586] FX This research was supported by grant 5P01CA057586 from the NCI of the National Institutes of Health. NR 41 TC 2 Z9 2 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD SEP PY 2013 VL 7 IS 3 BP 392 EP 403 DI 10.1007/s11764-013-0282-x PG 12 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 197WM UT WOS:000322883100011 PM 23595235 ER PT J AU Jena, AB Prasad, V AF Jena, Anupam B. Prasad, Vinay TI Duty Hour Reform in a Shifting Medical Landscape SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID MYOCARDIAL-INFARCTION; PATIENT SAFETY; RESIDENT; SUPERVISION; EMERGENCY; WORK; MORTALITY; EDUCATION; ERROR; CARE AB The circumstances that led to the death of Libby Zion in 1984 prompted national discussions about the impact of resident fatigue on patient outcomes. Nearly 30 years later, national duty hour reforms largely motivated by patient safety concerns have demonstrated a negligible impact of duty hour reductions on patient mortality. We suggest that the lack of an impact of duty hour reforms on patient mortality is due to a different medical landscape today than existed in 1984. Improvements in quality of care made possible by computerized order entry, automated medication checks, inpatient pharmacists, and increased resident supervision have, among other systemic changes, diminished the adverse impact that resident fatigue is able to have on patient outcomes. Given this new medical landscape, advocacy towards current and future duty hour reforms may be best justified by evidence of the impact of duty hour reform on resident wellbeing, education, and burnout. C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu; vinayak.prasad@nih.gov NR 23 TC 2 Z9 2 U1 0 U2 2 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 2013 VL 28 IS 9 BP 1238 EP 1240 DI 10.1007/s11606-013-2439-8 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700028 PM 23568191 ER PT J AU Leclezio, L Jansen, AC Whittemore, VH Whilmshurst, J Schlegel, B de Vries, PJ AF Leclezio, L. Jansen, A. C. Whittemore, V. H. Whilmshurst, J. Schlegel, B. de Vries, P. J. TI THE TUBEROUS SCLEROSIS COMPLEX ASSOCIATED NEUROPSYCHIATRIC DISORDERS (TAND) CHECKLIST - PILOT VALIDATION OF A NEW SCREENING TOOL FOR NEUROPSYCHIATRIC MANIFESTATIONS IN TSC SO JOURNAL OF INTELLECTUAL DISABILITY RESEARCH LA English DT Meeting Abstract DE TSC; TAND C1 [Leclezio, L.; de Vries, P. J.] Univ Cape Town, Div Child & Adolescent Psychiat, ZA-7700 Rondebosch, South Africa. [Jansen, A. C.] Vrije Univ Brussel, Pediat Neurol Unit, UZ Brussel, Brussels, Belgium. [Whittemore, V. H.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Whilmshurst, J.; Schlegel, B.] Univ Cape Town, Dept Paediat Neurol, Red Cross War Mem Childrens Hosp, ZA-7700 Rondebosch, South Africa. RI Jansen, Anna/P-3121-2014 OI Jansen, Anna/0000-0002-3835-2824 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0964-2633 J9 J INTELL DISABIL RES JI J. Intell. Disabil. Res. PD SEP PY 2013 VL 57 IS 9 BP 800 EP 800 PG 1 WC Education, Special; Genetics & Heredity; Clinical Neurology; Psychiatry; Rehabilitation SC Education & Educational Research; Genetics & Heredity; Neurosciences & Neurology; Psychiatry; Rehabilitation GA 201DS UT WOS:000323121500021 ER PT J AU Yaniv, Y Sirenko, S Ziman, BD Spurgeon, HA Maltsev, VA Lakatta, EG AF Yaniv, Yael Sirenko, Syevda Ziman, Bruce D. Spurgeon, Harold A. Maltsev, Victor A. Lakatta, Edward G. TI New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: Bradycardic effects of ivabradine are linked to suppression of intracellular Ca2+ cycling SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Sinoatrial nodal pacemaker cells; Ca2+ cycling; Ion channels; Physiology; Sarcoplasmic reticulum ID HEART-RATE REDUCTION; RYANODINE RECEPTOR; CARDIAC PREPARATIONS; RABBIT; PHOSPHORYLATION; SIZE; DEPOLARIZATION; MECHANISM; CHANNELS; SYSTEM AB Beneficial clinical bradycardic effects of ivabradine (IVA) have been interpreted solely on the basis of If inhibition, because IVA specifically inhibits I-f in sinoatrial nodal pacemaker cells (SANC). However, it has been recently hypothesized that SANC normal automaticity is regulated by crosstalk between an "M clock," the ensemble of surface membrane ion channels, and a "Ca2+ clock," the sarcoplasmic reticulum (SR). We tested the hypothesis that crosstalk between the two clocks regulates SANC automaticity, and that indirect suppression of the Ca2+ clock further contributes to IVA-induced bradycardia. IVA (3 mu M) not only reduced If amplitude by 45 +/- 6% in isolated rabbit SANC, but the IVA-induced slowing of the action potential (AP) firing rate was accompanied by reduced SR Ca2+ load, slowed intracellular Ca2+ cycling kinetics, and prolonged the period of spontaneous local Ca2+ releases (LCRs) occurring during diastolic depolarization. Direct and specific inhibition of SERCA2 by cyclopiazonic acid (CPA) had effects similar to IVA on LCR period and AP cycle length. Specifically, the LCR period and AP cycle length shift toward longer times almost equally by either direct perturbations of the M clock (IVA) or the Ca2+ clock (CPA), indicating that the LCR period reports the crosstalk between the clocks. Our numerical model simulations predict that entrainment between the two clocks that involves a reduction in I-NCX( during diastolic depolarization is required to explain the experimentally AP firing rate reduction by IVA. In summary, our study provides new evidence that a coupled-clock system regulates normal cardiac pacemaker cell automaticity. Thus, IVA-induced bradycardia includes a suppression of both clocks within this system. Published by Elsevier Ltd. C1 [Yaniv, Yael; Sirenko, Syevda; Ziman, Bruce D.; Spurgeon, Harold A.; Maltsev, Victor A.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@mail.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX The work was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 27 TC 22 Z9 22 U1 0 U2 16 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD SEP PY 2013 VL 62 BP 80 EP 89 DI 10.1016/j.yjmcc.2013.04.026 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 198RV UT WOS:000322940900011 PM 23651631 ER PT J AU Goldstein, DS Sullivan, P Holmes, C Miller, GW Alter, S Strong, R Mash, DC Kopin, IJ Sharabi, Y AF Goldstein, David S. Sullivan, Patti Holmes, Courtney Miller, Gary W. Alter, Shawn Strong, Randy Mash, Deborah C. Kopin, Irwin J. Sharabi, Yehonatan TI Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE DOPAC; DOPAL; dopamine; DOPET; monoamine oxidase; Parkinson's disease ID REDUCED VESICULAR STORAGE; ALPHA-SYNUCLEIN; SUBSTANTIA-NIGRA; IN-VIVO; NEURODEGENERATIVE DISEASES; ALDEHYDE DEHYDROGENASE; KNOCKOUT MICE; HUMAN BRAIN; PC12 CELLS; 3,4-DIHYDROXYPHENYLACETALDEHYDE AB Intra-neuronal metabolism of dopamine (DA) begins with production of 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is toxic. According to the catecholaldehyde hypothesis,' DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson's disease (PD). We tested the feasibility of using post-mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase (ALDH) to the increased DOPAL levels found in PD. Theoretically, the DA:DOPA concentration ratio indicates vesicular uptake, and the 3,4-dihydroxyphenylacetic acid:DOPAL ratio indicates ALDH activity. We validated these indices in transgenic mice with very low vesicular uptake (VMAT2-Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD. VMAT2-Lo mice had markedly decreased DA:DOPA (50 vs. 1377, p<0.0001), and ALDH1A1,2 KO mice had decreased 3,4-dihydroxyphenylacetic acid:DOPAL (1.0 vs. 11.2, p<0.0001). In PD putamen, vesicular uptake was estimated to be decreased by 89% and ALDH activity by 70%. Elevated DOPAL levels in PD putamen reflect a combination of decreased vesicular uptake of cytosolic DA and decreased DOPAL detoxification by ALDH. C1 [Goldstein, David S.; Sullivan, Patti; Holmes, Courtney; Kopin, Irwin J.; Sharabi, Yehonatan] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Miller, Gary W.; Alter, Shawn] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Strong, Randy] South Texas Vet Hlth Care Network, San Antonio, TX USA. [Mash, Deborah C.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Sharabi, Yehonatan] Tel Aviv Univ, Sackler Fac Med, IL-52621 Tel Hashomer, Israel. RP Goldstein, DS (reprint author), 9000 Rockville Pike,Bldg 10 Rm 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov OI Miller, Gary/0000-0001-8984-1284 FU National Institute of Neurological Disorders and Stroke FX The research reported here was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke. We thank Margaret Basile and Margaret Wey for numerous tissue samples, neurochemical data from which were important for the present report. The Authors have no conflicts of interest to disclose. NR 52 TC 39 Z9 39 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2013 VL 126 IS 5 BP 591 EP 603 DI 10.1111/jnc.12345 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 204TV UT WOS:000323393400005 PM 23786406 ER PT J AU Gulvady, AA Ciolino, HP Cabrera, RM Jolly, CA AF Gulvady, Apeksha A. Ciolino, Henry P. Cabrera, Robert M. Jolly, Christopher A. TI Resveratrol inhibits the deleterious effects of diet-induced obesity on thymic function SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Thymus; Mouse; Obesity; Resveratrol; T cell; Diet ID CALORIC RESTRICTION; MICE; METABOLISM; INVOLUTION; CHILDREN; DISEASE AB Obesity is associated with an increased risk of infectious diseases. It has been shown to have deleterious effects on cell-mediated immunity, including reducing thymocyte numbers and altering responses of thymocytes to pathogens. In the current study, we examined the efficacy of the antiobesity phytochemical resveratrol in preventing the deleterious effects of a high-fat diet on thymic anatomy and function. Compared to C57BI/6 male mice fed a low-fat diet, mice on a high-fat diet had a significant increase in thymic weight and lipid content, and a disrupted anatomy, including a reduction of the medullary compartment and absence of a corticomedullary junction. There were a decrease in thymic cellularity and mature T-cell output, and a disrupted T-cell maturation, as evidenced by increased double-negative and decreased single- and double-positive thymocytes. Mice that had been fed resveratrol along with a high-fat diet had a dose-dependent reversal in all these parameters. Western blots from thymi showed that obese mice had lower levels of the key stimulators of lipid metabolism, phospho-5' adenosine monophosphate-activated protein kinase and its downstream target, carnitine palmitoyl transferase-1; this was restored to normal levels in resveratrol-fed mice. Resveratrol also reversed an increase in glycerol-3-phosphate acyltransferase-1, the enzyme that catalyzes the first step in triglycerol synthesis. Taken together, these results indicate that resveratrol is a potent inhibitor of the deleterious effects of diet-induced obesity on thymic anatomy and function, and this may hold promise in preventing obesity-related deficits in cell-mediated immunity. (C) 2013 Elsevier Inc. All rights reserved. C1 [Gulvady, Apeksha A.; Cabrera, Robert M.; Jolly, Christopher A.] Univ Texas Austin, Dept Nutr Sci, Dell Pediat Res Inst, Austin, TX 78723 USA. [Ciolino, Henry P.] NCI, Off Canc Ctr, Rockville, MD 20852 USA. RP Jolly, CA (reprint author), Univ Texas Austin, Dept Nutr Sci, Dell Pediat Res Inst, 1400 Barbara Jordan Blvd,R1800, Austin, TX 78723 USA. EM jolly@austin.utexas.edu NR 27 TC 6 Z9 6 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD SEP PY 2013 VL 24 IS 9 BP 1625 EP 1633 DI 10.1016/j.jnutbio.2013.02.003 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 204XP UT WOS:000323404900010 PM 23561698 ER PT J AU Jonnalagadda, SR Del Fiol, G Medlin, R Weir, C Fiszman, M Mostafa, J Liu, HF AF Jonnalagadda, Siddhartha Reddy Del Fiol, Guilherme Medlin, Richard Weir, Charlene Fiszman, Marcelo Mostafa, Javed Liu, Hongfang TI Automatically extracting sentences from Medline citations to support clinicians' information needs SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE clinical decision support; information needs; knowledge summary; natural language processing ID CLASSIFICATION MODELS; PHYSICIANS; QUESTIONS; CARE; SEARCH; MET AB Objective Online health knowledge resources contain answers to most of the information needs raised by clinicians in the course of care. However, significant barriers limit the use of these resources for decision-making, especially clinicians' lack of time. In this study we assessed the feasibility of automatically generating knowledge summaries for a particular clinical topic composed of relevant sentences extracted from Medline citations. Methods The proposed approach combines information retrieval and semantic information extraction techniques to identify relevant sentences from Medline abstracts. We assessed this approach in two case studies on the treatment alternatives for depression and Alzheimer's disease. Results A total of 515 of 564 (91.3%) sentences retrieved in the two case studies were relevant to the topic of interest. About one-third of the relevant sentences described factual knowledge or a study conclusion that can be used for supporting information needs at the point of care. Conclusions The high rate of relevant sentences is desirable, given that clinicians' lack of time is one of the main barriers to using knowledge resources at the point of care. Sentence rank was not significantly associated with relevancy, possibly due to most sentences being highly relevant. Sentences located closer to the end of the abstract and sentences with treatment and comparative predications were likely to be conclusive sentences. Our proposed technical approach to helping clinicians meet their information needs is promising. The approach can be extended for other knowledge resources and information need types. C1 [Jonnalagadda, Siddhartha Reddy; Liu, Hongfang] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Del Fiol, Guilherme; Weir, Charlene] Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA. [Fiszman, Marcelo] Natl Lib Med, Lister Hill Ctr, Bethesda, MD USA. [Medlin, Richard; Mostafa, Javed] Univ N Carolina, Chapel Hill, NC USA. [Weir, Charlene] VA Med Ctr, Salt Lake City, UT USA. RP Jonnalagadda, SR (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. EM siddhartha@mayo.edu OI Del Fiol, Guilherme/0000-0001-9954-6799 FU NSF [1117286]; NIH CTSA [UL1TR000083]; Agency for Healthcare Research and Quality [K01HS018352] FX JM and RM have been partially funded for this research through NSF Award 1117286 and the NIH CTSA Award UL1TR000083. GDF was supported by grant number K01HS018352 from the Agency for Healthcare Research and Quality. NR 34 TC 7 Z9 7 U1 2 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2013 VL 20 IS 5 BP 995 EP 1000 DI 10.1136/amiajnl-2012-001347 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 201UJ UT WOS:000323168200027 PM 23100128 ER PT J AU Shaikh, Q Kamal, AK AF Shaikh, Quratulain Kamal, Ayeesha Kamran TI My patient has carotid stenosis. Should he get stenting or endarterectomy? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 2 TC 0 Z9 0 U1 1 U2 1 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 2013 VL 63 IS 9 BP 1201 EP 1201 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 205QL UT WOS:000323459500029 PM 24601208 ER PT J AU Priola, SA Ward, AE McCall, SA Trifilo, M Choi, YP Solforosi, L Williamson, RA Cruite, JT Oldstone, MBA AF Priola, Suzette A. Ward, Anne E. McCall, Sherman A. Trifilo, Matthew Choi, Young Pyo Solforosi, Laura Williamson, R. Anthony Cruite, Justin T. Oldstone, Michael B. A. TI Lack of Prion Infectivity in Fixed Heart Tissue from Patients with Creutzfeldt-Jakob Disease or Amyloid Heart Disease SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; CHRONIC WASTING DISEASE; SINGLE AMINO-ACID; TRANSGENIC MICE; INCUBATION-TIME; PERIPHERAL-NERVES; BLOOD-TRANSFUSION; HAMSTER SCRAPIE; SKELETAL-MUSCLE; NERVOUS-SYSTEM AB In most forms of prion disease, infectivity is present primarily in the central nervous system or immune system organs such as spleen and lymph node. However, a transgenic mouse model of prion disease has demonstrated that prion infectivity can also be present as amyloid deposits in heart tissue. Deposition of infectious prions as amyloid in human heart tissue would be a significant public health concern. Although abnormal disease-associated prion protein (PrPSc) has not been detected in heart tissue from several amyloid heart disease patients, it has been observed in the heart tissue of a patient with sporadic Creutzfeldt-Jakob Disease (sCJD), the most common form of human prion disease. In order to determine whether prion infectivity can be found in heart tissue, we have inoculated formaldehyde fixed brain and heart tissue from two sCJD patients, as well as prion protein positive fixed heart tissue from two amyloid heart disease patients, into transgenic mice overexpressing the human prion protein. Although the sCJD brain samples led to clinical or subclinical prion infection and deposition of PrPSc in the brain, none of the inoculated heart samples resulted in disease or the accumulation of PrPSc. Thus, our results suggest that prion infectivity is not likely present in cardiac tissue from sCJD or amyloid heart disease patients. C1 [Priola, Suzette A.; Ward, Anne E.; Choi, Young Pyo] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [McCall, Sherman A.] USAMRIID, Ft Detrick, MD USA. [Trifilo, Matthew; Solforosi, Laura; Williamson, R. Anthony; Cruite, Justin T.; Oldstone, Michael B. A.] Scripps Res Inst, Dept Immunol Microbial Sci, La Jolla, CA 92037 USA. RP Priola, SA (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM spriola@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; USPHS [AG04342] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and USPHS grant AG04342. NR 52 TC 1 Z9 1 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9501 EP 9510 DI 10.1128/JVI.00692-13 PG 10 WC Virology SC Virology GA 201NO UT WOS:000323148500010 PM 23785217 ER PT J AU Chen, ZC Sosnovtsev, SV Bok, K Parra, GI Makiya, M Agulto, L Green, KY Purcell, RH AF Chen, Zhaochun Sosnovtsev, Stanislav V. Bok, Karin Parra, Gabriel I. Makiya, Michelle Agulto, Liane Green, Kim Y. Purcell, Robert H. TI Development of Norwalk Virus-Specific Monoclonal Antibodies with Therapeutic Potential for the Treatment of Norwalk Virus Gastroenteritis SO JOURNAL OF VIROLOGY LA English DT Article ID BLOOD GROUP ANTIGENS; HEPATITIS-C VIRUS; INFECTIOUS NONBACTERIAL GASTROENTERITIS; INFLUENZA-A-VIRUSES; MEMORY B-CELLS; 3-DIMENSIONAL STRUCTURE; NEUTRALIZING ANTIBODY; PROTECTIVE ANTIGEN; STRUCTURAL BASIS; VACCINIA VIRUS AB Passive immunoprophylaxis or immunotherapy with norovirus-neutralizing monoclonal antibodies (MAbs) could be a useful treatment for high-risk populations, including infants and young children, the elderly, and certain patients who are debilitated or immunocompromised. In order to obtain antinorovirus MAbs with therapeutic potential, we stimulated a strong adaptive immune response in chimpanzees to the prototype norovirus strain Norwalk virus (NV) (genogroup I. 1). A combinatorial phage Fab display library derived from mRNA of the chimpanzees' bone marrow was prepared, and four distinct Fabs reactive with Norwalk recombinant virus-like particles (rVLPs) were recovered, with estimated binding affinities in the subnanomolar range. Mapping studies showed that the four Fabs recognized three different conformational epitopes in the protruding (P) domain of NV VP1, the major capsid protein. The epitope of one of the Fabs, G4, was further mapped to a specific site involving a key amino acid residue, Gly365. One additional specific Fab (F11) was recovered months later from immortalized memory B cells and partially characterized. The anti-NV Fabs were converted into full-length IgG (MAbs) with human gamma 1 heavy chain constant regions. The anti-NV MAbs were tested in the two available surrogate assays for Norwalk virus neutralization, which showed that the MAbs could block carbohydrate binding and inhibit hemagglutination by NV rVLP. By mixing a single MAb with live Norwalk virus prior to challenge, MAbs D8 and B7 neutralized the virus and prevented infection in a chimpanzee. Because chimpanzee immunoglobulins are virtually identical to human immunoglobulins, these chimpanzee anticapsid MAbs may have a clinical application. C1 [Chen, Zhaochun; Makiya, Michelle; Agulto, Liane; Purcell, Robert H.] NIAID, Infect Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sosnovtsev, Stanislav V.; Bok, Karin; Parra, Gabriel I.; Green, Kim Y.] NIAID, Infect Dis Lab, Natl Inst Hlth, Cardiovasc Sect, Bethesda, MD 20892 USA. RP Chen, ZC (reprint author), NIAID, Infect Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM zchen@niaid.nih.gov; kgreen@niaid.nih.gov OI Parra, Gabriel/0000-0002-1102-4740 FU Intramural Research Program of the NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 68 TC 22 Z9 22 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9547 EP 9557 DI 10.1128/JVI.01376-13 PG 11 WC Virology SC Virology GA 201NO UT WOS:000323148500014 PM 23785216 ER PT J AU Magadan, JG Khurana, S Das, SR Frank, GM Stevens, J Golding, H Bennink, JR Yewdell, JW AF Magadan, Javier G. Khurana, Surender Das, Suman R. Frank, Gregory M. Stevens, James Golding, Hana Bennink, Jack R. Yewdell, Jonathan W. TI Influenza A Virus Hemagglutinin Trimerization Completes Monomer Folding and Antigenicity SO JOURNAL OF VIROLOGY LA English DT Article ID VIRAL MEMBRANE-PROTEINS; INTRACELLULAR-TRANSPORT; RECEPTOR-BINDING; MONOCLONAL-ANTIBODIES; NEUTRALIZING ANTIBODY; ENDOPLASMIC-RETICULUM; GOLGI-COMPLEX; FUSION; CELLS; SITE AB Influenza A virus (IAV) remains an important human pathogen largely because of antigenic drift, the rapid emergence of anti-body escape mutants that precludes durable vaccination. The most potent neutralizing antibodies interact with cognate epitopes in the globular "head" domain of hemagglutinin (HA), a homotrimeric glycoprotein. The H1 HA possesses five distinct regions defined by a large number of mouse monoclonal antibodies (MAbs), i.e., Ca1, Ca2, Cb, Sa, and Sb. Ca1-Ca2 sites require HA trimerization to attain full antigenicity, consistent with their locations on opposite sides of the trimer interface. Here, we show that full antigenicity of Cb and Sa sites also requires HA trimerization, as revealed by immunofluorescence microscopy of IAV-infected cells and biochemically by pulse-chase radiolabeling experiments. Surprisingly, epitope antigenicity acquired by HA trimerization persists following acid triggering of the globular domains dissociation and even after proteolytic release of monomeric heads from acid-treated HA. Thus, the requirement for HA trimerization by trimer-specific MAbs mapping to the Ca, Cb, and Sa sites is not dependent upon the bridging of adjacent monomers in the native HA trimer. Rather, complete antigenicity of HA (and, by inference, immunogenicity) requires a final folding step that accompanies its trimerization. Once this conformational change occurs, HA trimers themselves would not necessarily be required to induce a highly diverse neutralizing response to epitopes in the globular domain. C1 [Magadan, Javier G.; Das, Suman R.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Khurana, Surender; Frank, Gregory M.; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Stevens, James] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 47 TC 11 Z9 11 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9742 EP 9753 DI 10.1128/JVI.00471-13 PG 12 WC Virology SC Virology GA 201NO UT WOS:000323148500032 PM 23824811 ER PT J AU Arnold, MM Barro, M Patton, JT AF Arnold, Michelle M. Barro, Mario Patton, John T. TI Rotavirus NSP1 Mediates Degradation of Interferon Regulatory Factors through Targeting of the Dimerization Domain SO JOURNAL OF VIROLOGY LA English DT Article ID INNATE IMMUNE-RESPONSE; VIRAL NUCLEIC-ACIDS; CRYSTAL-STRUCTURE; TRANSCRIPTION FACTOR; ANTIVIRAL RESPONSES; IRF FAMILY; ACTIVATION; PROTEIN; PHOSPHORYLATION; EXPRESSION AB Rotavirus nonstructural protein NSP1 can inhibit expression of interferon (IFN) and IFN-stimulated gene products by inducing proteasome-mediated degradation of IFN-regulatory factors (IRFs), including IRF3, IRF5, and IRF7. All IRF proteins share an N-terminal DNA-binding domain (DBD), and IRF3, IRF5, and IRF7 contain a similar C-proximal IRF association domain (IAD) that mediates IRF dimerization. An autoinhibitory domain (ID) at the extreme C terminus interacts with the IAD, burying residues necessary for IRF dimerization. Phosphorylation of serine/threonine residues in the ID induces charge repulsions that unmask the IAD, enabling IRF dimerization and subsequent nuclear translocation. To define the region of IRF proteins targeted for degradation by NSP1, we generated IRF3 and IRF7 truncation mutants and transiently expressed each with simian SA11-4F NSP1. These assays indicated that the IAD represented a necessary and sufficient target for degradation. Because NSP1 did not mediate degradation of truncated forms of the IAD, NSP1 likely requires a structurally intact IAD for recognition and targeting of IRF proteins. IRF9, which contains an IAD-like region that directs interactions with signal inducer and activator of transcription (STAT) proteins, was also targeted for degradation by NSP1, while IRF1, which lacks an IAD, was not. Analysis of mutant forms of IRF3 unable to undergo dimerization or that were constitutively dimeric showed that both were targeted for degradation by NSP1. These results indicate that SA11-4F NSP1 can induce degradation of inactive and activated forms of IAD-containing IRF proteins (IRF3 to IRF9), allowing a multipronged attack on IFN-based pathways that promote antiviral innate and adaptive immune responses. C1 [Arnold, Michelle M.; Barro, Mario; Patton, John T.] NIAID, Rotavirus Mol Biol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Rotavirus Mol Biol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jpatton@niaid.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 65 TC 18 Z9 20 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9813 EP 9821 DI 10.1128/JVI.01146-13 PG 9 WC Virology SC Virology GA 201NO UT WOS:000323148500038 PM 23824805 ER PT J AU Petrovas, C Yamamoto, T Price, DA Rao, SS Klatt, NR Brenchley, JM Douek, DC Gostick, E Angermann, BR Grossman, Z Macallan, DC Meier-Schellersheim, M Koup, RA AF Petrovas, Constantinos Yamamoto, Takuya Price, David A. Rao, Srinivas S. Klatt, Nichole R. Brenchley, Jason M. Douek, Daniel C. Gostick, Emma Angermann, Bastian R. Grossman, Zvi Macallan, Derek C. Meier-Schellersheim, Martin Koup, Richard A. TI High Production Rates Sustain In Vivo Levels of PD-1(high) Simian Immunodeficiency Virus-Specific CD8 T Cells in the Face of Rapid Clearance SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-INFECTION; RHESUS MACAQUES; PD-1; TURNOVER; LYMPHOCYTES; EXPRESSION; CD4(+); VACCINATION; REGULATOR; SIVMAC251 AB Programmed Death 1 (PD-1) expression by human/simian immunodeficiency virus (HIV/SIV)-specific CD8 T cells has been associated with defective cytokine production and reduced in vitro proliferation capacity. However, the cellular mechanisms that sustain PD-1(high) virus-specific CD8 T cell responses during chronic infection are unknown. Here, we show that the PD-1(high) phenotype is associated with accelerated in vivo CD8 T cell turnover in SIV-infected rhesus macaques, especially within the SIV-specific CD8 T cell pool. Mathematical modeling of 5-bromo-2' deoxyuridine (BrdU) labeling dynamics demonstrated a significantly increased generation rate of PD-1(high) compared to PD-1(low) CD8 T cells in all memory compartments. Simultaneous analysis of Ki67 and BrdU kinetics revealed a complex in vivo turnover profile whereby only a small fraction of PD-1(high) cells, but virtually all PD-1(low) cells, returned to rest after activation. Similar kinetics operated in both chronic and acute SIV infection. Our data suggest that the persistence of PD-1(high) SIV-specific CD8 T cells in chronic infection is maintained in vivo by a mechanism involving high production coupled with a high disappearance rate. C1 [Petrovas, Constantinos; Yamamoto, Takuya; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Rao, Srinivas S.] NIAID, Lab Anim Med, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Price, David A.; Gostick, Emma] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. [Klatt, Nichole R.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Angermann, Bastian R.; Meier-Schellersheim, Martin] NIAID, Program Syst Immunol & Infect Dis Modeling, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Grossman, Zvi] Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel. [Grossman, Zvi] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Macallan, Derek C.] Univ London, St Georges Hosp, Div Clin Sci, Infect & Immun Res Ctr, London, England. RP Petrovas, C (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM petrovasc@mail.nih.gov; mms@niaid.nih.gov RI Yamamoto, Takuya/L-2642-2013; Price, David/C-7876-2013; OI Yamamoto, Takuya/0000-0003-3753-1211; Price, David/0000-0001-9416-2737; Macallan, Derek/0000-0002-3014-7148 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. D. A. P. is a Wellcome Trust Senior Investigator. NR 24 TC 5 Z9 5 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9836 EP 9844 DI 10.1128/JVI.01001-13 PG 9 WC Virology SC Virology GA 201NO UT WOS:000323148500040 PM 23824823 ER PT J AU Bamunusinghe, D Liu, QP Lu, XY Oler, A Kozak, CA AF Bamunusinghe, Devinka Liu, Qingping Lu, Xiaoyu Oler, Andrew Kozak, Christine A. TI Endogenous Gammaretrovirus Acquisition in Mus musculus Subspecies Carrying Functional Variants of the XPR1 Virus Receptor SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; CELL-SURFACE RECEPTOR; MOUSE XENOTROPIC GAMMARETROVIRUSES; LONG TERMINAL REPEATS; MITOCHONDRIAL-DNA; LABORATORY MOUSE; RETROVIRUS XMRV; WILD MICE; ORIGIN; SEQUENCE AB The xenotropic and polytropic mouse leukemia viruses (X-MLVs and P-MLVs, respectively) have different host ranges but use the same functionally polymorphic receptor, XPR1, for entry. Endogenous retroviruses (ERVs) of these 2 gammaretrovirus sub-types are largely segregated in different house mouse subspecies, but both MLV types are found in the classical strains of laboratory mice, which are genetic mosaics of 3 wild mouse subspecies. To describe the subspecies origins of laboratory mouse XP-MLV ERVs and their coevolutionary trajectory with their XPR1 receptor, we screened the house mouse subspecies for known and novel Xpr1 variants and for the individual full-length XP-MLV ERVs found in the sequenced C57BL mouse genome. The 12 X-MLV ERVs predate the origins of laboratory mice; they were all traced to Japanese wild mice and are embedded in the 5% of the laboratory mouse genome derived from the Asian Mus musculus musculus and, in one case, in the <1% derived from M. m. castaneus. While all 31 P-MLV ERVs map to the 95% of the laboratory mouse genome derived from P-MLV-infected M. m. domesticus, no C57BL P-MLV ERVs were found in wild M. m. domesticus. All M. m. domesticus mice carry the fully permissive XPR1 receptor allele, but all of the various restrictive XPR1 receptors, including the X-MLV-restricting laboratory mouse Xpr1(n) and a novel M. m. castaneus allele, originated in X-MLV-infected Asian mice. Thus, P-MLV ERVs show more insertional polymorphism than X-MLVs, and these differences in ERV acquisition and fixation are linked to subspecies-specific and functionally distinct XPR1 receptor variants. C1 [Bamunusinghe, Devinka; Liu, Qingping; Lu, Xiaoyu; Kozak, Christine A.] NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Oler, Andrew] NIAID, Bioinformat & Computat Biosci Branch, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, Bethesda, MD FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, Bethesda, MD. NR 56 TC 9 Z9 9 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9845 EP 9855 DI 10.1128/JVI.01264-13 PG 11 WC Virology SC Virology GA 201NO UT WOS:000323148500041 PM 23824809 ER PT J AU Ke, RA Lloyd-Smith, JO AF Ke, Ruian Lloyd-Smith, James O. TI Coadaptive Stability of Interfering Particles with HIV-1 When There Is an Evolutionary Conflict SO JOURNAL OF VIROLOGY LA English DT Letter ID IMMUNODEFICIENCY-VIRUS TYPE-1; DIMERIZATION; INFECTION; GENOMES; DESIGN C1 [Ke, Ruian; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ke, RA (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM ruian@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X NR 9 TC 1 Z9 1 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9959 EP 9959 DI 10.1128/JVI.00705-13 PG 1 WC Virology SC Virology GA 201NO UT WOS:000323148500056 PM 23943739 ER PT J AU Gao, N Yoon, GS Liu, X Mi, X Chen, W Standiford, TJ Yu, FSX AF Gao, N. Yoon, G. Sang Liu, X. Mi, X. Chen, W. Standiford, T. J. Yu, F-S X. TI Genome-wide transcriptional analysis of differentially expressed genes in flagellin-pretreated mouse corneal epithelial cells in response to Pseudomonas aeruginosa: involvement of S100A8/A9 SO MUCOSAL IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTOR; IN-VITRO; BACTERIAL-INFECTION; INNATE IMMUNITY; UP-REGULATION; CALPROTECTIN; DEFENSE; PROTEIN; INFLAMMATION; BINDING AB We previously showed that pre-exposure of the cornea to Toll-like receptor 5 ligand flagellin induces profound mucosal innate protection against infections by modifying gene expression. Taking advantage of easily procurable epithelial cell population, this study is the first report to use genome-wide cDNA microarray approach to document genes associated with flagellin-induced protection against Pseudomonas aeruginosa in corneal epithelial cells (CECs). Infection altered the expression of 675 genes (497 up and 178 down), while flagellin pretreatment followed by infection resulted in a great increase in 890 gene upregulated and 37 genes downregulated. Comparing these two groups showed 209 differentially expressed genes (157 up, 52 down). Notably, among 114 genes categorized as defense related, S100A8/A9 are the two most highly induced genes by flagellin, and their expression in the corneal was confirmed by realtime PCR and immunohistochemistry. Neutralization of S100A8 and, to a less extent, A9, resulted in significantly increased bacterial burden and severe keratitis. Collectively, our study identifies many differentially expressed genes by flagellin in CECs in response to Pseudomonas. These novel gene expression signatures provide new insights and clues into the nature of protective mechanisms established by flagellin and new therapeutic targets for reducing inflammation and for controlling microbial infection. C1 [Gao, N.; Mi, X.; Yu, F-S X.] Wayne State Univ, Sch Med, Dept Ophthalmol, Detroit, MI 48202 USA. [Yoon, G. Sang; Liu, X.; Yu, F-S X.] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI USA. [Liu, X.] Chinese Acad Med Sci, Dept Ophthalmol, Peking Union Med Coll Hosp, Beijing 100730, Peoples R China. [Chen, W.] Genom Core Lab Natl Inst Diabet & Digest & Kidney, Bethesda, MD USA. [Standiford, T. J.] Univ Michigan, Med Ctr, Dept Internal Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. RP Yu, FSX (reprint author), Wayne State Univ, Sch Med, Dept Ophthalmol, Detroit, MI 48202 USA. EM fyu@med.wayne.edu FU NIH/NEI [R01-EY010869, R01-EY017960, P30-EY004068, R01-HL097564]; Midwest Eye Bank; Research to Prevent Blindness FX This study was supported by grants NIH/NEI R01-EY010869, R01-EY017960, P30-EY004068, R01-HL097564, Midwest Eye Bank, Research to Prevent Blindness. NR 66 TC 8 Z9 8 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD SEP PY 2013 VL 6 IS 5 BP 993 EP 1005 DI 10.1038/mi.2012.137 PG 13 WC Immunology SC Immunology GA 203YV UT WOS:000323331800013 PM 23340821 ER PT J AU Overstreet, MG Gaylo, A Angermann, BR Hughson, A Hyun, YM Lambert, K Acharya, M Billroth-MacLurg, AC Rosenberg, AF Topham, DJ Yagita, H Kim, M Lacy-Hulbert, A Meier-Schellersheim, M Fowell, DJ AF Overstreet, Michael G. Gaylo, Alison Angermann, Bastian R. Hughson, Angela Hyun, Young-Min Lambert, Kris Acharya, Mridu Billroth-MacLurg, Alison C. Rosenberg, Alexander F. Topham, David J. Yagita, Hideo Kim, Minsoo Lacy-Hulbert, Adam Meier-Schellersheim, Martin Fowell, Deborah J. TI Inflammation-induced interstitial migration of effector CD4(+) T cells is dependent on integrin alpha(V) SO NATURE IMMUNOLOGY LA English DT Article ID DELAYED-TYPE HYPERSENSITIVITY; IN-VIVO; DENDRITIC CELLS; LEUKOCYTE MIGRATION; INFLUENZA INFECTION; LYMPH-NODES; V INTEGRINS; FIBRONECTIN; EXPRESSION; MOTILITY AB Leukocytes must traverse inflamed tissues to effectively control local infection. Although motility in dense tissues seems to be integrin independent and based on actomyosin-mediated protrusion and contraction, during inflammation, changes to the extracellular matrix (ECM) may necessitate distinct motility requirements. Indeed, we found that the interstitial motility of T cells was critically dependent on Arg-Gly-Asp (RGD)-binding integrins in the inflamed dermis. Inflammation-induced deposition of fibronectin was functionally linked to higher expression of integrin alpha(V) on effector CD4(+) T cells. By intravital multiphoton imaging, we found that the motility of CD4(+) T cells was dependent on alpha(V) expression. Selective blockade or knockdown of alpha(V) arrested T helper type 1 (T(H)1) cells in the inflamed tissue and attenuated local effector function. Our data demonstrate context-dependent specificity of lymphocyte movement in inflamed tissues that is essential for protective immunity. C1 [Overstreet, Michael G.; Gaylo, Alison; Hughson, Angela; Hyun, Young-Min; Lambert, Kris; Billroth-MacLurg, Alison C.; Topham, David J.; Kim, Minsoo; Fowell, Deborah J.] Univ Rochester, Aab Inst Biomed Sci, David H Smith Ctr Vaccine Biol & Immunol, Rochester, NY 14627 USA. [Overstreet, Michael G.; Gaylo, Alison; Hyun, Young-Min; Billroth-MacLurg, Alison C.; Topham, David J.; Kim, Minsoo; Fowell, Deborah J.] Univ Rochester, Dept Microbiol & Immunol, Rochester, NY USA. [Angermann, Bastian R.; Meier-Schellersheim, Martin] NIAID, Computat Biol Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Acharya, Mridu; Lacy-Hulbert, Adam] Massachusetts Gen Hosp, Dept Pediat, Program Dev Immunol, Boston, MA 02114 USA. [Acharya, Mridu; Lacy-Hulbert, Adam] Harvard Univ, Sch Med, Boston, MA USA. [Rosenberg, Alexander F.] Univ Rochester, Med Ctr, Div Allergy Immunol & Rheumatol, Rochester, NY 14642 USA. [Yagita, Hideo] Juntendo Univ, Dept Immunol, Tokyo, Japan. RP Fowell, DJ (reprint author), Univ Rochester, Aab Inst Biomed Sci, David H Smith Ctr Vaccine Biol & Immunol, Rochester, NY 14627 USA. EM deborah_fowell@urmc.rochester.edu OI Lacy-Hulbert, Adam/0000-0003-2162-0156 FU US National Institutes of Health [AI072690, AI088427, HL018208, HL087088, AI089079]; American Heart Association [11SDG7520018]; National Institute of Allergy and Infectious Diseases FX We thank N. Killeen (University of California, San Francisco) for WT15 mice; R. Locksley (University of California, San Francisco) for IFN-gamma reporter mice (Yeti mice); M. Nussenzweig (The Rockefeller University) for CD11c-YFP mice; R. Hynes (MIT) for Itga5fl/fl mice; B. Leon and F. Lund (University of Alabama) for H. polygyrus-infected tissue; R. Germain and J. Egen for technical assistance; K. Kasischke, L. Callahan, E. Brown and the University of Rochester Medical Center Multiphoton Core for support; Kihong Lim for technical assistance; J. Miller and S. Georas for comments on the manuscript; and members of the Fowell and Kim laboratories for discussions and support. Supported by the US National Institutes of Health (AI072690 and AI088427 to D. J. F.; HL018208 and HL087088 to M. K.; and AI089079 to M.G.O.), the American Heart Association (11SDG7520018 to Y.-M.H.) and the intramural program of the National Institute of Allergy and Infectious Diseases (B. R. A. and M.M.-S.). NR 55 TC 36 Z9 36 U1 0 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2013 VL 14 IS 9 BP 949 EP + DI 10.1038/ni.2682 PG 12 WC Immunology SC Immunology GA 204OS UT WOS:000323377700012 PM 23933892 ER PT J AU Song, R Zhang, HY Peng, XQ Su, RB Yang, RF Li, J Xi, ZX Gardner, EL AF Song, Rui Zhang, Hai-Ying Peng, Xiao-Qing Su, Rui-Bin Yang, Ri-Fang Li, Jin Xi, Zheng-Xiong Gardner, Eliot L. TI Dopamine D-3 receptor deletion or blockade attenuates cocaine-induced conditioned place preference in mice SO NEUROPHARMACOLOGY LA English DT Article DE Cocaine; Dopamine; D-3 receptor; YQA-14; Reward; Conditioned place preference ID WILD-TYPE MICE; AGONIST 7-OH-DPAT; SEEKING BEHAVIOR; KNOCKOUT MICE; RAT-BRAIN; RHESUS-MONKEYS; MUTANT MICE; LOCALIZATION; PHARMACOLOGY; ANTAGONISTS AB The dopamine (DA) D-3 receptor (D3R) has received much attention in medication development for treatment of addiction. However, the functional role of the D3R in drug reward and addiction has been a matter of debate. We recently reported that D-3 receptor-knockout (D-3(-/-)) mice display increased vulnerability to cocaine self-administration, which we interpret as a compensatory response to attenuated cocaine reward after D3R deletion. Here we report that D-3(-/-) mice displayed attenuated cocaine-induced conditioned place response (CPP) compared to wild-type mice. Similarly, blockade of brain D(3)Rs by YQA-14, a novel DA D-3 receptor antagonist, significantly and dose-dependently inhibits acquisition and expression of cocaine-induced CPP in WT mice, but not in D-3(-/-) mice. These findings suggest that: 1) D(3)Rs play an important role in mediating cocaine's rewarding effects; and 2) YQA-14 is a highly potent and selective D3R antagonist in vivo, which deserves further study as a candidate for treatment of cocaine addiction. Published by Elsevier Ltd. C1 [Song, Rui; Zhang, Hai-Ying; Peng, Xiao-Qing; Xi, Zheng-Xiong; Gardner, Eliot L.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Song, Rui; Su, Rui-Bin; Yang, Ri-Fang; Li, Jin] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. RP Li, J (reprint author), Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. EM lijin@nic.bmi.ac.cn; zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428; Yang, Rifang/0000-0001-8087-9614; Zhang, Haiying/0000-0003-0593-5940 FU U.S. National Institute on Drug Abuse Intramural Research Program; National Basic Research Program of China [2009CB522008]; Natural Science Foundation of China [81102425] FX This work was supported by the U.S. National Institute on Drug Abuse Intramural Research Program, the National Basic Research Program of China (Grant No. 2009CB522008) and the Natural Science Foundation of China (Grant No. 81102425). NR 36 TC 11 Z9 12 U1 0 U2 13 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 2013 VL 72 BP 82 EP 87 DI 10.1016/j.neuropharm.2013.04.042 PG 6 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 185CC UT WOS:000321941800010 PM 23643749 ER PT J AU Van Swearingen, AED Sanchez, CL Frisbee, SM Williams, A Walker, QD Korach, KS Kuhn, CM AF Van Swearingen, Amanda E. D. Sanchez, Cristina L. Frisbee, Suzanne M. Williams, Antonia Walker, Q. David Korach, Kenneth S. Kuhn, Cynthia M. TI Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha SO NEUROPHARMACOLOGY LA English DT Article DE Behavior; Cocaine; Dopamine; Estradiol; Mice; Ovariectomy ID CONDITIONED PLACE PREFERENCE; STRIATAL DOPAMINE RELEASE; TANDEM MASS-SPECTROMETRY; SELF-ADMINISTER COCAINE; VENTRAL TEGMENTAL AREA; LONG-TERM ESTROGEN; SEX-DIFFERENCES; ER-BETA; OVARIAN HORMONES; MESSENGER-RNA AB Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after cocaine administration. Ovx mice were replaced with vehicle (sesame oil) or 17 beta-estradiol (E2) for 2 days or 30 min prior to a cocaine challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ER alpha-selective agonist PPT or the ER beta-selective agonist DPN - were compared to Sham mice, and mice lacking either ER alpha (alpha ERKO) or ER beta (beta ERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 min of E2 replacement in Ovx mice increased cocaine responses to Sham levels. PPT replacement also increased the cocaine response relative to vehicle- or DPN- treated Ovx mice. alpha ERKO mice displayed modestly attenuated behavioral responses to novelty and cocaine compared to alpha WT littermates, but no behavioral differences were found between beta ERKO and beta WT mice. These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through ER alpha. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Van Swearingen, Amanda E. D.; Sanchez, Cristina L.; Frisbee, Suzanne M.; Williams, Antonia; Walker, Q. David; Kuhn, Cynthia M.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Sanchez, Cristina L.] Rhein Westfal TH Aachen, Clin Child & Adolescent Psychiat Psychosomat & Ps, D-52074 Aachen, Nordrhein Westf, Germany. [Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Kuhn, CM (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Room 100-B,Res Pk Bldg 2,POB 3813, Durham, NC 27710 USA. EM aedvs@email.unc.edu; cristina.sanchez@duke.edu; suzannefrisbee@alumni.ecu.edu; antonia.williams@yahoo.com; qdwalker@duke.edu; korach@niehs.nih.gov; ckuhn@duke.edu OI Sanchez, Cristina L./0000-0001-6380-4282; Korach, Kenneth/0000-0002-7765-418X FU NIDA [N01DA-9-7767, DA009079]; Division of Intramural Research of the NIEHS [Z01ES70065] FX The authors thank the laboratory of Dr. David Moody at the Center for Human Toxicology, University of Utah for the assessment of COC concentrations through NIDA Contract N01DA-9-7767. This work was supported by NIDA grant #DA009079 to CMK. Support was provided by the Division of Intramural Research of the NIEHS to KSK Z01ES70065. All experiments in this study comply with all applicable current laws in the United States. NR 103 TC 5 Z9 5 U1 0 U2 12 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 2013 VL 72 BP 236 EP 249 DI 10.1016/j.neuropharm.2013.04.015 PG 14 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 185CC UT WOS:000321941800026 PM 23608737 ER PT J AU Duan, Q van Gelderen, P Duyn, J AF Duan, Qi van Gelderen, Peter Duyn, Jeff TI Improved Bloch-Siegert based B-1 mapping by reducing off-resonance shift SO NMR IN BIOMEDICINE LA English DT Article DE high field MRI; flip angle; wavelength effects; B-1 mapping; transmit sense AB An MRI method based on the Bloch-Siegert (BS) shift phenomenon was recently proposed as a fast and precise way to map a radio frequency (RF) transmit field (B-1(+) field). For MRI at high field, the mapping sensitivity of this approach was limited by tissue heating associated with a BS irradiation pulse. To mitigate this, we investigated the possibility of lowering the off-resonance frequency of this pulse since theoretical analysis indicated that the sensitivity of Bloch-Siegert based B-1(+) mapping could be substantially improved when irradiating closer to resonance. Using optimized irradiation pulse shape and gradient crushers to minimize direct excitation effects, in vivo experiments on human brains at 7T confirmed improved sensitivity with this approach. Improved sensitivity translated into an 80% reduction in B-1(+) estimation errors without increasing tissue heating. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Duan, Qi; van Gelderen, Peter; Duyn, Jeff] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Duan, Q (reprint author), 10 Ctr Dr,Room B1D728,Bldg 10, Bethesda, MD 20892 USA. EM Qi.Duan@nih.gov RI Duan, Qi/J-7916-2016 OI Duan, Qi/0000-0002-2407-6611 FU National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. The authors would also like to thank Dr. Sacolick for providing the original Fermi pulse used in (5) and the reviewers of this and related studies submitted by our group for their constructive comments. NR 24 TC 10 Z9 10 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD SEP PY 2013 VL 26 IS 9 BP 1070 EP 1078 DI 10.1002/nbm.2920 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 200OO UT WOS:000323078700003 PM 23355474 ER PT J AU Navarathna, DHMLP Munasinghe, J Lizak, MJ Nayak, D McGavern, DB Roberts, DD AF Navarathna, Dhammika H. M. L. P. Munasinghe, Jeeva Lizak, Martin J. Nayak, Debasis McGavern, Dorian B. Roberts, David D. TI MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis SO NMR IN BIOMEDICINE LA English DT Article DE Candida albicans; murine disseminated candidiasis; blood-brain barrier; MRI; extracellular vascular contrast agent Gd-DTPA; ultrasmall iron oxide particles; intravital two-photon microscopy ID CENTRAL-NERVOUS-SYSTEM; IRON-OXIDE PARTICLES; USPIO-ENHANCED MR; INFECTIOUS OSTEOMYELITIS; MACROPHAGE INFILTRATION; CELL RECRUITMENT; VIRAL-INFECTION; IN-VITRO; ALBICANS; INFLAMMATION AB Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to these critical organs leads to the high mortality associated with such infections, and invasion across the blood-brain barrier can result in fungal meningoencephalitis. Candida albicans can penetrate a brain endothelial cell barrier in vitro through transcellular migration, but this mechanism has not been confirmed in vivo. MRI using the extracellular vascular contrast agent gadolinium diethylenetriaminepentaacetic acid demonstrated that integrity of the blood-brain barrier is lost during C. albicans invasion. Intravital two-photon laser scanning microscopy was used to provide the first real-time demonstration of C. albicans colonizing the living brain, where both yeast and filamentous forms of the pathogen were found. Furthermore, we adapted a previously described method utilizing MRI to monitor inflammatory cell recruitment into infected tissues in mice. Macrophages and other phagocytes were visualized in kidney and brain by the administration of ultrasmall iron oxide particles. In addition to obtaining new insights into the passage of C. albicans across the brain microvasculature, these imaging methods provide useful tools to study further the pathogenesis of C. albicans infections, to define the roles of Candida virulence genes in kidney versus brain infection and to assess new therapeutic measures for drug development. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Navarathna, Dhammika H. M. L. P.; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva; Lizak, Martin J.; Nayak, Debasis; McGavern, Dorian B.] NINDS, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NIH, Bldg 10,Room 2A33,10 Ctr Dr, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; OI Roberts, David/0000-0002-2481-2981; McGavern, Dorian/0000-0001-9568-545X FU National Institutes of Health, National Cancer Institute, Center for Cancer Research [Z01 SC 009173]; National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (DDR, Z01 SC 009173) and National Institute of Neurological Disorders and Stroke (MJL, DBM). NR 54 TC 8 Z9 8 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD SEP PY 2013 VL 26 IS 9 BP 1125 EP 1134 DI 10.1002/nbm.2926 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 200OO UT WOS:000323078700009 PM 23606437 ER PT J AU Blomberg, BA Akers, SR Saboury, B Mehta, NN Cheng, G Torigian, DA Lim, E Del Bello, C Werner, TJ Alavi, A AF Blomberg, Bjoern A. Akers, Scott R. Saboury, Babak Mehta, Nehal N. Cheng, Gang Torigian, Drew A. Lim, Esther Del Bello, Catherine Werner, Thomas J. Alavi, Abass TI Delayed time-point F-18-FDG PET CT imaging enhances assessment of atherosclerotic plaque inflammation SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE atherosclerosis; fluorine-18 fluorodeoxyglucose; multiple time-point imaging; positron emission tomography ID POSITRON-EMISSION-TOMOGRAPHY; VASCULAR INFLAMMATION; FLUORODEOXYGLUCOSE UPTAKE; LARGE ARTERIES; FDG-PET; RISK; RESOLUTION; WALL AB Objective The aim of this study was to determine the ideal circulation time of fluorine-18 fluorodeoxyglucose (F-18-FDG) in order to detect and quantify atherosclerotic plaque inflammation with PET computed tomography (CT) imaging.Methods Fifteen patients underwent multiple time-point imaging at approximate to 60, 120, and 180 min after F-18-FDG administration. For each time point, global assessment of aortic and carotid F-18-FDG uptake was determined qualitatively by visual assessment and semiquantitatively by calculation of the mean and maximum standardized uptake values (SUV) and the corresponding target-to-background ratio (TBR).Results Delayed imaging achieved significant improvement in visualization of atherosclerotic plaque inflammation [Friedman's (2) statistic (d.f.=2, n=15)=24.13, P<0.001, Kendall's W=0.80]. This observation was confirmed by semiquantitative image analysis. At 1 h, the aortic and carotid SUVmean-calculated TBR was 1.05 [95% confidence interval (CI)=0.98, 1.11] and 0.88 (95% CI=0.81, 0.96), respectively. At 3 h, the TBR significantly increased to 1.57 (95% CI=1.28, 1.86; P=0.001) for the aorta and to 1.61 (95% CI=1.36, 1.87; P<0.001) for the carotid arteries. SUVmax-calculated TBRs showed a similar increase over time.Conclusion One- and 2-h F-18-FDG PET CT imaging is suboptimal for global assessment of atherosclerotic plaque inflammation compared with imaging at 3 h. Our data support the utilization of 3-h delayed imaging to obtain optimal data for the detection and quantification of atherosclerotic plaque inflammation in human arteries. C1 [Blomberg, Bjoern A.; Saboury, Babak; Torigian, Drew A.; Alavi, Abass] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Blomberg, Bjoern A.; Saboury, Babak; Torigian, Drew A.; Werner, Thomas J.; Alavi, Abass] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Akers, Scott R.; Cheng, Gang; Lim, Esther; Del Bello, Catherine] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA USA. [Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Blomberg, Bjoern A.] Univ Utrecht, Sch Med, Univ Med Ctr Utrecht, Utrecht, Netherlands. RP Alavi, A (reprint author), 3400 Spruce St, Philadelphia, PA 19104 USA. EM abass.alavi@uphs.upenn.edu FU United States Department of Veterans Affairs (VISN 4 CPPF Grant) FX This study was supported in part by a grant from the United States Department of Veterans Affairs (VISN 4 CPPF Grant). NR 29 TC 11 Z9 12 U1 0 U2 3 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 2013 VL 34 IS 9 BP 860 EP 867 DI 10.1097/MNM.0b013e3283637512 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 202QA UT WOS:000323232000004 PM 23799532 ER PT J AU Akintoye, SO Boyce, AM Collins, MT AF Akintoye, Sunday O. Boyce, Alison M. Collins, Michael T. TI Dental perspectives in fibrous dysplasia and McCune-Albright syndrome SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID STIMULATORY G-PROTEIN; GS-ALPHA GENE; ACTIVATING MUTATIONS; SKELETAL PROGENITORS; BONE; OSTEOSARCOMA; MANAGEMENT; ENDOCRINE; SURGERY; LESIONS AB McCune-Albright syndrome (MAS) is a rare multisystem disorder characterized by the triad of polyostotic fibrous dysplasia (FD), endocrine disorders, and cafe-au-lait skin pigmentation. Ninety percent of MAS patients have FD lesions in the craniofacial area, resulting in significant orofacial deformity, dental disorders, bone pain, and compromised oral health. Maxillomandibular FD is also associated with dental developmental disorders, malocclusion, and high caries index. There are limited data on the outcomes of dental treatments in maxillomandibular FD/MAS patients, because clinicians and researchers have limited access to patients, and there are concerns that dental surgery may activate quiescent jaw FD lesions to grow aggressively. This report highlights current perspectives on dental management issues associated with maxillomandibular FD within the context of MAS. C1 [Akintoye, Sunday O.] Univ Penn, Sch Dent Med, Dept Oral Med, Philadelphia, PA 19104 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Bone Hlth Program, Div Orthopaed & Sports Med, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Akintoye, SO (reprint author), Univ Penn, Sch Dent Med, Dept Oral Med, Robert Schattner Room 211,240 South 40th St, Philadelphia, PA 19104 USA. EM akintoye@dental.upenn.edu FU National Institutes of Health/United States Department of Health and Human Services (NIH/DHHS), Bethesda, MD; National Institute of Dental and Craniofacial Research (NIDCR) [R21DE022826]; National Cancer Institute (NCI) [K22CA169089]; Division of Intramural Research NIDCR, a part of the Intramural Research Program of NIH/DHHS; Bone Health Program at Children's National Medical Center, Washington DC FX This work was supported in part by National Institutes of Health/United States Department of Health and Human Services (NIH/DHHS), Bethesda, MD, grant R21DE022826 from the National Institute of Dental and Craniofacial Research (NIDCR), and grant K22CA169089 from the National Cancer Institute (NCI) (S.O.A.); the Division of Intramural Research NIDCR, a part of the Intramural Research Program of NIH/DHHS (M.T.C. and A.M.B.); and the Bone Health Program at Children's National Medical Center, Washington DC (A.M.B.). NR 44 TC 6 Z9 6 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 EI 1528-395X J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD SEP PY 2013 VL 116 IS 3 BP E149 EP E155 DI 10.1016/j.oooo.2013.05.023 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 205ZM UT WOS:000323484300001 PM 23953425 ER PT J AU Shahzad, M Sivakumaran, TA Qaiser, TA Schultz, JM Hussain, Z Flanagan, M Bhinder, MA Kissell, D Greinwald, JH Khan, SN Friedman, TB Zhang, KJ Riazuddin, S Riazuddin, S Ahmed, ZM AF Shahzad, Mohsin Sivakumaran, Theru A. Qaiser, Tanveer A. Schultz, Julie M. Hussain, Zawar Flanagan, Megan Bhinder, Munir A. Kissell, Diane Greinwald, John H., Jr. Khan, Shaheen N. Friedman, Thomas B. Zhang, Kejian Riazuddin, Saima Riazuddin, Sheikh Ahmed, Zubair M. TI Genetic Analysis through OtoSeq of Pakistani Families Segregating Prelingual Hearing Loss SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE hearing loss; Usher syndrome; microdroplet PCR; next-generation sequencing; clinical diagnosis; genetic etiology; PDS; MYO7A; CDH23 ID SYNDROME TYPE-I; MYOSIN VIIA GENE; USHER-SYNDROME; NONSYNDROMIC DEAFNESS; MUTATION SPECTRUM; GENOMIC CAPTURE; DIVERSE ORIGINS; CDH23; HETEROGENEITY; GENERATION AB Objective To identify the genetic cause of prelingual sensorineural hearing loss in Pakistani families using a next-generation sequencing (NGS)-based mutation screening test named OtoSeq. Study Design Prospective study. Setting Research laboratory. Subjects and Methods We used 3 fluorescently labeled short tandem repeat (STR) markers for each of the known autosomal recessive nonsyndromic (DFNB) and Usher syndrome (USH) locus to perform a linkage analysis of 243 multigenerational Pakistani families segregating prelingual hearing loss. After genotyping, we focused on 34 families with potential linkage to MYO7A, CDH23, and SLC26A4. We screened affected individuals from a subset of these families using the OtoSeq platform to identify underlying genetic variants. Sanger sequencing was performed to confirm and study the segregation of mutations in other family members. For novel mutations, normal hearing individuals from ethnically matched backgrounds were also tested. Results Hearing loss was found to co-segregate with locus-specific STR markers for MYO7A in 32 families, CDH23 in 1 family, and SLC26A4 in 1 family. Using the OtoSeq platform, a microdroplet PCR-based enrichment followed by NGS, we identified mutations in 28 of the 34 families including 11 novel mutations. Sanger sequencing of these mutations showed 100% concordance with NGS data and co-segregation of the mutant alleles with the hearing loss phenotype in the respective families. Conclusion Using NGS-based platforms like OtoSeq in families segregating hearing loss will contribute to the identification of common and population-specific mutations, early diagnosis, genetic counseling, and molecular epidemiology. C1 [Shahzad, Mohsin; Riazuddin, Saima; Ahmed, Zubair M.] Cincinnati Childrens Hosp Res Fdn, Div Ophthalmol, Cincinnati, OH USA. [Sivakumaran, Theru A.; Flanagan, Megan; Kissell, Diane; Greinwald, John H., Jr.; Zhang, Kejian; Riazuddin, Saima; Ahmed, Zubair M.] Cincinnati Childrens Hosp Res Fdn, Human Genet, Cincinnati, OH USA. [Sivakumaran, Theru A.; Zhang, Kejian] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. [Qaiser, Tanveer A.; Hussain, Zawar; Bhinder, Munir A.; Khan, Shaheen N.; Riazuddin, Saima; Ahmed, Zubair M.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Schultz, Julie M.; Friedman, Thomas B.] NIDCD, Mol Genet Lab, NIH, Bethesda, MD USA. [Greinwald, John H., Jr.] Cincinnati Childrens Hosp Res Fdn, Cincinnati, OH USA. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Riazuddin, Sheikh] Univ Lahore, Lahore, Pakistan. RP Ahmed, ZM (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Pediat Ophthalmol, 3333 Burnet Ave,MLC 7003, Cincinnati, OH 45229 USA. EM zubair.ahmed@cchmc.org RI Nasim Khan, Shaheen/F-2135-2015 FU Intramural funds NIDCD [DC000039-15]; NIDCD/NIH [R01 DC011803, R01 DC012564]; RPB Foundation FX Intramural funds NIDCD DC000039-15 to Thomas B. Friedman. NIDCD/NIH research grant R01 DC011803 to Saima Riazuddin. Career Development Award from RPB Foundation to Zubair M. Ahmed. NIDCD/NIH research grant R01 DC012564 to Zubair M. Ahmed. NR 63 TC 9 Z9 9 U1 0 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2013 VL 149 IS 3 BP 478 EP 487 DI 10.1177/0194599813493075 PG 10 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 206BA UT WOS:000323489500021 PM 23770805 ER PT J AU Harry, GJ AF Harry, G. Jean TI Microglia during development and aging SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Microglia; P2X receptors; Aging; Development; Synapse stripping ID CENTRAL-NERVOUS-SYSTEM; TOLL-LIKE RECEPTORS; FOCAL CEREBRAL-ISCHEMIA; HUMAN ADULT MICROGLIA; TUMOR-NECROSIS-FACTOR; GLYCOSYLATION END-PRODUCTS; PURINERGIC P2X(7) RECEPTOR; DEVELOPING RAT-BRAIN; GLIAL TNF-ALPHA; ALZHEIMERS-DISEASE AB Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, and axonal degeneration. Changes in microglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microglia potentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging. Published by Elsevier Inc. C1 NIEHS, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Natl Toxicol Program Lab, MD C1-04,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU National Toxicology Program Division; National Institute of Environmental Health Sciences; National Institutes of Health; Department of Health and Human Services [1Z01ES101623, ES021164] FX This research was supported by the National Toxicology Program Division, the National Institute of Environmental Health Sciences, the National Institutes of Health, and the Department of Health and Human Services #1Z01ES101623 and ES021164. The views expressed in this article are those of the author and they do not necessarily represent the views or policies of the National Toxicology Program. NR 286 TC 88 Z9 92 U1 8 U2 68 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD SEP PY 2013 VL 139 IS 3 BP 313 EP 326 DI 10.1016/j.pharmthera.2013.04.013 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 204VH UT WOS:000323398900002 PM 23644076 ER PT J AU De Luca, P Moiola, CP Zalazar, F Gardner, K Vazquez, ES De Siervi, A AF De Luca, P. Moiola, C. P. Zalazar, F. Gardner, K. Vazquez, E. S. De Siervi, A. TI BRCA1 and p53 regulate critical prostate cancer pathways SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE BRCA1; p53; GADD153; DNA damage ID E-CADHERIN; TUMOR PROGRESSION; BREAST-CANCER; CELL-LINES; GENE; CARCINOMAS; EXPRESSION; HEDGEHOG; SUSCEPTIBILITY; TRANSCRIPTION AB BACKGROUND: Loss or mutations of the BRCA1 gene are associated with increased risk of breast and ovarian cancers and with prostate cancer (PCa) aggressiveness. Previously, we identified GADD153 as a target of BRCA1 protein, which increases doxorubicin sensitivity in human p53 -/- PCa cells (PC3). Considering that p53 is a crucial target in cancer therapy, in this work we investigated p53 role in the regulation of transcription of GADD153. METHODS: We performed reverse transcription quantitative PCR (RT-qPCR), western blot and luciferase assays to analyze GADD153 and/or BRCA1 expression in response to ultraviolet or doxorubicin exposure in PC3 p53 stable-transfected cells and LNCaP (p53 +/+) cells. BRCA1 protein recruitment to GADD153 promoter was studied by chromatin immunoprecipitation-qPCR. To assess expression of BRCA1 and/or p53 target genes, we used a panel of stable-transfected PCa cell lines. We finally analyzed these genes in vivo using BRCA1-depleted PCa xenograft models. RESULTS: We found that GADD153 was highly induced by doxorubicin in PC3 cells; however, this response was totally abolished in LNCaP (p53wt) and in p53-restituted PC3 cells. Furthermore, BRCA1 protein associates to GADD153 promoter after DNA damage in the presence of p53. Additionally, we demonstrated that BRCA1 and/or p53 modulate genes involved in DNA damage and cell cycle regulation (cyclin D1, BLM, BRCA2, DDB2, p21(WAF1/CIP1), H3F3B, GADD153, GADD45A, FEN1, CCNB2), EMT (E-cadherin, beta-catenin, vimentin, fibronectin, slug, snail) and Hedgehog pathways (SHH, IHH, DHH, Gli1, PATCH1). Furthermore, xenograft studies demonstrated that BRCA1 knockdown in PC3 cells increased tumor growth and modulated these genes in vivo. CONCLUSIONS: Although BRCA1 induces GADD153 in a p53 independent manner, p53 abolished GADD153 induction in response to DNA damage. In addition, several important PCa targets are modulated by BRCA1 and p53. Altogether, these data might be important to understand the therapy response of PCa patients. C1 [De Luca, P.; Moiola, C. P.; Zalazar, F.; Vazquez, E. S.; De Siervi, A.] Univ Buenos Aires, CONICET, IQUIBICEN, Dept Biol Chem,Sch Sci FCEN, Buenos Aires, DF, Argentina. [Gardner, K.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP De Siervi, A (reprint author), Univ Buenos Aires, CONICET, IQUIBICEN, Dept Biol Chem,Sch Sci FCEN, C1428EGA, Buenos Aires, DF, Argentina. EM adesiervi@qb.fcen.uba.ar FU Argentinean Agency of Science and Technology (ANPCyT) [PICT 2006-00228, PICT 2006-00367, PICT 2010-00431]; CONICET; NCI, NIH (USA) FX This research was supported by the Argentinean Agency of Science and Technology (ANPCyT PICT 2006-00228, PICT 2006-00367 and PICT 2010-00431). E. Vazquez and A. De Siervi are members of the career of scientific researcher at the National Research Council (CONICET). P De Luca holds postdoctoral fellowship from CONICET. C Moiola and F Zalazar hold PhD scholarships from CONICET. K. Gardner is a principal investigator at the NCI, NIH (USA). NR 31 TC 11 Z9 12 U1 0 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD SEP PY 2013 VL 16 IS 3 BP 233 EP 238 DI 10.1038/pcan.2013.12 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 201NK UT WOS:000323148100003 PM 23670255 ER PT J AU Forsythe, LP Rowland, JH Padgett, L Blaseg, K Siegel, SD Dingman, CM Gillis, TA AF Forsythe, Laura P. Rowland, Julia H. Padgett, Lynne Blaseg, Karyl Siegel, Scott D. Dingman, Chad M. Gillis, Theresa A. TI The cancer psychosocial care matrix: a community-derived evaluative tool for designing quality psychosocial cancer care delivery SO PSYCHO-ONCOLOGY LA English DT Article DE psychosocial; care delivery; cancer; survivorship ID CLINICAL-PRACTICE GUIDELINES; DISEASE PROGRESSION; ONCOLOGY SETTINGS; ROUTINE CANCER; DEPRESSION; PHYSICIANS; DISTRESS; BREAST; METAANALYSIS; PERFORMANCE AB Objective Although the Institute of Medicine provided a vision for effective psychosocial care for cancer survivors, limited guidance exists regarding the essential components of comprehensive care or progressive steps for implementing each component. This paper describes the development of a unique tool for assessing capacity to provide quality psychosocial care to cancer survivors and the results of the first implementation of this tool in community settings. Methods The psychosocial working group of the National Cancer Institute Community Cancer Centers Program (NCCCP) developed the Cancer Psychosocial Care Matrix assessment tool. All NCCCP sites (n=30, enrolled in 2007 and 2010) completed the matrix indicating their capacity for providing psychosocial care at entry into NCCCP (baseline') after 2years of NCCCP participation (2007 sites only) and within the coming year (future aspirations'). Results At baseline, matrix responses reflected few or no systematic processes in place for most components of comprehensive psychosocial care. However, reported capacity to deliver specific components improved at 2years post-NCCCP entry for the 2007 sites and in all NCCCP sites' future aspirations. Conclusions With growing demand on cancer centers to meet new metrics of quality care, the psychosocial matrix can help centers systematically identify and develop steps to address gap areas in their capacity to meet these new standards. The Cancer Psychosocial Care Matrix appears to enable evaluation of psychosocial programs, may promote intentions to improve psychosocial services, and can facilitate communication of best practices' among cancer centers. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Forsythe, Laura P.; Rowland, Julia H.; Padgett, Lynne] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Rockville, MD USA. [Forsythe, Laura P.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, NIH,DHHS, Rockville, MD USA. [Forsythe, Laura P.] Patient Ctr Outcomes Res Inst, Washington, DC 20036 USA. [Blaseg, Karyl] Billings Clin Canc Ctr, Billings, MT USA. [Siegel, Scott D.; Gillis, Theresa A.] Christiana Care Hlth Syst, Helen F Graham Canc Ctr, Newark, DE USA. [Dingman, Chad M.] Spartanburg Reg Healthcare Syst, Gibbs Canc Ctr, Spartanburg, SC USA. RP Forsythe, LP (reprint author), Patient Ctr Outcomes Res Inst, 1828 L St NW, Washington, DC 20036 USA. EM lforsythe@pcori.org FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The authors gratefully acknowledge the contributions of the psychosocial matrix working group: Karyl Blaseg, Chad M. Dingman, Theresa Gillis, Margaret Palmer, Julia H. Rowland, Scott D. Siegel, and Amber Ussin-Davey. We also gratefully acknowledge the efforts of all 30 NCCCP sites, including the 16 sites enrolled in 2007: Ascension-Seton (TX), Ascension-Columbia St. Mary's (WI), Ascension-St. Vincent (IN), Billings Clinic (MT), CHI-Penrose Cancer Center (CO), CHI-Good Samaritan (NE), CHI-St. Elizabeth (NE), CHI-St. Francis (NE), CHI-St. Joseph (MD), Christiana Care (DE), Hartford Hospital (CT), Our Lady of the Lake (LA), Sanford Hospital (SD), Spartanburg Regional Hospital (SC), St. Joseph Orange (CA), and St. Joseph's Candler (GA); and the 14 sites enrolled in 2010: Einstein Medical Center (PA), Geisinger Medical Center (PA), Gundersen Lutheran (WI), Lehigh Valley Hospital (PA), Maine Medical Center (ME), Mercy Medical Center (IA), Northside Hospital (GA), Norton Suburban Hospital (KY), Providence Portland Medical Center (OR), Saint Mary's Healthcare (MI), St. Joseph Mercy Hospital (MI), St. Luke's Regional Medical Center (IA), Queen's Medical Center (HI), and Waukesha Memorial Hospital (WI). Finally, we especially thank the NCCCP principal investigators for their commitment to this component of their contract and the representatives from each NCCCP site to the Survivorship and Palliative Care Committee. NR 49 TC 7 Z9 7 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD SEP PY 2013 VL 22 IS 9 BP 1953 EP 1962 DI 10.1002/pon.3254 PG 10 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 205NQ UT WOS:000323451500004 PM 23436558 ER PT J AU Jones, P Blunda, M Biegel, G Carlson, LE Biel, M Wiener, L AF Jones, Paul Blunda, Megan Biegel, Gina Carlson, Linda E. Biel, Matthew Wiener, Lori TI Can mindfulness-based interventions help adolescents with cancer? SO PSYCHO-ONCOLOGY LA English DT Article DE mindfulness; adolescents; cancer; mind-body interventions ID CHILDREN; TRIAL AB During the past 30years, there has been an increase in the incidence of cancer in adolescents. While recent studies have illustrated remarkable resilience in youth living with cancer, they can also face daunting acute and chronic adjustment struggles, cognitive and school problems, family and peer relational difficulties, depression, post-traumatic stress symptoms, and other anxiety disorders. Mindfulness-based interventions (MBIs), increasingly shown to be effective in a variety of medical and mental health settings, may be particularly beneficial for adolescents with cancer. This paper reviews evidence from clinical trials of MBIs showing a variety of benefits for adult cancer patients, adolescents with anxiety disorders and chronic pain, and clinically healthy teenagers, which collectively point to likely benefits of MBIs for teen cancer patients. The authors also explore ways that the particular psychological problems often faced by teen cancer patients, including anxiety about the future, may be especially well suited to mindfulness approaches such as learning to observe physical sensations, thoughts, and emotions, as well as cultivating compassion towards themselves and others. The paper concludes with an exploration of unanswered and potential research questions regarding the future use of MBIs with adolescents with cancer, and potentially with teenagers with other chronic diseases. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Jones, Paul; Blunda, Megan; Biegel, Gina; Carlson, Linda E.; Biel, Matthew; Wiener, Lori] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wiener, L (reprint author), NCI, Ctr Canc Res, Pediat Clin I SE, 10 Ctr Dr,Bldg 10,Room 1-6466, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This work is supported in part by the intramural Research Programs of the NIH, National Cancer Institute, Center for Cancer Research NR 19 TC 8 Z9 8 U1 3 U2 35 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD SEP PY 2013 VL 22 IS 9 BP 2148 EP 2151 DI 10.1002/pon.3251 PG 4 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 205NQ UT WOS:000323451500030 PM 23417883 ER PT J AU Bindewald, E Shapiro, BA AF Bindewald, Eckart Shapiro, Bruce A. TI Computational detection of abundant long-range nucleotide covariation in Drosophila genomes SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE Drosophila; RNA-RNA; covariation; interaction network; long-range interactions ID RNA-RNA INTERACTION; LARGE GENE LISTS; SECONDARY STRUCTURE PREDICTION; BASE-PAIRING PROBABILITIES; SEQUENCE ALIGNMENTS; SEMANTIC SIMILARITY; PARTITION-FUNCTION; GO TERMS; TOOL; NANOPARTICLES AB Functionally important nucleotide base-pairing often manifests itself in sequence alignments in the form of compensatory base changes (covariation). We developed a novel index-based computational method (CovaRNA) to detect long-range covariation on a genomic scale, as well as another computational method (CovStat) for determining the statistical significance of observed covariation patterns in alignment pairs. Here we present an all-versus-all search for nucleotide covariation in Drosophila genomic alignments. The search is genome wide, with the restriction that only alignments that correspond to euchromatic regions, which consist of at least 10 Drosophila species, are being considered (59% of the euchromatic genome of Drosophila melanogaster). We find that long-range covariations are especially prevalent between exons of mRNAs as well as noncoding RNAs; the majority of the observed covariations appear as not reverse complementary, but as synchronized mutations, which could be due to interactions with common interaction partners or due to the involvement of genomic elements that are antisense of annotated transcripts. The involved genes are enriched for functions related to regionalization as well as neural and developmental processes. These results are computational evidence that RNA-RNA long-range interactions are a widespread phenomenon that is of fundamental importance to a variety of cellular processes. C1 [Bindewald, Eckart] SAIC Frederick Inc, Basic Sci Program, Ctr Canc Res, Nanobiol Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Computational support by the NCI Advanced Biomedical Computing Center (ABCC) as well as the NIH Helix/Biowulf facility is highly appreciated. This work has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 55 TC 2 Z9 2 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD SEP PY 2013 VL 19 IS 9 BP 1171 EP 1182 DI 10.1261/rna.037630.112 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 203UP UT WOS:000323319600001 PM 23887147 ER PT J AU Malagon, F AF Malagon, Francisco TI RNase III is required for localization to the nucleoid of the 5 ' pre-rRNA leader and for optimal induction of rRNA synthesis in E. coli SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE Pre-rRNA; RNase III; nucleoid; ribosomal operon; Fis ID ESCHERICHIA-COLI; RIBONUCLEASE-III; QUALITY-CONTROL; BINDING-PROTEIN; GENE-EXPRESSION; TRANSCRIPTION; DEGRADATION; CELLS; BIOGENESIS; BACTERIA AB It has recently been demonstrated that ribosomes are preferentially localized outside the nucleoid in Escherichia coli, but little is known about the spatial regulation of pre-rRNA processing. In this work, I investigate the cellular distribution of leader pre-rRNAs using RNA-FISH. In contrast to mature rRNA, the 5' proximal leader region associates with the nucleoid, and this association occurs in an RNase III-dependent manner. Moreover, RNase III plays a role in the rapid induction of ribosomal operons during outgrowth and is essential in the absence of the transcriptional regulator Fis, suggesting a linkage of transcription and RNA processing for ribosomal operons in E. coli. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Malagon, F (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM malagonf@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX I thank Sankar Adhya for his constant and generous scientific and financial support and for critical comments on this manuscript. I also thank Donald Court, Susan Gottesman, and Nadim Majdalani for strains and plasmids; Donald Court, Brian Peddie, and Nadim Majdalani for comments; and Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 56 TC 4 Z9 4 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD SEP PY 2013 VL 19 IS 9 BP 1200 EP 1207 DI 10.1261/rna.038588.113 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 203UP UT WOS:000323319600004 PM 23893733 ER PT J AU Church, G AF Church, George TI Please Reanimate Reviving mammoths and other extinct creatures is a good idea SO SCIENTIFIC AMERICAN LA English DT Editorial Material C1 [Church, George] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Church, George] NIH, Ctr Excellence Genom Sci Harvard, Bethesda, MD USA. RP Church, G (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 3 Z9 3 U1 4 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD SEP PY 2013 VL 309 IS 3 BP 12 EP 12 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205RC UT WOS:000323461300011 PM 24003542 ER PT J AU Pinkerton, LE Hein, MJ Meyers, A Kamel, F AF Pinkerton, Lynne E. Hein, Misty J. Meyers, Alysha Kamel, Freya TI Assessment of ALS mortality in a cohort of formaldehyde-exposed garment workers SO AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; SURVIVAL; UPDATE C1 [Pinkerton, Lynne E.; Hein, Misty J.; Meyers, Alysha] NIOSH, Industrywide Studies Branch, Div Surveillance Hazard Evaluat & Field Studies, Cincinnati, OH 45226 USA. [Kamel, Freya] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Pinkerton, LE (reprint author), NIOSH, Industrywide Studies Branch, Div Surveillance Hazard Evaluat & Field Studies, 4676 Columbia Pkwy,R-15, Cincinnati, OH 45226 USA. EM lep5@cdc.gov OI Meyers, Alysha/0000-0002-6402-0145; Kamel, Freya/0000-0001-5052-6615 FU Intramural Research Program of the National Institute for Occupational Safety and Health; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported in part by the Intramural Research Program of the National Institute for Occupational Safety and Health and in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 14 TC 6 Z9 6 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8421 J9 AMYOTROPH LA SCL FR JI Amyotroph. Lateral Scher. Frontotemp. Degenerat. PD SEP PY 2013 VL 14 IS 5-6 BP 353 EP 355 DI 10.3109/21678421.2013.778284 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 196NR UT WOS:000322782800005 PM 23570513 ER PT J AU Fondell, E O'Reilly, EJ Fitzgerald, KC Falcone, GJ McCullough, ML Park, Y Kolonel, LN Ascherio, A AF Fondell, Elinor O'Reilly, Eilis J. Fitzgerald, Kathryn C. Falcone, Guido J. McCullough, Marjorie L. Park, Yikyung Kolonel, Laurence N. Ascherio, Alberto TI Magnesium intake and risk of amyotrophic lateral sclerosis: Results from five large cohort studies SO AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION LA English DT Article DE Amyotrophic lateral sclerosis; motor neuron disease; longitudinal cohort studies; epidemiology; magnesium ID FOOD FREQUENCY QUESTIONNAIRE; SOCIETY CANCER PREVENTION; BASE-LINE CHARACTERISTICS; DIETARY-INTAKE; DISEASE; DISORDERS; HEALTH; PATHOGENESIS; ASSOCIATION; SURVIVAL AB A low magnesium intake has been suggested to be associated with amyotrophic lateral sclerosis (ALS) in pathological and case-control studies, but prospective studies in humans are lacking. The relation between dietary intake of magnesium and ALS risk was explored in five large prospective cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study), comprising over 1,050,000 males and females contributing 1093 cases of ALS during a mean of 15 years of follow-up. Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. Results demonstrated that dietary magnesium intake was not associated with ALS risk, relative risk 1.07, 95% confidence interval 0.88-1.31 comparing the highest quintile of intake with the lowest. This finding does not support a protective effect of magnesium intake on ALS risk. Further analyses should explore magnesium intake in combination with heavy metal exposure and genetic variants affecting magnesium absorption. C1 [Fondell, Elinor; O'Reilly, Eilis J.; Fitzgerald, Kathryn C.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Falcone, Guido J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Fondell, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM efondell@hsph.harvard.edu RI Falcone, Guido/L-2287-2016; OI Falcone, Guido/0000-0002-6407-0302; Park, Yikyung/0000-0002-6281-489X FU National Institute of Neurological Diseases and Stroke [RO1 NS045893]; National Cancer Institute [PO1 CA87969, PO1 CA055075] FX This work was supported by a grant from the National Institute of Neurological Diseases and Stroke (RO1 NS045893) and by grants from the National Cancer Institute (PO1 CA87969 and PO1 CA055075). NR 37 TC 2 Z9 2 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8421 J9 AMYOTROPH LA SCL FR JI Amyotroph. Lateral Scher. Frontotemp. Degenerat. PD SEP PY 2013 VL 14 IS 5-6 BP 356 EP 361 DI 10.3109/21678421.2013.803577 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 196NR UT WOS:000322782800006 PM 23777266 ER PT J AU Fang, F Al-Chalabi, A Ronnevi, LO Turner, MR Wirdefeldt, K Kamel, F Ye, WM AF Fang, Fang Al-Chalabi, Ammar Ronnevi, Lars-Olof Turner, Martin R. Wirdefeldt, Karin Kamel, Freya Ye, Weimin TI Amyotrophic lateral sclerosis and cancer: A register-based study in Sweden SO AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION LA English DT Article DE Amyotrophic lateral sclerosis; cancer; melanoma; odds ratio; relative risk ID MOTOR-NEURON DISEASE; PARKINSONS-DISEASE; PROSPECTIVE COHORT; RISK-FACTOR; DIAGNOSIS; METAANALYSIS; SMOKING AB Comorbidity of cancer with ALS has been studied previously. Detailed description of the temporal relationship between cancer and ALS is, however, lacking. We conducted a nested case-control study of ALS in Sweden during 1987-2009, including 5481 cases of ALS identified from the Swedish Patient Register and 27,405 controls randomly selected from the general Swedish population. Odds ratios (ORs) for association of ALS with previous cancer diagnosis and incidence rate ratios (IRRs) of cancer after diagnosis were calculated to compare ALS patients with ALS-free individuals. Overall, a previous cancer diagnosis was not associated with subsequent risk of ALS (OR 1.00; 95% CI 0.91-1.10). No overall association was observed for any specific cancer type. An increased risk of ALS was observed during the first year after cancer diagnosis (OR 1.50; 95% CI 1.17-1.92). In contrast, a lower risk of cancer was observed in ALS patients after diagnosis compared with ALS-free individuals (IRR 0.84; 95% CI 0.69-1.02). The risk reduction was seen primarily two or more years after ALS diagnosis (IRR 0.64; 95% CI 0.45-0.88). Our results provide no evidence for comorbidity of cancer and ALS overall. Surveillance biases seem the most likely explanation for the limited associations detected. C1 [Fang, Fang; Wirdefeldt, Karin; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Ronnevi, Lars-Olof; Wirdefeldt, Karin] Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden. [Al-Chalabi, Ammar] Kings Coll London, Inst Psychiat, MRC, Ctr Neurodegenerat Res, London, England. [Turner, Martin R.] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. [Kamel, Freya] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. RP Fang, F (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, S-17177 Stockholm, Sweden. EM fang.fang@ki.se RI Al-Chalabi, Ammar/E-5361-2010; OI Al-Chalabi, Ammar/0000-0002-4924-7712; Fang, Fang/0000-0002-3310-6456; Kamel, Freya/0000-0001-5052-6615; Turner, Martin/0000-0003-0267-3180 FU Swedish Research Council; Swedish Society for Medical Research FX This study was supported by Swedish Research Council grants (F. F. and W. Y.) and the Swedish Society for Medical Research (F. F.). NR 26 TC 9 Z9 9 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8421 J9 AMYOTROPH LA SCL FR JI Amyotroph. Lateral Scher. Frontotemp. Degenerat. PD SEP PY 2013 VL 14 IS 5-6 BP 362 EP 368 DI 10.3109/21678421.2013.775309 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 196NR UT WOS:000322782800007 PM 23527497 ER PT J AU Myatt, L Clifton, RG Roberts, JM Spong, CY Wapner, RJ Thorp, JM Mercer, BM Peaceman, AM Ramin, SM Carpenter, MW Sciscione, A Tolosa, JE Saade, G Sorokin, Y Anderson, GD AF Myatt, L. Clifton, R. G. Roberts, J. M. Spong, C. Y. Wapner, R. J. Thorp, J. M., Jr. Mercer, B. M. Peaceman, A. M. Ramin, S. M. Carpenter, M. W. Sciscione, A. Tolosa, J. E. Saade, G. Sorokin, Y. Anderson, G. D. CA Eunice Kennedy Shriver Natl Inst TI Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population? SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE Angiogenesis; endoglin; platelet growth factor; pre-eclampsia; sFlt-1 ID PLACENTA GROWTH-FACTOR; FOR-GESTATIONAL-AGE; SOLUBLE ENDOGLIN; MATERNAL PLASMA; 1ST-TRIMESTER; WOMEN; 2ND-TRIMESTER; HYPERTENSION; MARKERS AB Objective To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women. Design A nested case-control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by preeclampsia and 468 normotensive nonproteinuric controls. Setting Amulticentre study in 16 academicmedical centres in the USA. Population Low-risk nulliparous women. Methods Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9-12, 15-18 and 23-26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics. Main outcome measures Change in PlGF, sFlt-1 and sEng. Results Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not preeclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64-99), 77% (95% CI 50-93) and 77% (95% CI 50-93) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester. Conclusion Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia. C1 [Myatt, L.] Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH USA. [Clifton, R. G.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Roberts, J. M.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Spong, C. Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Wapner, R. J.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Thorp, J. M., Jr.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Mercer, B. M.] Case Western Reserve Univ, MetroHlth Med Ctr, Dept Maternal Fetal Med, Cleveland, OH 44106 USA. [Peaceman, A. M.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Ramin, S. M.] Univ Texas Hlth Sci Ctr Houston, Dept Obstet Gynecol & Reprod Sci, Houston, TX 77030 USA. [Carpenter, M. W.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Sciscione, A.] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Tolosa, J. E.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Saade, G.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Sorokin, Y.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Anderson, G. D.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. RP Myatt, L (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Mail Code 7836,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM myattl@uthscsa.edu OI Peaceman, Alan/0000-0002-4515-4850 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, HD36801]; National Heart, Lung, and Blood Institute; National Center for Research Resources [M01 RR00080, UL1 RR024153, UL1 RR024989] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, and HD36801); the National Heart, Lung, and Blood Institute; and the National Center for Research Resources (M01 RR00080, UL1 RR024153, UL1 RR024989) and its contents do not necessarily represent the official view of NICHD, NHLBI, NCRR or NIH. NR 21 TC 36 Z9 37 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 J9 BJOG-INT J OBSTET GY JI BJOG PD SEP PY 2013 VL 120 IS 10 BP 1183 EP 1191 DI 10.1111/1471-0528.12128 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 199YT UT WOS:000323032500004 PM 23331974 ER PT J AU Brasky, TM Li, YL Jaworowicz, DJ Potischman, N Ambrosone, CB Hutson, AD Nie, J Shields, PG Trevisan, M Rudra, CB Edge, SB Freudenheim, JL AF Brasky, Theodore M. Li, Yanli Jaworowicz, David J., Jr. Potischman, Nancy Ambrosone, Christine B. Hutson, Alan D. Nie, Jing Shields, Peter G. Trevisan, Maurizio Rudra, Carole B. Edge, Stephen B. Freudenheim, Jo L. TI Pregnancy-related characteristics and breast cancer risk SO CANCER CAUSES & CONTROL LA English DT Article DE Gestational hypertension; Gestational diabetes; Nausea; Pre-eclampsia; Pregnancy weight gain; Vomiting ID HUMAN CHORIONIC-GONADOTROPIN; CARCINOMA IN-SITU; HYPEREMESIS GRAVIDARUM; POSTMENOPAUSAL WOMEN; SUBSEQUENT RISK; MATERNAL RISK; YOUNG-WOMEN; MCF-7 CELLS; EARLY-LIFE; NAUSEA AB Breast tissues undergo extensive physiologic changes during pregnancy, which may affect breast carcinogenesis. Gestational hypertension, preeclampsia/eclampsia, gestational diabetes, pregnancy weight gain, and nausea and vomiting (N&V) during pregnancy may be indicative of altered hormonal and metabolic profiles and could impact breast cancer risk. Here, we examined associations between these characteristics of a woman's pregnancy and her subsequent breast cancer risk. Participants were parous women that were recruited to a population-based case-control study (Western New York Exposures and Breast Cancer Study). Cases (n = 960), aged 35-79 years, had incident, primary, histologically confirmed breast cancer. Controls (n = 1,852) were randomly selected from motor vehicle records (< 65 years) or Medicare rolls (a parts per thousand yen65 years). Women were queried on their lifetime pregnancy experiences. Multivariable-adjusted logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs). N&V during pregnancy was inversely associated with breast cancer risk. Relative to those who never experienced N&V, ever experiencing N&V was associated with decreased risk (OR 0.69, 95 % CI 0.56-0.84) as were increased N&V severity (p trend < 0.001), longer duration (p trend < 0.01), and larger proportion of affected pregnancies (p trend < 0.0001) among women with a parts per thousand yen3 pregnancies. Associations were stronger for more recent pregnancies (< 5 years). Findings did not differ by menopausal status or breast cancer subtype including estrogen receptor and HER2 expression status. Other pregnancy characteristics examined were not associated with risk. We observed strong inverse associations between pregnancy N&V and breast cancer risk. Replication of these findings and exploration of underlying mechanisms could provide important insight into breast cancer etiology and prevention. C1 [Brasky, Theodore M.; Shields, Peter G.] Ohio State Univ, Coll Med, Div Canc Prevent & Control, Columbus, OH 43210 USA. [Brasky, Theodore M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43201 USA. [Li, Yanli; Jaworowicz, David J., Jr.; Nie, Jing; Rudra, Carole B.; Freudenheim, Jo L.] SUNY Buffalo, Dept Social & Prevent Med, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14260 USA. [Jaworowicz, David J., Jr.] Cognigen Corp, Dept Pharmacometr Serv, Buffalo, NY USA. [Potischman, Nancy] NCI, Off Associate Director, Appl Res Program, Bethesda, MD 20892 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Hutson, Alan D.] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Biostat, Buffalo, NY 14260 USA. [Trevisan, Maurizio] CUNY, Sch Biomed Educ, New York, NY 10021 USA. [Edge, Stephen B.] Roswell Pk Canc Inst, Dept Surg Oncol, Buffalo, NY 14263 USA. RP Brasky, TM (reprint author), Ohio State Univ, Ctr Comprehens Canc, 1590 N High St,Suite 525, Columbus, OH 43201 USA. EM Theodore.Brasky@osumc.edu FU National Institute on Alcohol Abuse and Alcoholism [P50-AA09802]; Department of Defense Breast Cancer Research Program [DAMD-179616202, DAMD 17030446] FX This work was supported in part by the National Institute on Alcohol Abuse and Alcoholism (P50-AA09802), and the Department of Defense Breast Cancer Research Program (DAMD-179616202, DAMD 17030446). NR 53 TC 9 Z9 9 U1 0 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2013 VL 24 IS 9 BP 1675 EP 1685 DI 10.1007/s10552-013-0242-9 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 197VF UT WOS:000322879200005 PM 23737027 ER PT J AU Cross, AJ Hollenbeck, AR Park, Y AF Cross, Amanda J. Hollenbeck, Albert R. Park, Yikyung TI A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine SO CANCER CAUSES & CONTROL LA English DT Article DE Demographic; Lifestyle; Risk factors; Small intestine; Cancer; Adenocarcinoma; Carcinoid ID SMALL-BOWEL CANCER; NEUROENDOCRINE TUMORS; COLORECTAL-CANCER; UNITED-STATES; EPIDEMIOLOGY; SURVIVAL; ASSOCIATION; SMOKING; COHORT AB Small intestinal cancer is increasing in the U.S.A, yet little is known about its etiology. Our aim was to prospectively evaluate risk factors for this malignancy by the two main histologic subtypes (adenocarcinomas and carcinoids). Hazard ratios and 95 % confidence intervals (CI) were estimated for all incident small intestinal cancers (n = 237), adenocarcinomas (n = 84), and malignant carcinoids (n = 124), by demographic and lifestyle factors among 498,376 men and women. Age was the only risk factor for adenocarcinomas (HR for a parts per thousand yen65 vs. 50-55 years = 3.12, 95 % CI 1.33, 7.31). Age (HR for a parts per thousand yen65 vs. 50-55 years = 3.31, 95 % CI 1.51, 7.28), male sex (HR = 1.44, 95 % CI 1.01, 2.05), body mass index (BMI, HR for a parts per thousand yen35 vs. 18.5-< 25 kg/m(2) = 1.95, 95 % CI 1.06, 3.58), and current menopausal hormone therapy use (HR = 1.94, 95 % CI 1.07, 3.50) were positively associated with malignant carcinoids. A family history of any cancer or colorectal cancer (HR = 1.42, 95 % CI 0.99, 2.03; 1.61, 0.97, 2.65, respectively), or a personal history of colorectal polyps (HR = 1.51, 95 % CI 0.92, 2.46) produced elevated, but not statistically significant, risks for malignant carcinoids. Race, education, diabetes, smoking, physical activity, and alcohol intake were not associated with either histologic subtype. Risk factors differed according to cancer subtype; only age was associated with adenocarcinomas, whereas age, male sex, BMI, and menopausal hormone therapy use were positively associated with malignant carcinoids. C1 [Cross, Amanda J.; Park, Yikyung] NCI, DCEG, DHHS, NIH, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC 20049 USA. RP Cross, AJ (reprint author), NCI, DCEG, DHHS, NIH, 6120 Execut Blvd, Rockville, MD 20852 USA. EM crossa@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX The authors would like to acknowledge Dr. Arthur Schatzkin who was the principal investigator of the NIH-AARP Diet and Health study and tragically passed away on January 20, 2011. 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, Atlanta, Georgia. Cancer incidence data from California were collected by the California Cancer Registry, California Department of Public Health's Cancer Surveillance and Research Branch, Sacramento, California. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, Lansing, Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (Miami, Florida) under contract with the Florida Department of Health, Tallahassee, Florida. The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Health Sciences Center School of Public Health, New Orleans, Louisiana. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health, Trenton, New Jersey. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry, Raleigh, North Carolina. 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, Phoenix, Arizona. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, State Health Division, State of Nevada Department of Health and Human Services, Las Vegas, Nevada. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management, in addition to Leslie Carroll and Adam Risch at Information Management Services for data support and analysis. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 32 TC 3 Z9 3 U1 0 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2013 VL 24 IS 9 BP 1737 EP 1746 DI 10.1007/s10552-013-0251-8 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 197VF UT WOS:000322879200011 PM 23812550 ER PT J AU Palmer, JR Boggs, DA Hatch, EE Troisi, R Titus-Ernstoff, L Strohsnitter, WC Adam, E Hoover, RN AF Palmer, Julie R. Boggs, Deborah A. Hatch, Elizabeth E. Troisi, Rebecca Titus-Ernstoff, Linda Strohsnitter, William C. Adam, Ervin Hoover, Robert N. TI Prenatal DES exposure in relation to breast size SO CANCER CAUSES & CONTROL LA English DT Article ID CANCER-RISK; MAMMARY-GLAND; UNITED-STATES; FOLLOW-UP; DIETHYLSTILBESTROL; AUGMENTATION; MOTHERS; NUMBER AB Prenatal DES exposure has been associated with increased risk of breast cancer, but the mechanisms are unknown. Larger bra cup size has also been associated with increased breast cancer risk, although not consistently. We investigated the relation of prenatal DES exposure to mammary gland mass, as estimated by bra cup size. In 2006, 3,222 DES-exposed and 1,463 unexposed women reported their bra cup size, band size (chest circumference), and weight at age 20. Prevalence ratios (PR) were calculated for DES exposure in relation to large bra cup size, with control for year of birth and study cohort. Primary analyses were carried out among women who reported a chest circumference of no more than 32 inches because their cup size would be less influenced by fat mass. Within this group, DES-exposed women had an estimated 45 % increased prevalence (95 % CI 0.97-2.18) of large cup size (C or greater) relative to unexposed women. The PR was further increased among women in this group who had a body mass index of < 21 at age 20: PR = 1.83 (95 % CI 1.11-3.00). The PR for high-dose DES exposure relative to no exposure was 1.67, 95 % CI 1.02-2.73, whereas there was no association of bra cup size with low-dose exposure. These results provide support for the hypothesis that in utero DES exposure may result in greater mammary gland mass. Taken together with previous research on bra size and breast cancer risk, these findings suggest a mechanism for a possible association of in utero DES exposure with increased risk of breast cancer. C1 [Palmer, Julie R.; Boggs, Deborah A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Palmer, Julie R.; Hatch, Elizabeth E.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. [Troisi, Rebecca; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Pediat, Lebanon, NH USA. [Titus-Ernstoff, Linda] Norris Cotton Canc Ctr, Lebanon, NH USA. [Strohsnitter, William C.] Tufts Univ New England Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. [Adam, Ervin] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. RP Palmer, JR (reprint author), Boston Univ, Slone Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. EM jpalmer@bu.edu OI Hatch, Elizabeth/0000-0001-7901-3928; Palmer, Julie/0000-0002-6534-335X FU National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services FX This research was support by a contract from the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. We thank the field center study managers, Diane Anderson, Elizabeth Barnard, Toni Oliver, Elaine Campbell, Polly Goralski, Kathleen Rowlings, Helen Bond, Ann Urbanovitch, and Kathyln Tucke. We also appreciate the support of Cathy Ann Grundmayer, Shelley Niwa, and Bob Saal of Westat, Inc., for study- wide coordination efforts. Finally, we thank the DES-exposed and unexposed daughters for their longstanding participation in this study. NR 30 TC 3 Z9 3 U1 1 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2013 VL 24 IS 9 BP 1757 EP 1761 DI 10.1007/s10552-013-0248-3 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 197VF UT WOS:000322879200013 PM 23775027 ER PT J AU Adiseshaiah, PP Clogston, JD McLeland, CB Rodriguez, J Potter, TM Neun, BW Skoczen, SL Shanmugavelandy, SS Kester, M Stern, ST McNeil, SE AF Adiseshaiah, Pavan P. Clogston, Jeffrey D. McLeland, Christopher B. Rodriguez, Jamie Potter, Timothy M. Neun, Barry W. Skoczen, Sarah L. Shanmugavelandy, Sriram S. Kester, Mark Stern, Stephan T. McNeil, Scott E. TI Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models SO CANCER LETTERS LA English DT Article DE Combination therapy; Autophagy; Ceramide ID MALIGNANT GLIOMA-CELLS; PORCINE KIDNEY-CELLS; INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; HEPATOCELLULAR-CARCINOMA; TARGETING AUTOPHAGY; CERAMIDE; TUMORIGENESIS; CYTOTOXICITY; INHIBITION AB Autophagy, a catabolic survival pathway, is gaining attention as a potential target in cancer. In human liver and colon cancer cells, treatment with an autophagy inducer, nanoliposomal C6-ceramide, in combination with the autophagy maturation inhibitor, vinblastine, synergistically enhanced apoptotic cell death. Combination treatment resulted in a marked increase in autophagic vacuole accumulation and decreased autophagy maturation, without diminution of the autophagy flux protein P62. In a colon cancer xenograft model, a single intravenous injection of the drug combination significantly decreased tumor growth in comparison to the individual treatments. Most importantly, the combination treatment did not result in increased toxicity as assessed by body weight loss. The mechanism of combination treatment-induced cell death both in vitro and in vivo appeared to be apoptosis. Supportive of autophagy flux blockade as the underlying synergy mechanism, treatment with other autophagy maturation inhibitors, but not autophagy initiation inhibitors, were similarly synergistic with C6-ceramide. Additionally, knockout of the autophagy protein Beclin-1 suppressed combination treatment-induced apoptosis in vitro. In conclusion, in vitro and in vivo data support a synergistic antitumor activity of the nanoliposomal C6-ceramide and vinblastine combination, potentially mediated by an autophagy mechanism. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Adiseshaiah, Pavan P.; Clogston, Jeffrey D.; McLeland, Christopher B.; Rodriguez, Jamie; Potter, Timothy M.; Neun, Barry W.; Skoczen, Sarah L.; Stern, Stephan T.; McNeil, Scott E.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA. [Shanmugavelandy, Sriram S.; Kester, Mark] Penn State Univ, Dept Pharmacol, Coll Med, Hershey, PA 17033 USA. RP Stern, ST (reprint author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA. EM sternstephan@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Ebberly Fund of Penn State College of Medicine FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The project was also funded, in part (MK), through support from the Ebberly Fund of Penn State College of Medicine. NR 50 TC 22 Z9 23 U1 0 U2 32 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 2013 VL 337 IS 2 BP 254 EP 265 DI 10.1016/j.canlet.2013.04.034 PG 12 WC Oncology SC Oncology GA 201JP UT WOS:000323138200013 PM 23664889 ER PT J AU Camargo, JF Lobo, SA Hsu, AP Zerbe, CS Wormser, GP Holland, SM AF Camargo, Jose F. Lobo, Stephen A. Hsu, Amy P. Zerbe, Christa S. Wormser, Gary P. Holland, Steven M. TI MonoMAC Syndrome in a Patient With a GATA2 Mutation: Case Report and Review of the Literature SO CLINICAL INFECTIOUS DISEASES LA English DT Review DE GATA2; MonoMAC; monocytopenia; mycobacterial infection; immunodeficiency ID SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; IMMUNODEFICIENCY; MYELODYSPLASIA; LYMPHEDEMA; DISEASE AB We report a case of MonoMAC syndrome in a patient with a GATA2 mutation and discuss the manifestations, diagnosis, and treatment of this novel immunodeficiency disorder. C1 [Camargo, Jose F.; Lobo, Stephen A.; Wormser, Gary P.] New York Med Coll, Dept Med, Div Infect Dis, Valhalla, NY 10595 USA. [Hsu, Amy P.; Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Camargo, JF (reprint author), New York Med Coll, Div Infect Dis, Munger Pavil,Rm 245, Valhalla, NY 10595 USA. EM josefcamargo@gmail.com FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 12 TC 20 Z9 20 U1 0 U2 6 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 SEP 1 PY 2013 VL 57 IS 5 BP 697 EP 699 DI 10.1093/cid/cit368 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 199DJ UT WOS:000322974400010 PM 23728141 ER PT J AU Kahn, JA Xu, JH Kapogiannis, BG Rudy, B Gonin, R Liu, N Wilson, CM Worrell, C Squires, KE AF Kahn, Jessica A. Xu, Jiahong Kapogiannis, Bill G. Rudy, Bret Gonin, Rene Liu, Nancy Wilson, Craig M. Worrell, Carol Squires, Kathleen E. TI Immunogenicity and Safety of the Human Papillomavirus 6, 11, 16, 18 Vaccine in HIV-Infected Young Women SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE immunogenicity; safety; human papillomavirus; vaccine; HIV infected ID CERVICAL INTRAEPITHELIAL NEOPLASIA; IMMUNODEFICIENCY-VIRUS TYPE-1; PARTICLE VACCINE; QUADRIVALENT VACCINE; DOUBLE-BLIND; EFFICACY; RISK; LESIONS; TRIAL; HPV AB Background. The objective of this study was to determine whether the 3-dose quadrivalent human papillomavirus (HPV) vaccine series (HPV-6, -11, -16, -18) is immunogenic and safe in young women infected with human immunodeficiency virus (HIV). Methods. We enrolled 99 women aged 16-23 years in a phase 2, open-label, multicenter trial, conducted from 2008 to 2011 by the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Outcome measures were immunogenicity 4 weeks after dose 3, measured by (1) geometric mean titers (GMTs) and (2) seroconversion rates for HPV-6, -11, -16, and -18, among those seronegative and HPV DNA negative for each type. Immune responses were compared to those of a historical comparison group of HIV-negative women (n = 267) using univariate methods. Clinical and laboratory adverse events were assessed after each dose. Results. The mean age of subjects was 21.4 years; 80% were non-Hispanic black, 69 were not taking antiretroviral therapy (ART), and 30 were taking ART. No differences in GMTs were noted among participants taking ART vs the comparison group, but GMTs were lower in participants not taking ART vs the comparison group for HPV-16 (2393 vs 3892 milli-Merck units per milliliter [mMU/mL], P = .012) and HPV-18 (463 vs 801 mMU/mL, P = .003). Seroconversion rates were 100% for HPV-6, -11, -16, and -18 among participants taking ART. Rates ranged from 92.3% (for HPV-18) to 100.0% (for HPV-6) among participants not taking ART. One severe adverse event (fatigue) was noted. Conclusions. In a sample of HIV-infected women who were HPV DNA and HPV seronegative, immune responses to HPV vaccination were generally robust and the vaccine was well tolerated. C1 [Kahn, Jessica A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kahn, Jessica A.] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. [Xu, Jiahong; Gonin, Rene; Liu, Nancy] Westat Corp, Rockville, MD USA. [Kapogiannis, Bill G.; Worrell, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. [Rudy, Bret] NYU, Sch Med, New York, NY USA. [Wilson, Craig M.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL USA. [Squires, Kathleen E.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. RP Kahn, JA (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Adolescent Med, MLC 4000,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM jessica.kahn@cchmc.org FU AIDS Interventions (ATN) from the National Institutes of Health through the NICHD [U01 HD 040533, U01 HD 040474]; National Institute on Drug Abuse; National Institute of Mental Health; National Institutes of Health [AI-51519]; Einstein Cancer Research Center from the National Cancer Institute [P30CA013330]; General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health, Department of Health and Human Services [M01RR020359]; University of Pennsylvania/Children's Hospital of Philadelphia [NCRRUL1-RR-024134]; Louisiana Board of Regents RC/EEP [RC/EEP06]; Merck Co, Inc. FX This work was supported by AIDS Interventions (ATN) from the National Institutes of Health (grant numbers U01 HD 040533 and U01 HD 040474) through the NICHD (to B. G. K., C. W.), with supplemental funding from the National Institute on Drug Abuse (N. Borek) and the National Institute of Mental Health (P. Brouwers, S. Allison). The study was scientifically reviewed by the ATN's Therapeutic Leadership Group. ATN-affiliated investigators and program staff supervised the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Network, scientific, and logistical support was provided by the ATN Coordinating Center (C. Wilson, C. Partlow) at The University of Alabama at Birmingham. Network operations and analytic support was provided by the ATN Data and Operations Center at Westat, Inc (J. Korelitz, B. Driver). The following ATN sites participated in this study: Children's National Medical Center (D'Angelo, Hagler, Trexler); Children's Hospital of Philadelphia (Douglas, Tanney, DiBenedetto); John H. Stroger Jr Hospital of Cook County and the Ruth M. Rothstein CORE Center (Martinez, Bojan, Jackson, Henry-Reid); University of Puerto Rico (Febo, Ayala-Flores, Fuentes-Gomez); Montefiore Medical Center (Futterman, Enriquez-Bruce, Campos); Tulane University Health Sciences Center (Abdalian, Kozina, Baker); University of Miami School of Medicine (Friedman, Maturo, Major-Wilson); Children's Diagnostic and Treatment Center (Puga, Leonard, Inman); St Jude's Children's Research Hospital (Flynn, Dillard); Children's Memorial (Garofalo, Brennan, Flanagan); University of South Florida, Tampa (Emmanuel, Straub, Lujan-Zilberman, Julian, Rebolledo); Children's Hospital of Los Angeles (Belzer, Flores, Tucker); Mount Sinai Medical Center (Steever, Geiger); and University of Maryland (Peralta, Gorle).; In addition, R. Burk utilized core facilities of the Einstein-Montefiore Center for AIDS funded by the National Institutes of Health (AI-51519) and the Einstein Cancer Research Center (grant number P30CA013330) from the National Cancer Institute. Two of the sites utilized their General Clinical Research Center/Pediatric Clinical Research Center for the study. The centers were supported by grants from the General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health, Department of Health and Human Services as follows: Children's National Medical Center (grant number M01RR020359) and University of Pennsylvania/Children's Hospital of Philadelphia (grant number NCRRUL1-RR-024134). The site at Tulane University Health Sciences Center utilized its Clinical and Translational Research Center for the study; the center was supported in whole or in part by funds provided through the Louisiana Board of Regents RC/EEP (grant number RC/EEP06). Vaccine and HPV GMTs were provided through the Investigator-Initiated Studies Program of Merck & Co, Inc. NR 33 TC 31 Z9 31 U1 0 U2 11 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 SEP 1 PY 2013 VL 57 IS 5 BP 735 EP 744 DI 10.1093/cid/cit319 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 199DJ UT WOS:000322974400017 PM 23667266 ER PT J AU Falcone, EL Adegbulugbe, AA Sheikh, V Imamichi, H Dewar, RL Hammoud, DA Sereti, I Lane, HC AF Falcone, E. Liana Adegbulugbe, Ademiposi A. Sheikh, Virginia Imamichi, Hiromi Dewar, Robin L. Hammoud, Dima A. Sereti, Irini Lane, H. Clifford TI Cerebrospinal Fluid HIV-1 Compartmentalization in a Patient With AIDS and Acute Varicella-Zoster Virus Meningomyeloradiculitis SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE human immunodeficiency virus; viral quasispecies; central nervous system compartmentalization; varicella-zoster virus; meningomyeloradiculitis ID CENTRAL-NERVOUS-SYSTEM; ANTIRETROVIRAL THERAPY; MYELITIS; TYPE-1; BLOOD; INFECTION; BRAIN; COMPLICATIONS; RESERVOIRS; SEQUENCES AB We report a case of AIDS presenting as varicella-zoster virus (VZV) meningomyeloradiculitis associated with human immunodeficiency virus (HIV) quasispecies compartmentalization within the cerebrospinal fluid (CSF), and a CSF viral load that was 1 log higher than in peripheral blood. Prolonged antiviral therapy for both VZV and HIV type 1 was associated with partial resolution. C1 [Falcone, E. Liana] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Sheikh, Virginia; Imamichi, Hiromi; Sereti, Irini; Lane, H. Clifford] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Adegbulugbe, Ademiposi A.] Washington Hosp Ctr, Dept Med, Infect Dis Sect, Washington, DC 20010 USA. [Dewar, Robin L.] NCI Frederick, Clin Serv Program, SAIC Frederick, Bethesda, MD USA. [Hammoud, Dima A.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Falcone, EL (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC, 10 Ctr Dr,Rm B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM emilia.falcone@nih.gov RI Hammoud, Dima/C-2286-2015 NR 28 TC 10 Z9 10 U1 0 U2 0 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 SEP 1 PY 2013 VL 57 IS 5 BP E135 EP E142 DI 10.1093/cid/cit356 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 199DJ UT WOS:000322974400001 PM 23728149 ER PT J AU Larochelle, A AF Larochelle, Andre TI Generation of red blood cells in vitro: monitoring the process for improved efficiency SO CYTOTHERAPY LA English DT Editorial Material ID STEM-CELLS; HEMATOPOIETIC STEM; PROGENITOR CELLS; DIFFERENTIATION; ERYTHROBLASTS; ENUCLEATION; TRANSFUSION; EXPANSION C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Larochelle, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10CRC,Room 5E-5130,9000 Rockville Pike, Bethesda, MD 20892 USA. EM larochea@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999, ZIA HL006172-01] NR 15 TC 2 Z9 2 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD SEP PY 2013 VL 15 IS 9 BP 1043 EP 1045 DI 10.1016/j.jcyt.2013.06.015 PG 3 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 201KU UT WOS:000323141300001 PM 23911006 ER PT J AU Zeng, XK Lin, XH Hou, SX AF Zeng, Xiankun Lin, Xinhua Hou, Steven X. TI The Osa-containing SWI/SNF chromatin-remodeling complex regulates stem cell commitment in the adult Drosophila intestine SO DEVELOPMENT LA English DT Article DE Chromatin-remodeling factor; SWI/SNF; Osa; Intestinal stem cells; Self-renewal; Differentiation; Drosophila ID TARGET GENES; MIDGUT; PROTEIN; DIFFERENTIATION; TRANSCRIPTION; PLURIPOTENCY; HOMEOSTASIS; ACTIVATION; SUPPRESSOR; HOMOLOGY AB The proportion of stem cells versus differentiated progeny is well balanced to maintain tissue homeostasis, which in turn depends on the balance of the different signaling pathways involved in stem cell self-renewal versus lineage-specific differentiation. In a screen for genes that regulate cell lineage determination in the posterior midgut, we identified that the Osa-containing SWI/SNF (Brahma) chromatin-remodeling complex regulates Drosophila midgut homeostasis. Mutations in subunits of the Osa-containing complex result in intestinal stem cell (ISC) expansion as well as enteroendocrine (EE) cell reduction. We further demonstrated that Osa regulates ISC self-renewal and differentiation into enterocytes by elaborating Notch signaling, and ISC commitment to differentiation into EE cells by regulating the expression of Asense, an EE cell fate determinant. Our data uncover a unique mechanism whereby the commitment of stem cells to discrete lineages is coordinately regulated by chromatin-remodeling factors. C1 [Zeng, Xiankun; Hou, Steven X.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Lin, Xinhua] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100101, Peoples R China. [Lin, Xinhua] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. RP Zeng, XK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. EM zengx2@mail.nih.gov; hous@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health; Strategic Priority Research Program of the Chinese Academy of Sciences Grant [XDA01010101]; Nature Sciences Foundation of China [31030049] FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Work in the X.L. laboratory was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences Grant [XDA01010101] and the Nature Sciences Foundation of China [31030049] to X.L. Deposited in PMC for release after 12 months. NR 42 TC 20 Z9 20 U1 1 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 1 PY 2013 VL 140 IS 17 BP 3532 EP 3540 DI 10.1242/dev.096891 PG 9 WC Developmental Biology SC Developmental Biology GA 200BN UT WOS:000323041400005 PM 23942514 ER PT J AU Kaneko, KJ DePamphilis, ML AF Kaneko, Kotaro J. DePamphilis, Melvin L. TI TEAD4 establishes the energy homeostasis essential for blastocoel formation SO DEVELOPMENT LA English DT Article DE Tead4; Blastocyst; Trophectoderm; Blastocoel; Oxidative stress; Anti-oxidant; Mouse ID PREIMPLANTATION MOUSE EMBRYOS; INNER CELL MASS; GENE-EXPRESSION; MAMMALIAN DEVELOPMENT; TRANSCRIPTION FACTORS; OXIDATIVE STRESS; AMINO-ACIDS; IN-VITRO; TROPHOBLAST DEVELOPMENT; TROPHECTODERM LINEAGE AB It has been suggested that during mouse preimplantation development, the zygotically expressed transcription factor TEAD4 is essential for specification of the trophectoderm lineage required for producing a blastocyst. Here we show that blastocysts can form without TEAD4 but that TEAD4 is required to prevent oxidative stress when blastocoel formation is accompanied by increased oxidative phosphorylation that leads to the production of reactive oxygen species (ROS). Both two-cell and eight-cell Tead4(-/-) embryos developed into blastocysts when cultured under conditions that alleviate oxidative stress, and Tead4(-/-) blastocysts that formed under these conditions expressed trophectoderm-associated genes. Therefore, TEAD4 is not required for specification of the trophectoderm lineage. Once the trophectoderm was specified, Tead4 was not essential for either proliferation or differentiation of trophoblast cells in culture. However, ablation of Tead4 in trophoblast cells resulted in reduced mitochondrial membrane potential. Moreover, Tead4 suppressed ROS in embryos and embryonic fibroblasts. Finally, ectopically expressed TEAD4 protein could localize to the mitochondria as well as to the nucleus, a property not shared by other members of the TEAD family. These results reveal that TEAD4 plays a crucial role in maintaining energy homeostasis during preimplantation development. C1 [Kaneko, Kotaro J.; DePamphilis, Melvin L.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Kaneko, KJ (reprint author), NICHHD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM KanekoK@mail.nih.gov FU Eunice Shriver Kennedy National Institute of Child Health and Human Development (NICHD) intramural research program FX This work was supported financially by the Eunice Shriver Kennedy National Institute of Child Health and Human Development (NICHD) intramural research program. Deposited in PMC for release after 12 months. NR 90 TC 19 Z9 19 U1 0 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 1 PY 2013 VL 140 IS 17 BP 3680 EP 3690 DI 10.1242/dev.093799 PG 11 WC Developmental Biology SC Developmental Biology GA 200BN UT WOS:000323041400019 PM 23903192 ER PT J AU Meerson, A Traurig, M Ossowski, V Fleming, JM Mullins, M Baier, LJ AF Meerson, A. Traurig, M. Ossowski, V. Fleming, J. M. Mullins, M. Baier, L. J. TI Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-alpha SO DIABETOLOGIA LA English DT Article DE ADIPOR1; ETS1; Insulin resistance; Leptin; MicroRNA; miR-221; Obesity; Pima; Tumour necrosis factor ID INSULIN-RESISTANCE; PPAR-GAMMA; ADIPOCYTE DIFFERENTIATION; SUBCUTANEOUS ADIPOSE; RECEPTOR-ALPHA; EXPRESSION; ETS; MIR-221; CANCER; TISSUE AB MicroRNAs (miRNAs) are short endogenous RNAs that regulate multiple biological processes including adipogenesis and fat metabolism. We sought to identify miRNAs that correlate with BMI and to elucidate their upstream regulation and downstream targets. Microarray-based expression profiling of 233 miRNAs was performed on subcutaneous abdominal adipose tissue biopsies from 29 non-diabetic Pima Indian participants. Correlation of the expression levels of eight miRNAs with BMI was assessed by quantitative reverse transcription (QRT) PCR in adipose samples from 80 non-diabetic Pima Indians with a BMI of 21.6-54.0 kg/m(2). The upstream regulation of one of these miRNAs, miR-221, was tested by treating cultured human pre-adipocytes with leptin, TNF-alpha and insulin. Predicted targets of miR-221 were validated using QRT-PCR, immunoblots and luciferase assays. The downstream effects of miR-221 overexpression were assayed by proteomic analysis. Expression levels of miR-221 were positively correlated with BMI (particularly in women) and fasting insulin concentrations, while the levels of miR-193a-3p and miR-193b-5p were negatively correlated with BMI; other miRNAs did not show significant associations in the 80 samples. miR-221 was downregulated by leptin and TNF-alpha treatment in cultured human pre-adipocytes. Conversely, miR-221 overexpression upregulated several proteins involved in fat metabolism, mimicking peroxisome proliferator-activated receptor (PPAR) activation. Furthermore, miR-221 directly downregulated the adiponectin receptor 1 (ADIPOR1) and the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1). Adiponectin signalling is known to promote insulin sensitivity, and ETS1 is crucial for angiogenesis. Our data suggest that miR-221 may contribute to the development of the insulin resistance that typically accompanies obesity, by affecting PPAR signalling pathways and by directly downregulating ADIPOR1 and ETS1. C1 [Meerson, A.; Traurig, M.; Ossowski, V.; Fleming, J. M.; Mullins, M.; Baier, L. J.] NIDDK, NIH, Phoenix, AZ 85004 USA. RP Baier, LJ (reprint author), NIDDK, NIH, 445 North 5th St, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov FU NIDDK FX This research was funded by the intramural programme of NIDDK. NR 51 TC 40 Z9 49 U1 3 U2 32 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2013 VL 56 IS 9 BP 1971 EP 1979 DI 10.1007/s00125-013-2950-9 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 200HV UT WOS:000323059800016 PM 23756832 ER PT J AU Franks, PW Christophi, CA Jablonski, KA Delahanty, LM Horton, ES Knowler, WC Florez, JC AF Franks, P. W. Christophi, C. A. Jablonski, K. A. Delahanty, L. M. Horton, E. S. Knowler, W. C. Florez, J. C. CA Diabet Prevention Program Res Grp TI RETRACTED ARTICLE: Common variation in PPARGC1A/B and progression to diabetes or change in metabolic traits following preventive interventions: the Diabetes Prevention Program (vol 59, pg 2672, 2010) SO DIABETOLOGIA LA English DT Correction C1 [Franks, P. W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Franks, P. W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Franks, P. W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Franks, P. W.; Christophi, C. A.; Jablonski, K. A.] Washington Univ, Diabet Prevent Program Coordinating Ctr, Ctr Biostat, Rockville, MD 20852 USA. [Delahanty, L. M.; Florez, J. C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Horton, E. S.; Florez, J. C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Knowler, W. C.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ USA. [Florez, J. C.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. RP Franks, PW (reprint author), Washington Univ, Diabet Prevent Program Coordinating Ctr, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM paul.franks@med.lu.se NR 1 TC 1 Z9 1 U1 6 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2013 VL 56 IS 9 BP 2102 EP 2102 DI 10.1007/s00125-013-2911-3 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 200HV UT WOS:000323059800033 ER PT J AU Islami, F Cao, Y Kamangar, F Nasrollahzadeh, D Marjani, HA Shakeri, R Fahimi, S Sotoudeh, M Dawsey, SM Abnet, CC Boffetta, P Malekzadeh, R AF Islami, Farhad Cao, Yin Kamangar, Farin Nasrollahzadeh, Dariush Marjani, Haji-Amin Shakeri, Ramin Fahimi, Saman Sotoudeh, Masoud Dawsey, Sanford M. Abnet, Christian C. Boffetta, Paolo Malekzadeh, Reza TI Reproductive factors and risk of esophageal squamous cell carcinoma in northern Iran: a case-control study in a high-risk area and literature review SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE case-control study; esophageal cancer; miscarriage; parity; reproductive; squamous cell carcinoma ID GASTRIC-CANCER; POSTMENOPAUSAL WOMEN; HORMONAL FACTORS; 1ST PREGNANCY; SEX-HORMONES; COHORT; METAANALYSIS; ESTROGEN; ALCOHOL; TOBACCO AB Several epidemiologic studies have suggested an inverse association between female reproductive factors and the risk of esophageal squamous cell carcinoma (ESCC), but the evidence is not conclusive. We examined the association of the number of pregnancies, live births, and miscarriages/stillbirths in women and the association of the number of children in both sexes with the risk of ESCC in Golestan Province, a high-risk area in Iran. Data from 297 histopathologically confirmed ESCC cases (149 women) and 568 controls (290 women) individually matched to cases for age, sex, and neighborhood of residence were included in this analysis. Conditional logistic regression was used to calculate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). The average numbers of live births and miscarriages/stillbirths among the controls were 8.2 and 0.8, respectively. Women with six or more live births were at approximate to 1/3 the risk of ESCC as those with 0-3 live births; the OR (95% CI) for having 6-7 live births was 0.33 (0.12-0.92). In contrast, the number of miscarriages/stillbirths was associated with an increase in the risk of ESCC. The OR (95% CI) for at least three versus no miscarriages/stillbirths was 4.43 (2.11-9.33). The number of children in women was suggestive of an inverse association with ESCC, but this association was not statistically significant; in men, no association was observed. The findings of this study support a protective influence of female hormonal factors on the risk of ESCC. However, further epidemiological and mechanistic studies are required to prove a protective association. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Islami, Farhad; Nasrollahzadeh, Dariush; Marjani, Haji-Amin; Shakeri, Ramin; Sotoudeh, Masoud; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Islami, Farhad; Cao, Yin; Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Islami, Farhad; Cao, Yin; Boffetta, Paolo] Mt Sinai Sch Med, Inst Transit Epidemiol, New York, NY 10029 USA. [Cao, Yin] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Dawsey, Sanford M.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Nasrollahzadeh, Dariush] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Fahimi, Saman] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Marjani, Haji-Amin] Golestan Univ Med Sci, Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. RP Islami, F (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, 1 Gustave L Levy Pl,POB 1057, New York, NY 10029 USA. EM farhad.islami@mssm.edu RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 FU Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX The Golestan Case-Control Study was supported by the Digestive Disease Research Center of Tehran University of Medical Sciences (grant number 82-603) and intramural funds of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The funding sources had no role in the design, conduct, statistical analysis and interpretation of results, or writing of the manuscript. NR 37 TC 8 Z9 9 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD SEP PY 2013 VL 22 IS 5 BP 461 EP 466 DI 10.1097/CEJ.0b013e32835c7f87 PG 6 WC Oncology SC Oncology GA 202OD UT WOS:000323226200013 PM 23238586 ER PT J AU Yan, T Li, QZ Li, YZ Li, ZH Zheng, G AF Yan, Ting Li, Qizhai Li, Yuanzhang Li, Zhaohai Zheng, Gang TI Genetic Association With Multiple Traits in the Presence of Population Stratification SO GENETIC EPIDEMIOLOGY LA English DT Article DE inverted regression; genomic control; MultiPhen; pleiotropy; proportional odds model; population structure; principal component analysis; variance inflation factor ID GENOME-WIDE ASSOCIATION; PRINCIPAL-COMPONENTS; QUANTITATIVE TRAITS; RARE VARIANTS; SUBSTRUCTURE; BINARY; TESTS; POWER; MODEL AB Testing association between a genetic marker and multiple-dependent traits is a challenging task when both binary and quantitative traits are involved. The inverted regression model is a convenient method, in which the traits are treated as predictors although the genetic marker is an ordinal response. It is known that population stratification (PS) often affects population-based association studies. However, how it would affect the inverted regression for pleiotropic association, especially with the mixed types of traits (binary and quantitative), is not examined and the performance of existing methods to correct for PS using the inverted regression analysis is unknown. In this paper, we focus on the methods based on genomic control and principal component analysis, and investigate type I error of pleiotropic association using the inverted regression model in the presence of PS with allele frequencies and the distributions (or disease prevalences) of multiple traits varying across the subpopulations. We focus on common alleles but simulation results for a rare variant are also reported. An application to the HapMap data is used for illustration. C1 [Yan, Ting] Cent China Normal Univ, Wuhan, Peoples R China. [Yan, Ting; Li, Zhaohai] George Washington Univ, Washington, DC USA. [Yan, Ting] Digital Syst Inc, Chevy Chase, MD USA. [Li, Qizhai] Chinese Acad Sci, Beijing, Peoples R China. [Li, Yuanzhang] Walter Reed Army Inst Res, Silver Spring, MD USA. [Zheng, Gang] NHLBI, Bethesda, MD 20892 USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov OI Li, Yuanzhang/0000-0001-8872-4430 FU Department of the Army In-House Laboratory Independent Research [W81XWH-11-C-0082]; Small Business Innovation Research [W81XWH11C0511] FX The part of effort (authors from GWU and WRAIR) is funded by Department of the Army In-House Laboratory Independent Research W81XWH-11-C-0082 and the Small Business Innovation Research W81XWH11C0511. The views expressed are those of the authors and should not be construed to represent the positions of the Department of the Army, Department of Defense, or National Institutes of Health. None of the authors have any associations, financial or otherwise, that may present a conflict of interest. The authors thank Paul O'Reilly for the thoughtful comments and suggestions. NR 29 TC 7 Z9 7 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD SEP PY 2013 VL 37 IS 6 BP 571 EP 580 DI 10.1002/gepi.21738 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 198GT UT WOS:000322911100005 PM 23740720 ER PT J AU Monzack, EL Cunningham, LL AF Monzack, Elyssa L. Cunningham, Lisa L. TI Lead roles for supporting actors: Critical functions of inner ear supporting cells SO HEARING RESEARCH LA English DT Review ID AVIAN AUDITORY EPITHELIUM; SENSORY HAIR-CELLS; GUINEA-PIG COCHLEA; GLUTAMATE-ASPARTATE TRANSPORTER; SPIRAL GANGLION NEURONS; LATERAL-LINE SYSTEM; CHICK COCHLEA; ACOUSTIC TRAUMA; MAMMALIAN COCHLEA; PRIMARY PHAGOCYTOSIS AB Many studies that aim to investigate the underlying mechanisms of hearing loss or balance disorders focus on the hair cells and spiral ganglion neurons of the inner ear. Fewer studies have examined the supporting cells that contact both of these cell types in the cochlea and vestibular end organs. While the roles of supporting cells are still being elucidated, emerging evidence indicates that they serve many functions vital to maintaining healthy populations of hair cells and spiral ganglion neurons. Here we review recent studies that highlight the critical roles supporting cells play in the development, function, survival, death, phagocytosis, and regeneration of other cell types within the inner ear. Many of these roles have also been described for glial cells in other parts of the nervous system, and lessons from these other systems continue to inform our understanding of supporting cell functions. This article is part of a Special Issue entitled "Annual Reviews 2013". Published by Elsevier B.V. C1 [Monzack, Elyssa L.; Cunningham, Lisa L.] Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. RP Cunningham, LL (reprint author), 5 Res Court,Room 2A-03, Rockville, MD 20850 USA. EM elyssa.monzack@nih.gov; lisa.cunningham@nih.gov FU NIDCD Division of Intramural Research FX The authors would like to thank Dr. Doris Wu, Dr. Matthew Kelley, Dr. Meghan Drummond, and Dr. Jonathan Bird for their helpful comments and suggestions on the manuscript. The authors are also grateful to Dr. Jonathan Gale for many thoughtful conversations about supporting cells as well as constructive notes on the development of the text and figures of this manuscript. This work was supported by the NIDCD Division of Intramural Research. NR 140 TC 25 Z9 26 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD SEP PY 2013 VL 303 SI SI BP 20 EP 29 DI 10.1016/j.heares.2013.01.008 PG 10 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 200TS UT WOS:000323094400003 PM 23347917 ER PT J AU Moseman, EA McGavern, DB AF Moseman, E. Ashley McGavern, Dorian B. TI The great balancing act: regulation and fate of antiviral T-cell interactions SO IMMUNOLOGICAL REVIEWS LA English DT Review DE T cells; cytotoxic T cells; viral infection; neuroimmunology; in vivo imaging; immunotherapies ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; CENTRAL-NERVOUS-SYSTEM; PERSISTENT VIRAL-INFECTION; IMMUNOLOGICAL SYNAPSE FORMATION; BLOOD-BRAIN-BARRIER; PRESENTING B-CELLS; MHC CLASS-I; DENDRITIC CELLS; LYMPH-NODES; IMMUNE-RESPONSES AB The fate of T lymphocytes revolves around a continuous stream of interactions between the T-cell receptor (TCR) and peptide-major histocompatibility complex (MHC) molecules. Beginning in the thymus and continuing into the periphery, these interactions, refined by accessory molecules, direct the expansion, differentiation, and function of T-cell subsets. The cellular context of T-cell engagement with antigen-presenting cells, either in lymphoid or non-lymphoid tissues, plays an important role in determining how these cells respond to antigen encounters. CD8(+) T cells are essential for clearance of a lymphocytic choriomeningitis virus (LCMV) infection, but the virus can present a number of unique challenges that antiviral T cells must overcome. Peripheral LCMV infection can lead to rapid cytolytic clearance or chronic viral persistence; central nervous system infection can result in T-cell-dependent fatal meningitis or an asymptomatic carrier state amenable to immunotherapeutic clearance. These diverse outcomes all depend on interactions that require TCR engagement of cognate peptide-MHC complexes. In this review, we explore the diversity in antiviral T-cell behaviors resulting from TCR engagement, beginning with an overview of the immunological synapse and progressing to regulators of TCR signaling that shape the delicate balance between immunopathology and viral clearance. C1 [Moseman, E. Ashley; McGavern, Dorian B.] NINDS, NIH, Bethesda, MD 20892 USA. RP McGavern, DB (reprint author), NINDS, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mcgavernd@mail.nih.gov OI McGavern, Dorian/0000-0001-9568-545X FU National Institutes of Health (NIH) FX This study was supported by the National Institutes of Health (NIH) intramural program. The authors have no conflicts of interest to declare. NR 171 TC 7 Z9 7 U1 0 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD SEP PY 2013 VL 255 IS 1 SI SI BP 110 EP 124 DI 10.1111/imr.12093 PG 15 WC Immunology SC Immunology GA 201OM UT WOS:000323150900009 PM 23947351 ER PT J AU Graham, BS AF Graham, Barney S. TI Advances in antiviral vaccine development SO IMMUNOLOGICAL REVIEWS LA English DT Review DE viral immunity; vaccine development; monoclonal antibodies; neutralizing antibody; structure-based vaccine design; vaccines ID RESPIRATORY SYNCYTIAL VIRUS; INFLUENZA-A VIRUSES; MEMORY B-CELLS; GP120 ENVELOPE GLYCOPROTEIN; HUMAN MONOCLONAL-ANTIBODIES; X-RAY-DIFFRACTION; NEUTRALIZING ANTIBODY; HIV-1 VACCINE; HUMAN-IMMUNOGLOBULIN; POTENT NEUTRALIZATION AB Antiviral vaccines have been the most successful biomedical intervention for preventing epidemic viral disease. Vaccination for smallpox in humans and rinderpest in cattle was the basis for disease eradication, and recent progress in polio eradication is promising. Although early vaccines were developed empirically by passage in live animals or eggs, more recent vaccines have been developed because of the advent of new technologies, particularly cell culture and molecular biology. Recent technological advances in gene delivery and expression, nanoparticles, protein manufacturing, and adjuvants have created the potential for new vaccine platforms that may provide solutions for vaccines against viral pathogens for which no interventions currently exist. In addition, the technological convergence of human monoclonal antibody isolation, structural biology, and high-throughput sequencing is providing new opportunities for atomic-level immunogen design. Selection of human monoclonal antibodies can identify immunodominant antigenic sites associated with neutralization and provide reagents for stabilizing and solving the structure of viral surface proteins. Understanding the structural basis for neutralization can guide selection of vaccine targets. Deep sequencing of the antibody repertoire and defining the ontogeny of the desired antibody responses can reveal the junctional recombination and somatic mutation requirements for B-cell recognition and affinity maturation. Collectively, this information will provide new strategic approaches for selecting vaccine antigens, formulations, and regimens. Moreover, it creates the potential for rational vaccine design and establishing a catalogue of vaccine technology platforms that would be effective against any given family or class of viral pathogens and improve our readiness to address new emerging viral threats. C1 NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, NIH, Vaccine Res Ctr, 40 Convent Dr Bldg 40,Rm 2502, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU National Institute of Allergy and Infectious Diseases FX I thank Dr. Julie E. Ledgerwood and Dr. Kayvon Modjarrad for thoughtful advice and suggestions. This study was supported by the intramural funding from the National Institute of Allergy and Infectious Diseases. The author has no conflicts of interest to declare. NR 89 TC 10 Z9 11 U1 9 U2 90 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD SEP PY 2013 VL 255 IS 1 SI SI BP 230 EP 242 DI 10.1111/imr.12098 PG 13 WC Immunology SC Immunology GA 201OM UT WOS:000323150900017 PM 23947359 ER PT J AU Minato, Y Ghosh, A Faulkner, WJ Lind, EJ Bartra, SS Plano, GV Jarrett, CO Hinnebusch, BJ Winogrodzki, J Dibrov, P Hase, CC AF Minato, Yusuke Ghosh, Amit Faulkner, Wyatt J. Lind, Erin J. Bartra, Sara Schesser Plano, Gregory V. Jarrett, Clayton O. Hinnebusch, B. Joseph Winogrodzki, Judith Dibrov, Pavel Haese, Claudia C. TI Na+/H+ Antiport Is Essential for Yersinia pestis Virulence SO INFECTION AND IMMUNITY LA English DT Article ID LOW-CALCIUM RESPONSE; ESCHERICHIA-COLI; VIBRIO-CHOLERAE; NHAB; PH; RESISTANCE; HOMEOSTASIS; EXPRESSION; INHIBITORS; BACTERIA AB Na+/H+ antiporters are ubiquitous membrane proteins that play a central role in the ion homeostasis of cells. In this study, we examined the possible role of Na+/H+ antiport in Yersinia pestis virulence and found that Y. pestis strains lacking the major Na+/H+ antiporters, NhaA and NhaB, are completely attenuated in an in vivo model of plague. The Y. pestis derivative strain lacking the nhaA and nhaB genes showed markedly decreased survival in blood and blood serum ex vivo. Complementation of either nhaA or nhaB in trans restored the survival of the Y. pestis nhaA nhaB double deletion mutant in blood. The nhaA nhaB double deletion mutant also showed inhibited growth in an artificial serum medium, Opti-MEM, and a rich LB-based medium with Na+ levels and pH values similar to those for blood. Taken together, these data strongly suggest that intact Na+/H+ antiport is indispensable for the survival of Y. pestis in the bloodstreams of infected animals and thus might be regarded as a promising noncanonical drug target for infections caused by Y. pestis and possibly for those caused by other blood-borne bacterial pathogens. C1 [Minato, Yusuke; Ghosh, Amit; Lind, Erin J.; Haese, Claudia C.] Oregon State Univ, Coll Vet Med, Dept Biomed Sci, Corvallis, OR 97331 USA. [Faulkner, Wyatt J.; Haese, Claudia C.] Oregon State Univ, Dept Microbiol, Coll Sci, Corvallis, OR 97331 USA. [Bartra, Sara Schesser; Plano, Gregory V.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. [Jarrett, Clayton O.; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Winogrodzki, Judith; Dibrov, Pavel] Univ Manitoba, Dept Microbiol, Winnipeg, MB R3T 2N2, Canada. RP Hase, CC (reprint author), Oregon State Univ, Coll Vet Med, Dept Biomed Sci, Corvallis, OR 97331 USA. EM hasec@science.oregonstate.edu FU National Institutes of Health [AI-064190-02, AI039575]; NSERC; Natural Sciences and Engineering Research Council of Canada; Division of Intramural Research, NIAID, NIH FX This research was supported by grants from the National Institutes of Health to C. C. H. (AI-064190-02) and G. V. P (AI039575) and from NSERC, the Natural Sciences and Engineering Research Council of Canada (to P. D. and J.W.). B.J.H. was supported by the Division of Intramural Research, NIAID, NIH. NR 38 TC 13 Z9 13 U1 0 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 2013 VL 81 IS 9 BP 3163 EP 3172 DI 10.1128/IAI.00071-13 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 201NM UT WOS:000323148300011 PM 23774602 ER PT J AU Kabeiseman, EJ Cichos, K Hackstadt, T Lucas, A Moore, ER AF Kabeiseman, Emily J. Cichos, Kyle Hackstadt, Ted Lucas, Andrea Moore, Elizabeth R. TI Vesicle-Associated Membrane Protein 4 and Syntaxin 6 Interactions at the Chlamydial Inclusion SO INFECTION AND IMMUNITY LA English DT Article ID TRANS-GOLGI NETWORK; ENDOGENOUSLY SYNTHESIZED SPHINGOMYELIN; TRACHOMATIS INCLUSION; SNARE COMPLEX; CULTURED FIBROBLASTS; MICROTUBULE NETWORK; ENDOCYTIC PATHWAY; PLASMA-MEMBRANE; INFECTED CELLS; RAB GTPASES AB The predominant players in membrane fusion events are the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family of proteins. We hypothesize that SNARE proteins mediate fusion events at the chlamydial inclusion and are important for chlamydial lipid acquisition. We have previously demonstrated that trans-Golgi SNARE syntaxin 6 localizes to the chlamydial inclusion. To investigate the role of syntaxin 6 at the chlamydial inclusion, we examined the localization and function of another trans-Golgi SNARE and syntaxin 6-binding partner, vesicle-associated membrane protein 4 (VAMP4), at the chlamydial inclusion. In this study, we demonstrate that syntaxin 6 and VAMP4 colocalize to the chlamydial inclusion and interact at the chlamydial inclusion. Furthermore, in the absence of VAMP4, syntaxin 6 is not retained at the chlamydial inclusion. Small interfering RNA (siRNA) knockdown of VAMP4 inhibited chlamydial sphingomyelin acquisition, correlating with a log decrease in infectious progeny. VAMP4 retention at the inclusion was shown to be dependent on de novo chlamydial protein synthesis, but unlike syntaxin 6, VAMP4 recruitment is observed in a species-dependent manner. Notably, VAMP4 knockdown inhibits sphingomyelin trafficking only to inclusions in which it localizes. These data support the hypothesis that VAMP proteins play a central role in mediating eukaryotic vesicular interactions at the chlamydial inclusion and, thus, support chlamydial lipid acquisition and chlamydial development. C1 [Kabeiseman, Emily J.; Cichos, Kyle; Lucas, Andrea; Moore, Elizabeth R.] Univ S Dakota, Div Basic Biomed Sci, Sanford Sch Med, Vermillion, SD 57069 USA. [Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs, Hamilton, MT USA. RP Moore, ER (reprint author), Univ S Dakota, Div Basic Biomed Sci, Sanford Sch Med, Vermillion, SD 57069 USA. EM Lisa.Moore@usd.edu FU NIAID [1 K22 AI089856-01A1]; USD/SSOM/BBS; NIAID/NIH FX This work was supported by an NIAID K22 award (1 K22 AI089856-01A1) and USD/SSOM/BBS start-up funds both awarded to E.R.M. and an award from the Intramural Research Program at NIAID/NIH to T.H. NR 70 TC 7 Z9 7 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 2013 VL 81 IS 9 BP 3326 EP 3337 DI 10.1128/IAI.00584-13 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 201NM UT WOS:000323148300026 PM 23798538 ER PT J AU Kuhar, DT Henderson, DK Struble, KA Heneine, W Thomas, V Cheever, LW Gomaa, A Panlilio, AL AF Kuhar, David T. Henderson, David K. Struble, Kimberly A. Heneine, Walid Thomas, Vasavi Cheever, Laura W. Gomaa, Ahmed Panlilio, Adelisa L. CA US Public Hlth Serv Working Grp TI Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID TO-CHILD TRANSMISSION; PRIOR ANTIRETROVIRAL THERAPY; CARE WORKERS; HIV-INFECTION; NEEDLESTICK INJURY; HUMAN BITE; TYPE-1 INFECTION; LACTIC-ACIDOSIS; PREGNANCY; RISK AB This report updates US Public Health Service recommendations for the management of healthcare personnel (HCP) who experience occupational exposure to blood and/or other body fluids that might contain human immunodeficiency virus (HIV). Although the principles of exposure management remain unchanged, recommended HIV postexposure prophylaxis (PEP) regimens and the duration of HIV follow-up testing for exposed personnel have been updated. This report emphasizes the importance of primary prevention strategies, the prompt reporting and management of occupational exposures, adherence to recommended HIV PEP regimens when indicated for an exposure, expert consultation in management of exposures, follow-up of exposed HCP to improve adherence to PEP, and careful monitoring for adverse events related to treatment, as well as for virologic, immunologic, and serologic signs of infection. To ensure timely postexposure management and administration of HIV PEP, clinicians should consider occupational exposures as urgent medical concerns, and institutions should take steps to ensure that staff are aware of both the importance of and the institutional mechanisms available for reporting and seeking care for such exposures. The following is a summary of recommendations: (1) PEP is recommended when occupational exposures to HIV occur; (2) the HIV status of the exposure source patient should be determined, if possible, to guide need for HIV PEP; (3) PEP medication regimens should be started as soon as possible after occupational exposure to HIV, and they should be continued for a 4-week duration; (4) new recommendationPEP medication regimens should contain 3 (or more) antiretroviral drugs (listed in Appendix A) for all occupational exposures to HIV; (5) expert consultation is recommended for any occupational exposures to HIV and at a minimum for situations described in Box 1; (6) close follow-up for exposed personnel (Box 2) should be provided that includes counseling, baseline and follow-up HIV testing, and monitoring for drug toxicity; follow-up appointments should begin within 72 hours of an HIV exposure; and (7) new recommendationif a newer fourth-generation combination HIV p24 antigen--HIV antibody test is utilized for follow-up HIV testing of exposed HCP, HIV testing may be concluded 4 months after exposure (Box 2); if a newer testing platform is not available, follow-up HIV testing is typically concluded 6 months after an HIV exposure. C1 [Kuhar, David T.; Panlilio, Adelisa L.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Henderson, David K.] NIH, Off Deputy Director Clin Care, Ctr Clin, Bethesda, MD 20892 USA. [Struble, Kimberly A.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Heneine, Walid; Thomas, Vasavi] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. [Cheever, Laura W.] US Hlth Resources & Serv Adm, HIV AIDS Bur, Rockville, MD 20857 USA. [Gomaa, Ahmed] NIOSH, Div Surveillance Hazard Evaluat & Hlth Studies, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. RP Kuhar, DT (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. FU Bristol-Myers Squibb; Janssen; Merck; ViiV; GlaxoSmithKline; Gilead FX The expert panel consultants report the following competing interests: J.A. has a board membership with and has received funding from Bristol-Myers Squibb, Janssen, Merck, and ViiV; J.E. has consulted for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, and ViiV and has received grant funding from Bristol-Myers Squibb, GlaxoSmithKline, Merck, and ViiV; M. S. S. has consulted for Bristol-Myers Squibb, Gilead, Janssen, Merck, and ViiV and has received grant funding from Bristol-Myers Squibb, Gilead, Merck, and ViiV; M. L. T. owns Merck stock. All other authors report no conflicts of interest relevant to this article. NR 76 TC 98 Z9 102 U1 2 U2 19 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD SEP 1 PY 2013 VL 34 IS 9 BP 875 EP 892 DI 10.1086/672271 PG 18 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 195LD UT WOS:000322702900001 PM 23917901 ER PT J AU Li, QTQ Lee, RX Liang, HS Wang, GD Li, JLM Zhong, YH Reed, E AF Li, Quentin Q. Lee, Rebecca X. Liang, Huasheng Wang, Gangduo Li, Jueli M. Zhong, Yuhua Reed, Eddie TI beta-Elemene enhances susceptibility to cisplatin in resistant ovarian carcinoma cells via downregulation of ERCC-1 and XIAP and inactivation of JNK SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE apoptosis; cisplatin resistance; beta-elemene; Chinese medicine; ovarian cancer; excision repair cross-complementation group-1; X-linked inhibitor of apoptosis protein; c-Jun NH2-terminal kinase ID NUCLEOTIDE EXCISION-REPAIR; MESSENGER-RNA EXPRESSION; PLATINUM-DNA ADDUCT; LUNG-CANCER CELLS; SOLID TUMOR-CELLS; INDUCED APOPTOSIS; PROSTATE-CANCER; ANTICANCER CHEMOTHERAPY; SIGNAL-TRANSDUCTION; SYNTHETIC ANALOGS AB beta-Elemene is a promising new plant-derived drug with broad-spectrum anticancer activity. It also increases cisplatin cytotoxicity and enhances cisplatin sensitivity in resistant human carcinoma cells. However, little is known about the mechanism of its action. To explore the potential therapeutic application of beta-elemene as a drug-resistance modulator, this study investigated the underlying mechanism of beta-elemene activity in cisplatin-resistant ovarian cancer cells. beta-Elemene enhanced cisplatin sensitivity to a much greater extent in chemoresistant A2780/CP70 and MCAS human ovarian carcinoma cells compared to the chemosensitive parental cell line A2780. The dose-modifying factors for cisplatin were between 35 and 60 for A2780/CP70 cells and between 1.6 and 2.5 for A2780 cells. In the cisplatin-resistant ovarian carcinoma cells, beta-elemene abrogated cisplatin-induced expression of excision repair cross-complementation group-1 (ERCC-1), a marker gene in the nucleotide excision repair pathway that repairs cisplatin-caused DNA damage. In addition, beta-elemene not only reduced the level of X-linked inhibitor of apoptosis protein (XIAP), but also downregulated cisplatin-mediated XIAP expression in chemoresistant cells. Furthermore, beta-elemene blocked the cisplatin-stimulated increase in the level of phosphorylated c-Jun NH2-terminal kinase (JNK) in these cells. These novel findings suggest that the beta-elemene enhancement of cisplatin sensitivity in human chemoresistant ovarian cancer cells is mediated at least in part through the impairment of DNA repair activity and the activation of apoptotic signaling pathways, thereby making resistant ovarian cancer cells susceptible to cisplatin-induced cell death. C1 [Liang, Huasheng; Zhong, Yuhua] Beihai Inst Endocrine & Metab Dis, Beihai 536000, Guangxi, Peoples R China. [Li, Quentin Q.; Reed, Eddie] NIH, Bethesda, MD 20892 USA. [Li, Quentin Q.; Lee, Rebecca X.; Wang, Gangduo; Reed, Eddie] W Virginia Univ, Sch Med, Morgantown, WV 26506 USA. [Li, Jueli M.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. RP Li, QTQ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov; flowchaos@aliyun.com FU Natural Science Foundation of Science and Technology Department of Guangxi Province [0991294]; Guangxi Scientific Research and Technological Development Program [200901059]; National Institutes of Health [P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003]; West Virginia University School of Medicine Research Grant FX This publication was made possible by grants from the Natural Science Foundation of Science and Technology Department of Guangxi Province (no. 0991294); the Guangxi Scientific Research and Technological Development Program (no. 200901059); and by grants from the National Institutes of Health (nos. P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003) and a West Virginia University School of Medicine Research Grant (to Q.Q.L.). NR 73 TC 17 Z9 19 U1 0 U2 12 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD SEP PY 2013 VL 43 IS 3 BP 721 EP 728 DI 10.3892/ijo.2013.1996 PG 8 WC Oncology SC Oncology GA 190XD UT WOS:000322375900005 PM 23817665 ER PT J AU Iranzo, J Lobkovsky, AE Wolf, YI Koonin, EV AF Iranzo, Jaime Lobkovsky, Alexander E. Wolf, Yuri I. Koonin, Eugene V. TI Evolutionary Dynamics of the Prokaryotic Adaptive Immunity System CRISPR-Cas in an Explicit Ecological Context SO JOURNAL OF BACTERIOLOGY LA English DT Article ID NATURAL MICROBIAL COMMUNITIES; SULFATE-REDUCING BACTERIA; WADDEN SEA; STREPTOCOCCUS-THERMOPHILUS; VERTICAL-DISTRIBUTION; POPULATION-DYNAMICS; DEFENSE SYSTEMS; BLACK SMOKER; DIVERSITY; RNA AB A stochastic, agent-based mathematical model of the coevolution of the archaeal and bacterial adaptive immunity system, CRISPR-Cas, and lytic viruses shows that CRISPR-Cas immunity can stabilize the virus-host coexistence rather than leading to the extinction of the virus. In the model, CRISPR-Cas immunity does not specifically promote viral diversity, presumably because the selection pressure on each single proto-spacer is too weak. However, the overall virus diversity in the presence of CRISPR-Cas grows due to the increase of the host and, accordingly, the virus population size. Above a threshold value of total viral diversity, which is proportional to the viral mutation rate and population size, the CRISPR-Cas system becomes ineffective and is lost due to the associated fitness cost. Our previous modeling study has suggested that the ubiquity of CRISPR-Cas in hyperthermophiles, which contrasts its comparative low prevalence in mesophiles, is due to lower rates of mutation fixation in thermal habitats. The present findings offer a complementary, simpler perspective on this contrast through the larger population sizes of mesophiles compared to hyperthermophiles, because of which CRISPR-Cas can become ineffective in mesophiles. The efficacy of CRISPR-Cas sharply increases with the number of proto-spacers per viral genome, potentially explaining the low information content of the proto-spacer-associated motif (PAM) that is required for spacer acquisition by CRISPR-Cas because a higher specificity would restrict the number of spacers available to CRISPR-Cas, thus hampering immunity. The very existence of the PAM might reflect the tradeoff between the requirement of diverse spacers for efficient immunity and avoidance of autoimmunity. C1 [Iranzo, Jaime] INTA CSIC, Ctr Astrobiol, Madrid, Spain. [Lobkovsky, Alexander E.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov RI Iranzo, Jaime/H-5197-2011 OI Iranzo, Jaime/0000-0002-4538-7726 FU Comunidad de Madrid [MODELICO S2009/ESP-1691]; Spanish MINECO [FIS2011-27569]; U.S. Department of Health and Human Services FX J.I. is supported by Comunidad de Madrid through a research grant and project MODELICO S2009/ESP-1691 and Spanish MINECO through project FIS2011-27569.; A.E.L., Y.I.W., and E.V.K. are supported by intramural funds from the U.S. Department of Health and Human Services (to the National Library of Medicine). NR 88 TC 15 Z9 15 U1 0 U2 35 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2013 VL 195 IS 17 BP 3834 EP 3844 DI 10.1128/JB.00412-13 PG 11 WC Microbiology SC Microbiology GA 200DM UT WOS:000323047900005 PM 23794616 ER PT J AU Cunnington, AJ Bretscher, MT Nogaro, SI Riley, EM Walther, M AF Cunnington, Aubrey J. Bretscher, Michael T. Nogaro, Sarah I. Riley, Eleanor M. Walther, Michael TI Comparison of parasite sequestration in uncomplicated and severe childhood Plasmodium falciparum malaria SO JOURNAL OF INFECTION LA English DT Article DE Cerebral malaria; Microcirculation; Lactic acid; Sequestration; HRP2; Anaemia; Parasite Biomass ID CEREBRAL MALARIA; AFRICAN CHILDREN; RANDOMIZED-TRIAL; ADJUNCTIVE THERAPY; MALAWIAN CHILDREN; PATHOGENESIS; MANAGEMENT; MORTALITY; AGE; PATHOPHYSIOLOGY AB Objectives: To determine whether sequestration of parasitized red blood cells differs between children with uncomplicated and severe Plasmodium falciparum malaria. Methods: We quantified circulating-, total-and sequestered-parasite biomass, using a mathematical model based on plasma concentration of P. falciparum histidine rich protein 2, in Gambian children with severe (n = 127) and uncomplicated (n = 169) malaria. Results: Circulating-and total-, but not sequestered-, parasite biomass estimates were significantly greater in children with severe malaria than in those with uncomplicated malaria. Sequestered biomass estimates in children with hyperlactataemia or prostration were similar to those in uncomplicated malaria, whereas sequestered biomass was higher in patients with severe anaemia, and showed a trend to higher values in cerebral malaria and fatal cases. Blood lactate concentration correlated with circulating-and total-, but not sequestered parasite biomass. These findings were robust after controlling for age, prior antimalarial treatment and clonality of infection, and over a realistic range of variation in model parameters. Conclusion: Extensive sequestration is not a uniform requirement for severe paediatric malaria. The pathophysiology of hyperlactataemia and prostration appears to be unrelated to sequestered parasite biomass. Different mechanisms may underlie different severe malaria syndromes, and different therapeutic strategies may be required to improve survival. Published by Elsevier Ltd on behalf of The British Infection Association. C1 [Cunnington, Aubrey J.; Bretscher, Michael T.; Nogaro, Sarah I.; Riley, Eleanor M.] Univ London London Sch Hyg & Trop Med, Dept Immunol & Infect, Fac Infect & Trop Dis, London WC1E 7HT, England. [Cunnington, Aubrey J.; Nogaro, Sarah I.; Walther, Michael] Med Res Council UK Labs, Banjul, Gambia. [Cunnington, Aubrey J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Paediat Sect, London W2 1PG, England. [Walther, Michael] NIAID, Immune Regulat Sect, Lab Malaria Immunol & Vaccinol, Div Intramural Res,NIH, Rockville, MD 20852 USA. RP Walther, M (reprint author), NIAID, Immune Regulat Sect, Lab Malaria Immunol & Vaccinol, Div Intramural Res,NIH, Twinbrook 2 Rm 239 A,12441 Parklawn Dr, Rockville, MD 20852 USA. EM Michael.Walther@nih.gov RI Riley, Eleanor/C-8960-2013; OI Riley, Eleanor/0000-0003-3447-3570; Cunnington, Aubrey/0000-0002-1305-3529 FU Medical Research Council, UK [G0701427] FX This work was supported by core funding from the Medical Research Council, UK to the malaria research programme, and a Medical Research Council, UK, clinical research training fellowship [G0701427 to A.J.C.]. NR 57 TC 11 Z9 11 U1 0 U2 13 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 J9 J INFECTION JI J. Infect. PD SEP PY 2013 VL 67 IS 3 BP 220 EP 230 DI 10.1016/j.jinf.2013.04.013 PG 11 WC Infectious Diseases SC Infectious Diseases GA 195XO UT WOS:000322737300007 PM 23623771 ER PT J AU Kumar, NP Sridhar, R Banurekha, VV Jawahar, MS Nutman, TB Babu, S AF Kumar, Nathella Pavan Sridhar, Rathinam Banurekha, Vaithilingam V. Jawahar, Mohideen S. Nutman, Thomas B. Babu, Subash TI Expansion of Pathogen-Specific T-Helper 1 and T-Helper 17 Cells in Pulmonary Tuberculosis With Coincident Type 2 Diabetes Mellitus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE T cells; bacterial; cytokines; tuberculosis; diabetes mellitus ID MYCOBACTERIUM-TUBERCULOSIS; INTERFERON-GAMMA; IMMUNE-RESPONSES; IFN-GAMMA; MICE; DISEASE; RESISTANCE; CHALLENGE; INFECTION; SYSTEM AB Background. Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis, although the immunological mechanisms underlying this interaction remain unexplored. The influence of poorly controlled diabetes on pathogen-specific T-helper 1 (Th1) and T-helper 17 (Th17) responses have not been examined. Methods. To identify the role of Th1 and Th17 cells in tuberculosis with coincident DM, we examined mycobacteria-specific immune responses in the whole blood of individuals who had tuberculosis with DM and compared them to those in individuals who had tuberculosis without DM. Results. Tuberculosis coincident with DM is characterized by elevated frequencies of monofunctional and dual-functional CD4(+) Th1 cells following Mycobacterium tuberculosis antigen stimulation and elevated frequencies of Th17 subsets at both baseline and following antigen stimulation. This was associated with increased systemic (plasma) levels of both Th1 and Th17 cytokines and decreased baseline frequencies of natural regulatory T cells but not interleukin 10 or transforming growth factor beta. Conclusions. Therefore, our data reveal that tuberculosis in persons with DM is characterized by elevated frequencies of Th1 and Th17 cells, indicating that DM is associated with an alteration in the immune response to tuberculosis, leading to a biased induction of Th1- and Th17-mediated cellular responses and likely contributing to increased immune pathology in M. tuberculosis infection. C1 [Kumar, Nathella Pavan; Babu, Subash] Natl Inst Hlth Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Kumar, Nathella Pavan; Banurekha, Vaithilingam V.; Jawahar, Mohideen S.] Natl Inst Res TB, Madras, Tamil Nadu, India. [Sridhar, Rathinam] Govt Stanley Med Hosp, Madras, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Babu, Subash] SAIC Frederick, Frederick, MD USA. RP Babu, S (reprint author), Natl Inst Res TB, NIH ICER, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health 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. NR 34 TC 36 Z9 38 U1 0 U2 9 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 2013 VL 208 IS 5 BP 739 EP 748 DI 10.1093/infdis/jit241 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 198YB UT WOS:000322958900006 PM 23715661 ER PT J AU Kalams, SA Parker, SD Elizaga, M Metch, B Edupuganti, S Hural, J De Rosa, S Carter, DK Rybczyk, K Frank, I Fuchs, J Koblin, B Kim, DH Joseph, P Keefer, MC Baden, LR Eldridge, J Boyer, J Sherwat, A Cardinali, M Allen, M Pensiero, M Butler, C Khan, AS Yan, J Sardesai, NY Kublin, JG Weiner, DB AF Kalams, Spyros A. Parker, Scott D. Elizaga, Marnie Metch, Barbara Edupuganti, Srilatha Hural, John De Rosa, Stephen Carter, Donald K. Rybczyk, Kyle Frank, Ian Fuchs, Jonathan Koblin, Beryl Kim, Denny H. Joseph, Patrice Keefer, Michael C. Baden, Lindsey R. Eldridge, John Boyer, Jean Sherwat, Adam Cardinali, Massimo Allen, Mary Pensiero, Michael Butler, Chris Khan, Amir S. Yan, Jian Sardesai, Niranjan Y. Kublin, James G. Weiner, David B. CA NIAID HIV Vaccine Trials Network TI Safety and Comparative Immunogenicity of an HIV-1 DNA Vaccine in Combination with Plasmid Interleukin 12 and Impact of Intramuscular Electroporation for Delivery SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE vaccination; electroporation; plasmid cytokine adjuvant ID T-CELL RESPONSES; IN-VIVO ELECTROPORATION; IMMUNE-RESPONSES; RHESUS MACAQUES; CANDIDATE VACCINE; PHASE-1 SAFETY; GROWTH-FACTOR; CYTOKINE; VIREMIA; IL-12 AB Background. DNA vaccines have been very poorly immunogenic in humans but have been an effective priming modality in prime-boost regimens. Methods to increase the immunogenicity of DNA vaccines are needed. Methods. HIV Vaccine Trials Network (HVTN) studies 070 and 080 were multicenter, randomized, clinical trials. The human immunodeficiency virus type 1 (HIV-1) PENNVAX(R)-B DNA vaccine (PV) is a mixture of 3 expression plasmids encoding HIV-1 Clade B Env, Gag, and Pol. The interleukin 12 (IL-12) DNA plasmid expresses human IL-12 proteins p35 and p40. Study subjects were healthy HIV-1-uninfected adults 18-50 years old. Four intramuscular vaccinations were given in HVTN 070, and 3 intramuscular vaccinations were followed by electroporation in HVTN 080. Cellular immune responses were measured by intracellular cytokine staining after stimulation with HIV-1 peptide pools. Results. Vaccination was safe and well tolerated. Administration of PV plus IL-12 with electroporation had a significant dose-sparing effect and provided immunogenicity superior to that observed in the trial without electroporation, despite fewer vaccinations. A total of 71.4% of individuals vaccinated with PV plus IL-12 plasmid with electroporation developed either a CD4(+) or CD8(+) T-cell response after the second vaccination, and 88.9% developed a CD4(+) or CD8(+) T-cell response after the third vaccination. Conclusions. Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans. C1 [Kalams, Spyros A.; Rybczyk, Kyle] Vanderbilt Univ, Div Infect Dis, Dept Med, Sch Med, Nashville, TN 37232 USA. [Kalams, Spyros A.; Rybczyk, Kyle] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Parker, Scott D.] Univ Alabama Birmingham, Div Infect Dis, Dept Med, Med Ctr, Birmingham, AL USA. [Elizaga, Marnie; Metch, Barbara; Hural, John; De Rosa, Stephen; Carter, Donald K.; Kublin, James G.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Edupuganti, Srilatha] Emory Univ, Atlanta, GA 30322 USA. [Frank, Ian] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Boyer, Jean; Weiner, David B.] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. [Khan, Amir S.; Yan, Jian; Sardesai, Niranjan Y.] Inovio Pharmaceut, Blue Bell, PA USA. [Fuchs, Jonathan] San Francisco Dept Hlth, San Francisco, CA USA. [Koblin, Beryl] New York Blood Ctr, Lab Infect Dis Prevent, New York, NY 10021 USA. [Keefer, Michael C.] Univ Rochester, Sch Med & Dent, New York, NY USA. [Eldridge, John] Profectus BioSci, Tarrytown, NY USA. [Kim, Denny H.] Astellas Pharma US, Northbrook, IL USA. [Joseph, Patrice] Grp Haitien Etud Sarcome Kaposi & Infect Opportun, Port Au Prince, Haiti. [Baden, Lindsey R.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Sherwat, Adam; Cardinali, Massimo; Allen, Mary; Pensiero, Michael; Butler, Chris] NIAID, Bethesda, MD 20892 USA. RP Kalams, SA (reprint author), Vanderbilt Univ, Med Ctr, 1161 21st Ave South,MCN A2207, Nashville, TN 37232 USA. EM s.kalams@vanderbilt.edu RI Weiner, David/H-8579-2014; OI Allen, Mary/0000-0001-8163-0714 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069452, UM1 AI069418, UM1 AI069511, UM1 AI069421, UM1 AI069412, UM1 AI069470, UM1 AI069439, UM1 AI069534, UM1 AI069496, P01-AI071739]; HVDDT [HHSN272200800063C]; CTSA [UL1TR000445] FX This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grants UM1 AI068614 [to the HVTN Core FHCRC], UM1 AI068635 [to SCHARP], UM1 AI068618 [to the HVTN Laboratory program FHCRC], UM1 AI069452 [to UAB], UM1 AI069418 [to Emory], UM1 AI069511 [to Rochester], UM1 AI069421 [to GHESKIO], UM1 AI069412 [to BWH], UM1 AI069470 [to the New York Blood Center-Bronx, NY Blood Center-Union Square, and Columbia University], UM1 AI069439 [to Vanderbilt], UM1 AI069534 [to UPENN], UM1 AI069496 [to SFDPH], P01-AI071739 [to Penn], HVDDT contract HHSN272200800063C [to Inovio], and CTSA award no. UL1TR000445 to Vanderbilt.). NR 44 TC 60 Z9 60 U1 0 U2 10 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 2013 VL 208 IS 5 BP 818 EP 829 DI 10.1093/infdis/jit236 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 198YB UT WOS:000322958900014 PM 23840043 ER PT J AU Tobian, AAR Grabowski, MK Serwadda, D Newell, K Ssebbowa, P Franco, V Nalugoda, F Wawer, MJ Gray, RH Quinn, TC Reynolds, SJ AF Tobian, Aaron A. R. Grabowski, Mary K. Serwadda, David Newell, Kevin Ssebbowa, Paschal Franco, Veronica Nalugoda, Fred Wawer, Maria J. Gray, Ronald H. Quinn, Thomas C. Reynolds, Steven J. CA Rakai Hlth Sci Program TI Reactivation of Herpes Simplex Virus Type 2 After Initiation of Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE herpes simplex virus type 2 (HSV-2); human immunodeficiency virus (HIV); immune reconstitution inflammatory syndrome (IRIS); acyclovir; reactivation; Uganda ID RECONSTITUTION INFLAMMATORY SYNDROME; PLACEBO-CONTROLLED TRIAL; GENITAL ULCER DISEASE; HIV-1 ACQUISITION; DOUBLE-BLIND; INFECTION; WOMEN; UGANDA; RAKAI; MEN AB Background. The association between initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection and possible herpes simplex virus type 2 (HSV-2) shedding and genital ulcer disease (GUD) has not been evaluated. Methods. GUD and vaginal HSV-2 shedding were evaluated among women coinfected with HIV and HSV-2 (n = 440 for GUD and n = 96 for HSV-2 shedding) who began ART while enrolled in a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Monthly vaginal swabs were tested for HSV-2 shedding, using a real-time quantitative polymerase chain reaction assay. Prevalence risk ratios (PRRs) of GUD were estimated using log binomial regression. Random effects logistic regression was used to estimate odds ratios (ORs) of HSV-2 shedding. Results. Compared with pre-ART values, GUD prevalence increased significantly within the first 3 months after ART initiation (adjusted PRR, 1.94; 95% confidence interval [CI], 1.04-3.62) and returned to baseline after 6 months of ART (adjusted PRR, 0.80; 95% CI,.35-1.80). Detection of HSV-2 shedding was highest in the first 3 months after ART initiation (adjusted OR, 2.58; 95% CI, 1.48-4.49). HSV-2 shedding was significantly less common among women receiving acyclovir (adjusted OR, 0.13; 95% CI, .04-.41). Conclusions. The prevalence of HSV-2 shedding and GUD increased significantly after ART initiation, possibly because of immune reconstitution inflammatory syndrome. Acyclovir significantly reduced both GUD and HSV-2 shedding and should be considered to mitigate these effects following ART initiation. C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. [Franco, Veronica; Quinn, Thomas C.; Reynolds, Steven J.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21287 USA. [Grabowski, Mary K.; Wawer, Maria J.; Gray, Ronald H.; Reynolds, Steven J.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Newell, Kevin] SAIC Frederick, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Serwadda, David; Ssebbowa, Paschal; Nalugoda, Fred; Wawer, Maria J.; Gray, Ronald H.; Reynolds, Steven J.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN26 1200800001E]; NIH [1K23AI093152-01A1]; Doris Duke Charitable Foundation [22006.02]; [PO1 AI-30731-19] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH; and in part by program project grant PO1 AI-30731-19); the National Cancer Institute, NIH (contract HHSN26 1200800001E); the NIH (grant 1K23AI093152-01A1 to A. A. R. T.); and the Doris Duke Charitable Foundation (Clinician Scientist Development Award 22006.02 to A. A. R. T.). NR 34 TC 15 Z9 15 U1 0 U2 13 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 2013 VL 208 IS 5 BP 839 EP 846 DI 10.1093/infdis/jit252 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 198YB UT WOS:000322958900016 PM 23812240 ER PT J AU Muller, M Jochemsen, HM Visseren, FLJ Grool, AM Launer, LJ van der Graaf, Y Geerlings, MI AF Muller, M. Jochemsen, H. M. Visseren, F. L. J. Grool, A. M. Launer, L. J. van der Graaf, Y. Geerlings, M. I. CA SMART-Study Grp TI Low blood pressure and antihypertensive treatment are independently associated with physical and mental health status in patients with arterial disease: the SMART study SO JOURNAL OF INTERNAL MEDICINE LA English DT Article DE antihypertensive treatment; blood pressure; cardiovascular disease; mental health; physical health ID QUALITY-OF-LIFE; UNITED-STATES; 2ND MANIFESTATIONS; DRUG-TREATMENT; EPIC-NORFOLK; OLDER-ADULTS; HYPERTENSION; POPULATION; DEPRESSION; MORTALITY AB Objective. To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease. Design and setting. Cross-sectional analyses were conducted within the single-centre Secondary Manifestations of ARTerial disease (SMART) study, in a hospital care setting. Subjects. A total of 5877 patients (mean age 57 years) with symptomatic and asymptomatic arterial disease underwent standardized vascular screening. Main outcome measure. The primary outcome was self-rated physical and mental health assessed using the 36-item short-form health survey. Results. In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment were associated with poorer health status independent of important confounders including BP levels; adjusted mean differences [95% confidence interval (CI)] in physical and mental health between n = 0 and n >= 3 antihypertensives were -1.2 (-2.1; -0.3) and -3.5 (-4.4; -2.6), respectively. Furthermore, both lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independent of antihypertensive treatment. Mean differences (95% CI) in physical and mental health status per SD decrease in systolic BP were -0.56 (-0.84; -0.27) and -0.32 (-0.61; -0.03) and per SD decrease in diastolic BP were -0.50 (-0.78; -0.23) and -0.08 (-0.36; 0.20), respectively. The association between low BP and poor health status was particularly present in patients with coronary artery disease. Conclusions. In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These findings suggest that different underlying mechanisms may explain these independent associations. C1 [Muller, M.] Vrije Univ Amsterdam Med Ctr, Dept Internal Med, Amsterdam, Netherlands. [Muller, M.; Jochemsen, H. M.; Grool, A. M.; van der Graaf, Y.; Geerlings, M. I.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Muller, M.; Launer, L. J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Jochemsen, H. M.] Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands. [Visseren, F. L. J.] Univ Med Ctr Utrecht, Dept Vasc Med, Utrecht, Netherlands. [Grool, A. M.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. RP Geerlings, MI (reprint author), Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. EM m.geerlings@umcutrecht.nl FU Netherlands Organization for Scientific Research [904-65-095]; Internationale Stichting Alzheimer Onderzoek [09502]; Alzheimer Nederland [WE. 15-2011-02] FX We gratefully acknowledge the members of the SMART Study Group of the University Medical Center Utrecht: A. Algra, MD, PhD, Julius Center for Health Sciences and Primary Care and Rudolf Magnus Institute for Neurosciences, Department of Neurology; P. A. Doevendans, MD, PhD, Department of Cardiology; Y. van der Graaf, MD, PhD, D. E. Grobbee, MD, PhD and G. E. H. M. Rutten, MD, PhD, Julius Center for Health Sciences and Primary Care; L.J. Kappelle, MD, PhD, Department of Neurology; W. P. Th.M. Mali, MD, PhD, Department of Radiology; F. L. Moll, MD, PhD, Department of Vascular Surgery; and F.L.J. Visseren, MD, PhD, Department of Vascular Medicine. This study was supported by a programme grant from the Netherlands Organization for Scientific Research (project no. 904-65-095) and research grants from the Internationale Stichting Alzheimer Onderzoek (project no. 09502) and Alzheimer Nederland (project no. WE. 15-2011-02). NR 32 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD SEP PY 2013 VL 274 IS 3 BP 241 EP 251 DI 10.1111/joim.12069 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 198FM UT WOS:000322907600005 PM 23527863 ER PT J AU Segre, JA AF Segre, Julia A. TI What Does It Take to Satisfy Koch's Postulates Two Centuries Later?: Microbial Genomics and Propionibacteria acnes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article AB For two centuries, Koch's postulates have set the gold standard for establishing the microbiological etiology of infection and disease. Genomic sequencing now brings finer resolution to both bacterial strain variation and the host genetic state that may predispose to disease. In this issue of the JID, Fitz-Gibbons and colleagues present strain-based resolution of Propionibacterium acnes and its association with the common teenage malady acne vulgaris. Here I examine how Koch's postulates were envisioned and incorporate this finer resolution of both host and microbial states. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Bldg 49 Room 4A26, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov FU Intramural NIH HHS [ZIA HG000180-12] NR 8 TC 6 Z9 6 U1 2 U2 21 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 2013 VL 133 IS 9 BP 2141 EP 2142 DI 10.1038/jid.2013.260 PG 2 WC Dermatology SC Dermatology GA 202GY UT WOS:000323203300011 PM 23842116 ER PT J AU Jones, RJ Gu, DM Bjorklund, CC Kuiatse, I Remaley, AT Bashir, T Vreys, V Orlowski, RZ AF Jones, Richard J. Gu, Dongmin Bjorklund, Chad C. Kuiatse, Isere Remaley, Alan T. Bashir, Tarig Vreys, Veronique Orlowski, Robert Z. TI The Novel Anticancer Agent JNJ-26854165 Induces Cell Death through Inhibition of Cholesterol Transport and Degradation of ABCA1 SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DENSITY-LIPOPROTEIN-RECEPTOR; ACUTE MYELOGENOUS LEUKEMIA; MULTIPLE-MYELOMA; GENE-EXPRESSION; MESSENGER-RNA; LDL RECEPTOR; TRAFFICKING; DISEASE; EFFLUX; APOPTOSIS AB JNJ-26854165 (serdemetan) has previously been reported to inhibit the function of the E3 ligase human double minute 2, and we initially sought to characterize its activity in models of mantle cell lymphoma (MCL) and multiple myeloma (MM). Serdemetan induced a dose-dependent inhibition of proliferation in both wildtype (wt) and mutant (mut) p53 cell lines, with IC50 values from 0.25 to 3 mu M/l, in association with an S phase cell cycle arrest. Caspase-3 activation was primarily seen in wtp53-bearing cells but also occurred in mutp53-bearing cells, albeit to a lesser extent. 293T cells treated with JNJ-26854165 and serdemetan-resistant fibroblasts displayed accumulation of cholesterol within endosomes, a phenotype reminiscent of that seen in the ATP-binding cassette subfamily A member-1 (ABCA1) cholesterol transport disorder, Tangiers disease. MM and MCL cells had decreased cholesterol efflux and electron microscopy demonstrated the accumulation of lipid whorls, confirming the lysosomal storage disease phenotype. JNJ-26854165 induced induction of cholesterol regulatory genes, sterol regulatory element-binding transcription factor-1 and -2, liver X receptors alpha and beta, along with increased expression of Niemann-Pick disease type-C1 and -C2. However, JNJ-26854165 induced enhanced ABCA1 turnover despite enhancing transcription. Finally, ABCA1 depletion resulted in enhanced sensitivity to JNJ-26854165. Overall, these findings support the hypothesis that serdemetan functions in part by inhibiting cholesterol transport and that this pathway is a potential new target for the treatment of MCL and MM. C1 [Jones, Richard J.; Gu, Dongmin; Bjorklund, Chad C.; Kuiatse, Isere; Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77054 USA. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77054 USA. [Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. [Bashir, Tarig; Vreys, Veronique] Janssen Res & Dev, Beerse, Belgium. RP Jones, RJ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, 7455 Fannin St,Unit 403, Houston, TX 77054 USA. EM rjones@mdanderson.org FU Cancer Center Support Grant [CA16672] FX Flow cytometry services were provided by the MD Anderson Flow Cytometry Core Facility, and electron microscopy was performed at the MD Anderson Electron Microscopy Core Facility with the assistance of Kenneth Dunner, which are supported by the Cancer Center Support Grant (CA16672). The authors are grateful to Shubin Xiong for the gift of the p53-/- and dual p53-/- and HDM-2-/- MEF cells (Houston, Texas) and to Masanori Daibata for SP-53 cells (Kochi University, Kochi, Japan). NR 51 TC 9 Z9 9 U1 0 U2 13 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD SEP PY 2013 VL 346 IS 3 BP 381 EP 392 DI 10.1124/jpet.113.204958 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 201RE UT WOS:000323159900005 PM 23820125 ER PT J AU Gasior, M Tang, R Rogawski, MA AF Gasior, Maciej Tang, Rebecca Rogawski, Michael A. TI Long-Lasting Attenuation of Amygdala-Kindled Seizures after Convection-Enhanced Delivery of Botulinum Neurotoxins A and B into the Amygdala in Rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TOXIN-A; TETANUS TOXIN; DOUBLE-BLIND; SPINAL-CORD; EPILEPSY; INJECTION; RELEASE; BRAIN; TRANSMITTERS AB Botulinum neurotoxins (BoNTs) are well recognized to cause potent, selective, and long-lasting neuroparalytic actions by blocking cholinergic neurotransmission to muscles and glands. There is evidence that BoNT isoforms can also inhibit neurotransmission in the brain. In this study, we examined whether locally delivered BoNT/A and BoNT/B can attenuate kindling measures in amygdala-kindled rats. Male rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received a single infusion of vehicle or BoNT/A or BoNT/B at doses of 1, 3.2, or 10 ng over a 20-minute period by convection-enhanced delivery. Electrographic (EEG) and behavioral kindling measures were determined at selected times during the 3- to 64-day period after the infusion. BoNT/B produced a dose-dependent elevation in after-discharge threshold and duration and a reduction in the seizure stage and duration of behavioral seizures that lasted for up to 50 days after infusion. BoNT/A had similar effects on EEG measures; behavioral seizure measures were also reduced, but the effect did not reach statistical significance. The effects of both toxins on EEG and behavioral measures progressively resolved during the latter half of the observation period. Animals gained weight normally, maintained normal body temperature, and did not show altered behavior. This study demonstrates for the first time that locally delivered BoNTs can produce prolonged inhibition of brain excitability, indicating that they could be useful for the treatment of brain disorders, including epilepsy, that would benefit from long-lasting suppression of neurotransmission within a circumscribed brain region. C1 [Gasior, Maciej; Tang, Rebecca; Rogawski, Michael A.] NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. [Rogawski, Michael A.] Univ Calif Davis, Sch Med, Dept Neurol, Sacramento, CA 95817 USA. RP Rogawski, MA (reprint author), Univ Calif Davis, Sch Med, Dept Neurol, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA. EM rogawski@ucdavis.edu RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 FU National Institutes of Health National Institute of Neurological Disorders and Stroke [NS002877, NS072094, NS079202]; Intramural Research Program of the National Institutes of Health [National Institute of Neurological Disorders and Stroke] FX This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS002877, NS072094, NS079202]; and the Intramural Research Program of the National Institutes of Health [National Institute of Neurological Disorders and Stroke]. NR 40 TC 3 Z9 3 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD SEP PY 2013 VL 346 IS 3 BP 528 EP 534 DI 10.1124/jpet.113.205070 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 201RE UT WOS:000323159900019 PM 23772062 ER PT J AU Tooley, PW Browning, M Leighty, RM AF Tooley, Paul W. Browning, Marsha Leighty, Robert M. TI Inoculum Density Relationships for Infection of Some Eastern US Forest Species by Phytophthora ramorum SO JOURNAL OF PHYTOPATHOLOGY LA English DT Article DE epidemiology; ramorum blight; sudden oak death ID PARASITICA VAR-NICOTIANAE; OAK DEATH PATHOGEN; COLLETOTRICHUM-COCCODES; WETNESS DURATION; PLANT-AGE; SUSCEPTIBILITY; CALIFORNIA; RESISTANCE; INOCULATION; TEMPERATURE AB Our objectives were to establish inoculum density relationships between P.ramorum and selected hosts using detached leaf and whole-plant inoculations. Young plants and detached leaves of Quercus prinus (Chestnut oak), Q.rubra (Northern red oak), Acer rubrum (red maple), Kalmia latifolia (mountain laurel) and Rhododendron Cunningham's White' were dip-inoculated with varying numbers of P.ramorum sporangia, and the total number of diseased and healthy leaves recorded following incubation at 20 degrees C and 100% relative humidity. Calibration threshold estimates for obtaining 50% infected leaves based on linear analysis ranged from 36 to 750 sporangia/ml for the five hosts. Half-life (LD50) estimates (the number of spores for which the per cent of diseased leaves reaches 50% of its total) from asymptotic regression analysis ranged from 94 to 319 sporangia/ml. Statistically significant differences (P=0.0076) were observed among hosts in per cent infection in response to increased inoculum density. Inoculum threshold estimates based on studies with detached leaves were comparable to those obtained using whole plants. P.ramorum hosts and will be useful in disease prediction and for development of pest risk assessments. C1 [Tooley, Paul W.; Browning, Marsha] ARS, Foreign Dis Weed Sci Res Unit, USDA, Ft Detrick, MD 21702 USA. [Leighty, Robert M.] Frederick Natl Lab Canc Res, Data Management Serv, Frederick, MD 21702 USA. RP Tooley, PW (reprint author), ARS, Foreign Dis Weed Sci Res Unit, USDA, 1301 Ditto Ave, Ft Detrick, MD 21702 USA. EM paul.tooley@ars.usda.gov FU USDA Forest Service; Pacific Southwest Research Station FX We gratefully acknowledge the funding for this project provided by the USDA Forest Service, Pacific Southwest Research Station, and the technical assistance of Kristin Henderson. NR 44 TC 5 Z9 5 U1 1 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0931-1785 J9 J PHYTOPATHOL JI J. Phytopathol. PD SEP PY 2013 VL 161 IS 9 BP 595 EP 603 DI 10.1111/jph.12107 PG 9 WC Plant Sciences SC Plant Sciences GA 195NB UT WOS:000322708500001 ER PT J AU Khraiwesh, H Lopez-Dominguez, JA Lopez-Lluch, G Navas, P de Cabo, R Ramsey, JJ Villalba, JM Gonzalez-Reyes, JA AF Khraiwesh, Husam Lopez-Dominguez, Jose A. Lopez-Lluch, Guillermo Navas, Placido de Cabo, Rafael Ramsey, Jon J. Villalba, Jose M. Gonzalez-Reyes, Jose A. TI Alterations of Ultrastructural and Fission/Fusion Markers in Hepatocyte Mitochondria From Mice Following Calorie Restriction With Different Dietary Fats SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Calorie restriction; Dietary fat; Hepatocyte; Mice; Mitochondrial ultrastructure; Mitochondrial fission and fusion ID SKELETAL-MUSCLE MITOCHONDRIA; OXYGEN SPECIES PRODUCTION; RAT-LIVER MITOCHONDRIA; OXIDATIVE DNA-DAMAGE; PROTON LEAK; SHORT-TERM; PEROXIDE PRODUCTION; FISCHER-344 RATS; ACID-COMPOSITION; RHESUS-MONKEYS AB We analyzed ultrastructural changes and markers of fission/fusion in hepatocyte mitochondria from mice submitted to 40% calorie restriction (CR) for 6 months versus ad-libitum-fed controls. To study the effects of dietary fat under CR, animals were separated into three CR groups with soybean oil (also in controls), fish oil, and lard. CR induced differential changes in hepatocyte and mitochondrial size, in the volume fraction occupied by mitochondria, and in the number of mitochondria per hepatocyte. The number of cristae per mitochondrion was significantly higher in all CR groups compared with controls. Proteins related to mitochondrial fission (Fis1 and Drp1) increased with CR, but no changes were detected in proteins involved in mitochondrial fusion (Mfn1, Mfn2, and OPA1). Although many of these changes could be attributed to CR regardless of dietary fat, changing membrane lipid composition by different fat sources did modulate the effects of CR on hepatocyte mitochondria. C1 [Khraiwesh, Husam; Lopez-Dominguez, Jose A.; Villalba, Jose M.; Gonzalez-Reyes, Jose A.] Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Cordoba 14014, Spain. [Lopez-Lluch, Guillermo; Navas, Placido] Univ Pablo Olavide, Ctr Andaluz Biol Desarrollo, Inst Salud Carlos III, CSIC,CIBERER, Seville, Spain. [de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Ramsey, Jon J.] Univ Calif Davis, VM Mol Biosci, Davis, CA 95616 USA. RP Gonzalez-Reyes, JA (reprint author), Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Campus Rabanales,Edificio Severo Ochoa,3A Planta, Cordoba 14014, Spain. EM bc1gorej@uco.es RI Gonzalez-Reyes, Jose A/K-1367-2014; Lopez-Lluch, Guillermo/N-4742-2014; de Cabo, Rafael/J-5230-2016; OI Gonzalez-Reyes, Jose A/0000-0003-1918-5490; Lopez-Lluch, Guillermo/0000-0001-9830-8502; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIH [1R01AG028125-01A1]; Ministerio de Economia y Competitividad [BFU2011-23578]; Junta de Andalucia Proyectos de Excelencia [P09-CVI-4887]; Junta de Andalucia Proyectos Internacionales; Junta de Andalucia [BIO-276]; University of Cordoba [BIO-276]; Agencia Espanola de Cooperacion Internacional al Desarrollo; Spanish Ministerio de Educacion FX This work was supported by NIH grant 1R01AG028125-01A1 (to J.J.R., P.N., and J.M.V.), Ministerio de Economia y Competitividad BFU2011-23578 (to J.M.V.), Junta de Andalucia Proyectos de Excelencia grant P09-CVI-4887 (to J.M.V.), Junta de Andalucia Proyectos Internacionales grant (to J.M.V.), and BIO-276 (Junta de Andalucia and the University of Cordoba, to J.M.V.). H. K. was funded by a predoctoral fellowship of the Agencia Espanola de Cooperacion Internacional al Desarrollo and BIO-276. J.A.L.D. was funded by a predoctoral fellowship of the Spanish Ministerio de Educacion and BIO-276. NR 61 TC 14 Z9 14 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD SEP PY 2013 VL 68 IS 9 BP 1023 EP 1034 DI 10.1093/gerona/glt006 PG 12 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 198HL UT WOS:000322913000005 PM 23403066 ER PT J AU Gharib, AM Zahiri, H Matta, J Pettigrew, RI Abd-Elmoniem, KZ AF Gharib, Ahmed M. Zahiri, Homeira Matta, Jatin Pettigrew, Roderic I. Abd-Elmoniem, Khaled Z. TI Feasibility of coronary artery wall thickening assessment in asymptomatic coronary artery disease using phase-sensitive dual-inversion recovery MRI at 3 T SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Atherosclerosis; Coronary artery imaging; Vessel wall; Black blood MRI; Phase sensitive; Dual-inversion recovery; 3 T ID MAGNETIC-RESONANCE ANGIOGRAPHY; VESSEL-WALL; NAVIGATOR CORRECTION; COMPUTED-TOMOGRAPHY; INITIAL-EXPERIENCE; SPATIAL-RESOLUTION; MOTION CORRECTION; IMAGE QUALITY; ATHEROSCLEROSIS; TESLA AB Objectives: The purpose of this study was to (a) investigate the image quality of phase-sensitive dual-inversion recovery (PS-DIR) coronary wall imaging in healthy subjects and in subjects with known coronary artery disease (CAD) and to (b) investigate the utilization of PS-DIR at 3 T in the assessment of coronary artery thickening in subjects with asymptomatic but variable degrees of CAD. Materials and Methods: A total of 37 subjects participated in this institutional review board-approved and HIPAA-compliant study. These included 21 subjects with known CAD as identified on multidetector computed tomography angiography (MDCT). Sixteen healthy subjects without known history of CAD were included. All subjects were scanned using free-breathing PS-DIR magnetic resonance imaging (MRI) for the assessment of coronary wall thickness at 3 T. Lumen-tissue contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR) and quantitative vessel parameters including lumen area and wall thickness were measured. Statistical analyses were performed. Results: PS-DIR was successfully completed in 76% of patients and in 88% of the healthy subjects. Phase-sensitive signed-magnitude reconstruction, compared to modulus-magnitude images, significantly improved lumen-tissue CNR in healthy subjects (26.73 +/- 11.95 vs. 14.65 +/- 9.57, P < .001) and in patients (21.45 +/- 7.61 vs. 16.65 +/- 5.85, P < .001). There was no difference in image CNR and SNR between groups. In arterial segments free of plaques, coronary wall was thicker in patients in comparison to healthy subjects (1.74 +/- 0.27 mm vs. 1.17 +/- 0.14 mm, P < .001), without a change in lumen area (4.51 +/- 2.42 mm(2) vs. 5.71 +/- 3.11 mm(2), P = .25). Conclusions: This is the first study to demonstrate the feasibility of successfully obtaining vessel wall images at 3 T using PS-DIR in asymptomatic patients with known variable degrees of CAD as detected by MDCT. This was achieved with a fixed subject-invariant planning of blood signal nulling. With that limitation alleviated, PS-DIR coronary wall MRI is capable of detecting arterial thickening and positive arterial remodeling at 3 T in asymptomatic CAD. Published by Elsevier Inc. C1 [Gharib, Ahmed M.; Matta, Jatin; Abd-Elmoniem, Khaled Z.] Natl Inst Diabet & Digest & Kidney Dis, Biomed & Metab Imaging Branch, NIH, Bethesda, MD USA. [Zahiri, Homeira] NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Pettigrew, Roderic I.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Abd-Elmoniem, KZ (reprint author), NIH, Clin Res Ctr, Bldg 10, Bethesda, MD 20892 USA. EM abdelmoniemkz@mail.nih.gov RI Gharib, Ahmed/O-2629-2016; Abd-Elmoniem, Khaled/B-9289-2008 OI Gharib, Ahmed/0000-0002-2476-481X; Abd-Elmoniem, Khaled/0000-0002-1001-1702 FU Intramural NIH HHS [Z99 DK999999] NR 49 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD SEP PY 2013 VL 31 IS 7 BP 1051 EP 1058 DI 10.1016/j.mri.2013.03.011 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 198TG UT WOS:000322944600003 PM 23642801 ER PT J AU Dabire, KR Sawadodgo, S Diabate, A Toe, KH Kengne, P Ouari, A Costantini, C Gouagna, C Simard, F Baldet, T Lehmann, T Gibson, G AF Dabire, K. R. Sawadodgo, S. Diabate, A. Toe, K. H. Kengne, P. Ouari, A. Costantini, C. Gouagna, C. Simard, F. Baldet, T. Lehmann, T. Gibson, G. TI Assortative mating in mixed swarms of the mosquito Anopheles gambiae s.s. M and S molecular forms, in Burkina Faso, West Africa SO MEDICAL AND VETERINARY ENTOMOLOGY LA English DT Article DE Anopheles gambiae s.s.; assortative mating; mate recognition; mating behaviour; mixed swarm; molecular forms; Burkina Faso ID INSECTICIDE RESISTANCE; MALARIA TRANSMISSION; TRANSGENIC MOSQUITOS; INCIPIENT SPECIATION; TRANSFERRED SPERM; DNA ANALYSIS; CULICIDAE; DIPTERA; BEHAVIOR; COMPLEX AB The molecular form composition of Anopheles gambiae Giles s.s. (Diptera: Culicidae) mating swarms and the associated mating pairs (copulae) were investigated during two rainy seasons (July to October, 2005 and July to November, 2006) in the villages of Soumousso and Vallee du Kou (VK7). Although the habitats of these villages differ markedly, sympatric populations of M and S molecular forms of An. gambiae s.s. occur in both places periodically. The main aim was to assess the degree to which these molecular forms mate assortatively. In Soumousso, a wooded savannah habitat, the majority of swarm samples consisted of only S-form males (21/28), although a few M-form males were found in mixed M- and S-form swarms. In VK7, a rice growing area, the majority of swarm samples consisted of only M-form males (38/62), until October and November 2006, when there were nearly as many mixed-form as single-form swarms. Overall, approximate to 60% of M- and S-form swarms were temporally or spatially segregated; the two forms were effectively prevented from encountering each other. Of the remaining 40% of swarms, however, only about half were single-form and the rest were mixed-form. Of the 33 copulae collected from mixed-form swarms, only four were mixed-form pairs, significantly fewer than expected by random pairing between forms ((2) = 10.34, d.f. = 2, P < 0.01). Finally, all specimens of inseminated females were of the same form as the sperm contained within their spermatheca (n = 91), even for the four mixed-form copulae. These findings indicate that assortative mating occurs within mixed-form swarms, mediated most probably by close-range mate recognition cues. C1 [Dabire, K. R.; Sawadodgo, S.; Diabate, A.; Toe, K. H.; Ouari, A.] IRSS, Bobo Dioulasso, West Africa, Burkina Faso. [Kengne, P.; Costantini, C.; Gouagna, C.; Simard, F.] Univ Montpellier 2, Univ Montpellier 1, IRD, MIVEGEC, Montpellier, France. [Baldet, T.] Ctr Rech Entomol Cotonou, Ctr Cooperat Int Rech Agron Dev, IRD, Cotonou, Benin. [Lehmann, T.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Gibson, G.] Univ Greenwich Medway, Nat Resources Inst, Dept Agr Hlth & Environm, Chatham, Kent, England. RP Dabire, KR (reprint author), IRSS Ctr Muraz, BP 390, Bobo Dioulasso, West Africa, Burkina Faso. EM dabire_roch@hotmail.com RI SIMARD, Frederic/J-9489-2016 OI SIMARD, Frederic/0000-0002-2871-5329 FU Multilateral Initiative on Malaria (MIM) Project through UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) [A60098]; TDR Programme [A50299] FX This study was financially supported by the Multilateral Initiative on Malaria (MIM) Project A60098 through the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) and by a grant from the TDR Programme to G.G. (A50299). The authors are grateful to the populations of Soumousso and Vallee du Kou who made this study possible. We thank Stephen Young (NRI) for assistance with statistical analyses and Jeremi Rouamba (IRSS) for the maps of VK7 and Soumousso. NR 45 TC 20 Z9 20 U1 1 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-283X J9 MED VET ENTOMOL JI Med. Vet. Entomol. PD SEP PY 2013 VL 27 IS 3 BP 298 EP 312 DI 10.1111/j.1365-2915.2012.01049.x PG 15 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 199KC UT WOS:000322992400007 PM 23360106 ER PT J AU Xu, LY Panel, V Ma, XR Du, C Hugendubler, L Gavrilova, O Liu, A McLaughlin, T Kaestner, KH Muellera, E AF Xu, Lingyan Panel, Valentine Ma, Xinran Du, Chen Hugendubler, Lynne Gavrilova, Oksana Liu, Alice McLaughlin, Tracey Kaestner, Klaus H. Muellera, Elisabetta TI The Winged Helix Transcription Factor Foxa3 Regulates Adipocyte Differentiation and Depot-Selective Fat Tissue Expansion SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEAR FACTOR 3-GAMMA; ADIPOSE-TISSUE; HEPATOCYTE; METABOLISM; GENES AB Conversion of mesenchymal stem cells into terminally differentiated adipocytes progresses sequentially through regulated transcriptional steps. While it is clear that the late phases of adipocyte maturation are governed by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma), less is known about the transcriptional control of the initial stages of differentiation. To identify early regulators, we performed a small interfering RNA (siRNA) screen of Forkhead-box genes in adipocytes and show here for the first time that the winged helix factor Foxa3 promotes adipocyte differentiation by cooperating with C/EBP beta and -delta to transcriptionally induce PPAR gamma expression. Furthermore, we demonstrate that mice with genetic ablation of Foxa3 have a selective decrease in epididymal fat depot and a cell-autonomous defect to induce PPAR gamma specifically in their visceral adipocytes. In obese subjects, FOXA3 is differentially expressed in visceral and subcutaneous adipose depots. Overall, our study implicates Foxa3 in the regulation of adipocyte differentiation and depot-selective adipose tissue expansion. C1 [Xu, Lingyan; Panel, Valentine; Ma, Xinran; Du, Chen; Hugendubler, Lynne; Muellera, Elisabetta] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD USA. [Liu, Alice; McLaughlin, Tracey] Stanford Univ, Med Ctr, Dept Med, Div Endocrinol, Stanford, CA 94305 USA. [Kaestner, Klaus H.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Kaestner, Klaus H.] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. RP Muellera, E (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. EM elisabettam@niddk.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; [P01-DK049210] FX This research was supported by P01-DK049210 (to K.H.K.) and by the Intramural Research Program of the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases (to E.M.). NR 18 TC 10 Z9 10 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2013 VL 33 IS 17 BP 3392 EP 3399 DI 10.1128/MCB.00244-13 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 196ZY UT WOS:000322817600001 PM 23798556 ER PT J AU Wang, TTY Schoene, NW Kim, EK Kim, YS AF Wang, Thomas T. Y. Schoene, Norberta W. Kim, Eun-Kyung Kim, Young S. TI Pleiotropic effects of the sirtuin inhibitor sirtinol involves concentration-dependent modulation of multiple nuclear receptor-mediated pathways in androgen-responsive prostate cancer cell LNCaP SO MOLECULAR CARCINOGENESIS LA English DT Article DE androgen; estrogen; insulin-like growth factor-1; xenobiotic metabolism; sirtinol; sirtuin ID SACCHAROMYCES-CEREVISIAE; CYCLE ARREST; SIR2; P21(WAF1/CIP1); IDENTIFICATION; DEACETYLASES; RESVERATROL; PROGRESSION; ACTIVATION; SENESCENCE AB Sirtinol is a purported specific inhibitor of the nicotinamide adenine dinucleotide (NAD)-dependent type III histone deacetylase (also known as sirtuin). Sirtinol has been used extensively to identify chemopreventive/chemotherapeutic agents that modulate the sirtuins. However, the molecular effect of sirtinol other than serving as sirtuin inhibitor in cells is less clear. The present study addressed this deficiency in the literature. Based on structural similarity with plant-derived cancer preventive/therapeutic compounds such as 3', 3'-diindolylmethane, resveratrol, and genistein, we hypothesized that sirtinol may act on pathways similar to that affected by these compounds in the human prostate cancer cell LNCaP. We found that treatment of LNCaP cells with sirtinol led to concentration-dependent effects on multiple pathways. Sirtinol inhibited LNCaP cell cycle and growth that was correlated with up-regulation of cyclin-dependent kinase inhibitor 1A mRNA and protein levels. This effect of sirtinol may due in part to modulation of androgen, estrogen, and insulin-like growth factor-1 mediated pathways as sirtinol treatment led to inhibition of mRNA and protein expression of marker genes involved in these pathways. We also found sirtinol activates aryl hydrocarbon-dependent pathways in LNCaP cells. The effects of sirtinol were observed at 25 mu M, a concentration lower than Ki (38 mu M) for sirtuin activity. Based on these results we reasoned that sirtinol exerts pleiotropic effects in cells and that biological effects of sirtinol may not be due solely to inhibition of sirtuin. (c) 2012 Wiley Periodicals, Inc. C1 [Wang, Thomas T. Y.; Schoene, Norberta W.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Kim, Eun-Kyung; Kim, Young S.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Wang, TTY (reprint author), ARS, Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, 10300 Baltimore Ave,Bldg 307C,Room 132, Beltsville, MD 20705 USA. FU National Cancer Institute; [1235-51530-053-00D] FX We would like to thank Drs. Allison Yates and Joseph Urban for reviewing this manuscript. This work was supported by US appropriated funds to USDA project number 1235-51530-053-00D (TTYW, NWS) and the National Cancer Institute (E-KK, YSK). NR 30 TC 8 Z9 9 U1 3 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2013 VL 52 IS 9 BP 676 EP 685 DI 10.1002/mc.21906 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 198FZ UT WOS:000322908900002 PM 22495798 ER PT J AU Zhang, Q Pan, J Wang, Y Lubet, R You, M AF Zhang, Qi Pan, Jing Wang, Yian Lubet, Ronald You, Ming TI Beetroot red (betanin) inhibits vinyl carbamate- and benzo(a)pyrene-induced lung tumorigenesis through apoptosis SO MOLECULAR CARCINOGENESIS LA English DT Article DE betanin; vinyl carbamate; benzo(a)pyrene; CD31; caspase-3; PARP ID A/J MICE; CANCER CHEMOPREVENTION; EXTRACT; CARCINOGENESIS; TUMORS; ANTIOXIDANTS; PROGRESSION; ADRIAMYCIN; CASPASES; EFFICACY AB Betanin, also called beetroot red, has been extensively used as a food colorant. In this study, the chemopreventive activity of betanin by oral consumption was investigated in two mouse lung tumor models. Vinyl carbamate (VC) and benzo(a)pyrene (B(a)P) were used to induce lung tumors, and female A/J mice were treated with betanin in drinking water. Betanin significantly decreased tumor multiplicity and tumor load induced by both carcinogens. Tumor multiplicity and tumor load were decreased by 20% and 39% in the VC lung model, and by 46% and 65% in the B(a)P lung model, respectively. Betanin reduced the number of CD31+ endothelial microvessels and increased the expression of caspase-3, suggesting that the lung tumor inhibitory effects were through induction of apoptosis and inhibition of angiogenesis. Betanin also induced apoptosis through activated caspase-3, -7, -9, and PARP in human lung cancer cell lines. Our data show that betanin significantly inhibits lung tumorigenesis in A/J mice and merits investigation as a chemopreventive agent for human lung cancer. (c) 2012 Wiley Periodicals, Inc. C1 [Zhang, Qi; Pan, Jing; Wang, Yian; You, Ming] Washington Univ, Dept Surg, Sch Med, St Louis, MO 63110 USA. [Lubet, Ronald] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Dept Surg, Campus Box 8109,660 South Euclid Ave, St Louis, MO 63110 USA. NR 23 TC 6 Z9 8 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2013 VL 52 IS 9 BP 686 EP 691 DI 10.1002/mc.21907 PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 198FZ UT WOS:000322908900003 PM 22456940 ER PT J AU Hall, JM Korach, KS AF Hall, Julie M. Korach, Kenneth S. TI Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis SO MOLECULAR CARCINOGENESIS LA English DT Article DE endocrine disrupting chemicals (EDCs); ovarian cancer; estrogen receptor; cell proliferation; CXCL12; CXCR4 ID ESTROGEN-RECEPTOR-ALPHA; GENOME-WIDE ANALYSIS; BREAST-CANCER; GENE-EXPRESSION; CHEMOKINE CXCL12; BISPHENOL-A; ACTIVATION; MECHANISMS; GENISTEIN; CARCINOMA AB The majority of ovarian cancers over-express the estrogen receptor (ER) and grow in response to estrogens. We previously demonstrated that ER induction of the chemokine CXCL12 (stromal cell-derived factor-1) is required for estradiol (E2)-stimulated proliferation of human ovarian carcinoma cells. In the current study, we report that known endocrine disrupting chemicals (EDCs) display mitogenic activities in ovarian cancer cells via their ability to activate the ER and upregulate CXCL12 expression. Notably, the EDCs genistein, bisphenol A and HPTE stimulated both cell proliferation and induction of CXCL12 mRNA and protein in a manner comparable to estradiol. The effects were completely attenuated by the ER antagonist ICI 182,780, revealing that observed activities of these agents were receptor-mediated. In cell proliferation assays, the mitogenic effects of estradiol and EDCs were obviated by siRNAs targeting CXCL12 and restored upon addition of exogenous CXCL12. Furthermore, an inhibitor to the CXCL12 receptor CXCR4 completely attenuated growth-stimulatory effects of E2 and EDCs. These studies highlight a potential role of EDCs possessing estrogenic activities in the etiology of ovarian cancer. Moreover, they suggest that the ER-CXCL12-CXCR4 signaling axis may represent a promising target for development of therapeutics for ER+ ovarian cancers. (c) 2012 Wiley Periodicals, Inc. C1 [Hall, Julie M.] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, JM (reprint author), Campbell Univ, Coll Pharm & Hlth Sci, POB 1090, Buies Creek, NC 27506 USA. OI Korach, Kenneth/0000-0002-7765-418X FU Division of Intramural Research, National Institutes of Environmental Health Sciences, National Institutes of Health [Z01ES70065] FX This work was supported by the Division of Intramural Research, National Institutes of Environmental Health Sciences, National Institutes of Health to KSK (Z01ES70065). NR 49 TC 16 Z9 16 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2013 VL 52 IS 9 BP 715 EP 725 DI 10.1002/mc.21913 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 198FZ UT WOS:000322908900006 PM 22549810 ER PT J AU Fukuda, Y Takenaka, K Sparreboom, A Cheepala, SB Wu, CP Ekins, S Ambudkar, SV Schuetz, JD AF Fukuda, Yu Takenaka, Kazumasa Sparreboom, Alex Cheepala, Satish B. Wu, Chung-Pu Ekins, Sean Ambudkar, Suresh V. Schuetz, John D. TI Human Immunodeficiency Virus Protease Inhibitors Interact with ATP Binding Cassette Transporter 4/Multidrug Resistance Protein 4: A Basis for Unanticipated Enhanced Cytotoxicity SO MOLECULAR PHARMACOLOGY LA English DT Article ID MRP4 CONFERS RESISTANCE; HIV-INFECTED PATIENTS; MULTIDRUG-RESISTANCE; BREAST-CANCER; IN-VITRO; EFFLUX TRANSPORTER; ABC TRANSPORTERS; ANTIVIRAL DRUGS; P-GLYCOPROTEIN; CELL-LINES AB Human immunodeficiency virus (HIV) pharmacotherapy, by combining different drug classes such as nucleoside analogs and HIV protease inhibitors (PIs), has increased HIV-patient life expectancy. Consequently, among these patients, an increase in non-HIV-associated cancers has produced a patient cohort requiring both HIV and cancer chemotherapy. We hypothesized that multidrug resistance protein 4/ATP binding cassette transporter 4 (MRP4/ABCC4), a widely expressed transporter of nucleoside-based antiviral medications as well as cancer therapeutics might interact with PIs. Among the PIs evaluated (nelfinavir, ritonavir, amprenavir, saquinavir, and indinavir), only nelfinavir both effectively stimulated MRP4 ATPase activity and inhibited substrate-stimulated ATPase activity. Saos2 and human embryonic kidney 293 cells engineered to overexpress MRP4 were then used to assess transport and cytotoxicity. MRP4 expression reduced intracellular accumulation of nelfinavir and consequently conferred survival advantage to nelfinavir cytotoxicity. Nelfinavir blocked Mrp4-mediated export, which is consistent with its ability to increase the sensitivity of MRP4-expressing cells to methotrexate. In contrast, targeted inactivation of Abcc4/Mrp4 in mouse cells specifically enhanced nelfinavir and 9-(2-phosphonylmethoxyethyl) adenine cytotoxicity. These results suggest that nelfinavir is both an inhibitor and substrate of MRP4. Because nelfinavir is a new MRP4/ABCC4 substrate, we developed a MRP4/ABCC4 pharmacophore model, which showed that the nelfinavir binding site is shared with chemotherapeutic substrates such as adefovir and methotrexate. Our studies reveal, for the first time, that nelfinavir, a potent and cytotoxic PI, is both a substrate and inhibitor of MRP4. These findings suggest that HIV-infected cancer patients receiving nelfinavir might experience both enhanced antitumor efficacy and unexpected adverse toxicity given the role of MRP4/ABCC4 in exporting nucleoside-based antiretroviral medications and cancer chemotherapeutics. C1 [Fukuda, Yu; Takenaka, Kazumasa; Sparreboom, Alex; Cheepala, Satish B.; Schuetz, John D.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Wu, Chung-Pu; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ekins, Sean] Collaborat Chem, Fuquay Varina, NC USA. RP Schuetz, JD (reprint author), St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 262 Danny Thomas Pl,MS 313, Memphis, TN 38105 USA. EM John.Schuetz@stjude.org FU ALSAC; National Institutes of Health National Institute of General Medical Science [2R01-GM60904]; National Institutes of Health National Cancer Institute [P30-CA21745, P30-CA21865, P30-CA021765]; Intramural Research Program of the National Institutes of Health [National Cancer Institute Center for Cancer Research] FX This work was supported by ALSAC; the National Institutes of Health National Institute of General Medical Science [Grant 2R01-GM60904]; and the National Institutes of Health National Cancer Institute [Grants P30-CA21745, P30-CA21865, and P30-CA021765]. C.-P. W. and S. V. A. were supported by the Intramural Research Program of the National Institutes of Health [National Cancer Institute Center for Cancer Research]. S. E. is an employee of Collaborations in Chemistry and consults for Collaborative Drug Discovery Inc., as well as companies in the pharmaceutical industry, and has no conflicts of interest with this work. NR 50 TC 16 Z9 16 U1 1 U2 13 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2013 VL 84 IS 3 BP 361 EP 371 DI 10.1124/mol.113.086967 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 200BQ UT WOS:000323041900007 PM 23775562 ER PT J AU Arroyo, ECJ Arroyo, J AF Cabib, Enrico Arroyo, Javier TI How carbohydrates sculpt cells: chemical control of morphogenesis in the yeast cell wall SO NATURE REVIEWS MICROBIOLOGY LA English DT Article ID MOTHER-BUD NECK; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; GROWTH-CONTROL; CHITIN; PROTEINS; CYTOKINESIS; RING; BIOSYNTHESIS; ARCHITECTURE AB In budding yeast, the neck that connects the mother and daughter cell is the site of essential functions such as organelle trafficking, septum formation and cytokinesis. Therefore, the morphology of this region, which depends on the surrounding cell wall, must be maintained throughout the cell cycle. Growth at the neck is prevented, redundantly, by a septin ring inside the cell membrane and a chitin ring in the cell wall. Here, we describe recent work supporting the hypothesis that attachment of the chitin ring, which forms at the mother-bud neck during budding, to beta-1,3-glucan in the cell wall is necessary to stop growth at the neck. Thus, in this scenario, chemistry controls morphogenesis. C1 [Cabib, Enrico] NIDDK, Lab Biochem & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Arroyo, Javier] Univ Complutense Madrid, Fac Farm, Dept Microbiol 2, E-28040 Madrid, Spain. [Arroyo, Javier] Inst Ramon y Cajal Invest Sanitarias, Madrid 28040, Spain. RP Arroyo, ECJ (reprint author), NIDDK, Lab Biochem & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM enricoc@bdg10.niddk.nih.gov RI Arroyo, Javier/E-9308-2016 OI Arroyo, Javier/0000-0002-1971-1721 FU US National Institutes of Health grant (as part of the Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases); Spanish Government Ministry of Economy and Competitiveness [BIO2010-22146]; Universidad Complutense de Madrid [GR58/08]; Comunidad de Madrid [S2010/BDM-2414]; European Science Foundation [06-RNP-132] FX The authors thank V. Cid, O. Cohen-Fix, P. Perez, M. Reidy and C. Vazquez de Aldana for critical reading of the manuscript, and R. Garcia for help with the figures. E. C. was supported by a US National Institutes of Health grant (as part of the Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases). J.A. acknowledges all the members of his laboratory for their dedicated work, and C. Nombela and the Special Chair in Genomics and Proteomics for their support. Research in the J.A. laboratory is supported by the Spanish Government Ministry of Economy and Competitiveness (grant BIO2010-22146), the Universidad Complutense de Madrid (grant GR58/08), the Comunidad de Madrid (grant S2010/BDM-2414) and the European Science Foundation (grant 06-RNP-132). NR 66 TC 0 Z9 0 U1 5 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 EI 1740-1534 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD SEP PY 2013 VL 11 IS 9 BP 648 EP 655 DI 10.1038/nrmicro3090 PG 8 WC Microbiology SC Microbiology GA 202HU UT WOS:000323205500013 ER PT J AU Ananth, CV Wilcox, AJ Gyamfi-Bannerman, C AF Ananth, Cande V. Wilcox, Allen J. Gyamfi-Bannerman, Cynthia TI Obstetrical Interventions for Term First Deliveries in the US SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE obstetrical interventions; elective deliveries; caesarean delivery; labour induction ID UNITED-STATES; NEONATAL-MORTALITY; CESAREAN DELIVERY; VAGINAL BIRTHS; PRETERM BIRTH; OUTCOMES; RATES; RISK; SECTION; INFANT AB Background: Labour induction and caesarean are increasingly done without clinical indication. However, little is known about the prevalence of such interventions, or the characteristics of women who receive them. We used the 2003 revision of the US birth certificates to summarise recorded interventions and to characterise maternal profiles associated with such interventions. Methods: We carried out a retrospective study of 2.35 million primiparous women delivering singleton live births at 37-44 weeks in the US from 2005 to 2008. We used the 2003 revision of the birth certificate to define delivery categories: 'indicated' were those with induced labour or pre-labour caesarean for hypertension, diabetes, chorioamnionitis, failed cephalic version at >= 40 weeks, growth restriction (<3rd centile), or post-term (>= 42 weeks); those with pre-labour caesarean with breech at >= 39 weeks; or those with caesarean with labour lasting >= 12h, failed trial of labour, vacuum/forceps extraction, or fetal intolerance to labour. Remaining deliveries with induction/caesarean were classified as non-indicated' and all other deliveries 'spontaneous'. Results: Half of all term first births (50%) were delivered after intervention, and half of interventions were non-indicated (26% of all deliveries). Women with interventions were more likely to deliver on a weekday. Non-indicated interventions were more common among socially advantaged women. Conclusions: Nearly a quarter of US term first deliveries had an indicated intervention, and another quarter received intervention without a recorded clinical indication. Both numbers are probably underestimates. C1 [Ananth, Cande V.; Gyamfi-Bannerman, Cynthia] Columbia Univ, Dept Obstet & Gynecol, Med Ctr, New York, NY 10032 USA. [Ananth, Cande V.] Columbia Univ, Dept Epidemiol, Joseph L Mailman Sch Publ Hlth, New York, NY 10032 USA. [Wilcox, Allen J.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Ananth, CV (reprint author), Columbia Univ, Coll Phys & Surg, Dept Obstet & Gynecol, Med Ctr, 622 W 168th St, New York, NY 10032 USA. EM cande.ananth@columbia.edu OI Wilcox, Allen/0000-0002-3376-1311 FU NIH, National Institute of Environmental Health Sciences FX Allen Wilcox's work is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 23 TC 7 Z9 7 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2013 VL 27 IS 5 BP 442 EP 451 DI 10.1111/ppe.12068 PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 198IA UT WOS:000322914700003 PM 23930780 ER PT J AU Schisterman, EF Cole, SR Ye, AJ Platt, RW AF Schisterman, Enrique F. Cole, Stephen R. Ye, Aijun Platt, Robert W. TI Accuracy Loss Due to Selection Bias in Cohort Studies with Left Truncation SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Selection bias; fixed left truncation; variable left truncation ID SPONTANEOUS-ABORTION; SURVIVAL ANALYSIS; PROBABILITY; MODELS; AGE AB Background: Selection is a common problem in paediatric and perinatal epidemiology, and truncation can be thought of as missing person time that can result in selection bias. Left truncation, also known as late or staggered entry, may induce selection bias and/or adversely affect precision. There are two kinds of left truncation: fixed left truncation where the start of follow-up is initiated at a set time, and variable left truncation where follow-up begins at a stochastically varying time-point. Methods: Using data from a time-to-pregnancy study, augmented by a simulation study, we demonstrate the effects of fixed and variable truncation on estimates of the hazard ratio. Results: First, fixed or variable non-differential left truncation results in a loss of precision. Fixed or variable differential left truncation results in a bias either towards or away from the null as well as a loss of precision. The extent and direction of this bias is a function of the size and direction of the association between exposure and outcome, and occurs in common scenarios and under a wide range of conditions. Conclusions: As demonstrated in simulation studies, selection bias due to left truncation could have a serious impact on inferences, especially in the case of fixed or variable differential left truncation. When present in epidemiologic studies, proper accounting for left truncation is just as important as proper accounting for right censoring. C1 [Schisterman, Enrique F.; Ye, Aijun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20854 USA. [Cole, Stephen R.] UNC Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Platt, Robert W.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Platt, Robert W.] McGill Univ, Dept Pediat, Montreal, PQ H3A 2T5, Canada. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Executive Blvd,7B03, Rockville, MD 20854 USA. EM schistee@mail.nih.gov OI Platt, Robert/0000-0002-5981-8443; Schisterman, Enrique/0000-0003-3757-641X NR 30 TC 17 Z9 17 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2013 VL 27 IS 5 BP 491 EP 502 DI 10.1111/ppe.12073 PG 12 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 198IA UT WOS:000322914700008 PM 23930785 ER PT J AU Ahrens, K Schisterman, E AF Ahrens, Katherine Schisterman, Enrique TI Untitled SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Letter C1 [Ahrens, Katherine; Schisterman, Enrique] NICHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20892 USA. RP Ahrens, K (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, 6100 Bldg,Room 7B05, Rockville, MD 20892 USA. EM katherine.ahrens@nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2013 VL 27 IS 5 BP 503 EP 503 DI 10.1111/ppe.12065 PG 1 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 198IA UT WOS:000322914700009 PM 23930786 ER PT J AU Schug, TT Heindel, JJ Camacho, L Delclos, KB Howard, P Johnson, AF Aungst, J Keefe, D Newbold, R Walker, NJ Zoeller, RT Bucher, JR AF Schug, Thaddeus T. Heindel, Jerrold J. Camacho, Luisa Delclos, K. Barry Howard, Paul Johnson, Anne F. Aungst, Jason Keefe, Dennis Newbold, Retha Walker, Nigel J. Zoeller, R. Thomas Bucher, John R. TI A new approach to synergize academic and guideline-compliant research: The CLARITY-BPA research program SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE Bisphenol A; NIEHS; FDA; NTP; Consortium-based research; Low dose ID BISPHENOL-A AB Recently, medical research has seen a strong push toward translational research, or "bench to bedside" collaborations, that strive to enhance the utility of laboratory science for improving medical treatment. The success of that paradigm supports the potential application of the process to other fields, such as risk assessment. Close collaboration among academic, government, and industry scientists may enhance the translation of scientific findings to regulatory decision making. The National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively academic and guideline-compliant research. An initial proof-of-concept collaboration, the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), uses bisphenol A (BPA) as a test chemical. The CLARITY-BPA program combines a core perinatal guideline-compliant 2-year chronic toxicity study with mechanistic studies/endpoints conducted by academic investigators. Twelve extramural grantees were selected by NIEHS through an RFA-based initiative to participate in the overall study design and conduct disease-relevant investigations using tissues and animals from the core study. While the study is expected to contribute to our understanding of potential effects of BPA, it also has ramifications beyond this specific focus. Through CLARITY-BPA, NIEHS has established an unprecedented level of collaboration among extramural grantees and regulatory researchers. By drawing upon the strengths of academic and regulatory expertise and research approaches, CLARITY-BPA represents a potential new model for filling knowledge gaps, enhancing quality control, informing chemical risk assessment, and identifying new methods or endpoints for regulatory hazard assessments. Published by Elsevier Inc. C1 [Schug, Thaddeus T.; Heindel, Jerrold J.] NIEHS, NIH, Div Extramural Res, Res Triangle Pk, NC 27709 USA. [Camacho, Luisa; Delclos, K. Barry] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Howard, Paul] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Johnson, Anne F.] MDB Inc, Durham, NC 27713 USA. [Aungst, Jason; Keefe, Dennis] US FDA, Off Food Addit Safety, College Pk, MD 20740 USA. [Newbold, Retha; Walker, Nigel J.; Bucher, John R.] NIEHS, NIH, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Zoeller, R. Thomas] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. RP Schug, TT (reprint author), Div Extramural Res, 530 Davis Dr,Room 3041 Mail Drop K3-15, Morrisville, NC 27560 USA. EM Schugt@niehs.nih.gov RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU NIEHS [HHSN273201100086U] FX This article is the work product of a group that includes employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA); however, the statements, opinions, or conclusions contained herein do not necessarily represent the statements, opinions, or conclusions of FDA, NIEHS, NIH or the United States government. Anne Johnson is employed by MDB, Inc. under a contract to NIEHS (HHSN273201100086U). The authors declare they have no actual or potential competing financial interests. NR 18 TC 18 Z9 18 U1 1 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP PY 2013 VL 40 BP 35 EP 40 DI 10.1016/j.reprotox.2013.05.010 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 197KE UT WOS:000322849300005 PM 23747832 ER PT J AU Bhutani, D Zonder, J Valent, J Tageja, N Ayash, L Deol, A Al-Kadhimi, Z Abrams, J Lum, L Ratanatharathorn, V Uberti, J Abidi, MH AF Bhutani, Divaya Zonder, Jeffrey Valent, Jason Tageja, Nishant Ayash, Lois Deol, Abhinav Al-Kadhimi, Zaid Abrams, Judith Lum, Lawrence Ratanatharathorn, Voravit Uberti, Joseph Abidi, Muneer H. TI Evaluating the effects of lenalidomide induction therapy on peripheral stem cells collection in patients undergoing autologous stem cell transplant for multiple myeloma SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Lenalidomide; Multiple myeloma; Peripheral stem cells collection ID INITIAL THERAPY; MOBILIZATION; DEXAMETHASONE; ENGRAFTMENT; CHEMOTHERAPY; THALIDOMIDE; TRIAL AB Lenalidomide (LEN) is a relatively new and very effective therapy for multiple myeloma (MM). Prior LEN therapy is associated with an increased risk of peripheral blood stem cell collection (PBSC) failure, particularly with filgrastim (G-CSF) alone. We performed a retrospective chart review of 319 consecutive MM patients who underwent apheresis to collect PBSCs for the first autologous stem cell transplant (ASCT). The median number of PBSCs collected in the LEN (+) group was significantly less than the LEN (-) group (6.34 vs. 7.52 x 10(6) CD34(+) cells/kg; p = 0.0004). In addition, the median number of apheresis sessions required for adequate PBSCs collection were significantly more in the LEN (+) group as compared to LEN (-) group (2 vs. 1 sessions; p = 0.002). In the LEN (+) group, there was a negative correlation between PBSCs collected and prior number of cycles of LEN (p = 0.0001). Rate of PBSC collection failure was 9 % in the LEN (+) group and 5 % in the LEN (-) group (p = 0.16). Only six patients who failed PBSC collection with G-CSF were able to collect adequate PBSCs with G-CSF + plerixafor. LEN exposure had no effect on neutrophil or platelet recovery post-ASCT. Up to four cycles of LEN exposure have minimal negative impact on PBSC collection. Despite prolong exposure of LEN, PBSC collection was adequate for two ASCTs in the majority of patients and post-ASCT engraftment was not longer than expected; however, clinical relevance (complication rate, quality of life, cost) of prolonged LEN exposure on both PBSC and ASCT, should be evaluated in prospective clinical trials. C1 [Bhutani, Divaya; Zonder, Jeffrey; Ayash, Lois; Deol, Abhinav; Al-Kadhimi, Zaid; Abrams, Judith; Lum, Lawrence; Ratanatharathorn, Voravit; Uberti, Joseph; Abidi, Muneer H.] Karmanos Canc Inst, Dept Bone Marrow Transplantat, Detroit, MI 48201 USA. [Valent, Jason] Cleveland Clin, Cleveland, OH 44106 USA. [Bhutani, Divaya; Ayash, Lois; Deol, Abhinav; Al-Kadhimi, Zaid; Abrams, Judith; Lum, Lawrence; Ratanatharathorn, Voravit; Uberti, Joseph; Abidi, Muneer H.] Wayne State Univ, Detroit, MI USA. [Tageja, Nishant] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Abidi, MH (reprint author), Karmanos Canc Inst, Dept Bone Marrow Transplantat, 4100 John R,4 HWCRC,Rm 4257, Detroit, MI 48201 USA. EM abidim@karmanos.org OI Abidi, Muneer/0000-0002-9936-6031 FU NCI NIH HHS [P30 CA022453] NR 20 TC 1 Z9 1 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2013 VL 21 IS 9 BP 2437 EP 2442 DI 10.1007/s00520-013-1808-5 PG 6 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 194IY UT WOS:000322626600009 PM 23591714 ER PT J AU Waidyanatha, S Johnson, JD Hong, SP Robinson, VG Gibbs, S Graves, SW Hooth, MJ Smith, CS AF Waidyanatha, Suramya Johnson, Jerry D. Hong, S. Peter Robinson, Veronica Godfrey Gibbs, Seth Graves, Steven W. Hooth, Michelle J. Smith, Cynthia S. TI Toxicokinetics of alpha-thujone following intravenous and gavage administration of alpha-thujone or alpha- and beta-thujone mixture in male and female F344/N rats and B6C3F1 mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Thujone; Gavage; Toxicokinetics; Bioavailability; Rodents; Neurotoxicity ID ABSINTHE; MEDICINES; WORMWOOD; POISON; FOODS; SAGE AB Plants containing thujone have widespread use and hence have significant human exposure. alpha-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of alpha-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of alpha-thujone or a mixture of alpha- and beta-thujone (which will be referred to as alpha,beta-thujone). Absorption of alpha-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of alpha-thujone following administration of alpha-thujone or alpha,beta-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. C-max and AUC(infinity) increased greater than proportional to the dose in female rats following administration of alpha-thujone and in male and female mice following administration of alpha,beta-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC(infinity) for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of a-thujone and alpha,beta-thujone, respectively (p-value < 0.0001 for all comparisons). Following both intravenous and gavage administration, et-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of alpha-thujone and alpha,beta-thujone where females were more sensitive than males of both species to alpha-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to alpha-thujone concentration. Published by Elsevier Inc. C1 [Waidyanatha, Suramya; Robinson, Veronica Godfrey; Hooth, Michelle J.; Smith, Cynthia S.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Johnson, Jerry D.; Hong, S. Peter; Gibbs, Seth; Graves, Steven W.] Battelle Mem Inst, Columbus, OH 43201 USA. RP Waidyanatha, S (reprint author), NIEHS, Div Natl Toxicol Program, 111 Alexander Dr,POB 12233,MD K2-07, Res Triangle Pk, NC 27709 USA. EM waidyanathas@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services [N01-ES-55551] FX This study was conducted for the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services, under Contract No. N01-ES-55551. The authors are grateful to Drs Michael DeVito and Chad Blystone for their review of the manuscript. NR 26 TC 3 Z9 4 U1 3 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 1 PY 2013 VL 271 IS 2 BP 216 EP 228 DI 10.1016/j.taap.2013.05.001 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 200ST UT WOS:000323091900010 PM 23669748 ER PT J AU Glineur, SF Renshaw, RW Percopo, CM Dyer, KD Dubovi, EJ Domachowske, JB Rosenberg, HF AF Glineur, Stephanie F. Renshaw, Randall W. Percopo, Caroline M. Dyer, Kimberly D. Dubovi, Edward J. Domachowske, Joseph B. Rosenberg, Helene F. TI Novel pneumoviruses (PnVs): Evolution and inflammatory pathology SO VIROLOGY LA English DT Article DE Inflammation; Neutrophil; Type I interferon; Chemokine ID RESPIRATORY SYNCYTIAL VIRUS; MICE MUS-DOMESTICUS; PNEUMONIA VIRUS; NATURAL HOST; RAT COLONIES; SUBGROUP-A; INFECTION; MOUSE; PVM; IDENTIFICATION AB A previous report of a novel pneumovirus (PnV) isolated from the respiratory tract of a dog described its significant homology to the rodent pathogen, pneumonia virus of mice (PVM). The original PnV-Ane4 pathogen replicated in and could be re-isolated in infectious state from mouse lung but elicited minimal mortality compared to PVM strain J3666. Here we assess phylogeny and physiologic responses to 10 new PnV isolates. The G/glycoprotein sequences of all PnVs include elongated amino-termini when compared to the characterized PVMs, and suggest division into groups A and B. While we observed significant differences in cytokine production and neutrophil recruitment to the lungs of BALB/c mice in response to survival doses (50 TCID50 units) of representative group A (114378-10-29-KY-F) and group B (7968-11-OK) PnVs, we observed no evidence for positive selection (dN > dS) among the PnV/PnV, PVM/PnV or PVM/PVM G/glycoprotein or F/fusion protein sequence pairs. Published by Elsevier Inc. C1 [Glineur, Stephanie F.; Percopo, Caroline M.; Dyer, Kimberly D.; Rosenberg, Helene F.] NIAID, Natl Inst Hlth, Lab Allerg Dis, Inflammat Immunobiol Sect, Bethesda, MD 20892 USA. [Renshaw, Randall W.; Dubovi, Edward J.] Cornell Univ, Coll Vet Med, Anim Hlth Diagnost Ctr, Ithaca, NY 14851 USA. [Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. RP Rosenberg, HF (reprint author), NIAID, Natl Inst Hlth, Lab Allerg Dis, Inflammat Immunobiol Sect, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID Division of Intramural Research Project [AI000943]; Huynen Foundation (University of Liege, Belgium); Rotary Foundation; Rotary International FX The authors thank Ms. Melissa Laverack and Ms. Nancy Zylich, Animal Health Diagnostic Center, College of Veterinary Medicine, Cornell University, for research technical support. Work presented in this manuscript is supported by funds from the NIAID Division of Intramural Research Project #AI000943 to HFR. SG was an awardee of the Huynen Foundation (University of Liege, Belgium) and the Rotary Foundation, Rotary International. NR 34 TC 7 Z9 7 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2013 VL 443 IS 2 BP 257 EP 264 DI 10.1016/j.virol.2013.05.011 PG 8 WC Virology SC Virology GA 195FC UT WOS:000322686700009 PM 23763766 ER PT J AU Castillo, BS Nguyen, N Wahed, A Tholpady, A AF Castillo, Brian S. Nguyen, Nghia Wahed, Amer Tholpady, Ashok TI Monoclonal Gammopathy Causing Acquired Fanconi Syndrome in a Preterm Infant SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Castillo, Brian S.] UT Houston Med Sch, Houston, TX USA. [Nguyen, Nghia; Wahed, Amer] Univ Texas Houston, Houston, TX USA. [Tholpady, Ashok] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2013 VL 140 SU 1 MA 43 BP 43 EP 43 PG 1 WC Pathology SC Pathology GA V40HA UT WOS:000209468500044 ER PT J AU Coakley, MF Leerkes, MR Barnett, J Gabrielian, AE Noble, K Weber, MN Huyen, Y AF Coakley, Meghan F. Leerkes, Maarten R. Barnett, Jason Gabrielian, Andrei E. Noble, Karlynn Weber, M. Nick Huyen, Yentram TI UNLOCKING THE POWER OF BIG DATA AT THE NATIONAL INSTITUTES OF HEALTH SO BIG DATA LA English DT Article AB The era of "big data'' presents immense opportunities for scientific discovery and technological progress, with the potential to have enormous impact on research and development in the public sector. In order to capitalize on these benefits, there are significant challenges to overcome in data analytics. The National Institute of Allergy and Infectious Diseases held a symposium entitled "Data Science: Unlocking the Power of Big Data'' to create a forum for big data experts to present and share some of the creative and innovative methods to gleaning valuable knowledge from an overwhelming flood of biological data. A significant investment in infrastructure and tool development, along with more and better-trained data scientists, may facilitate methods for assimilation of data and machine learning, to overcome obstacles such as data security, data cleaning, and data integration. C1 [Coakley, Meghan F.; Leerkes, Maarten R.; Barnett, Jason; Gabrielian, Andrei E.; Noble, Karlynn; Weber, M. Nick; Huyen, Yentram] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Huyen, Y (reprint author), NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, OSMO,OD,NIH, 10401 Fernwood Rd,Room 2A11,Mail Stop Code 4821, Bethesda, MD 20892 USA. EM huyeny@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 8 TC 1 Z9 1 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2167-6461 EI 2167-647X J9 BIG DATA JI Big Data PD SEP PY 2013 VL 1 IS 3 BP 183 EP 186 DI 10.1089/big.2013.0012 PG 4 WC Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods SC Computer Science GA V42XJ UT WOS:000209646200012 PM 27442200 ER PT J AU Linehan, WM AF Linehan, W. Marston TI Evaluation and screening for hereditary renal cell cancers SO CUAJ-CANADIAN UROLOGICAL ASSOCIATION JOURNAL LA English DT Editorial Material C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr MSC 1107,CRC Room 1W-5940, Bethesda, MD 20892 USA. EM WML@nih.gov NR 4 TC 3 Z9 3 U1 0 U2 0 PU CANADIAN UROLOGICAL ASSOCIATION PI DORVAL PA 185 DORVAL AVENUE, STE 401, DORVAL, QC H9S 5J9, CANADA SN 1911-6470 EI 1920-1214 J9 CUAJ-CAN UROL ASSOC JI CUAJ-Can. Urol. Assoc. J. PD SEP-OCT PY 2013 VL 7 IS 9-10 BP 324 EP 325 DI 10.5489/cuaj.1685 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AO9SW UT WOS:000341698100035 PM 24319510 ER PT J AU de Koning, HJ Plevritis, SK Meza, R ten Haaf, K Munshi, VN Pinsky, PF Hazelton, WD Feuer, EJ McMahon, PM AF de Koning, H. J. Plevritis, S. K. Meza, R. ten Haaf, K. Munshi, V. N. Pinsky, P. F. Hazelton, W. D. Feuer, E. J. McMahon, P. M. CA CISNET Lung Modeling Grp TI Benefits and harms of computed tomography lung cancer screening programs for high risk populations - using evidence from the 2 largest randomized controlled trials on lung cancer screening worldwide SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [de Koning, H. J.; ten Haaf, K.] Erasmus MC, Publ Hlth, Rotterdam, Netherlands. [Plevritis, S. K.] Stanford Univ, Stanford, CA 94305 USA. [Meza, R.] Univ Michigan, Ann Arbor, MI 48109 USA. [Munshi, V. N.; McMahon, P. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pinsky, P. F.; Feuer, E. J.; CISNET Lung Modeling Grp] NCI, Bethesda, MD 20892 USA. [Hazelton, W. D.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA14 BP S7 EP S7 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600019 ER PT J AU Giaccone, G Bazhenova, L Nemunaitis, J Juhasz, E Ramlau, R van den Heuvel, MM Lal, R Dunlop, DJ Carrier, E Fakhrai, H AF Giaccone, G. Bazhenova, L. Nemunaitis, J. Juhasz, E. Ramlau, R. van den Heuvel, M. M. Lal, R. Dunlop, D. J. Carrier, E. Fakhrai, H. TI A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Giaccone, G.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bazhenova, L.] Univ Calif San Diego, Med Oncol Branch, Moores Canc Ctr, Ctr Canc Res, La Jolla, CA USA. [Nemunaitis, J.] Mary Crowley Med Res Ctr, Med Oncol Branch, Ctr Canc Res, Dallas, TX USA. [Juhasz, E.] Koranyi Natl Inst TB & Pulmonol I & XIV, Pulmonol, Budapest, Hungary. [Ramlau, R.] Ctr Lung Dis & TB, Pulmonol, Poznan, Poland. [van den Heuvel, M. M.] Antoni van Leeuwenhoek Ziekenhuis, Pulmonol, Amsterdam, Netherlands. [Lal, R.] Guys Hosp, Med Oncol, London SE1 9RT, England. [Dunlop, D. J.] Glasgow Royal Infirm, Med Oncol, Glasgow G4 0SF, Lanark, Scotland. [Carrier, E.; Fakhrai, H.] NovaRx Corp, Med Oncol, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA2 BP S2 EP S3 PG 2 WC Oncology SC Oncology GA V40HV UT WOS:000209470600007 ER PT J AU Paoletti, X Le Tourneau, C Collette, L Rizzo, E Lacombe, D Olmos, D Siu, L Percy, Y Seymour, L Kaye, SB Verweij, J Massard, C Postel-Vinay, S Soria, J AF Paoletti, X. Le Tourneau, C. Collette, L. Rizzo, E. Lacombe, D. Olmos, D. Siu, L. Percy, Y. Seymour, L. Kaye, S. B. Verweij, J. Massard, C. Postel-Vinay, S. Soria, J. CA DLT-TARGETT DLT Toxicity TI Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of non-cytotoxic agents SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Massard, C.; Postel-Vinay, S.; Soria, J.] Inst Gustave Roussy, Dept Med, DITEP, Villejuif, France. [Paoletti, X.] Inst Curie, Dept Stat, Paris, France. [Le Tourneau, C.] Inst Curie, Dept Med Oncol, Paris, France. [Collette, L.; Rizzo, E.] EORTC Headquarters, Dept Stat, Brussels, Belgium. [Lacombe, D.] EORTC Headquarters, Brussels, Belgium. [Olmos, D.] Spanish Natl Canc Res Ctr CNIO, Clin Res Programme, Prostate Canc & Genitourinary Tumours Clin Res Un, Madrid, Spain. [Siu, L.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Percy, Y.] NCI, Bethesda, MD 20892 USA. [Percy, Y.] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Seymour, L.] NCIC Clin Trials Grp, Kingston, ON, Canada. [Kaye, S. B.] Royal Marsden Hosp, Inst Canc Res, Drug Dev Unit, Sutton, Surrey, England. [Verweij, J.] Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA8 BP S5 EP S5 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600013 ER PT J AU Ahuja, S Henneke, I Knudsen, L Gochuico, BR Ruppert, C Ochs, M Korfei, M Seeger, W Guenther, A Mahavadi, P AF Ahuja, Saket Henneke, Ingrid Knudsen, Lars Gochuico, Bernadette R. Ruppert, Clemens Ochs, Matthias Korfei, Martina Seeger, Werner Guenther, Andreas Mahavadi, Poornima TI Deficient autophagy in Hermansky-Pudlak syndrome associated interstitial pneumonia (HPSIP) SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Interstitial lung disease; Epithelial cell; Animal models C1 [Ahuja, Saket; Henneke, Ingrid; Ruppert, Clemens; Korfei, Martina; Seeger, Werner; Guenther, Andreas; Mahavadi, Poornima] Univ Giessen, Dept Internal Med, D-35392 Giessen, Germany. [Ahuja, Saket; Henneke, Ingrid; Ruppert, Clemens; Korfei, Martina; Seeger, Werner; Guenther, Andreas; Mahavadi, Poornima] Marburg Lung Ctr, D-35392 Giessen, Germany. [Knudsen, Lars; Ochs, Matthias] Hannover Med Sch, Inst Funct & Appl Anat, Hannover, Germany. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Ochs, Matthias] German Ctr Lung Res, DZL, Hannover, Germany. [Seeger, Werner; Guenther, Andreas] German Ctr Lung Res, DZL, Giessen, Germany. [Guenther, Andreas] Agaples Lung Clin, Waldhof Elgershausen, Greifenstein, Germany. EM saket.biotech@gmail.com; Ingrid.Henneke@innere.med.uni-giessen.de; Knudsen.Lars@mh-hannover.de; gochuicb@mail.nih.gov; Clemens.Ruppert@innere.med.uni-giessen.de; ochs.matthias@mh-hannover.de; Martina.Korfei@innere.med.uni-giessen.de; werner.seeger@innere.med.uni-giessen.de; andreas.guenther@innere.med.uni-giessen.de; Poornima.Mahavadi@innere.med.uni-giessen.de NR 0 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 4838 PG 2 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370404479 ER PT J AU Geraghty, P Hardigan, A Wallace, A Mirochnitchenko, O Thankachen, J D'Armiento, J Foronjy, R AF Geraghty, Patrick Hardigan, Andrew Wallace, Alison Mirochnitchenko, Oleg Thankachen, Jincy D'Armiento, Jeanine Foronjy, Robert TI The GPx1-PTP1B-PP2A axis: A key determinant of airway inflammation and alveolar destruction SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE COPD - mechanism; Anti-inflammatory; Cell biology C1 [Geraghty, Patrick; Hardigan, Andrew; Thankachen, Jincy; Foronjy, Robert] Columbia Univ, St Lukes Roosevelt Hosp Ctr, Med, New York, NY 10019 USA. [Wallace, Alison] Univ British Columbia, Surg, Vancouver, BC V6T 1Z3, Canada. [Mirochnitchenko, Oleg] NIH, Div Comparat Med, Bethesda, MD 20892 USA. [D'Armiento, Jeanine] Columbia Univ, Med Ctr, Anesthesiol, New York, NY 10032 USA. EM pgeraghty@chpnet.org; andrewhardigan@gmail.com; amrwallace@gmail.com; oleg.mirochnitchenko@nih.gov; jincy.thankachen@gmail.com; jmd12@columbia.edu; rforonjy@chpnet.org NR 0 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 3004 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370400208 ER PT J AU Havland, I Lundholm, C Lichtenstein, P Niderheiser, J Ganiban, J Spotts, E Walum, H Reiss, D Almqvist, C AF Havland, Ida Lundholm, Cecilia Lichtenstein, Paul Niderheiser, Jenae Ganiban, Jody Spotts, Erica Walum, Hasse Reiss, David Almqvist, Catarina TI Maternal anxiety and adolescent asthma: Children of twin design suggest familial effects SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Asthma - mechanism; Environment; Genetics C1 [Havland, Ida; Lundholm, Cecilia; Lichtenstein, Paul; Walum, Hasse; Almqvist, Catarina] Karolinska Inst, Epidemiol & Biostat, Stockholm, Sweden. [Niderheiser, Jenae] Penn State Univ, Psychol, University Pk, PA 16802 USA. [Ganiban, Jody] George Washington Univ, Psychol, Washington, DC USA. [Spotts, Erica] NIH, Div Behav & Social Res, Bethesda, MD 20892 USA. [Reiss, David] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Almqvist, Catarina] Astrid Lindgren Childrens Hosp, Womens & Childrens Hlth, Stockholm, Sweden. EM ida.havland@gmail.com; cecilia.lundholm@ki.se; Paul.Lichtenstein@ki.se; jenaemn@psu.edu; jmganiban@gmail.com; spottse@od.nih.gov; hasse.walum@ki.se; dxreiss@earthlink.net; Catarina.Almqvist@ki.se NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 7216 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370401223 ER PT J AU Kistemaker, L Bos, S Hylkema, M Hiemstra, P Wess, J Meurs, H Kerstjens, H Gosens, R AF Kistemaker, Loes Bos, Sophie Hylkema, Machteld Hiemstra, Pieter Wess, Jurgen Meurs, Herman Kerstjens, Huib Gosens, Reinoud TI The muscarinic M-3 receptor regulates allergen-induced airway remodeling in mice SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Asthma - mechanism; Pharmacology; Inflammation C1 [Kistemaker, Loes; Bos, Sophie; Meurs, Herman; Gosens, Reinoud] Univ Groningen, Mol Pharmacol, Groningen, Netherlands. [Hylkema, Machteld] Univ Med Ctr Groningen, Pathol & Med Biol, NL-9713 AV Groningen, Netherlands. [Hiemstra, Pieter] Leiden Univ, Med Ctr, Pulmonol, Leiden, Netherlands. [Wess, Jurgen] NIDDK, Bioorgan Chem, Bethesda, MD 20892 USA. [Kerstjens, Huib] Univ Med Ctr Groningen, Resp Med, NL-9713 AV Groningen, Netherlands. [Kistemaker, Loes; Bos, Sophie; Hylkema, Machteld; Meurs, Herman; Kerstjens, Huib; Gosens, Reinoud] Univ Groningen, GRIAC Res Inst, Groningen, Netherlands. EM l.e.m.kistemaker@rug.nl; i.s.t.bos@rug.nl; m.n.hylkema@umcg.nl; p.s.hiemstra@lumc.nl; jurgenw@helix.nih.gov; h.meurs@rug.nl; h.a.m.kerstjens@umcg.nl; r.gosens@rug.nl NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 1067 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370403419 ER PT J AU Moberg, M Palchamy, E Wouters, E Vestbo, J Ferrucci, L Rutten, E AF Moberg, Mia Palchamy, Elango Wouters, Emiel Vestbo, Jorgen Ferrucci, Luigi Rutten, Erica TI Relationship between vitamin D status and lung function in the Baltimore longitudinal study of aging SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Epidemiology; Biomarkers; Lung growth/development C1 [Moberg, Mia] Hvidovre Univ Hosp, Dept Resp Med, DK-2650 Hvidovre, Denmark. [Palchamy, Elango; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21225 USA. [Wouters, Emiel; Rutten, Erica] Ctr Expertise Chron Organ Failure CIRO, Program Dev Ctr, NL-6085 Horn, Netherlands. [Vestbo, Jorgen] Odense Univ Hosp, Dept Resp Med, DK-5000 Odense, Denmark. EM miamoberg@hotmail.com; elangop@mail.nih.gov; e.wouters@mumc.nl; joergen.vestbo@ouh.regionsyddanmark.dk; ferruccilu@mail.nih.gov; ericarutten@ciro-horn.nl NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 1104 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370401164 ER EF