FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Rosner, JL Martin, RG AF Rosner, Judah L. Martin, Robert G. TI Reduction of Cellular Stress by TolC-Dependent Efflux Pumps in Escherichia coli Indicated by BaeSR and CpxARP Activation of spy in Efflux Mutants SO JOURNAL OF BACTERIOLOGY LA English DT Article ID MULTIPLE-ANTIBIOTIC-RESISTANCE; ENTERICA SEROVAR TYPHIMURIUM; 2-COMPONENT REGULATORY SYSTEM; OUTER-MEMBRANE; TRANSCRIPTIONAL ACTIVATION; MULTIDRUG-RESISTANCE; RESPONSE SYSTEMS; MARA; SOXS; EXPRESSION AB Escherichia coli has nine inner membrane efflux pumps which complex with the outer membrane protein TolC and cognate membrane fusion proteins to form tripartite transperiplasmic pumps with diverse functions, including the expulsion of antibiotics. We recently observed that tolC mutants have elevated activities for three stress response regulators, MarA, SoxS, and Rob, and we suggested that TolC-dependent efflux is required to prevent the accumulation of stressful cellular metabolites. Here, we used spy::lacZ fusions to show that two systems for sensing/repairing extracytoplasmic stress, BaeRS and CpxARP, are activated in the absence of TolC-dependent efflux. In either tolC mutants or bacteria with mutations in the genes for four TolC-dependent efflux pumps, spy expression was increased 6- to 8-fold. spy encodes a periplasmic chaperone regulated by the BaeRS and CpxARP stress response systems. The overexpression of spy in tolC or multiple efflux pump mutants also depended on these systems. spy overexpression was not due to acetate, ethanol, or indole accumulation, since external acetate had only a minor effect on wild-type cells, ethanol had a large effect that was not CpxA dependent, and a tolC tnaA mutant which cannot accumulate internal indole overexpressed spy. We propose that, unless TolC-dependent pumps excrete certain metabolites, the metabolites accumulate and activate at least five different stress response systems. C1 [Rosner, Judah L.; Martin, Robert G.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rosner, JL (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM jlrosner@helix.nih.gov FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. NR 65 TC 27 Z9 27 U1 1 U2 29 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 MAR PY 2013 VL 195 IS 5 BP 1042 EP 1050 DI 10.1128/JB.01996-12 PG 9 WC Microbiology SC Microbiology GA 117NY UT WOS:000316961400014 PM 23264577 ER PT J AU Mason, JL Lei, M Faupel-Badger, JM Ginsburg, EP Seger, YR DiJoseph, L Schnell, JD Wiest, JS AF Mason, Julie L. Lei, Ming Faupel-Badger, Jessica M. Ginsburg, Erika P. Seger, Yvette R. DiJoseph, Leo Schnell, Joshua D. Wiest, Jonathan S. TI Outcome Evaluation of the National Cancer Institute Career Development Awards Program SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Evaluation; Career development; Training; Outcomes ID BIOMEDICAL SCIENCES; SEX-DIFFERENCES AB The National Cancer Institute (NCI) career development (K) awards program supports investigators to develop their cancer research programs and achieve independence. The NCI Center for Cancer Training conducted a K program evaluation by analyzing outcomes of awardees and individuals who applied to the program but were not funded. The evaluation covered seven NCI mechanisms (K01, K07, K08, K11, K22, K23, and K25) between 1980 and 2008. Descriptive statistics and regression modeling were performed on the full cohort (n = 2,893 individuals, 4,081 K applications) and a comparison cohort described herein. K awardees proportionately received more subsequent NIH grants and authored more publications, and time to first R01 grant was unaffected. Of those not pursuing research, K awardees were more likely to participate in activities signaling continued scientific engagement. The NCI K program had a positive impact, not only on participants' biomedical research careers but also on achieving outcomes significant to the scientific enterprise. C1 [Mason, Julie L.; Lei, Ming; Faupel-Badger, Jessica M.; Ginsburg, Erika P.; Wiest, Jonathan S.] NCI, Ctr Canc Training, Off Director, Rockville, MD 20852 USA. [Seger, Yvette R.; DiJoseph, Leo; Schnell, Joshua D.] Discovery Log, Rockville, MD USA. RP Mason, JL (reprint author), NCI, Ctr Canc Training, Off Director, 6116 Execut Blvd,Suite 700,MSC 8346, Rockville, MD 20852 USA. EM masonjl@mail.nih.gov RI Schnell, Joshua/J-4000-2012; Seger, Yvette/A-5423-2010 OI Schnell, Joshua/0000-0001-9241-7441; Mason, Julie/0000-0002-5144-175X; Seger, Yvette/0000-0003-2099-4244 FU National Institutes of Health Evaluation Set-Aside Program [10-2008-NCI]; NIH Office of Program Evaluation and Performance, Office of the Director, and NIH [HHSN261201000135U] FX Partial support for this study came from the National Institutes of Health Evaluation Set-Aside Program (10-2008-NCI), administered by the NIH Office of Program Evaluation and Performance, Office of the Director, and NIH contract HHSN261201000135U to Discovery Logic, a Thomson Reuters business. The authors also acknowledge the contributions made by the NCI K outcome evaluation advisory committee including Drs. James Corrigan, Larry Solomon, Melissa Stick, and Rodney Ulane of the NIH; Dr. Joanne Tornow of the National Science Foundation; and Dr. Laurel Haak from Discovery Logic, a Thomson Reuters business. The authors are grateful to have had permission to use data from the National Science Foundation Doctorate Records File (Steve Cohen, Darius Singpurwalla) and the Association of American Medical Colleges Faculty Roster (Hershel Alexander). A portion of the data used in this report was made available by the International Cancer Research Partnership (Karen Parker, NCI liaison). The authors wish to thank the American Association for Cancer Research (Robin Felder, Kristin Johnson), the American Society of Clinical Oncology (Deana Welch, Elizabeth Reyna), and the Federation of American Societies for Experimental Biology (Howard Garrison, Kim Kline) for the membership directory data. NR 17 TC 7 Z9 7 U1 3 U2 6 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 MAR PY 2013 VL 28 IS 1 BP 9 EP 17 DI 10.1007/s13187-012-0444-y PG 9 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 115OE UT WOS:000316820900003 PM 23292841 ER PT J AU Faupel-Badger, J Nelson, DE Marcus, S Kudura, A Nghiem, E AF Faupel-Badger, Jessica Nelson, David E. Marcus, Stephen Kudura, Aisha Nghiem, Elaine TI Evaluating Postgraduate Public Health and Biomedical Training Program Outcomes SO JOURNAL OF CANCER EDUCATION LA English DT Review DE Career; Evaluation; Fellowship; Postdoctoral ID FELLOWSHIP PROGRAM; CANCER PREVENTION; NEXT-GENERATION; MEDICINE; SCIENCES; CAREER; EPIDEMIOLOGY; SCIENTISTS; EXPERIENCE; CAPACITY AB To identify recent studies in the scientific literature that evaluated structured postgraduate public health and biomedical training programs and reported career outcomes among individual trainees, a comprehensive search of several databases was conducted to identify published studies in English between January 1995 and January 2012. Studies of interest included those that evaluated career outcomes for trainees completing full-time public health or biomedical training programs of at least 12 months duration, with structured training offered on-site. Of the over 600 articles identified, only 13 met the inclusion criteria. Six studies evaluated US federal agency programs and six were of university-based programs. Seven programs were solely or predominantly of physicians, with only one consisting mainly of PhDs. Most studies used a cohort or cross-sectional design. The studies were mainly descriptive, with only four containing statistical data. Type of employment was the most common outcome measure (n = 12) and number of scientific publications (n = 6) was second. The lack of outcomes evaluation data from postgraduate public health and biomedical training programs in the published literature is a lost opportunity for understanding the career paths of trainees and the potential impact of training programs. Suggestions for increasing interest in conducting and reporting evaluation studies of these structured postgraduate training programs are provided. C1 [Faupel-Badger, Jessica; Nelson, David E.; Kudura, Aisha; Nghiem, Elaine] NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [Marcus, Stephen] NIGMS, NIH, Bethesda, MD USA. RP Faupel-Badger, J (reprint author), NCI, Canc Prevent Fellowship Program, NIH, 6120 Execut Blvd,Suite 150E, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 37 TC 4 Z9 4 U1 0 U2 6 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 MAR PY 2013 VL 28 IS 1 BP 18 EP 26 DI 10.1007/s13187-012-0437-x PG 9 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 115OE UT WOS:000316820900004 PM 23225110 ER PT J AU Williams, MJ Otero, IV Harford, JB AF Williams, Makeda J. Otero, Isabel V. Harford, Joe B. TI Evaluation of the Impact of NCI's Summer Curriculum on Cancer Prevention on Participants from Low- and Middle-Income Countries SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer control; Knowledge transfer; Low-and middle-income countries AB The National Cancer Institute (NCI) Summer Curriculum on Cancer Prevention provides scientists and health care professionals training in principles and practices of cancer prevention and control, and molecular biology and genetics of cancer. Originally intended for US scientists, the curriculum's enrollment of international scientists has increased steadily. The objective of the current study was to evaluate the curriculum's impact on knowledge, skills, and career accomplishments of the international participants from low- and middle-income countries. International participants from 1998 to 2009 completed questionnaires regarding knowledge, overall experience, and accomplishments directly associated with the curriculum. Almost all respondents agreed that the curriculum enhanced their knowledge and skills, prepared them to contribute to cancer control activities in their home countries, and addressed specific needs and achieve research goals. The NCI Summer Curriculum on Cancer Prevention gives international participants a unique opportunity to enhance their knowledge and effectively contribute to cancer control activities in their home country. C1 [Williams, Makeda J.; Otero, Isabel V.; Harford, Joe B.] NCI, Ctr Global Hlth, NIH, Bethesda, MD 20892 USA. RP Williams, MJ (reprint author), NCI, Ctr Global Hlth, NIH, 6130 Execut Blvd,Suite100, Bethesda, MD 20892 USA. EM willimak@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 12 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2013 VL 28 IS 1 BP 27 EP 32 DI 10.1007/s13187-013-0455-3 PG 6 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 115OE UT WOS:000316820900005 PM 23355281 ER PT J AU Lonser, RR Wind, JJ Nieman, LK Weil, RJ DeVroom, HL Oldfield, EH AF Lonser, Russell R. Wind, Joshua J. Nieman, Lynnette K. Weil, Robert J. DeVroom, Hetty L. Oldfield, Edward H. TI Outcome of Surgical Treatment of 200 Children With Cushing's Disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TRANSSPHENOIDAL SURGERY; PITUITARY-ADENOMAS; DIAGNOSIS; EPIDEMIOLOGY; CHILDHOOD; REMISSION; TUMORS AB Context: Factors influencing the outcome of surgical treatment of pediatric Cushing's disease (CD) have not been fully established. Objective: The aim of this study was to examine features influencing the outcome of surgery for pediatric CD. Design: In this prospective observational study, the clinical, imaging, endocrinological, and operative outcomes were analyzed in consecutive patients treated at the National Institutes of Health (NIH) from 1982 through 2010. Setting: The study was conducted in a tertiary referral center. Results: Two hundred CD patients (106 females, 94 males) were included. Mean age at symptom development was 10.6 +/- 3.6 years (range, 4.0 to 19.0 y). Mean age at NIH operation was 13.7 +/- 3.7 years. Twenty-seven patients (13%) had prior surgery at another institution. Magnetic resonance imaging identified adenomas in 97 patients (50%). When positive, magnetic resonance imaging accurately defined a discrete adenoma in 96 of the 97 patients (99%), which was more accurate than the use of ACTH ratios during inferior petrosal sinus sampling to determine adenoma lateralization (accurate in 72% of patients without prior surgery). A total of 195 of the 200 patients (98%) achieved remission after surgery (189 [97%] were hypocortisolemic; 6 [3%] were eucortisolemic postoperatively). Factors associated with initial remission (P<.05) included identification of an adenoma at surgery, immunohistochemical ACTH-producing adenoma, and noninvasive ACTH adenoma. Younger age, smaller adenoma, and absence of cavernous sinus wall or other dural invasion were associated with long-term remission (P<.05). A minimum morning serum cortisol of less than 1 mu g/dl after surgery had a positive predictive value for lasting remission of 96%. Conclusions: With rare disorders, such as pediatric CD, enhanced outcomes are obtained by evaluation and treatment at centers with substantial experience. Resection of pituitary adenomas in pediatric CD in that setting can be safe, effective, and durable. Early postoperative endocrine testing predicts lasting remission. Because lasting remission is associated with younger age at surgery, smaller adenomas, and lack of dural invasion, early diagnosis should improve surgical outcome. (J Clin Endocrinol Metab 98: 892-901, 2013) C1 [Lonser, Russell R.; Wind, Joshua J.; DeVroom, Hetty L.; Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Weil, Robert J.] Cleveland Clin Fdn, Brain Tumor & Neurooncol Ctr, Dept Neurosurg, Cleveland, OH 44108 USA. [Oldfield, Edward H.] Univ Virginia, Dept Neurol Surg, Univ Virginia Hlth Sci Ctr, Charlottesville, VA 22908 USA. RP Oldfield, EH (reprint author), Univ Virginia, Dept Neurol Surg, POB 800212, Charlottesville, VA 22908 USA. EM eho4u@virginia.edu FU Intramural Research Programs of the National Institute of Neurologic Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Development at the National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Institute of Neurologic Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Development at the National Institutes of Health. NR 23 TC 23 Z9 23 U1 0 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2013 VL 98 IS 3 BP 892 EP 901 DI 10.1210/jc.2012-3604 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110BN UT WOS:000316417200033 PM 23372173 ER PT J AU Boyce, AM Shawker, TH Hill, SC Choyke, PL Hill, MC James, R Yovetich, NA Collins, MT Gafni, RI AF Boyce, Alison M. Shawker, Thomas H. Hill, Suvimol C. Choyke, Peter L. Hill, Michael C. James, Robert Yovetich, Nancy A. Collins, Michael T. Gafni, Rachel I. TI Ultrasound is Superior to Computed Tomography for Assessment of Medullary Nephrocalcinosis in Hypoparathyroidism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CALCIUM-SENSING RECEPTOR; HYPOCALCEMIA; MUTATIONS; CHILDREN; HYPERCALCIURIA; DISORDERS; KIDNEY; RINGS AB Context: Nephrocalcinosis is a complication of hypoparathyroidism and other metabolic disorders. Imaging modalities include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities, and standard clinical practice is not defined. Objective: The objective of the study was to determine the preferred method for assessing nephrocalcinosis. Design: The design of the study was a retrospective, blinded analysis. Setting: The study was conducted at a clinical research center. Patients: Twenty-two hypoparathyroid subjects and 7 controls participated in the study. Interventions: Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale with 0 meaning no nephrocalcinosis and 3 meaning severe nephrocalcinosis. Main Outcome Measures: Intraobserver, interobserver, and interdevice agreements were measured. Results: Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and only 19% had higher CT scores. Of nephro-calcinosis seen on US and notCT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P < .01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0. Conclusions: US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis. (J Clin Endocrinol Metab 98: 989-994, 2013) C1 [Boyce, Alison M.] Childrens Natl Med Ctr, Div Orthopaed & Sports Med, Bone Hlth Program, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Boyce, Alison M.; Collins, Michael T.; Gafni, Rachel I.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Clin Skeletal Dis Branch, Bethesda, MD 20892 USA. [Shawker, Thomas H.; Hill, Suvimol C.] NIH, Radiol & Imaging Sci Branch, Bethesda, MD 20892 USA. [Boyce, Alison M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hill, Michael C.] George Washington Univ Hosp, Dept Radiol, Washington, DC 20037 USA. [James, Robert; Yovetich, Nancy A.] Rho Inc, Chapel Hill, NC 27517 USA. RP Boyce, AM (reprint author), Childrens Natl Med Ctr, Div Endocrinol & Diabet, 111 Michigan Ave NW, Washington, DC 20010 USA. EM aboyce@childrensnational.org FU Division of Intramural Research; National Institute of Dental and Craniofacial Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Department of Health and Human Services; Bone Health Program, Children's National Medical Center FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, and the Bone Health Program, Children's National Medical Center. NR 24 TC 6 Z9 6 U1 1 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2013 VL 98 IS 3 BP 989 EP 994 DI 10.1210/jc.2012-2747 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110BN UT WOS:000316417200046 PM 23348401 ER PT J AU Lai, GY Park, Y Hartge, P Hollenbeck, AR Freedman, ND AF Lai, Gabriel Y. Park, Yikyung Hartge, Patricia Hollenbeck, Albert R. Freedman, Neal D. TI The Association Between Self-Reported Diabetes and Cancer Incidence in the NIH-AARP Diet and Health Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID EPIDEMIOLOGIC EVIDENCE; LARGE COHORT; RISK; MELLITUS; METAANALYSIS; GLUCOSE; INSULIN AB Context: Epidemiological studies have observed associations between diabetes and a number of different cancers. Yet the association with cancer overall and the interrelationship of diabetes and obesity with cancer have been unclear. Objective, Design, Setting, and Participants: We evaluated the association between self-reported diabetes and cancer incidence in the NIH-AARP (National Institutes of Health-American Association of Retired Persons) Diet and Health Study, a prospective cohort in which 295 276 men and 199 591 women completed a questionnaire in 1995-1996 and were followed up for cancer through 2006. Main Outcome Measures: Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer incidence, overall and by type, were estimated from multivariate Cox proportional hazards models. Results: Diabetes was positively associated with total incident cancer in women (1.07, 95% CI 1.02-1.12) but inversely in men (0.96, 95% CI 0.93-0.98). However, diabetes was inversely associated with prostate cancer (HR 0.74, 95% CI 0.70-0.78), which constituted 42% of cancers in men. After excluding prostate cancer, diabetes was also positively associated with cancer in men (HR 1.09, 95% CI 1.04-1.14). By site, diabetes was positively associated with anal, bladder, colon, kidney, liver, pancreatic, rectal, and stomach cancers and in women with endometrial cancer. We also evaluated the joint effect of obesity and diabetes and observed that diabetes conferred additional risk, beyond that of overweight or obesity, for cancer overall, excluding prostate, and for certain sites including the bladder, colon, endometrium, kidney, liver, pancreas, rectum, and stomach. Conclusion: Our results suggest an etiological role for diabetes in a number of cancers, independent of obesity, and that preventing diabetes may contribute to reduced cancer risk. (J Clin Endocrinol Metab 98: E497-E502, 2013) C1 [Lai, Gabriel Y.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Lai, Gabriel Y.; Park, Yikyung; Freedman, Neal D.] NCI, Ctr Canc Training, Nutrit Epidemiol Branch, Bethesda, MD 20892 USA. [Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hartge, Patricia] NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] Amer Assoc Retired Persons, Washington, DC 20049 USA. RP Lai, GY (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320,MSC7232, Bethesda, MD 20892 USA. EM laigy@mail.nih.gov RI Freedman, Neal/B-9741-2015; OI Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS NR 20 TC 14 Z9 15 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2013 VL 98 IS 3 BP E497 EP E502 DI 10.1210/jc.2012-3335 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110BN UT WOS:000316417200011 PM 23408570 ER PT J AU Rahbari, R Kitano, M Zhang, L Bommareddi, S Kebebew, E AF Rahbari, Reza Kitano, Mio Zhang, Lisa Bommareddi, Swaroop Kebebew, Electron TI RTN4IP1 Is Down-Regulated in Thyroid Cancer and Has Tumor-Suppressive Function SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID APOPTOSIS-INDUCING GENE; BRAF MUTATION; INCREASING INCIDENCE; UNITED-STATES; N-MYC; NOGO; NEUROBLASTOMA; EXPRESSION; MIGRATION; REST AB Context: Previously we identified RTN4IP1 to be differentially expressed in thyroid cancer by sex and the gene is located on chromosome 6q21, a chromosomal region frequently deleted or with loss of heterozygosity in a variety of human malignancies including thyroid cancer. Objective: Because the expression and function of this gene is unknown, we sought to characterize its expression in normal, hyperplastic, and benign and malignant thyroid tissue samples and to evaluate its function in cancer cells. Design: RTN4IP1 expression was analyzed in normal and hyperplastic thyroid tissue and benign and malignant thyroid tissue samples. In 3 thyroid cancer cell lines (TPC1 from a papillary thyroid cancer, FTC133 from a follicular thyroid cancer, XTC1 from a Hurthle cell carcinoma), small interfering RNA knockdown of RTN4IP1 was used to determine its role in regulating the hallmarks of malignant cell phenotype (cellular proliferation, migration, apoptosis, invasion, tumor spheroid formation, anchorage independent growth). Results: We found RTN4IP1 mRNA expression was significantly down- regulated in follicular and papillary thyroid cancer as compared with normal, hyperplastic, and benign thyroid neoplasms (P < .05). Moreover, RTN4IP1 mRNA expression was significantly lower in larger papillary thyroid cancers (P < .05). Small interfering RNA knockdown of RTN4IP1 expression increased cellular proliferation (2- to 4-fold) in all 3 of the cell lines tested and increased cellular invasion (1.5- to 3-fold) and migration (2- to 7.5-fold), colony formation (3- to 6-fold), and tumor spheroid formation (P < .05) in 2 of the 3 cell lines tested (FTC-133 and XTC1). Conclusions: This is the first study to characterize the expression and function of RTN4IP1 in cancer. Our results demonstrate RTN4IP1 is down- regulated in thyroid cancer and is associated with larger papillary thyroid cancer and that it regulates malignant cell phenotype. These findings, taken together, suggest that RTN4IP1 has a tumor-suppressive function and may regulate thyroid cancer progression. (J Clin Endocrinol Metab 98: E446-E454, 2013) C1 [Rahbari, Reza; Kitano, Mio; Zhang, Lisa; Bommareddi, Swaroop; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), Clin Res Ctr, Endocrine Oncol Branch, Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 35 TC 6 Z9 6 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2013 VL 98 IS 3 BP E446 EP E454 DI 10.1210/jc.2012-3180 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110BN UT WOS:000316417200005 PM 23393170 ER PT J AU O'Connor, SJ Grazier, KL AF O'Connor, Stephen J. Grazier, Kyle L. TI Interview with Kyle L. Grazier, PhD, Professor and Chair, Department of Health Management and Policy, University of Michigan, Ann Arbor SO JOURNAL OF HEALTHCARE MANAGEMENT LA English DT Editorial Material C1 [Grazier, Kyle L.] Univ Michigan, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Grazier, Kyle L.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. [Grazier, Kyle L.] NIH, Clin & Translat Sci Award Inst, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL HEALTHCARE EXEC HEALTH ADMINISTRATION PRESS PI CHICAGO PA ONE NORTH FRANKLIN ST SUITE 1700, CHICAGO, IL 60606 USA SN 1096-9012 J9 J HEALTHC MANAG JI J. Healthc. Manag. PD MAR-APR PY 2013 VL 58 IS 2 BP 80 EP 83 PG 4 WC Health Policy & Services SC Health Care Sciences & Services GA 115RQ UT WOS:000316830000002 ER PT J AU Liang, JR He, J Zhu, S Zhao, WN Zhang, YM Ito, Y Sun, WJ AF Liang, Jinru He, Jiao Zhu, Sha Zhao, Wenna Zhang, Yongmin Ito, Yoichiro Sun, Wenji TI PREPARATION OF MAIN IRIDOID GLYCOSIDES IN FRUCTUS CORNI BY MACROPOROUS RESIN COLUMN CHROMATOGRAPHY AND COUNTERCURRENT CHROMATOGRAPHY SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE countercurrent chromatography; Fructus Corni; loganin; macroporous resin column chromatography; morroniside; sweroside ID MORRONISIDE; LOGANIN; MICE; CONSTITUENTS; PURIFICATION; INFLAMMATION; SCOPOLAMINE; OFFICINALIS; CELLS; HSCCC AB Loganin, sweroside, and morroniside, three main iridoid glycosides from Fructus Corni were successfully separated by macroporous resin column chromatography and countercurrent chromatography (CCC). In the first step, D101 macroporous resin was selected for cleaning-up, water was used to elute the column to remove the undesired constituents and then 50% aqueous ethanol was used to elute the targets. The total content of three iridoid glycosides was 51.1% in this process. In the second step, the obtained crude sample was then isolated by CCC using a two-phase solvent system composed of dichloromethane-methanol-n-butanol-water-acetic acid (5:5:2:4:0.1, v/v/v/v/v). From 100mg of a crude sample, 12.6mg of loganin, 5.9mg of sweroside, and 28.5mg of morroniside were obtained with purities of 98.6%, 97.3%, and 99.1% and total recoveries of 90.4%, 91.8%, and 89.1%, respectively, after a two-step purification. The HPLC quantitative analysis and response surface methodology were used for optimization of the separation condition and the target compounds were identified by ESI-MS, 1H NMR, and 13C NMR. C1 [Liang, Jinru; He, Jiao; Zhu, Sha; Zhao, Wenna; Sun, Wenji] NW Univ Xian, Biomed Key Lab Shaanxi Prov, Xian 710069, Peoples R China. [Zhang, Yongmin] Univ Paris 06, Inst Parisien Chim Mol, Paris, France. [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Sun, WJ (reprint author), NW Univ Xian, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. EM cxbml@nwu.edu.cn FU Northwest University Graduate Innovation and Creativity Funds of the People's Republic of China [10YZZ34] FX The authors thank Prof. Xinsheng Li of Shaanxi University of Technology for assistance in ESI-MS experiments. Financial support from Northwest University Graduate Innovation and Creativity Funds of the People's Republic of China (10YZZ34) is gratefully acknowledged. NR 29 TC 6 Z9 8 U1 0 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1082-6076 J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD MAR 1 PY 2013 VL 36 IS 8 BP 983 EP 999 DI 10.1080/10826076.2012.683914 PG 17 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 113HU UT WOS:000316658000001 PM 24899790 ER PT J AU Algin, O Turkbey, B Ozmen, E Ocakoglu, G Karaoglanoglu, M Arslan, H AF Algin, Oktay Turkbey, Baris Ozmen, Evrim Ocakoglu, Gokhan Karaoglanoglu, Mustafa Arslan, Halil TI Evaluation of spontaneous third ventriculostomy by three-dimensional sampling perfection with application-optimized contrasts using different flip-angle evolutions (3D-SPACE) sequence by 3T MR imaging: Preliminary results with variant flip-angle mode SO JOURNAL OF NEURORADIOLOGY LA English DT Article DE Spontaneous third ventriculostomy; Obstructive hydrocephalus; Magnetic resonance imaging; 3D-SPACE; Phase-contrast cine MRI ID SINGLE-SLAB; CISTERNOGRAPHY; 3D-CISS; SPACE; 3D AB Purpose: This prospective study aimed to evaluate the use of three-dimensional sampling perfection with application-optimized contrasts using different flip-angle evolutions (3D-SPACE) in the diagnosis of spontaneous third ventriculostomy (STY) and to compare it with phase-contrast cine magnetic resonance imaging (PC-MRI). Methods: PC-MRI and 3D-SPACE images were obtained in 15 patients with hydrocephalus for evaluation of STY as well as in 10 control cases. The presence of STY was evaluated visually by two experienced radiologists on both PC-MRI and 3D-SPACE images, and the results were statistically compared. Results: There was a strong correlation between PC-MRI and SPACE scores for both readers (correlation coefficient [r] = 0.784; P = 0.001). There was also a good correlation between PC-MRI scores and consensus-based results. Interobserver reliabilities were strong for all STY scores. In addition, there was excellent correlation between 3D-SPACE scores and consensus-based results (first reader's kappa value: 0.87; second reader's kappa value: 1). Conclusion: 3D-SPACE can provide morphological physiological information for the evaluation of STY with no need for additional PC-MRI analysis or other sequences. As a non-invasive test, it can also be included among the first line of choices of MRI sequences for patients with obstructive hydrocephalus. (C) 2011 Elsevier Masson SAS. All rights reserved. C1 [Algin, Oktay; Ozmen, Evrim; Karaoglanoglu, Mustafa; Arslan, Halil] Ataturk Training & Res Hosp, Dept Radiol, TR-06050 Ankara, Turkey. [Turkbey, Baris] NCI, NIH, Bethesda, MD 20892 USA. [Ocakoglu, Gokhan] Uludag Univ, Biostat Dept, Fac Med, Gorukle, Bursa, Turkey. RP Algin, O (reprint author), Ataturk Training & Res Hosp, Dept Radiol, TR-06050 Ankara, Turkey. EM droktayalgin@gmail.com; bturkbey@yahoo.com; evrimkilicdr@gmail.com; gocakoglu@gmail.com; mustafakaraoglanoglu@hotmail.com; drhalilarslan@hotmail.com NR 24 TC 11 Z9 15 U1 1 U2 6 PU MASSON EDITEUR PI MOULINEAUX CEDEX 9 PA 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE SN 0150-9861 J9 J NEURORADIOLOGY JI J. Neuroradiol. PD MAR PY 2013 VL 40 IS 1 BP 11 EP 18 DI 10.1016/j.neurad.2011.12.003 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 119IX UT WOS:000317092100002 PM 22305437 ER PT J AU Ziadloo, A Xie, JW Frenkel, V AF Ziadloo, Ali Xie, Jianwu Frenkel, Victor TI Pulsed focused ultrasound exposures enhance locally administered gene therapy in a murine solid tumor model SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID RADIATION-FORCE; CANCER-THERAPY; VIRAL VECTORS; NAKED DNA; DELIVERY; VIRUS; MELANOMA; TRANSPORT; PRESSURE AB Gene therapy by intratumoral injection is a promising approach for treating solid tumors. However, this approach has limited success due to insufficient distribution of gene vectors used for gene delivery. Previous studies have shown that pulsed-focused ultrasound (pFUS) can enhance both systemic and local delivery of therapeutic agents in solid tumors and other disease models. Here, murine squamous cell carcinoma flank tumors were treated with single intratumoral injection of naked tumor necrosis factor-alpha (TNF-alpha) plasmid, either with or without a preceding pFUS exposure. The exposures were given at 1MHz, at a spatial average, temporal peak intensity of 2660W cm(-2), using 50 ms pulses, given at a pulse repetition frequency of 1 Hz. One hundred pulses were given at individual raster points, spaced evenly over the projected surface of the tumor at a distance of 2 mm. Exposures alone had no effect on tumor growth. Significant growth inhibition was observed with injection of TNF-a plasmid, and tumor growth was further inhibited with pFUS. Improved results with pFUS correlated with larger necrotic regions in histological sections and improved distribution and penetration of fluorescent surrogate nanoparticles. Electron microscopy demonstrated enlarged gaps between cells in exposed tissue, and remote acoustic palpation showed decreases in tissue stiffness after pFUS. Combined, these results suggest pFUS effects may be reducing barriers for tissue transport and additionally lowering interstitial fluid pressure to further improve delivery and distribution of injected plasmid for greater therapeutic effects. This suggests that pFUS could potentially be beneficial for improving local gene therapy treatment of human malignancies. (C) 2013 Acoustical Society of America. [http://dx.doi.org/10.1121/1.4789390] C1 [Ziadloo, Ali; Xie, Jianwu; Frenkel, Victor] NIH, Mol Imaging Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Frenkel, Victor] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. RP Frenkel, V (reprint author), Catholic Univ Amer, Dept Biomed Engn, 620 Michigan Ave NE, Washington, DC 20064 USA. EM frenkel@cua.edu FU Clinical Center, National Institutes of Health (NIH) FX The authors would like to especially thank Dr. B. O'Neill of Methodist Hospital in Houston for his contributions to the RAP data, and K Nagashima of the National Cancer Institute for his assistance with the electron microscopy. We would also like to express our gratitude to Dr. Yves Boucher of Harvard University for his thoughtful insights on core topics related to this study. This research was supported in part by the intra-mural research program of the Clinical Center, National Institutes of Health (NIH). NR 33 TC 8 Z9 8 U1 2 U2 10 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD MAR PY 2013 VL 133 IS 3 BP 1827 EP 1834 DI 10.1121/1.4789390 PG 8 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 108NP UT WOS:000316300900072 PM 23464051 ER PT J AU Banks, P Campo, E Jaffe, ES Kinney, MC Collins, RD Piris, MA Swerdlow, SH AF Banks, Peter Campo, Elias Jaffe, Elaine S. Kinney, Marsha C. Collins, Robert D. Angel Piris, Miguel Swerdlow, Steve H. TI A collection of memories of Professor Karl Lennert OBITUARY SO LEUKEMIA LA English DT Biographical-Item C1 [Banks, Peter] Ventana Roche, Tucson, AZ USA. [Banks, Peter] Univ N Carolina, Chapel Hill, NC USA. [Campo, Elias] European Assoc Haematopathol, Barcelona, Spain. [Campo, Elias] Univ Barcelona, Hosp Clin, Hematopathol Unit, Barcelona, Spain. [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Kinney, Marsha C.] Univ Texas Hlth Sci Ctr San Antonio, Soc Hematopathol, San Antonio, TX 78229 USA. [Kinney, Marsha C.] Univ Texas Hlth Sci Ctr San Antonio, Div Hematopathol, San Antonio, TX 78229 USA. [Collins, Robert D.] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37212 USA. [Angel Piris, Miguel] IFIMAV, Santander, Spain. [Swerdlow, Steve H.] Univ Pittsburgh, Div Hematopathol, Sch Med, Pittsburgh, PA USA. RP Banks, P (reprint author), Ventana Roche, Tucson, AZ USA. RI Piris, Miguel/B-7067-2008 OI Piris, Miguel/0000-0001-5839-3634 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAR PY 2013 VL 27 IS 3 BP 522 EP 522 DI 10.1038/leu.2012.340 PG 1 WC Oncology; Hematology SC Oncology; Hematology GA 112JA UT WOS:000316587300003 ER PT J AU Min, DJ Ezponda, T Kim, MK Will, CM Martinez-Garcia, E Popovic, R Basrur, V Elenitoba-Johnson, KS Licht, JD AF Min, D-J Ezponda, T. Kim, M. K. Will, C. M. Martinez-Garcia, E. Popovic, R. Basrur, V. Elenitoba-Johnson, K. S. Licht, J. D. TI MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC SO LEUKEMIA LA English DT Article DE MMSET; t(4;14); multiple myeloma; proliferation; c-MYC; miR-126* ID MULTIPLE-MYELOMA; HISTONE METHYLTRANSFERASE; REPRESSION ACTIVITY; FGFR3 EXPRESSION; GENE-EXPRESSION; HDAC INHIBITORS; LYSINE 36; LEUKEMIA; CANCER; TRANSCRIPTION AB Multiple myeloma (MM) represents the malignant proliferation of terminally differentiated B cells, which, in many cases, is associated with the maintenance of high levels of the oncoprotein c-MYC. Overexpression of the histone methyltransferase MMSET (WHSC1/NSD2), due to t(4;14) chromosomal translocation, promotes the proliferation of MM cells along with global changes in chromatin; nevertheless, the precise mechanisms by which MMSET stimulates neoplasia remain incompletely understood. We found that MMSET enhances the proliferation of MM cells by stimulating the expression of c-MYC at the post-transcriptional level. A microRNA (miRNA) profiling experiment in t(4;14) MM cells identified miR-126* as an MMSET-regulated miRNA predicted to target c-MYC mRNA. We show that miR-126* specifically targets the 3'-untranslated region (3'-UTR) of c-MYC, inhibiting its translation and leading to decreased c-MYC protein levels. Moreover, the expression of this miRNA was sufficient to decrease the proliferation rate of t(4;14) MM cells. Chromatin immunoprecipitation analysis showed that MMSET binds to the miR-126* promoter along with the KAP1 corepressor and histone deacetylases, and is associated with heterochromatic modifications, characterized by increased trimethylation of H3K9 and decreased H3 acetylation, leading to miR-126* repression. Collectively, this study shows a novel mechanism that leads to increased c-MYC levels and enhanced proliferation of t(4;14) MM, and potentially other cancers with high MMSET expression. Leukemia (2013) 27, 686-694; doi:10.1038/leu.2012.269 C1 [Min, D-J; Ezponda, T.; Will, C. M.; Martinez-Garcia, E.; Popovic, R.; Licht, J. D.] Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Kim, M. K.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Basrur, V.; Elenitoba-Johnson, K. S.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. RP Licht, JD (reprint author), Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, 303 East Super St,Lurie 5-123, Chicago, IL 60611 USA. EM j-licht@northwestern.edu FU NIH [CA123204]; Leukemia and Lymphoma Specialized Center of Research; NIH Physical Science Oncology Center [U54CA143869]; Epizyme, Inc.; European Hematology Association; NRSA [HL099177]; Alfonso Martin Escudero fellowship FX We thank Dr Louis Staudt for providing the MMSET-shRNA cells and Dr Marcus Peter for helpful suggestions. This work was supported by NIH Grant CA123204, a Leukemia and Lymphoma Specialized Center of Research grant, a NIH Physical Science Oncology Center Grant U54CA143869 and Epizyme, Inc. (to JDL). EM-G was supported by a European Hematology Association Fellowship, RP by NRSA HL099177 and TE by an Alfonso Martin Escudero fellowship. NR 54 TC 26 Z9 32 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAR PY 2013 VL 27 IS 3 BP 686 EP 694 DI 10.1038/leu.2012.269 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 112JA UT WOS:000316587300023 PM 22972034 ER PT J AU Garrido, C Santizo, VG Mullers, P Soriano, DR Avila, GB Dean, M Jimenez-Morales, S AF Garrido, Claudia Giron Santizo, Veronica Muellers, Petra Rigaud Soriano, Daphney Bendfeldt Avila, Giovana Dean, Michael Jimenez-Morales, Silvia TI Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia SO MEDICAL ONCOLOGY LA English DT Article DE TPMT gene; Thiopurine therapy; Childhood acute lymphoblastic leukemia; Ethnic groups; Guatemala ID INFLAMMATORY-BOWEL-DISEASE; GENETIC-POLYMORPHISM; CAUCASIAN POPULATION; MAINTENANCE THERAPY; IRANIAN POPULATION; ETHNIC-DIFFERENCES; MOLECULAR ANALYSIS; ENZYME-ACTIVITY; TPMT VARIANTS; PHARMACOGENETICS AB Thiopurine S-methyltransferase (TPMT) polymorphisms affect the enzyme's activity and are predictive for the efficacy and toxicity of thiopurine treatment of acute lymphoblastic leukemia (ALL), autoimmune diseases and organ transplants. Because inter-ethnic differences in the distribution of these polymorphisms have been documented, we sequenced the TMPT gene in 95 Guatemalans, yet identified no new alleles. We also determined the frequency of the TPMT*2, *3A, *3B and *3C alleles in 270 admixed and 177 indigenous pediatric patients with ALL and healthy subjects from Guatemala using TaqMan assays and DNA sequencing. Among the 447 subjects genotyped, 10.0 % of the ALL cases and 13.6 % of the healthy controls were heterozygous for one of the four TPMT variants screened. The genotype frequencies in ALL and control populations were 0.7 and 1.7 % for TPMT*1/*2, 7.4 and 10 % for TPMT*1/*3A, 0.3 and 0 % for TPMT*1/*B, and 1.5 and 1.1 % for TPMT*1/*C, respectively (p = 0.30). No statistically significant differences between admixed and indigenous ALL (p = 0.67) or controls (p = 0.41) groups were detected; however, 17 % of the admixed healthy group bore one TPMT mutant allele, and they have one of the highest reported frequencies of TPMT mutant allele carriers. Because of the clinical implications of these variants for therapeutic response, TPMT allele testing should be considered in all Guatemalan patients to reduce adverse side-effects from thiopurine drug treatments. C1 [Garrido, Claudia; Giron Santizo, Veronica; Muellers, Petra; Rigaud Soriano, Daphney; Bendfeldt Avila, Giovana] Unidad Nacl Oncol Pediat, Guatemala City, Guatemala. [Bendfeldt Avila, Giovana; Dean, Michael; Jimenez-Morales, Silvia] NCI, Expt Immunol Lab, Human Genet Sect, Canc & Inflammat Program, Frederick, MD 21702 USA. [Jimenez-Morales, Silvia] Natl Inst Genom Med, Lab Immunogen & Metab Dis, Mexico City, DF, Mexico. RP Dean, M (reprint author), NCI, Expt Immunol Lab, Human Genet Sect, Canc & Inflammat Program, Frederick, MD 21702 USA. EM deanm@mail.nih.gov; sjimenez@inmegen.gob.mx RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU Ayudame de Vivir Foundation; St. Judes Children's Hospital; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Dr. Federico Antillon and the staff of the UNOP for making this study possible, as well as the patients and their parents. We thank Drs. Bert Gold, Kate Im, Wei Tan and Julie Sawitzke and Lisa Garland for reading the manuscript and George Velez and Dr. Victor Santana for assistance in ethical approvals. The work was supported by the Ayudame de Vivir Foundation, St. Judes Children's Hospital and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 51 TC 5 Z9 5 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD MAR PY 2013 VL 30 IS 1 AR 474 DI 10.1007/s12032-013-0474-2 PG 7 WC Oncology SC Oncology GA 115GO UT WOS:000316800800148 PM 23377985 ER PT J AU Li, QQ Wang, GD Huang, FR Li, JLM Cuff, CF Reed, E AF Li, Q. Quentin Wang, Gangduo Huang, Furong Li, Jueli M. Cuff, Christopher F. Reed, Eddie TI Sensitization of lung cancer cells to cisplatin by beta-elemene is mediated through blockade of cell cycle progression: antitumor efficacies of beta-elemene and its synthetic analogs SO MEDICAL ONCOLOGY LA English DT Article DE Cell cycle arrest; Lung cancer; Cisplatin resistance; Chinese medicine; beta-Elemene; Synthetic analogs ID DNA-DAMAGE CHECKPOINT; TUMOR-CELLS; MAMMALIAN-CELLS; CARCINOMA-CELLS; SUPPORTIVE CARE; MOLECULAR-BASIS; CHEMOTHERAPY; ARREST; ACTIVATION; PROTEIN AB The development of effective agents for overcoming platinum chemoresistance in lung carcinoma continues to have high priority. We have demonstrated recently that beta-elemene, a novel antitumor compound, enhances cisplatin activity by triggering lung cancer cell death via apoptosis. Here, we investigated whether beta-elemene acts synergistically with cisplatin to inhibit non-small cell lung cancer (NSCLC) cell proliferation by blocking cell cycle progression. beta-Elemene substantially increased the suppressive effect of cisplatin on cell growth and proliferation in the NSCLC cell lines H460 and A549. Furthermore, beta-elemene augmented cisplatin in the cell cycle arrest of NSCLC cells at G(2)/M. This was associated with upregulated checkpoint kinase (CHK2) expression and reduced CDC2 activity (i.e., increased phosphorylation of CDC2 on Tyr-15 and decreased phosphorylation of CDC2 on Thr-161). Moreover, beta-elemene and cisplatin in combination clearly decreased the protein levels of cyclin B1 and CDC25C and increased the levels of p21(Cip1/Waf1), p27(Kip1), and GADD45 in these cells, compared with the effects of either agent alone at the same concentration. These results suggest that the beta-elemene-enhanced inhibitory effect of cisplatin on lung carcinoma cell proliferation is regulated by a CHK2-mediated CDC25C/CDC2/cyclin B1 signaling pathway and leads to the blockade of cell cycle progression at G2/M. A comparison of the cytotoxic efficacies of beta-elemene and three synthetic analogs (beta-elemenol, beta-elemenal, and beta-elemene fluoride) in the two lung cancer cell lines revealed that beta-elemenol and beta-elemene fluoride had the same antitumor efficacy as beta-elemene, whereas beta-elemenal was appreciably more potent than beta-elemene. Thus, although all three synthetic analogs of beta-elemene considerably suppressed NSCLC cell growth and proliferation, beta-elemenal may have greater potential as an anticancer alternative to beta-elemene in treating lung cancer and other tumors. C1 [Li, Q. Quentin; Wang, Gangduo; Huang, Furong; Cuff, Christopher F.; Reed, Eddie] W Virginia Univ, Sch Med, Morgantown, WV 26506 USA. [Li, Q. Quentin; Reed, Eddie] NCI, NIH, Bethesda, MD 20892 USA. [Li, Jueli M.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. RP Li, QQ (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov FU National Institutes of Health [P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003]; West Virginia University School of Medicine Research Grant FX This study was supported by grants from the National Institutes of Health (No. P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, and P20RR16440-040003) and a West Virginia University School of Medicine Research Grant (to Q. Q. Li). NR 56 TC 11 Z9 12 U1 0 U2 22 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD MAR PY 2013 VL 30 IS 1 AR 488 DI 10.1007/s12032-013-0488-9 PG 11 WC Oncology SC Oncology GA 115GO UT WOS:000316800800162 PM 23397083 ER PT J AU Li, QQ Lee, RX Liang, HS Zhong, YH Reed, E AF Li, Qingdi Quentin Lee, Rebecca X. Liang, Huasheng Zhong, Yuhua Reed, Eddie TI Enhancement of cisplatin-induced apoptosis by beta-elemene in resistant human ovarian cancer cells SO MEDICAL ONCOLOGY LA English DT Article DE Apoptosis; Cisplatin resistance; beta-Elemene; Chinese medicine; Ovarian cancer ID MITOCHONDRIAL PERMEABILITY TRANSITION; LUNG-CANCER; CASPASE ACTIVATION; CYCLE ARREST; TUMOR-CELLS; DEATH; INDUCTION; PATHWAYS; THERAPY; COMBINATION AB beta-Elemene is a new anticancer compound extracted from the Chinese medicinal herb Rhizoma zedoariae. We have shown previously that beta-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity via blocking cell cycle progression at G2/M phase in resistant ovarian tumor cells. In the current study, we asked whether beta-elemene-augmented cisplatin activity in ovarian carcinoma cells is mediated through the induction of apoptosis. Here, we show that beta-elemene triggered apoptotic cell death in chemoresistant human ovarian cancer A2780/CP and MCAS cells in a dose-and time-dependent fashion, as assessed by six different apoptosis assays. Intriguingly, beta-elemene was a stronger inducer of apoptosis than cisplatin in this model system, and a synergistic effect on induction of cell death was observed when the tumor cells were treated with both agents. Furthermore, beta-elemene plus cisplatin exposure significantly disrupted the mitochondrial transmembrane potential (Delta Psi(m)) and increased the release of cytochrome c from mitochondria into the cytoplasm. The combination treatment with both compounds also induced increases in caspase-3/8/9 activities and caspase-9 cleavage, enhanced protein expression of Bax and phosphorylation of Bcl-2 at Ser-70, and reduced the protein levels of Bcl-2 and Bcl-X-L in the platinum-resistant ovarian cancer cells. Taken together, these data indicate that beta-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced apoptosis and that the augmented effect of beta-elemene on cisplatin cytotoxicity and sensitivity in resistant ovarian tumor cells is mediated through a mitochondria-and caspase-dependent cell death pathway. C1 [Li, Qingdi Quentin; Liang, Huasheng; Zhong, Yuhua] Beihai Inst Endocrine & Metab Dis, Beihai 536000, Guangxi, Peoples R China. [Li, Qingdi Quentin; Lee, Rebecca X.; Reed, Eddie] W Virginia Univ, Ctr Canc, Morgantown, WV 26506 USA. [Li, Qingdi Quentin] NCI, NIH, Bethesda, MD 20892 USA. RP Li, QQ (reprint author), Beihai Inst Endocrine & Metab Dis, Beihai 536000, Guangxi, Peoples R China. EM quentinli2004@yahoo.com; zhongyh111@163.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) and 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 West Virginia University School of Medicine Research Grant (to Q. Q. Li). NR 55 TC 16 Z9 22 U1 0 U2 20 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD MAR PY 2013 VL 30 IS 1 AR 424 DI 10.1007/s12032-012-0424-4 PG 13 WC Oncology SC Oncology GA 115GO UT WOS:000316800800102 PM 23277286 ER PT J AU Druz, A Son, YJ Betenbaugh, M Shiloach, J AF Druz, Aliaksandr Son, Young-Jin Betenbaugh, Michael Shiloach, Joseph TI Stable inhibition of mmu-miR-466h-5p improves apoptosis resistance and protein production in CHO cells SO METABOLIC ENGINEERING LA English DT Article DE MicroRNA; Apoptosis; CHO cells ID HAMSTER OVARY CELLS; MAMMALIAN-CELLS; ANTIBODY PRODUCTIVITY; MONOCLONAL-ANTIBODY; OVER-EXPRESSION; GENE-EXPRESSION; DOWN-REGULATION; BATCH CULTURES; MICRORNAS; OVEREXPRESSION AB MiRNAs have been shown to be involved in regulation of multiple cellular processes including apoptosis. Since a single miRNA can affect the expression of several genes, the utilization of miRNAs for apoptosis engineering in mammalian cells can be more efficient than the conventional approach of manipulating a single gene. Mmu-miR-466h-5p was previously shown to have a pro-apoptotic role in CHO cells by reducing the expression of several anti-apoptotic genes and its transient inhibition delayed both the activation of Caspase-3/7 and the loss of cell viability. The present study evaluates the effect of stable inhibition of mmu-miR-466h-5p in CHO cells on their ability to resist apoptosis onset and their production properties. The expression of mmu-miR-466h-5p in the engineered anti-miR-466h CHO cell line was significantly lower than in the negative control and the parental CHO cells. These engineered cells reached higher maximum viable cell density and extended viability compared with negative control and parental CHO cells in batch cell cultures which resulted in the 53.8% and 41.6% increase of integral viable cells. The extended viability of anti-miR-466h CHO cells was the result of delayed Caspase-3/7 activation by more than 35 h, and the increased levels of its anti-apoptotic gene targets (smo, stat5a, dad1, birc6, and bcl2l2) to between 2.1- and 12.5-fold compared with the negative control CHO in apoptotic conditions. The expression of secreted alkaline phosphatase (SEAP) increased 43% and the cell-specific productivity increased 11% in the stable pools of anti-miR-466h CHO compared with the stable pools of negative control CHO cells. The above results demonstrate the potential of this novel approach to create more productive cell lines through stable manipulation of specific miRNA expression. Published by Elsevier Inc. C1 [Druz, Aliaksandr; Son, Young-Jin; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. [Druz, Aliaksandr; Betenbaugh, Michael] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. RP Shiloach, J (reprint author), 9000 Rockville Pike,Buillding 14A,Room 173, Bethesda, MD 20892 USA. EM yossi@nih.gov RI Betenbaugh, Michael J./A-3252-2010 OI Betenbaugh, Michael J./0000-0002-6336-4659 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding was provided by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The authors would like to thank Mrs. D. Livnat for critical editorial assistance. NR 43 TC 27 Z9 27 U1 1 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7176 J9 METAB ENG JI Metab. Eng. PD MAR PY 2013 VL 16 BP 87 EP 94 DI 10.1016/j.ymben.2012.12.004 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 113DW UT WOS:000316647700010 PM 23376592 ER PT J AU Schuck, P Zhao, HY AF Schuck, Peter Zhao, Huaying TI Guest Editor's Introduction Biophysical methods for the study of protein interactions SO METHODS LA English DT Editorial Material C1 [Schuck, Peter; Zhao, Huaying] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 NR 12 TC 1 Z9 1 U1 1 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD MAR 1 PY 2013 VL 59 IS 3 BP 259 EP 260 DI 10.1016/j.ymeth.2013.03.003 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 117UM UT WOS:000316978600001 PM 23522094 ER PT J AU Sherman, E Barr, VA Samelson, LE AF Sherman, Eilon Barr, Valarie A. Samelson, Lawrence E. TI Resolving multi-molecular protein interactions by photoactivated localization microscopy SO METHODS LA English DT Article DE Protein interactions; Super resolution microscopy; Photoactivated localization microscopy; Single molecule; Second order statistics; T cell activation; Microclusters ID CELL ANTIGEN RECEPTOR; FLUORESCENT PROTEINS; SIGNALING MOLECULES; LIVING CELLS; SUPERRESOLUTION; PROBES; COMPLEXES; NANOSCOPY; PALM AB Multi-molecular protein complexes are critical to many cellular functions, including signaling, DNA transcription and enzymatic reactions. In spite of their importance, current research techniques such as biochemistry and diffraction-limited microscopy cannot resolve the heterogeneity and nanoscale organization of protein complexes in intact cells. Here we describe a technique that enables the study of multi-molecular protein complexes at the single molecule level in intact cells. The technique uses photoactivated localization microscopy (PALM) to resolve individual proteins with a resolution down to 20 nm in intact cells, and second-order statistics to study the spatial interactions of the proteins. We demonstrate the feasibility of this technique by studying signaling complexes that form in activated T cells. We first use single color PALM imaging and univariate second-order statistics to resolve the clustering of Linker for Activation of T cells (LAT) at the plasma membrane (PM) of the cells. We then use two color PALM and bivariate second-order statistics to resolve the interaction of LAT with key interacting proteins. We discuss potential caveats in studying molecular clustering and the robustness of the technique to study bimolecular interactions. Our proposed technique, combined with older techniques, could help shed new light on the nature of multimolecular protein complexes and their significance to cell function. Published by Elsevier Inc. C1 [Sherman, Eilon; Barr, Valarie A.; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, CCR, NIH, Bldg 37, Bethesda, MD 20892 USA. EM sherman@phys.huji.ac.il; samelsonl@helix.nih.-gov RI Sherman, Eilon /B-3688-2014 OI Sherman, Eilon /0000-0002-7403-6036 FU Intramural Research Programs of the National Cancer Institute (The Center for Cancer Research) FX The authors would like to thank Subhadra Banerjee and Barbara J Taylor at the FACS CORE Facility (NIH, NCI), Zeiss, Harald Hess (HHMI, Janelia Farm) for providing the PALM software, Wolfgang Losert (UMD) for multiple discussions on data analyses, Thorstan Wiegand (Helmholtz Centre for Environmental Research - UFZ) for providing us his point-pattern analyses software and Connie Sommers (NIH, NCI) for her comments on the manuscript. This research was supported by the Intramural Research Programs of the National Cancer Institute (The Center for Cancer Research). NR 35 TC 10 Z9 10 U1 2 U2 42 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD MAR 1 PY 2013 VL 59 IS 3 BP 261 EP 269 DI 10.1016/j.ymeth.2012.12.002 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 117UM UT WOS:000316978600002 PM 23266704 ER PT J AU Inagaki, S Ghirlando, R Grisshammer, R AF Inagaki, Sayaka Ghirlando, Rodolfo Grisshammer, Reinhard TI Biophysical characterization of membrane proteins in nanodiscs SO METHODS LA English DT Article DE Membrane protein; Nanodisc; Lipid bilayer; Dynamic light scattering; Analytical ultracentrifugation; Lipid charge ID SEDIMENTATION COEFFICIENT DISTRIBUTIONS; PHOSPHOLIPID-BILAYER NANODISCS; NANOSCALE LIPID-BILAYERS; RAT NEUROTENSIN RECEPTOR; ANALYTICAL ULTRACENTRIFUGATION; MONOMERIC RHODOPSIN; CYTOCHROME-P450 3A4; ESCHERICHIA-COLI; CORRELATION SPECTROSCOPY; HETEROLOGOUS EXPRESSION AB Nanodiscs are self-assembled discoidal phospholipid bilayers surrounded and stabilized by membrane scaffold proteins (MSPs), that have become a powerful and promising tool for the study of membrane proteins. Even though their reconstitution is highly regulated by the type of MSP and phospholipid input, a biophysical characterization leading to the determination of the stoichiometry of MSP, lipid and membrane protein is essential. This is important for biological studies, as the oligomeric state of membrane proteins often correlates with their functional activity. Typically combinations of several methods are applied using, for example, modified samples that incorporate fluorescent labels, along with procedures that result in nanodisc disassembly and lipid dissolution. To obtain a comprehensive understanding of the native properties of nanodiscs, modification-free analysis methods are required. In this work we provide a strategy, using a combination of dynamic light scattering and analytical ultracentrifugation, for the biophysical characterization of unmodified nanodiscs. In this manner we characterize the nanodisc preparation in terms of its overall polydispersity and characterize the hydrodynamically resolved nanodisc of interest in terms of its sedimentation coefficient, Stokes' radius and overall protein and lipid stoichiometry. Functional and biological applications are also discussed for the study of the membrane protein embedded in nanodiscs under defined experimental conditions. Published by Elsevier Inc. C1 [Inagaki, Sayaka; Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Rockville, MD 20852 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20814 USA. RP Ghirlando, R (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Room 208,5 Mem Dr, Bethesda, MD 20814 USA. EM inagakisn@ninds.nih.gov; rodolfo.ghirlando@nih.gov; rkgriss@helix.nih.gov RI Grisshammer, Reinhard/C-3089-2015 FU Intramural Research Program of the National Institutes of Health (National Institute of Neurological Disorders and Stroke); Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) FX This research was supported by the Intramural Research Program of the National Institutes of Health (SI, RGr: National Institute of Neurological Disorders and Stroke; RGh: National Institute of Diabetes and Digestive and Kidney Diseases). NR 104 TC 38 Z9 38 U1 2 U2 72 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD MAR 1 PY 2013 VL 59 IS 3 BP 287 EP 300 DI 10.1016/j.ymeth.2012.11.006 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 117UM UT WOS:000316978600005 PM 23219517 ER PT J AU Seidel, SAI Dijkman, PM Lea, WA van den Bogaart, G Jerabek-Willemsen, M Lazic, A Joseph, JS Srinivasan, P Baaske, P Simeonov, A Katritch, I Melo, FA Ladbury, JE Schreiber, G Watts, A Braun, D Duhr, S AF Seidel, Susanne A. I. Dijkman, Patricia M. Lea, Wendy A. van den Bogaart, Geert Jerabek-Willemsen, Moran Lazic, Ana Joseph, Jeremiah S. Srinivasan, Prakash Baaske, Philipp Simeonov, Anton Katritch, Ilia Melo, Fernando A. Ladbury, John E. Schreiber, Gideon Watts, Anthony Braun, Dieter Duhr, Stefan TI Microscale thermophoresis quantifies biomolecular interactions under previously challenging conditions SO METHODS LA English DT Article DE Microscale thermophoresis; Binding affinity; Label-free; Bioliquids; Dimerization; Cooperativity ID ISOTHERMAL TITRATION CALORIMETRY; PROTEIN-PROTEIN INTERACTIONS; SURFACE-PLASMON RESONANCE; NUCLEIC ACID INTERACTIONS; NEUROTENSIN RECEPTOR; LIGAND-BINDING; METHYLTRANSFERASE G9A; MODULAR ARCHITECTURE; COUPLED RECEPTORS; STRUCTURAL BASIS AB Microscale thermophoresis (MST) allows for quantitative analysis of protein interactions in free solution and with low sample consumption. The technique is based on thermophoresis, the directed motion of molecules in temperature gradients. Thermophoresis is highly sensitive to all types of binding-induced changes of molecular properties, be it in size, charge, hydration shell or conformation. In an all-optical approach, an infrared laser is used for local heating, and molecule mobility in the temperature gradient is analyzed via fluorescence. In standard MST one binding partner is fluorescently labeled. However, MST can also be performed label-free by exploiting intrinsic protein UV-fluorescence. Despite the high molecular weight ratio, the interaction of small molecules and peptides with proteins is readily accessible by MST. Furthermore, MST assays are highly adaptable to fit to the diverse requirements of different biomolecules, such as membrane proteins to be stabilized in solution. The type of buffer and additives can be chosen freely. Measuring is even possible in complex bioliquids like cell lysate allowing close to in vivo conditions without sample purification. Binding modes that are quantifiable via MST include dimerization, cooperativity and competition. Thus, its flexibility in assay design qualifies MST for analysis of biomolecular interactions in complex experimental settings, which we herein demonstrate by addressing typically challenging types of binding events from various fields of life science. (C) 2013 Elsevier Inc. All rights reserved. C1 [Seidel, Susanne A. I.; Braun, Dieter] Univ Munich, D-80799 Munich, Germany. [Dijkman, Patricia M.; Watts, Anthony] Univ Oxford, Dept Biochem, Biomembrane Struct Unit, Oxford OX1 3QU, England. [Lea, Wendy A.; Simeonov, Anton] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Srinivasan, Prakash] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [van den Bogaart, Geert] Radboud Univ Nijmegen, Dept Tumor Immunol, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [Joseph, Jeremiah S.; Katritch, Ilia] Scripps Res Inst, La Jolla, CA 92037 USA. [Melo, Fernando A.; Ladbury, John E.] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Melo, Fernando A.; Ladbury, John E.] Univ Texas MD Anderson Canc Ctr, Ctr Biomol Struct & Funct, Houston, TX 77030 USA. [Schreiber, Gideon] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Lazic, Ana] NanoTemper Technol Inc, San Francisco, CA 94111 USA. [Jerabek-Willemsen, Moran; Baaske, Philipp; Duhr, Stefan] NanoTemper Technol GmbH, D-81369 Munich, Germany. RP Duhr, S (reprint author), NanoTemper Technol GmbH, Flossergasse 4, D-81369 Munich, Germany. EM Stefan.duhr@physik.uni-muenchen.de RI van den Bogaart, Geert/A-1089-2014; Melo, Fernando/A-6242-2013; OI van den Bogaart, Geert/0000-0003-2180-6735; Dijkman, Patricia/0000-0001-6799-2399 FU Nano Initiative Munich (NIM); Center for NanoScience (CeNS); Ludwig Maximilians Universitat Munchen (LMU) Initiative Functional Nanosystems; Deutsche Forschungsgemeinschaft; NIH Common Fund's Structural Biology Program [P50 GM073197]; Medical Research Council (MRC) [G0900076]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences, US National Institutes of Health FX The authors thank Dr. Alan Goddard and Eleanor Healey for making AlexaFluor488-neurotensin. We also thank Dr. Masoud Vedadi (University of Toronto) for provision of the G9a protein. Dr. Mohammed Yousef (Bio-Rad Laboratories) is thanked for his expert advice during the initial chip set up on the ProteOn system. In addition Peter Rottgermann and Christof Mast are thanked for help with figures. The work of S.A.I.S. and D.B. was supported by the Nano Initiative Munich (NIM), the Center for NanoScience (CeNS), the Ludwig Maximilians Universitat Munchen (LMU) Initiative Functional Nanosystems and the Deutsche Forschungsgemeinschaft. The work by J.S.J. and I.K was supported by the NIH Common Fund's Structural Biology Program Grant P50 GM073197. The work of P.M.D. and A.W. was supported by the Medical Research Council (MRC) grant G0900076 to A.W. The work by P.S., W.A.L., and A.S. was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, US National Institutes of Health. NR 71 TC 125 Z9 127 U1 9 U2 110 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD MAR 1 PY 2013 VL 59 IS 3 BP 301 EP 315 DI 10.1016/j.ymeth.2012.12.005 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 117UM UT WOS:000316978600006 PM 23270813 ER PT J AU Jin, AJ Lafer, EM Peng, JQ Smith, PD Nossal, R AF Jin, Albert J. Lafer, Eileen M. Peng, Jennifer Q. Smith, Paul D. Nossal, Ralph TI Unraveling protein-protein interactions in clathrin assemblies via atomic force spectroscopy SO METHODS LA English DT Article DE Clathrin triskelion and clathrin-coated vesicles; Single molecular force spectroscopy (SMFS); Single particle force spectroscopy (SPFS); Atomic force microscopy (AFM); Macromolecular assembly; Protein interaction and protein folding ID COATED VESICLES; MEDIATED ENDOCYTOSIS; MOLECULAR-DYNAMICS; MACROMOLECULAR MECHANICS; MAGNETIC TWEEZERS; MASS-SPECTROMETRY; ENTRY PATHWAY; MICROSCOPY; CELLS; ADHESION AB Atomic force microscopy (AFM), single molecule force spectroscopy (SMFS), and single particle force spectroscopy (SPFS) are used to characterize intermolecular interactions and domain structures of clathrin triskelia and clathrin-coated vesicles (CCVs). The latter are involved in receptor-mediated endocytosis (RME) and other trafficking pathways. Here, we subject individual triskelia, bovine-brain CCVs, and reconstituted clathrin-AP180 coats to AFM-SMFS and AFM-SPFS pulling experiments and apply novel analytics to extract force-extension relations from very large data sets. The spectroscopic fingerprints of these samples differ markedly, providing important new information about the mechanism of CCV uncoating. For individual triskelia, SMFS reveals a series of events associated with heavy chain alpha-helix hairpin unfolding, as well as cooperative unraveling of several hairpin domains. SPFS of clathrin assemblies exposes weaker clathrin-clathrin interactions that are indicative of inter-leg association essential for RME and intracellular trafficking. Clathrin-AP180 coats are energetically easier to unravel than the coats of CCVs, with a non-trivial dependence on force-loading rate. Published by Elsevier Inc. C1 [Jin, Albert J.; Peng, Jennifer Q.; Smith, Paul D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, DHHS, Bethesda, MD 20892 USA. [Lafer, Eileen M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Integrat & Med Biophys, NIH, DHHS, Bethesda, MD 20892 USA. RP Jin, AJ (reprint author), NIBIB, LCIMB, NIH, Bldg 13 Rm 3N17, Bethesda, MD 20892 USA. EM jina@mail.nih.gov; nossalr@mail.nih.gov OI Jin, Albert/0000-0003-3826-1081 FU NIH-NINDS [NS029051]; National Institute of Biomedical Imaging and Bioengineering (NIBIB); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX We thank Dr. Svetlana Kotova (National Institutes of Health (NIH), currently Laboratory of Modified Polymer Systems, N.N.Semenov Institute of Chemical Physics of the Russian Academy of Sciences, Moscow, Russia) and Dr. Kondury Prasad (University of Texas Health Science Center at San Antonio) for contributions during the early stage of this study and technical assistance. We also are very grateful to Dr. Dan Sackett (NIH) for helpful comments and technical assistance. This work was supported in part by an extramural grant (EML, NIH-NINDS NS029051) and by the intramural research programs of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 79 TC 2 Z9 2 U1 2 U2 39 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD MAR 1 PY 2013 VL 59 IS 3 BP 316 EP 327 DI 10.1016/j.ymeth.2012.12.006 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 117UM UT WOS:000316978600007 PM 23270814 ER PT J AU Zhao, HY Gorshkova, II Fu, GL Schuck, P AF Zhao, Huaying Gorshkova, Inna I. Fu, Gregory L. Schuck, Peter TI A comparison of binding surfaces for SPR biosensing using an antibody-antigen system and affinity distribution analysis SO METHODS LA English DT Article DE Optical biosensing; Binding kinetics; Protein immobilization; Surface plasmon resonance; Protein interaction; Affinity distribution ID CHIMPANZEE/HUMAN MONOCLONAL-ANTIBODIES; PLASMON RESONANCE BIOSENSORS; PROTEIN-PROTEIN INTERACTIONS; MASS-TRANSPORT LIMITATION; DISSOCIATION KINETICS; LIGAND-BINDING; IN-VITRO; HETEROGENEITY; EQUILIBRIUM; CONSTANTS AB The application of optical biosensors in the study of macromolecular interactions requires immobilization of one binding partner to the surface. It is often highly desirable that the immobilization is uniform and does not affect the thermodynamic and kinetic binding parameters to soluble ligands. To achieve this goal, a variety of sensor surfaces, coupling strategies and surface chemistries are available. Previously, we have introduced a technique for determining the distribution of affinities and kinetic rate constants from families of binding and dissociation traces acquired at different concentrations of soluble ligand. In the present work, we explore how this affinity distribution analysis can be useful in the assessment and optimization of surface immobilization. With this goal, using an antibody-antigen interaction as a model system, we study the activity, thermodynamic and kinetic binding parameters, and heterogeneity of surface sites produced with different commonly used sensor surfaces, at different total surface densities and with direct immobilization or affinity capture. Published by Elsevier Inc. C1 [Zhao, Huaying; Gorshkova, Inna I.; Fu, Gregory L.; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Zhao, HY (reprint author), NIH, Bldg 13,Rm 3N17,13 South Dr, Bethesda, MD 20892 USA. EM zhaoh3@mail.nih.gov; schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 46 TC 10 Z9 10 U1 0 U2 32 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD MAR 1 PY 2013 VL 59 IS 3 BP 328 EP 335 DI 10.1016/j.ymeth.2012.12.007 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 117UM UT WOS:000316978600008 PM 23270815 ER PT J AU Gamazon, ER Badner, JA Cheng, L Zhang, C Zhang, D Cox, NJ Gershon, ES Kelsoe, JR Greenwood, TA Nievergelt, CM Chen, C McKinney, R Shilling, PD Schork, NJ Smith, EN Bloss, CS Nurnberger, JI Edenberg, HJ Foroud, T Koller, DL Scheftner, WA Coryell, W Rice, J Lawson, WB Nwulia, EA Hipolito, M Byerley, W McMahon, FJ Schulze, TG Berrettini, WH Potash, JB Zandi, PP Mahon, PB McInnis, MG Zollner, S Zhang, P Craig, DW Szelinger, S Barrett, TB Liu, C AF Gamazon, E. R. Badner, J. A. Cheng, L. Zhang, C. Zhang, D. Cox, N. J. Gershon, E. S. Kelsoe, J. R. Greenwood, T. A. Nievergelt, C. M. Chen, C. McKinney, R. Shilling, P. D. Schork, N. J. Smith, E. N. Bloss, C. S. Nurnberger, J. I. Edenberg, H. J. Foroud, T. Koller, D. L. Scheftner, W. A. Coryell, W. Rice, J. Lawson, W. B. Nwulia, E. A. Hipolito, M. Byerley, W. McMahon, F. J. Schulze, T. G. Berrettini, W. H. Potash, J. B. Zandi, P. P. Mahon, P. B. McInnis, M. G. Zoellner, S. Zhang, P. Craig, D. W. Szelinger, S. Barrett, T. B. Liu, C. TI Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants SO MOLECULAR PSYCHIATRY LA English DT Article DE bipolar disorder; eQTL; GWAS; mQTL ID GENOME-WIDE ASSOCIATION; HUMAN-DISEASE; EPIGENETICS AB We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P-bonferroni < 0.05) from two other GWA studies (TGen + GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder. Molecular Psychiatry (2013) 18, 340-346; doi:10.1038/mp.2011.174; published online 3 January 2012 C1 [Gamazon, E. R.; Cox, N. J.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Badner, J. A.; Gershon, E. S.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Cheng, L.; Zhang, C.; Chen, C.; Liu, C.] Univ Illinois, Dept Psychiat, Chicago, IL 60607 USA. [Zhang, D.] Zhejiang Univ, Sch Med, Hangzhou, Zhejiang, Peoples R China. [Kelsoe, J. R.; Greenwood, T. A.; Nievergelt, C. M.; McKinney, R.; Shilling, P. D.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Schork, N. J.; Smith, E. N.; Bloss, C. S.] Scripps Genom Med & Scripps Translat Sci Inst, La Jolla, CA USA. [Nurnberger, J. I.; Koller, D. L.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA. [Edenberg, H. J.; Foroud, T.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Scheftner, W. A.] Rush Univ, Dept Psychiat, Chicago, IL 60612 USA. [Coryell, W.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Rice, J.] Washington Univ, Div Biostat, St Louis, MO USA. [Lawson, W. B.; Nwulia, E. A.; Hipolito, M.] Howard Univ, Dept Psychiat, Washington, DC 20059 USA. [Byerley, W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [McMahon, F. J.; Schulze, T. G.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Schulze, T. G.] Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Berrettini, W. H.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Potash, J. B.; Zandi, P. P.; Mahon, P. B.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [McInnis, M. G.; Zoellner, S.; Zhang, P.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Craig, D. W.; Szelinger, S.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. [Barrett, T. B.] Portland VA Med Ctr, Dept Psychiat, Portland, OR USA. RP Liu, C (reprint author), Univ Illinois, Dept Psychiat, 900 S Ashland Ave,Room 1006, Chicago, IL 60607 USA. EM cliu@psych.uic.edu RI Schulze, Thomas/H-2157-2013; Zhang, Peng/N-2920-2014; OI Zhang, Peng/0000-0003-1182-1392; Nievergelt, Caroline/0000-0001-5766-8923; Lawson, William/0000-0002-9324-7090; McMahon, Francis/0000-0002-9469-305X; Greenwood, Tiffany/0000-0002-6080-6503; Nurnberger, John/0000-0002-7674-1767; Edenberg, Howard/0000-0003-0344-9690; Gamazon, Eric/0000-0003-4204-8734 FU PAAR (Pharmacogenetics of Anti-cancer Agents Research) [U01 GM61393]; ENDGAMe (ENhancing Development of Genome-wide Association Methods) initiative [U01 HL084715]; Genotype-Tissue Expression project (GTeX) [R01 MH090937]; [5R01MH080425] FX This work was funded by 5R01MH080425 (to CL), PAAR (Pharmacogenetics of Anti-cancer Agents Research; U01 GM61393), ENDGAMe (ENhancing Development of Genome-wide Association Methods) initiative (U01 HL084715), and the Genotype-Tissue Expression project (GTeX) (R01 MH090937) (to NJC). NR 28 TC 57 Z9 57 U1 1 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2013 VL 18 IS 3 BP 340 EP 346 DI 10.1038/mp.2011.174 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112BZ UT WOS:000316568100011 PM 22212596 ER PT J AU Silberberg, SD AF Silberberg, Shai D. TI Should clinicians care about preclinical animal research? SO NEUROLOGY LA English DT Editorial Material ID IMPROVE C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Silberberg, SD (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM SilberbS@ninds.nih.gov NR 9 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 IS 12 BP 1072 EP 1073 DI 10.1212/WNL.0b013e3182886a51 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 113NF UT WOS:000316674000005 PM 23509045 ER PT J AU Chiossi, G Lai, YL Landon, MB Spong, CY Rouse, DJ Varner, MW Caritis, SN Sorokin, Y O'Sullivan, MJ Sibai, BM Thorp, JM Ramin, SM Mercer, BM AF Chiossi, Giuseppe Lai, Yinglei Landon, Mark B. Spong, Catherine Y. Rouse, Dwight J. Varner, Michael W. Caritis, Steve N. Sorokin, Yoram O'Sullivan, Mary J. Sibai, Baha M. Thorp, John M. Ramin, Susan M. Mercer, Brian M. CA Eunice Kennedy Shriver Natl Inst C TI Timing of Delivery and Adverse Outcomes in Term Singleton Repeat Cesarean Deliveries SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID RESPIRATORY MORBIDITY; LATE-PRETERM; RISK; SECTION; PREGNANCY; LABOR; STILLBIRTH; TRIAL AB OBJECTIVE: To compare the maternal and neonatal risks of elective repeat cesarean delivery compared with pregnancy continuation at different gestational ages, starting from 37 weeks. METHODS: We analyzed the composite maternal and neonatal outcomes of repeat cesarean deliveries studied prospectively over 4 years at 19 U.S. centers. Maternal outcome was a composite of pulmonary edema, cesarean hysterectomy, pelvic abscess, thromboembolism, pneumonia, transfusion, or death. Composite neonatal outcome consisted of respiratory distress, transient tachypnea, necrotizing enterocolitis, sepsis, ventilation, seizure, hypoxic-ischemic encephalopathy, neonatal intensive care unit admission, 5-minute Apgar of 3 or lower, or death. Outcomes after elective repeat cesarean delivery without labor at each specific gestational age were compared with outcomes for all who were delivered later as a result of labor onset, specific obstetric indications, or both. RESULTS: Twenty-three thousand seven hundred ninety-four repeat cesarean deliveries were included. Elective delivery at 37 weeks of gestation had significantly higher risks of adverse maternal outcome (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.06-2.31), whereas elective delivery at 39 weeks of gestation was associated with better maternal outcome when compared with pregnancy continuation (OR 0.51, 95% CI 0.36-0.72). Elective repeat cesarean deliveries at 37 and 38 weeks of gestation had significantly higher risks of adverse neonatal outcome (37 weeks OR 2.02, 95% CI 1.73-2.36; 38 weeks OR 1.39 95% CI 1.24-1.56), whereas delivery at 39 and 40 weeks of gestation presented better neonatal outcome as opposed to pregnancy continuation (39 weeks OR 0.79, 95% CI 0.68-0.92; 40 weeks OR 0.57, 95% CI 0.43-0.75). CONCLUSION: In women with prior cesarean delivery, 39 weeks of gestation is the optimal time for repeat cesarean delivery for both mother and neonate. (Obstet Gynecol 2013;121:561-9) DOI: http://10.1097/AOG.0b013e3182822193 C1 Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. Univ North Carolina Chapel Hill, Dept Obstet & Gynecol, Chapel Hill, NC USA. Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX USA. Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Chiossi, G (reprint author), Univ Texas Med Branch, Dept Obstet & Gynecol, Div Maternal & Fetal Med, 301 Univ Blvd, Galveston, TX 77555 USA. EM Ossidi74seppie@yahoo.it RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) [HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) (HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, and HD36801) and its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NICHD or the NIH. NR 25 TC 23 Z9 23 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2013 VL 121 IS 3 BP 561 EP 569 DI 10.1097/AOG.0b013e3182822193 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112QN UT WOS:000316607600011 PM 23635619 ER PT J AU Spong, CY Berghella, V Wenstrom, KD Mercer, BM Saade, GR AF Spong, Catherine Y. Berghella, Vincenzo Wenstrom, Katharine D. Mercer, Brian M. Saade, George R. TI Preventing the First Cesarean Delivery: Summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Berghella, Vincenzo] Thomas Jefferson Univ, Jefferson Med Coll, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. [Wenstrom, Katharine D.] Women & Infants Hosp Rhode Isl, Dept Obstet & Gynecol, Div Maternal Fetal Med, Providence, RI 02908 USA. [Mercer, Brian M.] Case Western Reserve Univ, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. RP Spong, CY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 1 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2013 VL 121 IS 3 BP 687 EP 687 DI 10.1097/AOG.0b013e3182854b36 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112QN UT WOS:000316607600032 PM 23635640 ER PT J AU Ito, S Barrett, AJ AF Ito, Sawa Barrett, A. John TI Gauchers Disease-A Reappraisal of Hematopoietic Stem Cell Transplantation SO PEDIATRIC HEMATOLOGY AND ONCOLOGY LA English DT Review DE ERT; Gaucher's disease; hematology (nonmalignant); HSCT ID BONE-MARROW-TRANSPLANTATION; ENZYME REPLACEMENT THERAPY; VERSUS-HOST-DISEASE; QUALITY-OF-LIFE; PARKINSONS-DISEASE; CD34(+) CELLS; TYPE-1; EXPERIENCE; GLUCOCEREBROSIDASE; THALASSEMIA AB Hematopoietic stem cell transplantation (HSCT), first performed in 1984, was the first treatment approach for Gaucher's disease (GD) which had curative intent. The early successes in HSCT were soon eclipsed by the introduction of a highly effective enzyme replacement therapy (ERT), which has remained the single most widely used treatment. Experience with HSCT is limited to about 50 reported cases, mainly performed in the last century, with an overall survival around 85%. HSCT typically achieves complete correction of visceral and bony changes and can fully stabilize neurological features in otherwise progressive type II and III GD. ERT, in contrast, is completely safe and effective, but is limited by cost, incomplete resolution of visceral, hematological, and bony features in some patients, and lack of neurological correction in type II and III disease. In this review, we summarize and compare HSCT and ERT. With 20 years of experience of ERT, its limitations as well as its advantages are now well delineated. Meanwhile progress in HSCT over the last decade suggests that transplantation would today represent a very safe curative approach for GD offering one time complete correction of the disease, contrasting with the lifelong need for ERT with its associated expense and dependence on sophisticated drug manufacture. Additionally, unlike ERT, HSCT can be beneficial for neurological forms of GD. We conclude that the time has come to re-evaluate HSCT in selected patients with GD where ERT is less likely to fully eradicate symptoms of the disease. C1 [Ito, Sawa; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Ito, S (reprint author), NHLBI, NIH, Hematol Branch, Ctr Dr Bldg 10, Bethesda, MD 20892 USA. EM itos2@nhlbi.nih.gov NR 63 TC 8 Z9 10 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0888-0018 J9 PEDIATR HEMAT ONCOL JI Pediatr. Hematol. Oncol. PD MAR PY 2013 VL 30 IS 2 BP 61 EP 70 DI 10.3109/08880018.2012.762076 PG 10 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 112BS UT WOS:000316567400001 PM 23363328 ER PT J AU Suarez-Jimenez, B Gore, HE Hachey, J King, HM Lacreuse, A AF Suarez-Jimenez, Benjamin Gore, Heather E. Hachey, Julie King, Hanna M. Lacreuse, Agnes TI Testosterone modulation of anxiety in gonadally-suppressed male rhesus monkeys: A role for gonadotropins? SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Androgens; Anxiety; Emotion; Fear; Luteinizing hormone; Leuprolide acetate; Macaque ID HUMAN CHORIONIC-GONADOTROPIN; MACAQUES MACACA-MULATTA; ELEVATED PLUS-MAZE; ADULT MALE RATS; LUTEINIZING-HORMONE; SPATIAL MEMORY; INDIVIDUAL-DIFFERENCES; CHALLENGE HYPOTHESIS; EMOTIONAL REACTIVITY; ANDROGEN TREATMENT AB Testosterone (T) has repeatedly been shown to have anxiolytic properties in rodents, but findings in primates are more mixed. To examine the effects of exogenous T on anxiety, we tested pharmacologically-castrated adult male rhesus monkeys in a modified version of the Human Intruder Paradigm, which measured defensive responses to an unfamiliar human staring directly at them for 2 min. Monkeys were tested at 2 week intervals during 4 experimental conditions lasting 4 weeks each: at baseline, during treatment with the gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (200 mu g/kg; Lupron phase), during treatment with Lupron + T enanthate (TE, 5 mg/kg; TE phase) and during treatment with Lupron + oil vehicle (oil phase). We found that the number of anxious behaviors was lower during periods of low T (Lupron only and Lupron + oil phases) than during the Lupron + TE phase. No change in pacing or watching behavior was observed. Thus, in contrast to rodent data, we found no evidence for anxiolytic properties of T in male rhesus monkeys. Rather, T supplementation restored baseline levels of anxiety in Lupron-treated monkeys. These discrepant findings may be best explained by the low levels of gonadotropins achieved by the GnRH agonist. We suggest that Lupron-induced luteinizing hormone (LH) suppression reduced anxiety and that this effect was abolished by T administration. This interpretation is consistent with the view that T increases emotional reactivity to a potential threat and facilitates adaptive arousal response in face of immediate social challenge. (C) 2013 Elsevier Inc. All rights reserved. C1 [Suarez-Jimenez, Benjamin; Gore, Heather E.; Hachey, Julie; King, Hanna M.; Lacreuse, Agnes] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Suarez-Jimenez, Benjamin] Univ Massachusetts, Postbaccalaureate Res Educ Program, Amherst, MA 01003 USA. [Suarez-Jimenez, Benjamin] NIMH, NIH, Bethesda, MD 20892 USA. RP Lacreuse, A (reprint author), Univ Massachusetts, Dept Psychol, 135 Hicks Way, Amherst, MA 01003 USA. EM alacreuse@psych.umass.edu FU NIH [GM086264 UMass Amherst PREP] FX Benjamin Suarez-Jimenez was supported by NIH grant GM086264 UMass Amherst PREP. We greatly thank the 8 human intruders for their participation in the study and two anonymous reviewers for their significant input on the paper. NR 87 TC 1 Z9 1 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD MAR PY 2013 VL 104 BP 97 EP 104 DI 10.1016/j.pbb.2013.01.004 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 112LT UT WOS:000316594400012 PM 23333155 ER PT J AU Cuaron, JA Dulal, S Song, Y Singh, AK Montelongo, CE Yu, WQ Nagarajan, V Jayaswal, RK Wilkinson, BJ Gustafson, JE AF Cuaron, Jesus A. Dulal, Santosh Song, Yang Singh, Atul K. Montelongo, Cesar E. Yu, Wanqin Nagarajan, Vijayaraj Jayaswal, Radheshyam K. Wilkinson, Brian J. Gustafson, John E. TI Tea Tree Oil-Induced Transcriptional Alterations in Staphylococcus aureus SO PHYTOTHERAPY RESEARCH LA English DT Article DE tea tree oil; Staphylococcus aureus; transcriptomics; heat shock; vra ID WALL-ACTIVE ANTIBIOTICS; GRAM-POSITIVE BACTERIA; HEAT-SHOCK RESPONSE; METHICILLIN-RESISTANT; MELALEUCA-ALTERNIFOLIA; ESCHERICHIA-COLI; STRESS STIMULON; GENE-EXPRESSION; TOLERANCE; IDENTIFICATION AB Tea tree oil (TTO) is a steam distillate of Melaleuca alternifolia that demonstrates broad-spectrum antibacterial activity. This study was designed to document how TTO challenge influences the Staphylococcus aureus transcriptome. Overall, bioinformatic analyses (S. aureus microarray meta-database) revealed that both ethanol and TTO induce related transcriptional alterations. TTO challenge led to the down-regulation of genes involved with energy-intensive transcription and translation, and altered the regulation of genes involved with heat shock (e.g. clpC, clpL, ctsR, dnaK, groES, groEL, grpE and hrcA) and cell wall metabolism (e.g. cwrA, isaA, sle1, vraSR and vraX). Inactivation of the heat shock gene dnaK or vraSR which encodes a two-component regulatory system that responds to peptidoglycan biosynthesis inhibition led to an increase in TTO susceptibility which demonstrates a protective role for these genes in the S. aureus TTO response. A gene (mmpL) encoding a putative resistance, nodulation and cell division efflux pump was also highly induced by TTO. The principal antimicrobial TTO terpene, terpinen-4-ol, altered ten genes in a transcriptional direction analogous to TTO. Collectively, this study provides additional insight into the response of a bacterial pathogen to the antimicrobial terpene mixture TTO. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Cuaron, Jesus A.; Dulal, Santosh; Montelongo, Cesar E.; Yu, Wanqin; Gustafson, John E.] New Mexico State Univ, Dept Biol, Microbiol Grp, Las Cruces, NM 88003 USA. [Song, Yang; Singh, Atul K.; Jayaswal, Radheshyam K.; Wilkinson, Brian J.] Illinois State Univ, Dept Biol Sci, Microbiol Grp, Normal, IL 61790 USA. [Nagarajan, Vijayaraj] NIAID, Bioinformat & Computat Biosci Branch, OCICB, NIH, Bethesda, MD 20892 USA. RP Gustafson, JE (reprint author), New Mexico State Univ, Dept Biol, MSC 3AF,POB 30001, Las Cruces, NM 88003 USA. EM jgustafs@nmsu.edu RI Luan, Gan/B-3211-2015; song, yang/P-1033-2015 FU National Institutes of Health [SC1GM083882-01, S06 GM61222-05, R25 GM07667-30, 1R15AI084006]; National Center for Research Resources [5P20RR016480-12]; National Institute of General Medical Sciences from the National Institutes of Health [8 P20 GM103451-12] FX All authors wish to acknowledge the former and ongoing support from the National Institutes of Health: SC1GM083882-01 (JEG); S06 GM61222-05 (JC, NMSU-MBRS-RISE PROGRAM); R25 GM07667-30 (NMSU-MARC PROGRAM) and 1R15AI084006 (BJW). This project was also supported by grants from the National Center for Research Resources (5P20RR016480-12) and the National Institute of General Medical Sciences (8 P20 GM103451-12) from the National Institutes of Health. Special thanks to Professor Thomas V. Riley, Dr. Christine Carson (University of Western Australia) and Paul Bolster (P. Guinane Pty. Ltd. New South Wales, Australia) for their help in the acquisition of TTO utilized in this study. NR 52 TC 11 Z9 12 U1 2 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-418X J9 PHYTOTHER RES JI Phytother. Res. PD MAR PY 2013 VL 27 IS 3 BP 390 EP 396 DI 10.1002/ptr.4738 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 103ZN UT WOS:000315958400013 PM 22619070 ER PT J AU Busse, B Smith, S AF Busse, Brad Smith, Stephen TI Automated Analysis of a Diverse Synapse Population SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID VESICULAR GLUTAMATE; NERVOUS-SYSTEM; NEURONS; BRAIN; PLASTICITY; CELLS; TRANSPORTER-2; MECHANISMS; DOPAMINE; SECTIONS AB Synapses of the mammalian central nervous system are highly diverse in function and molecular composition. Synapse diversity per se may be critical to brain function, since memory and homeostatic mechanisms are thought to be rooted primarily in activity-dependent plastic changes in specific subsets of individual synapses. Unfortunately, the measurement of synapse diversity has been restricted by the limitations of methods capable of measuring synapse properties at the level of individual synapses. Array tomography is a new high-resolution, high-throughput proteomic imaging method that has the potential to advance the measurement of unit-level synapse diversity across large and diverse synapse populations. Here we present an automated feature extraction and classification algorithm designed to quantify synapses from high-dimensional array tomographic data too voluminous for manual analysis. We demonstrate the use of this method to quantify laminar distributions of synapses in mouse somatosensory cortex and validate the classification process by detecting the presence of known but uncommon proteomic profiles. Such classification and quantification will be highly useful in identifying specific subpopulations of synapses exhibiting plasticity in response to perturbations from the environment or the sensory periphery. C1 [Busse, Brad] Stanford Univ, Biophys Program, Stanford, CA 94305 USA. [Busse, Brad] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Smith, Stephen] Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. RP Busse, B (reprint author), Stanford Univ, Biophys Program, Stanford, CA 94305 USA. EM bbusse@gmail.com FU NIH/NINDS [R01NS075252, R01NS077601]; Collaborative Innovation Award from the Howard Hughes Medical Institute [43667]; Gatsby Charitable Trust; Mathers Foundation FX This work was supported by grants R01NS075252 and R01NS077601 from the NIH/NINDS, a Collaborative Innovation Award (#43667) from the Howard Hughes Medical Institute, and grants from the Gatsby Charitable Trust and the Mathers Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 9 Z9 9 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2013 VL 9 IS 3 AR e1002976 DI 10.1371/journal.pcbi.1002976 PG 14 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 116EA UT WOS:000316864200047 PM 23555213 ER PT J AU Handel, A Brown, J Stallknecht, D Rohani, P AF Handel, Andreas Brown, Justin Stallknecht, David Rohani, Pejman TI A Multi-scale Analysis of Influenza A Virus Fitness Trade-offs due to Temperature-dependent Virus Persistence SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID ADAPTIVE IMMUNE-RESPONSE; AVIAN INFLUENZA; WITHIN-HOST; ENVIRONMENTAL TRANSMISSION; INFECTIOUS-DISEASES; ANAS-PLATYRHYNCHOS; EVOLUTION; DYNAMICS; PATHOGENS; VIRULENCE AB Successful replication within an infected host and successful transmission between hosts are key to the continued spread of most pathogens. Competing selection pressures exerted at these different scales can lead to evolutionary trade-offs between the determinants of fitness within and between hosts. Here, we examine such a trade-off in the context of influenza A viruses and the differential pressures exerted by temperature-dependent virus persistence. For a panel of avian influenza A virus strains, we find evidence for a trade-off between the persistence at high versus low temperatures. Combining a within-host model of influenza infection dynamics with a between-host transmission model, we study how such a trade-off affects virus fitness on the host population level. We show that conclusions regarding overall fitness are affected by the type of link assumed between the within- and between-host levels and the main route of transmission (direct or environmental). The relative importance of virulence and immune response mediated virus clearance are also found to influence the fitness impacts of virus persistence at low versus high temperatures. Based on our results, we predict that if transmission occurs mainly directly and scales linearly with virus load, and virulence or immune responses are negligible, the evolutionary pressure for influenza viruses to evolve toward good persistence at high within-host temperatures dominates. For all other scenarios, influenza viruses with good environmental persistence at low temperatures seem to be favored. C1 [Handel, Andreas] Univ Georgia, Dept Epidemiol & Biostat, Coll Publ Hlth, Athens, GA 30602 USA. [Brown, Justin; Stallknecht, David] Univ Georgia, Coll Vet Med, Dept Populat Hlth, Athens, GA USA. [Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Handel, A (reprint author), Univ Georgia, Dept Epidemiol & Biostat, Coll Publ Hlth, Athens, GA 30602 USA. EM ahandel@uga.edu OI Handel, Andreas/0000-0002-4622-1146 FU James S. McDonnell Foundation; National Science Foundation [DEB-0917853]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN266200700007C] FX PR was supported by the James S. McDonnell Foundation, the National Science Foundation (DEB-0917853) and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. JB was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN266200700007C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of any of the funding agencies. NR 89 TC 13 Z9 13 U1 0 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2013 VL 9 IS 3 AR e1002989 DI 10.1371/journal.pcbi.1002989 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 116EA UT WOS:000316864200058 PM 23555223 ER PT J AU Lengauer, T Nussinov, R AF Lengauer, Thomas Nussinov, Ruth TI New Methods Section in PLOS Computational Biology SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 [Lengauer, Thomas] Max Planck Inst Informat, D-66123 Saarbrucken, Germany. [Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc,Frederick Natl Lab Canc Res, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Lengauer, T (reprint author), Max Planck Inst Informat, D-66123 Saarbrucken, Germany. EM lengauer@mpi-inf.mpg.de NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2013 VL 9 IS 3 AR e1002972 DI 10.1371/journal.pcbi.1002972 PG 1 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 116EA UT WOS:000316864200043 ER PT J AU Volz, EM Koelle, K Bedford, T AF Volz, Erik M. Koelle, Katia Bedford, Trevor TI Viral Phylodynamics SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID INFLUENZA-A H3N2; EVOLUTIONARY DYNAMICS; POPULATION-DYNAMICS; GENETIC EVOLUTION; SEQUENCE DATA; MOLECULAR EPIDEMIOLOGY; SPONTANEOUS MUTATION; POSITIVE SELECTION; HIV-1 INFECTION; RABIES VIRUS AB Viral phylodynamics is defined as the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viral phylogenies. Since the coining of the term in 2004, research on viral phylodynamics has focused on transmission dynamics in an effort to shed light on how these dynamics impact viral genetic variation. Transmission dynamics can be considered at the level of cells within an infected host, individual hosts within a population, or entire populations of hosts. Many viruses, especially RNA viruses, rapidly accumulate genetic variation because of short generation times and high mutation rates. Patterns of viral genetic variation are therefore heavily influenced by how quickly transmission occurs and by which entities transmit to one another. Patterns of viral genetic variation will also be affected by selection acting on viral phenotypes. Although viruses can differ with respect to many phenotypes, phylodynamic studies have to date tended to focus on a limited number of viral phenotypes. These include virulence phenotypes, phenotypes associated with viral transmissibility, cell or tissue tropism phenotypes, and antigenic phenotypes that can facilitate escape from host immunity. Due to the impact that transmission dynamics and selection can have on viral genetic variation, viral phylogenies can therefore be used to investigate important epidemiological, immunological, and evolutionary processes, such as epidemic spread [2], spatio-temporal dynamics including metapopulation dynamics [3], zoonotic transmission, tissue tropism [4], and antigenic drift [5]. The quantitative investigation of these processes through the consideration of viral phylogenies is the central aim of viral phylodynamics. C1 [Volz, Erik M.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Koelle, Katia] Duke Univ, Dept Biol, Durham, NC USA. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bedford, Trevor] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. RP Volz, EM (reprint author), Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. EM erikvolz@umich.edu OI Bedford, Trevor/0000-0002-4039-5794; Volz, Erik/0000-0001-6268-8937 FU National Institutes of Health [5-K01-AI-091440-03]; NSF grant [NSF-EF-08-27416]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Newton International Fellowship from the Royal Society FX EMV was supported by grant 5-K01-AI-091440-03 from the National Institutes of Health. KK was supported by NSF grant NSF-EF-08-27416 and by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. TB was supported by a Newton International Fellowship from the Royal Society. The funders had no role in the preparation of the manuscript. NR 83 TC 61 Z9 61 U1 1 U2 43 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 MAR PY 2013 VL 9 IS 3 AR e1002947 DI 10.1371/journal.pcbi.1002947 PG 12 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 116EA UT WOS:000316864200020 PM 23555203 ER PT J AU Couch, FJ Wang, XS McGuffog, L Lee, A Olswold, C Kuchenbaecker, KB Soucy, P Fredericksen, Z Barrowdale, D Dennis, J Gaudet, MM Dicks, E Kosel, M Healey, S Sinilnikova, OM Lee, A Bacot, F Vincent, D Hogervorst, FBL Peock, S Stoppa-Lyonnet, D Jakubowska, A Radice, P Schmutzler, RK Domchek, SM Piedmonte, M Singer, CF Friedman, E Thomassen, M Hansen, TVO Neuhausen, SL Szabo, CI Blanco, I Greene, MH Karlan, BY Garber, J Phelan, CM Weitzel, JN Montagna, M Olah, E Andrulis, IL Godwin, AK Yannoukakos, D Goldgar, DE Caldes, T Nevanlinna, H Osorio, A Terry, MB Daly, MB van Rensburg, EJ Hamann, U Ramus, SJ Toland, AE Caligo, MA Olopade, OI Tung, N Claes, K Beattie, MS Southey, MC Imyanitov, EN Tischkowitz, M Janavicius, R John, EM Kwong, A Diez, O Balmana, J Barkardottir, RB Arun, BK Rennert, G Teo, SH Ganz, PA Campbell, I van der Hout, AH van Deurzen, CHM Seynaeve, C Garcia, EBG van Leeuwen, FE Meijers-Heijboer, HEJ Gille, JJP Ausems, MGEM Blok, MJ Ligtenberg, MJL Rookus, MA Devilee, P Verhoef, S van Os, TAM Wijnen, JT Frost, D Ellis, S Fineberg, E Platte, R Evans, DG Izatt, L Eeles, RA Adlard, J Eccles, DM Cook, J Brewer, C Douglas, F Hodgson, S Morrison, PJ Side, LE Donaldson, A Houghton, C Rogers, MT Dorkins, H Eason, J Gregory, H McCann, E Murray, A Calender, A Hardouin, A Berthet, P Delnatte, C Nogues, C Lasset, C Houdayer, C Leroux, D Rouleau, E Prieur, F Damiola, F Sobol, H Coupier, I Venat-Bouvet, L Castera, L Gauthier-Villars, M Leone, M Pujol, P Mazoyer, S Bignon, YJ Zlowocka-Perlowska, E Gronwald, J Lubinski, J Durda, K Jaworska, K Huzarski, T Spurdle, AB Viel, A Peissel, B Bonanni, B Melloni, G Ottini, L Papi, L Varesco, L Tibiletti, MG Peterlongo, P Volorio, S Manoukian, S Pensotti, V Arnold, N Engel, C Deissler, H Gadzicki, D Gehrig, A Kast, K Rhiem, K Meindl, A Niederacher, D Ditsch, N Plendl, H Preisler-Adams, S Engert, S Sutter, C Varon-Mateeva, R Wappenschmidt, B Weber, BHF Arver, B Stenmark-Askmalm, M Loman, N Rosenquist, R Einbeigi, Z Nathanson, KL Rebbeck, TR Blank, SV Cohn, DE Rodriguez, GC Small, L Friedlander, M Bae-Jump, VL Fink-Retter, A Rappaport, C Gschwantler-Kaulich, D Pfeiler, G Tea, MK Lindor, NM Kaufman, B Paluch, SS Laitman, Y Skytte, AB Gerdes, AM Pedersen, IS Moeller, ST Kruse, TA Jensen, UB Vijai, J Sarrel, K Robson, M Kauff, N Mulligan, AM Glendon, G Ozcelik, H Ejlertsen, B Nielsen, FC Jonson, L Andersen, MK Ding, YC Steele, L Foretova, L Teule, A Lazaro, C Brunet, J Pujana, MA Mai, PL Loud, JT Walsh, C Lester, J Orsulic, S Narod, SA Herzog, J Sand, SR Tognazzo, S Agata, S Vaszko, T Weaver, J Stavropoulou, AV Buys, SS Romero, A de la Hoya, M Aittomaki, K Muranen, TA Duran, M Chung, WK Lasa, A Dorfling, CM Miron, A Benitez, J Senter, L Huo, DZ Chan, SB Sokolenko, AP Chiquette, J Tihomirova, L Friebel, TM Agnarsson, BA Lu, KH Lejbkowicz, F James, PA Hall, P Dunning, AM Tessier, D Cunningham, J Slager, SL Wang, C Hart, S Stevens, K Simard, J Pastinen, T Pankratz, VS Offit, K Easton, DF Chenevix-Trench, G Antoniou, AC AF Couch, Fergus J. Wang, Xianshu McGuffog, Lesley Lee, Andrew Olswold, Curtis Kuchenbaecker, Karoline B. Soucy, Penny Fredericksen, Zachary Barrowdale, Daniel Dennis, Joe Gaudet, Mia M. Dicks, Ed Kosel, Matthew Healey, Sue Sinilnikova, Olga M. Lee, Adam Bacot, Francois Vincent, Daniel Hogervorst, Frans B. L. Peock, Susan Stoppa-Lyonnet, Dominique Jakubowska, Anna Radice, Paolo Schmutzler, Rita Katharina Domchek, Susan M. Piedmonte, Marion Singer, Christian F. Friedman, Eitan Thomassen, Mads Hansen, Thomas V. O. Neuhausen, Susan L. Szabo, Csilla I. Blanco, Ignacio Greene, Mark H. Karlan, Beth Y. Garber, Judy Phelan, Catherine M. Weitzel, Jeffrey N. Montagna, Marco Olah, Edith Andrulis, Irene L. Godwin, Andrew K. Yannoukakos, Drakoulis Goldgar, David E. Caldes, Trinidad Nevanlinna, Heli Osorio, Ana Terry, Mary Beth Daly, Mary B. van Rensburg, Elizabeth J. Hamann, Ute Ramus, Susan J. Toland, Amanda Ewart Caligo, Maria A. Olopade, Olufunmilayo I. Tung, Nadine Claes, Kathleen Beattie, Mary S. Southey, Melissa C. Imyanitov, Evgeny N. Tischkowitz, Marc Janavicius, Ramunas John, Esther M. Kwong, Ava Diez, Orland Balmana, Judith Barkardottir, Rosa B. Arun, Banu K. Rennert, Gad Teo, Soo-Hwang Ganz, Patricia A. Campbell, Ian van der Hout, Annemarie H. van Deurzen, Carolien H. M. Seynaeve, Caroline Garcia, Encarna B. Gomez van Leeuwen, Flora E. Meijers-Heijboer, Hanne E. J. Gille, Johannes J. P. Ausems, Margreet G. E. M. Blok, Marinus J. Ligtenberg, Marjolijn J. L. Rookus, Matti A. Devilee, Peter Verhoef, Senno van Os, Theo A. M. Wijnen, Juul T. Frost, Debra Ellis, Steve Fineberg, Elena Platte, Radka Evans, D. Gareth Izatt, Louise Eeles, Rosalind A. Adlard, Julian Eccles, Diana M. Cook, Jackie Brewer, Carole Douglas, Fiona Hodgson, Shirley Morrison, Patrick J. Side, Lucy E. Donaldson, Alan Houghton, Catherine Rogers, Mark T. Dorkins, Huw Eason, Jacqueline Gregory, Helen McCann, Emma Murray, Alex Calender, Alain Hardouin, Agnes Berthet, Pascaline Delnatte, Capucine Nogues, Catherine Lasset, Christine Houdayer, Claude Leroux, Dominique Rouleau, Etienne Prieur, Fabienne Damiola, Francesca Sobol, Hagay Coupier, Isabelle Venat-Bouvet, Laurence Castera, Laurent Gauthier-Villars, Marion Leone, Melanie Pujol, Pascal Mazoyer, Sylvie Bignon, Yves-Jean Zlowocka-Perlowska, Elzbieta Gronwald, Jacek Lubinski, Jan Durda, Katarzyna Jaworska, Katarzyna Huzarski, Tomasz Spurdle, Amanda B. Viel, Alessandra Peissel, Bernard Bonanni, Bernardo Melloni, Giulia Ottini, Laura Papi, Laura Varesco, Liliana Tibiletti, Maria Grazia Peterlongo, Paolo Volorio, Sara Manoukian, Siranoush Pensotti, Valeria Arnold, Norbert Engel, Christoph Deissler, Helmut Gadzicki, Dorothea Gehrig, Andrea Kast, Karin Rhiem, Kerstin Meindl, Alfons Niederacher, Dieter Ditsch, Nina Plendl, Hansjoerg Preisler-Adams, Sabine Engert, Stefanie Sutter, Christian Varon-Mateeva, Raymonda Wappenschmidt, Barbara Weber, Bernhard H. F. Arver, Brita Stenmark-Askmalm, Marie Loman, Niklas Rosenquist, Richard Einbeigi, Zakaria Nathanson, Katherine L. Rebbeck, Timothy R. Blank, Stephanie V. Cohn, David E. Rodriguez, Gustavo C. Small, Laurie Friedlander, Michael Bae-Jump, Victoria L. Fink-Retter, Anneliese Rappaport, Christine Gschwantler-Kaulich, Daphne Pfeiler, Georg Tea, Muy-Kheng Lindor, Noralane M. Kaufman, Bella Paluch, Shani Shimon Laitman, Yael Skytte, Anne-Bine Gerdes, Anne-Marie Pedersen, Inge Sokilde Moeller, Sanne Traasdahl Kruse, Torben A. Jensen, Uffe Birk Vijai, Joseph Sarrel, Kara Robson, Mark Kauff, Noah Mulligan, Anna Marie Glendon, Gord Ozcelik, Hilmi Ejlertsen, Bent Nielsen, Finn C. Jonson, Lars Andersen, Mette K. Ding, Yuan Chun Steele, Linda Foretova, Lenka Teule, Alex Lazaro, Conxi Brunet, Joan Angel Pujana, Miquel Mai, Phuong L. Loud, Jennifer T. Walsh, Christine Lester, Jenny Orsulic, Sandra Narod, Steven A. Herzog, Josef Sand, Sharon R. Tognazzo, Silvia Agata, Simona Vaszko, Tibor Weaver, Joellen Stavropoulou, Alexandra V. Buys, Saundra S. Romero, Atocha de la Hoya, Miguel Aittomaki, Kristiina Muranen, Taru A. Duran, Mercedes Chung, Wendy K. Lasa, Adriana Dorfling, Cecilia M. Miron, Alexander Benitez, Javier Senter, Leigha Huo, Dezheng Chan, Salina B. Sokolenko, Anna P. Chiquette, Jocelyne Tihomirova, Laima Friebel, Tara M. Agnarsson, Bjarni A. Lu, Karen H. Lejbkowicz, Flavio James, Paul A. Hall, Per Dunning, Alison M. Tessier, Daniel Cunningham, Julie Slager, Susan L. Wang, Chen Hart, Steven Stevens, Kristen Simard, Jacques Pastinen, Tomi Pankratz, Vernon S. Offit, Kenneth Easton, Douglas F. Chenevix-Trench, Georgia Antoniou, Antonis C. CA KConFab Investigators SWE-BRCA Ontario Canc Genetics Network HEBON EMBRACE GEMO Study Collaborators BCFR CIMBA TI Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk SO PLOS GENETICS LA English DT Article ID COMMON VARIANTS; SUSCEPTIBILITY ALLELES; GENETIC-VARIANTS; MODIFIERS; INVESTIGATORS; POPULATION; CONSORTIUM; SELECTION; SUBTYPES; ZNF365 AB BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. C1 [Couch, Fergus J.; Wang, Xianshu; Cunningham, Julie; Stevens, Kristen] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Couch, Fergus J.; Cunningham, Julie; Stevens, Kristen] Mayo Clin, Rochester, MN USA. [McGuffog, Lesley; Lee, Andrew; Kuchenbaecker, Karoline B.; Barrowdale, Daniel; Dennis, Joe; Dicks, Ed; Peock, Susan; Frost, Debra; Fineberg, Elena; Platte, Radka; Easton, Douglas F.; Antoniou, Antonis C.; EMBRACE] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Olswold, Curtis; Fredericksen, Zachary; Kosel, Matthew; Slager, Susan L.; Wang, Chen; Hart, Steven; Pankratz, Vernon S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Soucy, Penny; Simard, Jacques] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Soucy, Penny; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Healey, Sue; Spurdle, Amanda B.; Chenevix-Trench, Georgia] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4006, Australia. [Sinilnikova, Olga M.; Calender, Alain; Leone, Melanie] Hosp Civils Lyon, Unite Mixte Genet Constitut Canc Frequents, Ctr Leon Berard, Lyon, France. [Sinilnikova, Olga M.; Damiola, Francesca; Mazoyer, Sylvie] Univ Lyon 1, INSERM U1052, CNRS UMR5286, Ctr Rech Cancerol Lyon, F-69365 Lyon, France. [Lee, Adam] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut MPET, Rochester, MN USA. [Bacot, Francois; Vincent, Daniel; Tessier, Daniel] Ctr Innovat Genome Quebec, Montreal, PQ, Canada. [Bacot, Francois; Vincent, Daniel; Tessier, Daniel] McGill Univ, Montreal, PQ, Canada. [Hogervorst, Frans B. L.; Verhoef, Senno] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Stoppa-Lyonnet, Dominique; Houdayer, Claude; Castera, Laurent; Gauthier-Villars, Marion] Inst Curie, Dept Tumour Biol, Paris, France. [Stoppa-Lyonnet, Dominique] Inst Curie, INSERM U830, Paris, France. [Stoppa-Lyonnet, Dominique; Houdayer, Claude] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Jakubowska, Anna; Zlowocka-Perlowska, Elzbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [KConFab Investigators] Peter MacCallum Canc Ctr, Kathleen Cuningham Consortium Res Familial Breast, Melbourne, Vic, Australia. [Radice, Paolo; Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predict Med, Milan, Italy. [Radice, Paolo; Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Schmutzler, Rita Katharina; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Schmutzler, Rita Katharina; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Integrated Oncol, Ctr Mol Med Cologne, Cologne, Germany. [SWE-BRCA] Lund Univ, Dept Oncol, Lund, Sweden. [Domchek, Susan M.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. 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[Neuhausen, Susan L.; Ding, Yuan Chun; Steele, Linda] City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA. [Szabo, Csilla I.] Univ Delaware, Ctr Translat Canc Res, Dept Biol Sci, Newark, DE USA. [Blanco, Ignacio; Teule, Alex] IDIBELL Catalan Inst Oncol, Genet Counseling Unit, Hereditary Canc Program, Barcelona, Spain. [Greene, Mark H.; Mai, Phuong L.; Loud, Jennifer T.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Garber, Judy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Phelan, Catherine M.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Weitzel, Jeffrey N.; Herzog, Josef; Sand, Sharon R.] City Hope Natl Med Ctr, Clin Canc Genet, City Hope Clin Canc Genet Community Res Network, Duarte, CA USA. [Montagna, Marco; Tognazzo, Silvia; Agata, Simona] Ist Oncol Veneto IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Olah, Edith; Vaszko, Tibor] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Yannoukakos, Drakoulis; Stavropoulou, Alexandra V.] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, IRRP, Athens, Greece. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [Caldes, Trinidad; Romero, Atocha; de la Hoya, Miguel] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Osorio, Ana] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. 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[Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. [Claes, Kathleen] Ghent Univ Hosp, Ctr Med Genet, Ghent, Belgium. [Beattie, Mary S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Beattie, Mary S.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Beattie, Mary S.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Imyanitov, Evgeny N.; Sokolenko, Anna P.] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Tischkowitz, Marc] McGill Univ, Program Canc Genet, Dept Human Genet, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, Vilnius, Lithuania. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. [Kwong, Ava] Hong Kong Sanat & Hosp, Hong Kong Hereditary Breast Canc Family Registry, Canc Genet Ctr, Hong Kong, Hong Kong, Peoples R China. [Diez, Orland] Univ Hosp Vall dHebron, Oncogenet Lab, Barcelona, Spain. [Diez, Orland] Vall dHebron Inst Oncol VHIO, Barcelona, Spain. [Balmana, Judith] Univ Hosp, Dept Med Oncol, Barcelona, Spain. [Barkardottir, Rosa B.] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Barkardottir, Rosa B.] Univ Iceland, Fac Med, BMC, Reykjavik, Iceland. [Arun, Banu K.; Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol & Clin Canc Genet, Houston, TX 77030 USA. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, Haifa, Israel. [Teo, Soo-Hwang] Univ Malaya, Canc Res Initiat Fdn, Sime Darby Med Ctr, Kuala Lumpur, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Canc Res Inst, Kuala Lumpur, Malaysia. [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. [Campbell, Ian] Peter MacCallum Canc Ctr, VBCRC Canc Genet Lab, Melbourne, Vic, Australia. [van der Hout, Annemarie H.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [van Deurzen, Carolien H. M.] Erasmus Univ, Dept Pathol, Family Canc Clin, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Seynaeve, Caroline] Erasmus Univ, Dept Med Oncol, Family Canc Clin, Med Ctr, Rotterdam, Netherlands. [Garcia, Encarna B. Gomez] MUMC, Dept Clin Genet, Sch Oncol & Dev Biol, Maastricht, Netherlands. [Garcia, Encarna B. Gomez] MUMC, GROW, Sch Oncol & Dev Biol, Maastricht, Netherlands. [van Leeuwen, Flora E.; Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Ausems, Margreet G. E. M.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Blok, Marinus J.] Maastricht Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Ligtenberg, Marjolijn J. L.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Ligtenberg, Marjolijn J. L.] Radboud Univ Nijmegen, Dept Pathol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Devilee, Peter; Wijnen, Juul T.] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [van Os, Theo A. M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Wijnen, Juul T.] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands. [HEBON] Netherlands Canc Inst, Hereditary Breast & Ovarian Canc Res Grp Netherla, Amsterdam, Netherlands. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, London, England. [Eeles, Rosalind A.] Inst Canc Res, Oncogenet Team, London SW3 6JB, England. [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, London, England. [Adlard, Julian] Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Eccles, Diana M.] Univ Southampton, Fac Med, Southampton Univ Hosp NHS Trust, Southampton SO9 5NH, Hants, England. [Cook, Jackie] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England. [Douglas, Fiona] Newcastle Upon Tyne Hosp NHS Trust, Inst Med Genet, Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England. [Hodgson, Shirley] St Georges Univ London, Dept Clin Genet, London, England. [Morrison, Patrick J.] Belfast Hlth & Social Care Trust, Northern Ireland Reg Genet Ctr, Belfast, Antrim, North Ireland. [Morrison, Patrick J.] Queens Univ Belfast, Dept Med Genet, Belfast, Antrim, North Ireland. [Side, Lucy E.] Great Ormond St Hosp Sick Children, North East Thames Reg Genet Serv, London WC1N 3JH, England. [Side, Lucy E.] UCL, Inst Womens Hlth, London, England. [Donaldson, Alan] St Michaels Hosp, Dept Clin Genet, Bristol, Avon, England. [Houghton, Catherine] Liverpool Womens NHS Fdn Trust, Cheshire & Merseyside Clin Genet Serv, Liverpool, Merseyside, England. [Rogers, Mark T.] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF4 4XW, S Glam, Wales. [Dorkins, Huw] Kennedy Galton Ctr, North West Thames Reg Genet Serv, Harrow, Middx, England. [Eason, Jacqueline] Nottingham Univ Hosp NHS Trust, Nottingham Clin Genet Serv, Nottingham, England. [Gregory, Helen] NHS Grampian, North Scotland Reg Genet Serv, Aberdeen, Scotland. [Gregory, Helen] Univ Aberdeen, Aberdeen, Scotland. [Murray, Alex] Singleton Hosp, All Wales Med Genet Serv, Swansea SA2 8QA, W Glam, Wales. [Hardouin, Agnes; Berthet, Pascaline] Ctr Francois Baclesse, F-14021 Caen, France. [Delnatte, Capucine] Ctr Rene Gauducheau, F-44035 Nantes, France. [Nogues, Catherine] Hop Rene Huguenin, Oncogenet Clin, Inst Curie, St Cloud, France. [Lasset, Christine] Ctr Leon Berard, Unite Prevent & Epidemiol Genet, F-69373 Lyon, France. [Lasset, Christine] Univ Lyon 1, CNRS UMR5558, F-69365 Lyon, France. [Leroux, Dominique] CHU Grenoble, Dept Genet, F-38043 Grenoble, France. [Leroux, Dominique] Univ Grenoble, Inst Albert Bonniot, Grenoble, France. [Rouleau, Etienne] Hop Rene Huguenin, Lab Oncogenet, Inst Curie, St Cloud, France. [Prieur, Fabienne] Ctr Hosp Univ St Etienne, Serv Genet Clin Chromosom & Mol, St Etienne, France. [Sobol, Hagay] Univ Aix Marseille 2, Dept Oncol Genet Prevent & Depistage, INSERM CIC P9502, Inst Paoli Calmettes, F-13284 Marseille 07, France. [Coupier, Isabelle; Pujol, Pascal] CHU Arnaud de Villeneuve, Unite Oncogenet, Montpellier, France. [Coupier, Isabelle] CRLCC Val dAurelle, Unite Oncogenet, Montpellier, France. [Venat-Bouvet, Laurence] Ctr Hosp Univ Dupuytren, Dept Med Oncol, Limoges, France. [Pujol, Pascal] CRCM Val dAurelle, INSERM 896, Montpellier, France. [Bignon, Yves-Jean] Univ Clermont Ferrand, Dept Oncogenet, Ctr Jean Perrin, Clermont Ferrand, France. Ctr Rech Cancerol Lyon, Natl Canc Genet Network, UNICANC Genet Grp, Paris, France. [GEMO Study Collaborators] Inst Curie, Paris, France. [Jaworska, Katarzyna] Warsaw Med Univ, Postgrad Sch Mol Med, Warsaw, Poland. [Viel, Alessandra] IRCCS, Div Expt Oncol 1, Ctr Riferimento Oncologico, Aviano, Italy. [Peissel, Bernard; Melloni, Giulia; Manoukian, Siranoush] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Ottini, Laura] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy. [Papi, Laura] Univ Florence, Unit Med Genet, Dept Clin Physiopathol, Florence, Italy. [Varesco, Liliana] IRCCS AOU San Martino IST Ist Nazl Ric Canc, Unit Hereditary Canc, Dept Epidemiol Prevent & Special Funct, Genoa, Italy. [Tibiletti, Maria Grazia] Osped Circolo Univ Insubria, UO Anat Patol, Varese, Italy. [Volorio, Sara; Pensotti, Valeria] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Volorio, Sara; Pensotti, Valeria] Cogentech Canc Genet Test Lab, Milan, Italy. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Kiel, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Deissler, Helmut] Univ Hosp Ulm, Ulm, Germany. [Gadzicki, Dorothea] Hannover Med Sch, Hannover, Germany. [Gehrig, Andrea] Univ Wurzburg, Inst Human Genet, Wurzburg, Germany. [Kast, Karin] Tech Univ Dresden, Dept Obstet & Gynaecol, Univ Hosp Carl Gustav Carus, D-01062 Dresden, Germany. [Meindl, Alfons; Engert, Stefanie] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-80290 Munich, Germany. [Niederacher, Dieter] Univ Dusseldorf, Dept Obstet & Gynaecol, Univ Med Ctr Dusseldorf, D-40225 Dusseldorf, Germany. [Ditsch, Nina] Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Plendl, Hansjoerg] Univ Kiel, Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel, Germany. [Preisler-Adams, Sabine] Univ Munster, Inst Human Genet, D-48149 Munster, Germany. [Sutter, Christian] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany. [Varon-Mateeva, Raymonda] Inst Med & Human Genet, Berlin, Germany. [Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [Arver, Brita] Karolinska Univ Hosp, Dept Pathol & Oncol, Stockholm, Sweden. [Stenmark-Askmalm, Marie] Linkoping Univ, Div Clin Genet, Dept Clin & Expt Med, Linkoping, Sweden. [Loman, Niklas] Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. [Rosenquist, Richard] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden. [Einbeigi, Zakaria] Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden. [Nathanson, Katherine L.; Rebbeck, Timothy R.] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Nathanson, Katherine L.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Blank, Stephanie V.] NYU, Sch Med, NYU Womens Canc Program, New York, NY USA. [Cohn, David E.] Ohio State Univ, Columbus Canc Council, Columbus, OH 43210 USA. [Rodriguez, Gustavo C.] Univ Chicago, North Shore Univ Hlth Syst, Div Gynecol Oncol, Evanston, IL USA. [Small, Laurie] Maine Womens Surg & Canc Ctr, Maine Med Ctr, Scarborough, ME USA. [Friedlander, Michael] Australia New Zealand GOG, ANZ GOTG Coordinating Ctr, Camperdown, NSW, Australia. [Bae-Jump, Victoria L.] Univ N Carolina, Chapel Hill, NC USA. [Lindor, Noralane M.] Mayo Clin Arizona, Dept Hlth Sci Res, Scottsdale, AZ USA. [Skytte, Anne-Bine] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Gerdes, Anne-Marie] Rigshosp, Dept Clincial Genet, Copenhagen, Denmark. [Pedersen, Inge Sokilde] Aalborg Univ Hosp, Sect Mol Diagnost, Dept Clin Biochem, Aalborg, Denmark. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. [Mulligan, Anna Marie; Ozcelik, Hilmi] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Mulligan, Anna Marie] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Ejlertsen, Bent] Copenhagen Univ Hosp, Dept Oncol, Rigshosp, Copenhagen, Denmark. [Andersen, Mette K.] Copenhagen Univ Hosp, Dept Clin Genet, Rigshosp, Copenhagen, Denmark. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Lazaro, Conxi] IDIBELL Catalan Inst Oncol, Mol Diagnost Unit, Hereditary Canc Program, Barcelona, Spain. [Brunet, Joan] IDIBGI Catalan Inst Oncol, Genet Counseling Unit, Hereditary Canc Program, Girona, Spain. [Angel Pujana, Miquel] IDIBELL Catalan Inst Oncol, Translat Res Lab, Breast Canc & Syst Biol Unit, Barcelona, Spain. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Weaver, Joellen] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Buys, Saundra S.] Univ Utah, Sch Med, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Duran, Mercedes] Univ Valladolid IBGM UVA, Inst Biol & Mol Genet, Valladolid, Spain. [Chung, Wendy K.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Chung, Wendy K.] Columbia Univ, Dept Med, New York, NY USA. [Lasa, Adriana] Hosp Santa Creu & Sant Pau, Genet Serv, Barcelona, Spain. [Miron, Alexander] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [BCFR] Canc Prevent Inst Calif, Breast Canc Family Registry, Fremont, CA USA. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Genotyping Unit, Madrid, Spain. [Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Senter, Leigha] Ohio State Univ, Ctr Comprehens Canc, Div Human Genet, Dept Internal Med, Columbus, OH 43210 USA. [Chan, Salina B.] Univ Calif San Francisco, Canc Risk Program, Helen Diller Family Canc Ctr, San Francisco, CA 94143 USA. [Chiquette, Jocelyne] Univ Quebec, Unite Rech Sante Populat, Ctr Malad Sein Deschenes Fabia, Ctr Rech FRSQ,Ctr Hosp, Quebec City, PQ, Canada. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Friebel, Tara M.] Univ Penn, Philadelphia, PA 19104 USA. [Agnarsson, Bjarni A.] Landspitali Univ Hosp, Reykjavik, Iceland. [Agnarsson, Bjarni A.] Univ Iceland, Sch Med, Reykjavik, Iceland. [Lejbkowicz, Flavio] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Lejbkowicz, Flavio] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [James, Paul A.] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia. [Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Dunning, Alison M.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Pastinen, Tomi] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Pastinen, Tomi] McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ, Canada. RP Couch, FJ (reprint author), Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. EM couch.fergus@mayo.edu; Antonis@srl.cam.ac.uk RI Spurdle, Amanda/A-4978-2011; Arnold, Norbert/E-3012-2010; pujana, Miguel Angel/N-3127-2014; Jakubowska, Anna/O-8050-2014; campbell, Ian/F-6006-2011; montagna, marco/E-2225-2012; Ligtenberg, Marjolijn/N-9666-2013; Wang, Chen/B-3244-2011; Sokolenko, Anna/G-3123-2013; Gronwald, Jacek/A-4576-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Osorio, Ana/I-4324-2014; Andrulis, Irene/E-7267-2013; friedlander, michael/G-3490-2013; Toland, Amanda/E-4202-2011; Joseph, Vijai/J-9158-2013; Radice, Paolo/O-3119-2013; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Blanco, Ignacio/D-2565-2013; Ditsch, Nina/F-6267-2014; James, Paul/G-2943-2014; Leroux, Dominique/G-7309-2014; Teo, Soo-hwang/H-2353-2014 OI Dunning, Alison Margaret/0000-0001-6651-7166; ROMERO, ATOCHA/0000-0002-1634-7397; Muranen, Taru/0000-0002-5895-1808; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Evans, Gareth/0000-0002-8482-5784; Ramus, Susan/0000-0003-0005-7798; Papi, Laura/0000-0003-4552-9517; Brunet, Joan/0000-0003-1945-3512; Kauff, Noah/0000-0001-7242-6156; Nevanlinna, Heli/0000-0002-0916-2976; Yannoukakos, Drakoulis/0000-0001-7509-3510; Rappaport-Fuerhauser, Christine/0000-0002-6820-0020; Spurdle, Amanda/0000-0003-1337-7897; Barrowdale, Daniel/0000-0003-1661-3939; Barton, David E/0000-0002-2031-9719; Dite, Gillian/0000-0002-2448-2548; Robson, Mark/0000-0002-3109-1692; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Devilee, Peter/0000-0002-8023-2009; Arnold, Norbert/0000-0003-4523-8808; pujana, Miguel Angel/0000-0003-3222-4044; montagna, marco/0000-0002-4929-2150; Ligtenberg, Marjolijn/0000-0003-1290-1474; Wang, Chen/0000-0003-2638-3081; Gronwald, Jacek/0000-0002-3643-2871; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Dennis, Joe/0000-0003-4591-1214; Janavicius, Ramunas/0000-0002-3773-8485; Osorio, Ana/0000-0001-8124-3984; friedlander, michael/0000-0002-6488-0604; Joseph, Vijai/0000-0002-7933-151X; Blanco, Ignacio/0000-0002-7414-7481; FU NIH [CA128978, P30 CA033752, R01CA74415, 1R01 CA149429-01]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defense Ovarian Cancer Idea award [W81XWH-10-1-0341]; Breast Cancer Research Foundation; Komen Foundation for the Cure; Cancer Research UK [C12292/A11174, C1287/A10118, C1287/A11990, C5047/A8385]; European Commission [223175 (HEALTH-F2-2009-223175)]; National Cancer Institute, National Institutes of Health under RFA [CA-06-503]; Breast Cancer Family Registry (BCFR); Cancer Care Ontario [U01 CA69467]; Cancer Prevention Institute of California [U01 CA69417]; Columbia University [U01 CA69398]; Fox Chase Cancer Center [U01 CA69631]; Huntsman Cancer Institute [U01 CA69446]; University of Melbourne [U01 CA69638]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; National Institutes of Health [P01 CA16094, R01 CA22435]; National Center for Research Resources; National Center for Advancing Translational Sciences, NIH [UL1 RR025764]; National Cancer Institute [P30 CA042014, RC4A153828, CA 27469, CA 37517, CA 101165]; Research Council of Lithuania [LIG-19/2010]; Lithuania (BFBOCC-LT); Hereditary Cancer Association (Paveldimo vezio asociacija); LSC [10.0010.08]; ESF [2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016]; Cancer Association of South Africa (CANSA); Morris and Horowitz Families Endowed Professorship; NEYE Foundation; Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA); Office of the Director, National Institutes of Health; Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumors"); Italian Association for Cancer Research (AIRC) [IG 8713]; Italian Minitry of Health; Italian Ministry of Education, University and Research, Centro di Ascolto Donne Operate al Seno (CAOS) association; DKFZ; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; NWO [91109024]; Pink Ribbon grant [110005]; BBMRI [CP46/NWO]; NIHR; Royal Marsden NHS Foundation Trust; University of Kansas Cancer Center; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; German Cancer Aid [109076]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlons-en!"; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Intramural Research Program, NCI, NIH; RETICC [06/0020/0021]; FIS [09/00859]; Instituto de Salud Carlos III; Spanish Ministry of Economy and Competitivity; European Regional Development Fund (ERDF); Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Hong Kong Hereditary Breast Cancer Family Registry; Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian Research [HU0115/NA/2008-3/OP-9]; Asociacion Espanola Contra el Cancer; Spanish Health Research Foundation; Ramon Areces Foundation; Carlos III Health Institute; Catalan Health Institute; Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, 2009SGR283]; Polish Foundation of Science; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Canadian Institutes of Health Research; Canadian Breast Cancer Research Alliance [019511]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Ministero dell'Istruzione, dell'Universitae della Ricerca; Ministero della Salute [RFPS 2006-5-341353, ACC2/R6.9]; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria; Cancer Councils of New South Wales, Tasmania; Cancer Councils of New South Wales, South Australia; Cancer Foundation of Western Australia; NHMRC; Cancer Australia [628333]; Jewish General Hospital; Quebec Ministry of Economic Development, Innovation, and Export Trade; Niehaus Clinical Cancer Genetics Initiative; Andrew Sabin Family Foundation; Lymphoma Foundation; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Intramural Research Program of the US National Cancer Institute, NIH; Westat, Rockville, MD [NO2-CP-11019-50, N02-CP-65504]; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), NY; Russian Foundation for Basic Research [11-04-00227, 12-04-00928, 12-04-01490]; Federal Agency for Science and Innovations, Russia [02.740.11.0780]; Royal Society [JP090615]; Ohio State University Comprehensive Cancer Center; Swedish Cancer Society; US National Cancer Institute (NIH/NCI); Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance,; Jonsson Comprehensive Cancer Center Foundation; UCSF Cancer Risk Program; Helen Diller Family Comprehensive Cancer Center; CRUK; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Rooney Family Foundation; Susan G. Komen Foundation for the Cure; Macdonald Family Foundation; Victorian Cancer Agency; Cancer Australia; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; [SAF2010-20493]; [5U01CA113916]; [R01CA140323] FX The study was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341), grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure; Cancer Research UK grants C12292/A11174 and C1287/A10118; the European Commission's Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175). Breast Cancer Family Registry Studies (BCFR): supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), and University of Melbourne (U01 CA69638). The Australian BCFR was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. Melissa C. Southey is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Carriers at FCCC were also identified with support from National Institutes of Health grants P01 CA16094 and R01 CA22435. The New York BCFR was also supported by National Institutes of Health grants P30 CA13696 and P30 ES009089. The Utah BCFR was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1 RR025764, and by Award Number P30 CA042014 from the National Cancer Institute. Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-19/2010, and Hereditary Cancer Association (Paveldimo vezio asociacija). Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr. 2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016. BRCA-gene mutations and breast cancer in South African women (BMBSA): BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. Beckman Research Institute of the City of Hope (BRICOH): Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship. BRICOH was supported by NIH R01CA74415 and NIH P30 CA033752. Copenhagen Breast Cancer Study (CBCS): The CBCS study was supported by the NEYE Foundation. Spanish National Cancer Centre (CNIO): This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493. City of Hope Cancer Center (COH): The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: Jeffrey N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health.; CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): CONSIT TEAM was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumors"), Italian Association for Cancer Research (AIRC, IG 8713), Italian Minitry of Health (Extraordinary National Cancer Program 2006, "Alleanza contro il Cancro" and "Progetto Tumori Femminili), Italian Ministry of Education, University and Research (Prin 2008) Centro di Ascolto Donne Operate al Seno (CAOS) association and by funds from Italian citizens who allocated the 561000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '561000'). German Cancer Research Center (DKFZ): The DKFZ study was supported by the DKFZ. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005, and the BBMRI grant CP46/NWO. Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Rosalind A. Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Canter (FCCC): The authors acknowledge support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): The GEMO study was supported by the Ligue National Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award and the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program. Gynecologic Oncology Group (GOG): This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), Statistical and Data Center (CA 37517), and GOG's Cancer Prevention and Control Committtee (CA 101165). Drs. Mark H. Greene and Phuong L. Mai were supported by funding from the Intramural Research Program, NCI, NIH. Hospital Clinico San Carlos (HCSC): HCSC was supported by RETICC 06/0020/0021, FIS research grant 09/00859, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitivity, and the European Regional Development Fund (ERDF). Helsinki Breast Cancer Study (HEBCS): The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation.; Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary (HUNBOCS): HUNBOCS was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. Institut Catala d'Oncologia (ICO): The ICO study was supported by the Asociacion Espanola Contra el Cancer, Spanish Health Research Foundation, Ramon Areces Foundation, Carlos III Health Institute, Catalan Health Institute, and Autonomous Government of Catalonia and contract grant numbers: ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, and 2009SGR283. International Hereditary Cancer Centre (IHCC): Supported by the Polish Foundation of Science. Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. Iceland Landspitali-University Hospital (ILUH): The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): INHERIT work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, the Canadian Breast Cancer Research Alliance grant 019511 and the Ministry of Economic Development, Innovation and Export Trade grant PSR-SIIRI-701. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics. Istituto Oncologico Veneto (IOVHBOCS): The IOVHBOCS study was supported by Ministero dell'Istruzione, dell'Universitae della Ricerca and Ministero della Salute ("Progetto Tumori Femminili" and RFPS 2006-5-341353, ACC2/R6.9"). Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Amanda B. Spurdle is an NHMRC Senior Research Fellow. The Clinical Follow Up Study was funded from 2001-2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia # 628333. Mayo Clinic (MAYO): MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. McGill University (MCGILL): The McGill Study was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation, and Export Trade. Memorial Sloan-Kettering Cancer Center (MSKCC): The MSKCC study was supported by Breast Cancer Research Foundation, Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Family Foundation, and Lymphoma Foundation. Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD 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). Women's College Research Institute, Toronto (NAROD): NAROD was supported by NIH grant: 1R01 CA149429-01. National Cancer Institute (NCI): Drs. Mark H.; Greene and Phuong L. Mai were supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. National Israeli Cancer Control Center (NICCC): NICCC is supported by Clalit Health Services in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N. N. Petrov Institute of Oncology (NNPIO): The NNPIO study has been supported by the Russian Foundation for Basic Research (grants 11-04-00227, 12-04-00928, and 12-04-01490), the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780), and through a Royal Society International Joint grant (JP090615). The Ohio State University Comprehensive Cancer Center (OSU-CCG): OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. South East Asian Breast Cancer Association Study (SEABASS): SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM. C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): The SMC study was partially funded through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium. Swedish Breast Cancer Study (SWE-BRCA): SWE-BRCA collaborators are supported by the Swedish Cancer Society. The University of Chicago Center for Clinical Cancer Genetics and Global Health (UCHICAGO): UCHICAGO is supported by grants from the US National Cancer Institute (NIH/NCI) and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. University of California Los Angeles (UCLA): The UCLA study was supported by the Jonsson Comprehensive Cancer Center Foundation and the Breast Cancer Research Foundation. University of California San Francisco (UCSF): The UCSF study was supported by the UCSF Cancer Risk Program and the Helen Diller Family Comprehensive Cancer Center. United Kingdom Familial Ovarian Cancer Registries (UKFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. University of Pennsylvania (UPENN): The UPENN study was supported by the National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855), Breast Cancer Research Foundation, Rooney Family Foundation, Susan G. Komen Foundation for the Cure, and the Macdonald Family Foundation. Victorian Familial Cancer Trials Group (VFCTG): The VFCTG study was supported by the Victorian Cancer Agency, Cancer Australia, and National Breast Cancer Foundation. Women's Cancer Research Initiative (WCRI): The WCRI at the Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 85 Z9 87 U1 11 U2 75 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 MAR PY 2013 VL 9 IS 3 AR e1003212 DI 10.1371/journal.pgen.1003212 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA 116EY UT WOS:000316866700002 PM 23544013 ER PT J AU Karyadi, DM Karlins, E Decker, B vonHoldt, BM Carpintero-Ramirez, G Parker, HG Wayne, RK Ostrander, EA AF Karyadi, Danielle M. Karlins, Eric Decker, Brennan vonHoldt, Bridgett M. Carpintero-Ramirez, Gretchen Parker, Heidi G. Wayne, Robert K. Ostrander, Elaine A. TI A Copy Number Variant at the KITLG Locus Likely Confers Risk for Canine Squamous Cell Carcinoma of the Digit SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DOMESTIC DOG; GENETIC-DETERMINANTS; HUMAN CANCER; COAT COLOR; MELANOMA; BREEDS; MODEL; TUMOR; HAIR AB The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs), who have increased risk for squamous cell carcinoma of the digit (SCCD), a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS) on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (P-raw = 1.60x10(-7); P-genome = 0.0066). Additional mapping resolved the region to the KIT Ligand (KITLG) locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72x10(-8)). Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders. C1 [Karyadi, Danielle M.; Karlins, Eric; Decker, Brennan; vonHoldt, Bridgett M.; Carpintero-Ramirez, Gretchen; Parker, Heidi G.; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [vonHoldt, Bridgett M.; Wayne, Robert K.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. RP Karyadi, DM (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Decker, Brennan/0000-0003-4516-7421; Ostrander, Elaine/0000-0001-6075-9738 FU Intramural Program of the National Human Genome Research Institute; American Kennel Club Canine Health Foundation [1052A] FX This work was supported by the Intramural Program of the National Human Genome Research Institute and the American Kennel Club Canine Health Foundation, grant number 1052A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 16 Z9 16 U1 0 U2 17 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 MAR PY 2013 VL 9 IS 3 AR e1003409 DI 10.1371/journal.pgen.1003409 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 116EY UT WOS:000316866700076 PM 23555311 ER PT J AU Nickels, S Truong, T Hein, R Stevens, K Buck, K Behrens, S Eilber, U Schmidt, M Haberle, L Vrieling, A Gaudet, M Figueroa, J Schoof, N Spurdle, AB Rudolph, A Fasching, PA Hopper, JL Makalic, E Schmidt, DF Southey, MC Beckmann, MW Ekici, AB Fletcher, O Gibson, L Silva, ID Peto, J Humphreys, MK Wang, J Cordina-Duverger, E Menegaux, F Nordestgaard, BG Bojesen, SE Lanng, C Anton-Culver, H Ziogas, A Bernstein, L Clarke, CA Brenner, H Muller, H Arndt, V Stegmaier, C Brauch, H Bruning, T Harth, V Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Lambrechts, D Smeets, D Neven, P Paridaens, R Flesch-Janys, D Obi, N Wang-Gohrke, S Couch, FJ Olson, JE Vachon, CM Giles, GG Severi, G Baglietto, L Offit, K John, EM Miron, A Andrulis, IL Knight, JA Glendon, G Mulligan, AM Chanock, SJ Lissowska, J Liu, JJ Cox, A Cramp, H Connley, D Balasubramanian, S Dunning, AM Shah, M Trentham-Dietz, A Newcomb, P Titus, L Egan, K Cahoon, EK Rajaraman, P Sigurdson, AJ Doody, MM Guenel, P Pharoah, PDP Schmidt, MK Hall, P Easton, DF Garcia-Closas, M Milne, RL Chang-Claude, J AF Nickels, Stefan Truong, Therese Hein, Rebecca Stevens, Kristen Buck, Katharina Behrens, Sabine Eilber, Ursula Schmidt, Martina Haeberle, Lothar Vrieling, Alina Gaudet, Mia Figueroa, Jonine Schoof, Nils Spurdle, Amanda B. Rudolph, Anja Fasching, Peter A. Hopper, John L. Makalic, Enes Schmidt, Daniel F. Southey, Melissa C. Beckmann, Matthias W. Ekici, Arif B. Fletcher, Olivia Gibson, Lorna Silva, Isabel dos Santos Peto, Julian Humphreys, Manjeet K. Wang, Jean Cordina-Duverger, Emilie Menegaux, Florence Nordestgaard, Borge G. Bojesen, Stig E. Lanng, Charlotte Anton-Culver, Hoda Ziogas, Argyrios Bernstein, Leslie Clarke, Christina A. Brenner, Hermann Mueller, Heiko Arndt, Volker Stegmaier, Christa Brauch, Hiltrud Bruening, Thomas Harth, Volker Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Lambrechts, Diether Smeets, Dominiek Neven, Patrick Paridaens, Robert Flesch-Janys, Dieter Obi, Nadia Wang-Gohrke, Shan Couch, Fergus J. Olson, Janet E. Vachon, Celine M. Giles, Graham G. Severi, Gianluca Baglietto, Laura Offit, Kenneth John, Esther M. Miron, Alexander Andrulis, Irene L. Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Chanock, Stephen J. Lissowska, Jolanta Liu, Jianjun Cox, Angela Cramp, Helen Connley, Dan Balasubramanian, Sabapathy Dunning, Alison M. Shah, Mitul Trentham-Dietz, Amy Newcomb, Polly Titus, Linda Egan, Kathleen Cahoon, Elizabeth K. Rajaraman, Preetha Sigurdson, Alice J. Doody, Michele M. Guenel, Pascal Pharoah, Paul D. P. Schmidt, Marjanka K. Hall, Per Easton, Doug F. Garcia-Closas, Montserrat Milne, Roger L. Chang-Claude, Jenny CA GENICA Network kConFab AOCS Management Grp TI Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MAMMOGRAPHIC DENSITY; 14Q24.1 RAD51L1; HORMONE-THERAPY; POOLED ANALYSIS; TUMOR SUBTYPES; VARIANTS; CONSORTIUM; FGFR2; WOMEN AB Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (P-interaction = 2.4 x 10(-6)) and between CASP8-rs17468277 and alcohol consumption (P-interaction = 3.1 x 10(-4)). Overall, the perallele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank >= 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (P-interaction = 5.3 x 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors. C1 [Nickels, Stefan; Behrens, Sabine; Eilber, Ursula; Vrieling, Alina; Rudolph, Anja; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence; Guenel, Pascal] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc U1018, Villejuif, France. [Hein, Rebecca] Univ Cologne, PMV Res Grp, Dept Child & Adolescent Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Stevens, Kristen; Olson, Janet E.; Vachon, Celine M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Buck, Katharina] Natl Ctr Tumor Dis, Dept Prevent Oncol, Heidelberg, Germany. [Schmidt, Martina] German Canc Res Ctr, Environm Epidemiol Unit, Heidelberg, Germany. [Haeberle, Lothar; Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Dept Gynecol & Obstet, Univ Hosp, D-91054 Erlangen, Germany. [Vrieling, Alina] Radboud Univ Nijmegen Med Ctr, Dept Hlth Evidence, Nijmegen, Netherlands. [Gaudet, Mia] Amer Canc Soc, Epidemiol Res Program, Div Canc Epidemiol, Atlanta, GA 30329 USA. [Figueroa, Jonine; Hall, Per] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Schoof, Nils] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Spurdle, Amanda B.] Queensland Inst Med Res, Herston, Qld 4006, Australia. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Hopper, John L.; Makalic, Enes; Schmidt, Daniel F.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Fletcher, Olivia] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Gibson, Lorna; Silva, Isabel dos Santos; Peto, Julian] London Sch Hyg & Trop Med, London WC1, England. [Humphreys, Manjeet K.; Wang, Jean; Easton, Doug F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Nordestgaard, Borge G.; Bojesen, Stig E.] Univ Copenhagen, Copenhagen Gen Populat Study, Herlev Univ Hosp, Copenhagen, Denmark. [Nordestgaard, Borge G.; Bojesen, Stig E.] Univ Copenhagen, Dept Clin Biochem, Herlev Univ Hosp, Copenhagen, Denmark. [Lanng, Charlotte] Univ Copenhagen, Dept Breast Surg, Herlev Univ Hosp, Copenhagen, Denmark. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Clarke, Christina A.; John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Clarke, Christina A.; John, Esther M.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Div Epidemiol, Stanford, CA 94305 USA. [Brenner, Hermann; Mueller, Heiko; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Ageing Res, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Bruening, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med German Social Accid In, Bochum, Germany. [Harth, Volker] Univ Saarland, Med Ctr, Inst & Outpatient Clin Occupat Med, Homburg, Germany. [Harth, Volker] Univ Saarland, Fac Med, Homburg, Germany. [Harth, Volker] Univ Med Ctr Hamburg Eppendorf, Inst Occupat Med & Maritime Med, Hamburg, Germany. Johanniter Krankenhaus, Dept Internal Med, Evangel Kliniken Bonn gGmbH, Bonn, Germany. Univ Bonn, Inst Pathol, Bonn, Germany. [GENICA Network] German Canc Res Ctr, Heidelberg, Germany. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Sch Med, Inst Clin Med, Dept Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Bioctr Kuopio, Canc Ctr Eastern Finland, Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Sch Med, Inst Clin Med, Dept Oncol, Kuopio, Finland. [kConFab; AOCS Management Grp] Peter MacCallum Canc Ctr, Kathleen Cuningham Fdn Resesarch Familial Breast, East Melbourne, Australia. [Lambrechts, Diether; Smeets, Dominiek] Katholieke Univ Leuven VIB, Vesalius Res Ctr, Louvain, Belgium. [Neven, Patrick; Paridaens, Robert] Univ Hosp Gasthuisberg, Multidisciplinary Breast Ctr, B-3000 Louvain, Belgium. [Flesch-Janys, Dieter; Obi, Nadia] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Flesch-Janys, Dieter; Obi, Nadia] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Miron, Alexander] Dana Farber Canc Inst, Boston, MA 02115 USA. [Andrulis, Irene L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Glendon, Gord] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Chanock, Stephen J.; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Liu, Jianjun] Genome Inst Singapore, Singapore, Singapore. [Cox, Angela; Cramp, Helen; Connley, Dan] Univ Sheffield, Inst Canc Studies, Dept Oncol, Sheffield, S Yorkshire, England. [Balasubramanian, Sabapathy] Univ Sheffield, Acad Unit Surg Oncol, Dept Oncol, Sheffield, S Yorkshire, England. [Dunning, Alison M.; Shah, Mitul; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Trentham-Dietz, Amy; Newcomb, Polly] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Newcomb, Polly] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Titus, Linda] Dartmouth Hitchcock Med Ctr, Dept Community & Family Med, Dept Pediat, Dartmouth Med Sch, Lebanon, NH 03766 USA. [Cahoon, Elizabeth K.; Rajaraman, Preetha; Sigurdson, Alice J.; Doody, Michele M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Schmidt, Marjanka K.] Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [Schmidt, Marjanka K.] Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Garcia-Closas, Montserrat] Inst Canc Res, Epidemiol Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Genet Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London, England. [Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Human Canc Genet Programme, Madrid, Spain. RP Nickels, S (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. EM j.chang-claude@dkfz.de RI Verdrengh, Evelien/H-4571-2012; Vrieling, Alina/A-2725-2016; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Brenner, Hermann/B-4627-2017; Spurdle, Amanda/A-4978-2011; Andrulis, Irene/E-7267-2013; Ekici, Arif/C-3971-2013; Knight, Julia/A-6843-2012; Garcia-Closas, Montserrat /F-3871-2015; Hartikainen, Jaana/E-6256-2015 OI Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Rudolph, Anja/0000-0001-7520-2035; Spurdle, Amanda/0000-0003-1337-7897; Garcia-Closas, Montserrat /0000-0003-1033-2650; FU Cancer Research UK [C1287/A10118, C1287/A12014, C490/A6187, C490/A10119, C490/A10124]; European Community [223175 (HEALTH-F2-2009-223175)]; European Union COST programme [BM0606]; Fondo de Investigacion Sanitario [PI11/00923]; Australian NHMRC; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); National Cancer Institute, National Institutes of Health under RFA [CA-06-503]; BCFR and Principal Investigators; Cancer Care Ontario [U01 CA69467]; Columbia University [U01 CA69398]; Fox Chase Cancer Center [U01 CA69631]; Huntsman Cancer Institute [U01 CA69446]; Cancer Prevention Institute of California [U01 CA69417]; University of Melbourne [U01 CA69638]; Georgetown University Medical Center Informatics Support Center [HHSN261200900010C]; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); Fondation de France; French National Institute of Cancer (INCa); National League against Cancer; National Agency for Environmental and Occupational Health and Food Safety (ANSES); National Agency for Research (ANR); Association for Research against Cancer (ARC); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; California Breast Cancer Act of 1993; National Institutes of Health [R01 CA77398]; Lon V Smith Foundation [LVS39420]; California Breast Cancer Research Fund [97-10500]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Deutsche Krebshilfe e.V. [70492, 70-2892-BR I]; Government Funding (EVO) of Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; Academy of Finland; University of Eastern Finland; National Breast Cancer Foundation; NHMRC; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; Cancer Foundation of Western Australia; NHMRC [145684, 288704, 454508, 199600]; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of Tasmania and Cancer Foundation of Western Australia; Stichting tegen Kanker [232-2008, 196-2010]; Hamburg Cancer Society; German Cancer Research Center; NIH [CA122340, CA128978]; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Australian NHMRC [209057, 251553, 504711]; National Cancer Institute, Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore (A*STAR); U.S. National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Marit and Hans Rausings Initiative Against Breast Cancer; Yorkshire Cancer Research and the Breast Cancer Campaign; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Massachusetts (KME) [R01CA47305]; Wisconsin (PAN) [R01 CA47147]; New Hampshire (LT-E) [R01CA69664]; Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA FX BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme [BM0606]. DF Easton is a Principal Research Fellow of CR-UK. RL Milne is supported by Fondo de Investigacion Sanitario (PI11/00923). The Australian Breast Cancer Family Registry (ABCFR; 1992-1995) was supported by the Australian NHMRC, the New South Wales Cancer Council, and the Victorian Health Promotion Foundation (Australia). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health, under RFA # CA-06-503, and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (U01 CA69417), University of Melbourne (U01 CA69638), and Georgetown University Medical Center Informatics Support Center (HHSN261200900010C). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating BCFR centres, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR. JL Hopper is an Australia Fellow and MC Southey is a Senior Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia. MC Southey and JL Hopper are Group Leaders of the Victorian Breast Cancer Research Consortium. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital. The CTS was supported by the California Breast Cancer Act of 1993, National Institutes of Health (grants R01 CA77398 and the Lon V Smith Foundation [LVS39420]), and the California Breast Cancer Research Fund (contract 97-10500). Collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ESTHER study was supportd by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe).; The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114; the Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GESBC was supported by the Deutsche Krebshilfe e.V. [70492] and genotyping in part by the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm [P. 685]. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation; the NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC [145684, 288704, 454508]. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC [199600]. AB Spurdle is supported by an NHMRC Senior Research Fellowship. LMBC is supported by the "Stichting tegen Kanker" (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center, and genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. The MCBCS was supported by the NIH grants [CA122340, CA128978] and a Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The Singapore and Swedish Breast Cancer Study (SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR); the U.S. National Institute of Health (NIH); the Susan G. Komen Breast Cancer Foundation; and Marit and Hans Rausings Initiative Against Breast Cancer. The SBCS was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. SEARCH is funded by grants from Cancer Research UK [C490/A6187, C490/A10119, C490/A10124] and the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The US3SS study was supported by Massachusetts (KME, R01CA47305), Wisconsin (PAN, R01 CA47147), and New Hampshire (LT-E, R01CA69664) centers and by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT study was funded by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 55 Z9 55 U1 5 U2 36 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 MAR PY 2013 VL 9 IS 3 AR e1003284 DI 10.1371/journal.pgen.1003284 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 116EY UT WOS:000316866700004 PM 23544014 ER PT J AU Tripathi, V Shen, Z Chakraborty, A Giri, S Freier, SM Wu, XL Zhang, YQ Gorospe, M Prasanth, SG Lal, A Prasanth, KV AF Tripathi, Vidisha Shen, Zhen Chakraborty, Arindam Giri, Sumanprava Freier, Susan M. Wu, Xiaolin Zhang, Yongqing Gorospe, Myriam Prasanth, Supriya G. Lal, Ashish Prasanth, Kannanganattu V. TI Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB SO PLOS GENETICS LA English DT Article ID CANCER-CELLS; CENP-E; CHROMOSOME ALIGNMENT; KINETOCHORE MOTOR; GENE-EXPRESSION; BREAST-CANCER; LUNG-CANCER; PROLIFERATION; CDK2; P53 AB The long noncoding MALAT1 RNA is upregulated in cancer tissues and its elevated expression is associated with hyperproliferation, but the underlying mechanism is poorly understood. We demonstrate that MALAT1 levels are regulated during normal cell cycle progression. Genome-wide transcriptome analyses in normal human diploid fibroblasts reveal that MALAT1 modulates the expression of cell cycle genes and is required for G1/S and mitotic progression. Depletion of MALAT1 leads to activation of p53 and its target genes. The cell cycle defects observed in MALAT1-depleted cells are sensitive to p53 levels, indicating that p53 is a major downstream mediator of MALAT1 activity. Furthermore, MALAT1-depleted cells display reduced expression of B-MYB (Mybl2), an oncogenic transcription factor involved in G2/M progression, due to altered binding of splicing factors on B-MYB pre-mRNA and aberrant alternative splicing. In human cells, MALAT1 promotes cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle-regulated transcription factors. These findings provide mechanistic insights on the role of MALAT1 in regulating cellular proliferation. C1 [Tripathi, Vidisha; Shen, Zhen; Chakraborty, Arindam; Giri, Sumanprava; Prasanth, Supriya G.; Prasanth, Kannanganattu V.] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL USA. [Freier, Susan M.] ISIS Pharmaceut, Carlsbad, CA 92008 USA. [Wu, Xiaolin] Frederick Natl Lab Canc Res, SAIC Frederick, Lab Mol Technol, Frederick, MD USA. [Zhang, Yongqing] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Tripathi, V (reprint author), Univ Illinois, Dept Cell & Dev Biol, Urbana, IL USA. EM kumarp@life.illinois.edu RI Shen, Zhen/C-8676-2013 FU American Cancer Society [RSG-11-174-01-RMC]; NIH [GM088252, GM099669]; NIA-IRP, NIH; Isis Pharmaceutical; [NSF0843604] FX This work was supported by grants from American Cancer Society (RSG-11-174-01-RMC) and NIH GM088252 to KVP and by grants NSF0843604 and NIH GM099669 to SGP. MG and YZ are supported by the NIA-IRP, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; SMF is an employee of Isis Pharmaceutical, receives salary from the company, and holds stock options. The other authors have declared that no competing interests exist. NR 101 TC 195 Z9 211 U1 2 U2 40 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 MAR PY 2013 VL 9 IS 3 AR e1003368 DI 10.1371/journal.pgen.1003368 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 116EY UT WOS:000316866700044 PM 23555285 ER PT J AU Westmoreland, JW Resnick, MA AF Westmoreland, James W. Resnick, Michael A. TI Coincident Resection at Both Ends of Random, gamma-Induced Double-Strand Breaks Requires MRX (MRN), Sae2 (Ctp1), and Mre11-Nuclease SO PLOS GENETICS LA English DT Article ID GROSS CHROMOSOMAL REARRANGEMENTS; SITE-DIRECTED MUTAGENESIS; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; DNA BREAKS; NUCLEASE ACTIVITY; MRE11 NUCLEASE; MRE11-RAD50-XRS2 COMPLEX; MEIOTIC RECOMBINATION; REPAIR AB Resection is an early step in homology-directed recombinational repair (HDRR) of DNA double-strand breaks (DSBs). Resection enables strand invasion as well as reannealing following DNA synthesis across a DSB to assure efficient HDRR. While resection of only one end could result in genome instability, it has not been feasible to address events at both ends of a DSB, or to distinguish 1- versus 2-end resections at random, radiation-induced "dirty" DSBs or even enzyme-induced "clean" DSBs. Previously, we quantitatively addressed resection and the role of Mre11/Rad50/Xrs2 complex (MRX) at random DSBs in circular chromosomes within budding yeast based on reduced pulsed-field gel electrophoretic mobility ("PFGEshift"). Here, we extend PFGE analysis to a second dimension and demonstrate unique patterns associated with 0-, 1-, and 2-end resections at DSBs, providing opportunities to examine coincidence of resection. In G2-arrested WT, Delta rad51 and Delta rad52 cells deficient in late stages of HDRR, resection occurs at both ends of gamma-DSBs. However, for radiation-induced and I-Scel-induced DSBs, 1- end resections predominate in MRX (MRN) null mutants with or without Ku70. Surprisingly, Sae2 (Ctp1/CtIP) and Mre11 nuclease-deficient mutants have similar responses, although there is less impact on repair. Thus, we provide direct molecular characterization of coincident resection at random, radiation-induced DSBs and show that rapid and coincident initiation of resection at gamma-DSBs requires MRX, Sae2 protein, and Mre11 nuclease. Structural features of MRX complex are consistent with coincident resection being due to an ability to interact with both DSB ends to directly coordinate resection. Interestingly, coincident resection at clean I-Scel-induced breaks is much less dependent on Mre11 nuclease or Sae2, contrary to a strong dependence on MRX complex, suggesting different roles for these functions at "dirty" and clean DSB ends. These approaches apply to resection at other DSBs. Given evolutionary conservation, the observations are relevant to DNA repair in human cells. C1 [Westmoreland, James W.; Resnick, Michael A.] NIEHS, Chromosome Stabil Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Westmoreland, JW (reprint author), NIEHS, Chromosome Stabil Sect, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov FU Intramural Research Program of the NIEHS (NIH, DHHS) [1 Z01 ES065073] FX This work was supported by the Intramural Research Program of the NIEHS (NIH, DHHS) under project 1 Z01 ES065073 (MAR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 11 Z9 11 U1 0 U2 4 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 MAR PY 2013 VL 9 IS 3 AR e1003420 DI 10.1371/journal.pgen.1003420 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 116EY UT WOS:000316866700081 PM 23555316 ER PT J AU Wu, Y Waite, LL Jackson, AU Sheu, WHH Absher, SBD Absher, D Arnett, DK Boerwinkle, E Bonnycastle, LL Carty, CL Cheng, I Cochran, B Croteau-Chonka, DC Dumitrescu, L Eaton, CB Franceschini, N Guo, XQ Henderson, BE Hindorff, LA Kim, E Kinnunen, L Komulainen, P Lee, WJ Le Marchand, L Lin, Y Lindstrom, J Lingaas-Holmen, O Mitchell, SL Narisu, N Robinson, JG Schumacher, F Stancaakovaa, A Sundvall, J Sung, YJ Swift, AJ Wang, WC Wilkens, L Wilsgaard, T Young, AM Adair, LS Ballantyne, CM Buzkova, P Chakravarti, A Collins, FS Duggan, D Feranil, AB Ho, LT Hung, YJ Hunt, SC Hveem, K Juang, JMJ Kesaniemi, AY Kuusisto, J Laakso, M Lakka, TA Lee, IT Leppert, MF Matise, TC Moilanen, L Njolstad, I Peters, U Quertermous, T Rauramaa, R Rotter, JI Saramies, J Tuomilehto, J Uusitupa, M Wang, TD Boehnke, M Haiman, CA Chen, YDI Kooperberg, C Assimes, TL Crawford, DC Hsiung, CA North, KE Mohlke, KL AF Wu, Ying Waite, Lindsay L. Jackson, Anne U. Sheu, Wayne H-H. Buyske, Steven Absher, Devin Arnett, Donna K. Boerwinkle, Eric Bonnycastle, Lori L. Carty, Cara L. Cheng, Iona Cochran, Barbara Croteau-Chonka, Damien C. Dumitrescu, Logan Eaton, Charles B. Franceschini, Nora Guo, Xiuqing Henderson, Brian E. Hindorff, Lucia A. Kim, Eric Kinnunen, Leena Komulainen, Pirjo Lee, Wen-Jane Le Marchand, Loic Lin, Yi Lindstrom, Jaana Lingaas-Holmen, Oddgeir Mitchell, Sabrina L. Narisu, Narisu Robinson, Jennifer G. Schumacher, Fred Stancakova, Alena Sundvall, Jouko Sung, Yun-Ju Swift, Amy J. Wang, Wen-Chang Wilkens, Lynne Wilsgaard, Tom Young, Alicia M. Adair, Linda S. Ballantyne, Christie M. Buzkova, Petra Chakravarti, Aravinda Collins, Francis S. Duggan, David Feranil, Alan B. Ho, Low-Tone Hung, Yi-Jen Hunt, Steven C. Hveem, Kristian Juang, Jyh-Ming J. Kesaniemi, Antero Y. Kuusisto, Johanna Laakso, Markku Lakka, Timo A. Lee, I-Te Leppert, Mark F. Matise, Tara C. Moilanen, Leena Njolstad, Inger Peters, Ulrike Quertermous, Thomas Rauramaa, Rainer Rotter, Jerome I. Saramies, Jouko Tuomilehto, Jaakko Uusitupa, Matti Wang, Tzung-Dau Boehnke, Michael Haiman, Christopher A. Chen, Yii-Der I. Kooperberg, Charles Assimes, Themistocles L. Crawford, Dana C. Hsiung, Chao A. North, Kari E. Mohlke, Karen L. TI Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-ARTERY-DISEASE; FUNCTIONAL POLYMORPHISM; GENOTYPE IMPUTATION; COMMON VARIANTS; COMPLEX TRAITS; RISK; GENE; LIPASE AB Genome-wide association studies (GWAS) have identified similar to 100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P, 1610 24 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies. C1 [Wu, Ying; Croteau-Chonka, Damien C.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA. [Waite, Lindsay L.; Absher, Devin] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Sheu, Wayne H-H.; Lee, I-Te] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrine & Metab, Taichung, Taiwan. [Sheu, Wayne H-H.; Ho, Low-Tone; Lee, I-Te] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Sheu, Wayne H-H.] Natl Def Med Ctr, Coll Med, Taipei, Taiwan. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Arnett, Donna K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Boerwinkle, Eric; Cochran, Barbara] Univ Texas Houston, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Bonnycastle, Lori L.; Lindstrom, Jaana; Narisu, Narisu; Swift, Amy J.; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Carty, Cara L.; Lin, Yi; Young, Alicia M.; Peters, Ulrike; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Cheng, Iona; Le Marchand, Loic; Wilkens, Lynne] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Dumitrescu, Logan; Mitchell, Sabrina L.; Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Family Med, Providence, RI 02912 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Epidemiol, Providence, RI 02912 USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Guo, Xiuqing; Kim, Eric; Rotter, Jerome I.; Chen, Yii-Der I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Henderson, Brian E.; Schumacher, Fred; Haiman, Christopher A.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Kinnunen, Leena; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Komulainen, Pirjo; Lakka, Timo A.; Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Kuopio, Finland. [Lee, Wen-Jane] Taichung Vet Gen Hosp, Dept Med Res, Taichung, Taiwan. [Lingaas-Holmen, Oddgeir; Hveem, Kristian] Norwegian Univ Sci & Technol, HUNT Res Ctr, Dept Publ Hlth & Gen Practice, Levanger, Norway. [Robinson, Jennifer G.] Univ Iowa, Iowa City, IA USA. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Sundvall, Jouko] Natl Inst Hlth & Welf, Dis Risk Unit, Helsinki, Finland. [Sung, Yun-Ju] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Wang, Wen-Chang; Hsiung, Chao A.] Natl Hlth Res Inst, Inst Populat Hlth Sci, Div Biostat & Bioinformat, Zhunan, Taiwan. [Wilsgaard, Tom; Njolstad, Inger] Univ Tromso, Dept Community Med, Fac Hlth Sci, Tromso, Norway. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Feranil, Alan B.] Univ San Carlos, Off Populat Studies Fdn, Cebu, Philippines. [Ho, Low-Tone] Taipei Vet Gen Hosp, Dept Internal Med, Taipei, Taiwan. [Ho, Low-Tone] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei, Taiwan. [Hung, Yi-Jen] Tri Serv Gen Hosp, Natl Def Med Ctr, Div Endocrinol & Metab, Taipei, Taiwan. [Hunt, Steven C.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Juang, Jyh-Ming J.; Wang, Tzung-Dau] Natl Taiwan Univ Hosp, Cardiovasc Ctr, Taipei, Taiwan. [Juang, Jyh-Ming J.; Wang, Tzung-Dau] Natl Taiwan Univ Hosp, Dept Internal Med, Div Cardiol, Taipei 100, Taiwan. [Juang, Jyh-Ming J.; Wang, Tzung-Dau] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Kesaniemi, Antero Y.] Univ Oulu, Dept Med, Inst Clin Med, Oulu, Finland. [Kesaniemi, Antero Y.] Oulu Univ Hosp, Clin Res Ctr, Oulu, Finland. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland. [Leppert, Mark F.] Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT 84132 USA. [Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Moilanen, Leena] Kuopio Univ Hosp, Dept Med, SF-70210 Kuopio, Finland. [Moilanen, Leena] Pirkanmaa Hosp Dist, Tampere, Finland. [Peters, Ulrike] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland. [Saramies, Jouko] South Karelia Cent Hosp, Lappeenranta, Finland. [Tuomilehto, Jaakko] South Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tuomilehto, Jaakko] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid, Spain. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Uusitupa, Matti] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland. [North, Kari E.; Mohlke, Karen L.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. RP Wu, Y (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA. EM mohlke@med.unc.edu RI Hsiung, Chao Agnes/E-3994-2010; kinnunen, leena/B-7059-2012; OI Buyske, Steven/0000-0001-8539-5416; kinnunen, leena/0000-0001-8739-4812; WANG, TZUNG-DAU/0000-0002-7180-3607; Juang, Jyh-Ming Jimmy/0000-0003-4767-7636; Lakka, Timo/0000-0002-9199-2871 FU National Human Genome Research Institute (NHGRI); NHGRI ARRA supplements; NHGRI PAGE program [U01HG004803, U01HG004802, U01HG004790]; 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, HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, 2 R01 HL55673-12, HL087647]; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; NIH [DK078150, TW05596, HL085144, DK062370, DK072193, DK093757]; U.S. 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]; PAGE Coordinating Center [U01HG004801-01]; National Institutes of Mental Health; National Health Research Institutes [PH-100-SP-01, BS-094-PP-01, PH-100-PP-03]; National Taiwan University Hospital [NTUH.98-N1266, NTUH100-N1775, NTUH101-N2010, NTUH101-N, VN101-04, NTUH 101-S1784]; NSC [96-2314-B-002-152, 101-2325-002-078, NSC 98-2314-B-075A-002-MY3]; National Science Council of Taiwan [NSC96-2314-B-002-151, NSC98-2314-B-002-122-MY2, NSC 100-2314-B-002-115]; Taichung Veterans General Hospital, Taichung, Taiwan [TCVGH-1013001C, TCVGH-1013002D]; hospital districts of Pirkanmaa; hospital districts of South Ostrobothnia; hospital districts of Central Finland; National Institute for Health and Welfare; Finnish Diabetes Association; Ministry of Social Affairs and Health in Finland; Academy of Finland [129293, 117844, 40758, 211497, 118590, 102318, 123885, 77299, 124243]; Commission of the European Communities; Directorate C-Public Health [2004310]; Finland's Slottery Machine Association; Kuopio University Hospital from Ministry of Health and Social Affairs [5254]; Finnish Funding Agency for Technology and Innovation [40058/07]; Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies, SYSDIET [070014]; Finnish Diabetes Research Foundation; Yrjo Jahnsson Foundation [56358]; Sigrid Juselius Foundation; Juho Vainio Foundation; TEKES [40058/07, 70103/06]; Ministry of Education and Culture of Finland [627]; Kuopio University Hospital [5207]; Finnish Heart Association; Paivikki and Sakari Sohlberg Foundation; European Commission [LSHM-CT-2004-005272]; City of Kuopio; Social Insurance Institution of Finland [4/26/2010]; Finnish Foundation for Cardiovascular Research; University of Eastern Finland; University of Tromso; Norwegian Research Council [185764]; [U01HG004798]; [U01HG004801]; [RR20649]; [ES10126]; [DK56350]; [1Z01-HG000024] FX The data and materials included in this report result from a collaboration among the following studies. PAGE: The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program was provided through the NHGRI PAGE program (U01HG004803 and its NHGRI ARRA supplement). 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, and N01-HC-55022. The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). 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 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. 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. 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 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. HyperGEN: The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673-12. CLHNS: The Cebu Longitudinal Health and Nutrition Survey (CLHNS) was supported by National Institutes of Health grants DK078150, TW05596, and HL085144 and pilot funds from RR20649, ES10126, and DK56350. TAICHI: The TAICHI Metabochip study was supported by NHLBI grant HL087647. Financial support for HALST was through grants from the National Health Research Institutes (PH-100-SP-01). The SAPPHIRe was supported by grants from the National Health Research Institutes (BS-094-PP-01 and PH-100-PP-03). The TCAGEN was partially supported by grants NTUH.98-N1266, NTUH100-N1775, NTUH101-N2010, NTUH101-N, VN101-04, and NTUH 101-S1784 from National Taiwan University Hospital, NSC 96-2314-B-002-152, and NSC 101-2325-002-078. The TACT was supported by grants from the National Science Council of Taiwan (NSC96-2314-B-002-151, NSC98-2314-B-002-122-MY2, and NSC 100-2314-B-002-115). The Taiwan Dragon and TACD were supported by grants from the National Science Council (NSC 98-2314-B-075A-002-MY3) and Taichung Veterans General Hospital, Taichung, Taiwan (TCVGH-1013001C; TCVGH-1013002D). FUSION 2: Support for FUSION was provided by NIH grants DK062370, DK072193, and intramural project number 1Z01-HG000024.; FIN-D2D2007: The FIN-D2D study has been financially supported by the hospital districts of Pirkanmaa, South Ostrobothnia, and Central Finland; the Finnish National Public Health Institute (current National Institute for Health and Welfare); the Finnish Diabetes Association; the Ministry of Social Affairs and Health in Finland; the Academy of Finland (grant number 129293); the Commission of the European Communities; Directorate C-Public Health (grant agreement no. 2004310); and Finland's Slottery Machine Association. DPS: The Finnish Diabetes Prevention Study (DPS) has been financially supported by grants from the Academy of Finland (117844 and 40758, 211497, and 118590), the EVO funding of the Kuopio University Hospital from Ministry of Health and Social Affairs (5254), Finnish Funding Agency for Technology and Innovation (40058/07), Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies, SYSDIET (070014), The Finnish Diabetes Research Foundation, Yrjo Jahnsson Foundation (56358), Sigrid Juselius Foundation, Juho Vainio Foundation, and TEKES grants 70103/06 and 40058/07. DR's EXTRA: Dose-Responses to Exercise Training (DR's EXTRA) study was supported by grants from Ministry of Education and Culture of Finland (627; 2004-2011), Academy of Finland (102318; 123885), Kuopio University Hospital, Finnish Diabetes Association, Finnish Heart Association, Paivikki and Sakari Sohlberg Foundation, and by grants from the European Commission FP6 Integrated Project (EXGENESIS); LSHM-CT-2004-005272, City of Kuopio and Social Insurance Institution of Finland (4/26/2010). METSIM: The METabolic Syndrome In Men Study (METSIM) was supported by grants from the Academy of Finland (grants 77299 and 124243), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Eastern Finland, Kuopio University Hospital (EVO grant 5207), and by National Institutes of Health grant DK093757. HUNT 2: The Nord-Trondelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology NTNU), Nord-Trondelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. TROMSO: This study was supported by University of Tromso, Norwegian Research Council (project number 185764). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 47 Z9 48 U1 1 U2 15 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 MAR PY 2013 VL 9 IS 3 AR e1003379 DI 10.1371/journal.pgen.1003379 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 116EY UT WOS:000316866700054 PM 23555291 ER PT J AU Resnik, DB Master, Z AF Resnik, David B. Master, Zubin TI Policies and Initiatives Aimed at Addressing Research Misconduct in High-Income Countries SO PLOS MEDICINE LA English DT Editorial Material ID RESPONSIBLE CONDUCT; RESEARCH INTEGRITY; NATIONAL-SURVEY; INSTRUCTION; SCIENCE C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Master, Zubin] Albany Med Coll, Alden March Bioeth Inst, Albany, NY 12208 USA. RP Resnik, DB (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 34 TC 12 Z9 12 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD MAR PY 2013 VL 10 IS 3 AR e1001406 DI 10.1371/journal.pmed.1001406 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 115GM UT WOS:000316800600010 PM 23555198 ER PT J AU Demers, JP Sgourakis, NG Gupta, R Loquet, A Giller, K Riedel, D Laube, B Kolbe, M Baker, D Becker, S Lange, A AF Demers, Jean-Philippe Sgourakis, Nikolaos G. Gupta, Rashmi Loquet, Antoine Giller, Karin Riedel, Dietmar Laube, Britta Kolbe, Michael Baker, David Becker, Stefan Lange, Adam TI The Common Structural Architecture of Shigella flexneri and Salmonella typhimurium Type Three Secretion Needles SO PLOS PATHOGENS LA English DT Article ID SOLID-STATE NMR; PROTEIN SECONDARY STRUCTURE; NUCLEAR-MAGNETIC-RESONANCE; III SECRETION; SYSTEM NEEDLE; CHEMICAL-SHIFT; AMYLOID FIBRILS; HIGH-RESOLUTION; FILAMENTOUS PHAGE; UCSF CHIMERA AB The Type Three Secretion System (T3SS), or injectisome, is a macromolecular infection machinery present in many pathogenic Gram-negative bacteria. It consists of a basal body, anchored in both bacterial membranes, and a hollow needle through which effector proteins are delivered into the target host cell. Two different architectures of the T3SS needle have been previously proposed. First, an atomic model of the Salmonella typhimurium needle was generated from solid-state NMR data. The needle subunit protein, PrgI, comprises a rigid-extended N-terminal segment and a helix-loop-helix motif with the N-terminus located on the outside face of the needle. Second, a model of the Shigella flexneri needle was generated from a high-resolution 7.7-angstrom cryo-electron microscopy density map. The subunit protein, MxiH, contains an N-terminal alpha-helix, a loop, another alpha-helix, a 14-residue-long beta-hairpin (Q51-Q64) and a C-terminal alpha-helix, with the N-terminus facing inward to the lumen of the needle. In the current study, we carried out solid-state NMR measurements of wild-type Shigella flexneri needles polymerized in vitro and identified the following secondary structure elements for MxiH: a rigid-extended N-terminal segment (S2-T11), an alpha-helix (L12-A38), a loop (E39-P44) and a C-terminal alpha-helix (Q45-R83). Using immunogold labeling in vitro and in vivo on functional needles, we located the N-terminus of MxiH subunits on the exterior of the assembly, consistent with evolutionary sequence conservation patterns and mutagenesis data. We generated a homology model of Shigella flexneri needles compatible with both experimental data: the MxiH solid-state NMR chemical shifts and the state-of-the-art cryoEM density map. These results corroborate the solid-state NMR structure previously solved for Salmonella typhimurium PrgI needles and establish that Shigella flexneri and Salmonella typhimurium subunit proteins adopt a conserved structure and orientation in their assembled state. Our study reveals a common structural architecture of T3SS needles, essential to understand T3SS-mediated infection and develop treatments. C1 [Demers, Jean-Philippe; Loquet, Antoine; Giller, Karin; Becker, Stefan; Lange, Adam] Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany. [Sgourakis, Nikolaos G.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Gupta, Rashmi; Kolbe, Michael] Max Planck Inst Infect Biol, Dept Cellular Microbiol, Berlin, Germany. [Riedel, Dietmar] Max Planck Inst Biophys Chem, Electron Microscopy Lab, D-37077 Gottingen, Germany. [Laube, Britta] Max Planck Inst Infect Biol, Core Facil Microscopy, Berlin, Germany. [Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. RP Demers, JP (reprint author), Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany. EM kolbe@mpiib-berlin.mpg.de; dabaker@u.washington.edu; sabe@nmr.mpibpc.mpg.de; adla@nmr.mpibpc.mpg.de RI Baker, David/K-8941-2012 OI Baker, David/0000-0001-7896-6217 FU Max Planck Society; Deutsche Forschungsgemeinschaft; NSERC of Canada; Fondation Bettencourt Schueller; EMBO; National Institutes of Health [1 R01 GM092802-01]; European Union Seventh Framework Program [261863 (Bio-NMR)]; European Research Council under the European Community FX This work was supported, in whole or in part, by the Max Planck Society, the Deutsche Forschungsgemeinschaft (Emmy Noether Fellowship to A. Lange), the NSERC of Canada (Postgraduate Scholarship to J. Demers), the Fondation Bettencourt Schueller and EMBO (to A. Loquet), the National Institutes of Health (1 R01 GM092802-01 to D. Baker), and the European Union Seventh Framework Program under Grant Agreement 261863 (Bio-NMR). The European Research Council has provided financial support to M. Kolbe under the European Community's Seventh Framework Programme (FP7/2007-2013). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 28 Z9 28 U1 3 U2 32 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 MAR PY 2013 VL 9 IS 3 AR e1003245 DI 10.1371/journal.ppat.1003245 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 117LB UT WOS:000316953800045 PM 23555258 ER PT J AU Nikolaitchik, OA Dilley, KA Fu, W Gorelick, RJ Tai, SHS Soheilian, F Ptak, RG Nagashima, K Pathak, VK Hu, WS AF Nikolaitchik, Olga A. Dilley, Kari A. Fu, William Gorelick, Robert J. Tai, S-H. Sheldon Soheilian, Ferri Ptak, Roger G. Nagashima, Kunio Pathak, Vinay K. Hu, Wei-Shau TI Dimeric RNA Recognition Regulates HIV-1 Genome Packaging SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; IN-VITRO; SECONDARY STRUCTURE; VIRAL REPLICATION; INITIATION SIGNAL; KISSING COMPLEX; MULTIPLE STAGES; MESSENGER-RNA; TYPE-1 RNA AB How retroviruses regulate the amount of RNA genome packaged into each virion has remained a long-standing question. Our previous study showed that most HIV-1 particles contain two copies of viral RNA, indicating that the number of genomes packaged is tightly regulated. In this report, we examine the mechanism that controls the number of RNA genomes encapsidated into HIV-1 particles. We hypothesize that HIV-1 regulates genome packaging by either the mass or copy number of the viral RNA. These two distinct mechanisms predict different outcomes when the genome size deviates significantly from that of wild type. Regulation by RNA mass would result in multiple copies of a small genome or one copy of a large genome being packaged, whereas regulation by copy number would result in two copies of a genome being packaged independent of size. To distinguish between these two hypotheses, we examined the packaging of viral RNA that was larger (approximate to 17 kb) or smaller (approximate to 3 kb) than that of wild-type HIV-1 (approximate to 9 kb) and found that most particles packaged two copies of the viral genome regardless of whether they were 17 kb or 3 kb. Therefore, HIV-1 regulates RNA genome encapsidation not by the mass of RNA but by packaging two copies of RNA. To further explore the mechanism that governs this regulation, we examined the packaging of viral RNAs containing two packaging signals that can form intermolecular dimers or intramolecular dimers (self-dimers) and found that one self-dimer is packaged. Therefore, HIV-1 recognizes one dimeric RNA instead of two copies of RNA. Our findings reveal that dimeric RNA recognition is the key mechanism that regulates HIV-1 genome encapsidation and provide insights into a critical step in the generation of infectious viruses. C1 [Nikolaitchik, Olga A.; Dilley, Kari A.; Tai, S-H. Sheldon; Pathak, Vinay K.; Hu, Wei-Shau] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Fu, William; Ptak, Roger G.] So Res Inst, Frederick, MD USA. [Gorelick, Robert J.] SAIC Frederick Inc, AIDS & Canc Virol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Soheilian, Ferri; Nagashima, Kunio] SAIC Frederick Inc, Electron Microscopy Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Nikolaitchik, OA (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM Wei-Shau.Hu@nih.gov FU Intramural AIDS Targeted Antiviral Program, NIH; Intramural Research Program of the Center for Cancer Research, NCI; NCI, NIH [HHSN261200800001E] FX This work was funded in part by the Intramural AIDS Targeted Antiviral Program, NIH, and the Intramural Research Program of the Center for Cancer Research, NCI, and in part (RJG, FS, and KN) with federal funds from the NCI, NIH, under Contract No. HHSN261200800001E to SAIC-Frederick, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 30 Z9 30 U1 0 U2 14 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 MAR PY 2013 VL 9 IS 3 AR e1003249 DI 10.1371/journal.ppat.1003249 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 117LB UT WOS:000316953800046 PM 23555259 ER PT J AU Tamerius, JD Shaman, J Alonso, WJ Bloom-Feshbach, K Uejio, CK Comrie, A Viboud, C AF Tamerius, James D. Shaman, Jeffrey Alonso, Wladmir J. Bloom-Feshbach, Kimberly Uejio, Christopher K. Comrie, Andrew Viboud, Cecile TI Environmental Predictors of Seasonal Influenza Epidemics across Temperate and Tropical Climates SO PLOS PATHOGENS LA English DT Article ID ABSOLUTE-HUMIDITY; RELATIVE-HUMIDITY; CONTACT NETWORK; UNITED-STATES; TRANSMISSION; VIRUS; SURVIVAL; MORTALITY; SINGAPORE; SYNCHRONY AB Human influenza infections exhibit a strong seasonal cycle in temperate regions. Recent laboratory and epidemiological evidence suggests that low specific humidity conditions facilitate the airborne survival and transmission of the influenza virus in temperate regions, resulting in annual winter epidemics. However, this relationship is unlikely to account for the epidemiology of influenza in tropical and subtropical regions where epidemics often occur during the rainy season or transmit year-round without a well-defined season. We assessed the role of specific humidity and other local climatic variables on influenza virus seasonality by modeling epidemiological and climatic information from 78 study sites sampled globally. We substantiated that there are two types of environmental conditions associated with seasonal influenza epidemics: "cold-dry" and "humid-rainy". For sites where monthly average specific humidity or temperature decreases below thresholds of approximately 11-12 g/kg and 18-21 degrees C during the year, influenza activity peaks during the cold-dry season (i.e., winter) when specific humidity and temperature are at minimal levels. For sites where specific humidity and temperature do not decrease below these thresholds, seasonal influenza activity is more likely to peak in months when average precipitation totals are maximal and greater than 150 mm per month. These findings provide a simple climate-based model rooted in empirical data that accounts for the diversity of seasonal influenza patterns observed across temperate, subtropical and tropical climates. C1 [Tamerius, James D.; Shaman, Jeffrey] Columbia Univ, New York, NY 10027 USA. [Tamerius, James D.; Shaman, Jeffrey; Alonso, Wladmir J.; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bloom-Feshbach, Kimberly] Mt Sinai Sch Med, New York, NY USA. [Uejio, Christopher K.] Florida State Univ, Dept Geog, Tallahassee, FL 32306 USA. [Comrie, Andrew] Univ Arizona, Sch Geog & Dev, Tucson, AZ USA. RP Tamerius, JD (reprint author), Columbia Univ, New York, NY 10027 USA. EM jt2684@columbia.edu FU Earth Institute Postdoctoral Fellowship program at Columbia University; Division of International Epidemiology and Population Studies; Fogarty International Center; National Institutes of Health; International Influenza Unit; Office of Global Affairs, Department of Health and Human Services; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; National Institutes of Health Models of Infectious Disease Agent Study program (MIDAS) [1U54GM088558] FX JDT acknowledges support from the Earth Institute Postdoctoral Fellowship program at Columbia University. Support was also provided by the in-house Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, which is funded by the International Influenza Unit, Office of Global Affairs, Department of Health and Human Services, the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the National Institutes of Health Models of Infectious Disease Agent Study program (MIDAS) through cooperative agreement 1U54GM088558. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 59 Z9 60 U1 0 U2 20 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 MAR PY 2013 VL 9 IS 3 AR e1003194 DI 10.1371/journal.ppat.1003194 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 117LB UT WOS:000316953800006 PM 23505366 ER PT J AU Panchision, DM AF Panchision, David M. TI Meeting Report: Using Stem Cells for Biological and Therapeutics Discovery in Mental Illness, April 2012 SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Induced pluripotent stem cells; Reprogramming; Direct cell conversion; Neural differentiation; Experimental models; Genomics; Neuron ID RETT-SYNDROME; NEURONS AB This report synthesizes the discussions during a workshop convened April 24-25, 2012, by the National Institute of Mental Health and the Foundation for the NIH in Bethesda, Maryland, that focused on progress and challenges in the use of patient-derived reprogrammed cells for basic biological discovery, target identification, screening, and drug development for mental illnesses such as schizophrenia, bipolar disorder, and autism spectrum disorders. The workshop revealed that the greatest progress has been made in reprogramming methods and agreed-upon standards for validating the resulting induced pluripotent stem cell lines. However, challenges remain in several areas, including efficiently generating and validating specific neural cell types with respect to regional identity, establishing assays with predictive validity to mental illness pathophysiology, and generating sufficient statistical power and data reproducibility across laboratories. A brainstorming session yielded a number of suggestions, including calls to (a) facilitate the replication of results by standardizing protocols and samples used across laboratories; (b) improve technology by generating cheaper/faster targeting methods, reporters, and assays; and (c) improve resource sharing and collaboration, with an emphasis on rapid sharing of new cell lines, technologies, and best practices, possibly incorporated into a public-private partnership. The meeting provided an important venue for academic, government, and private sector scientists to address potential opportunities for translational and clinical applications of reprogrammed cell research. A number of activities since the workshop have reflected the feedback from meeting participants. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:217-222 C1 NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. RP Panchision, DM (reprint author), NIMH, Div Neurosci & Basic Behav Sci, 6001 Execut Blvd,MSC 9641, Bethesda, MD 20892 USA. EM panchisiond@mail.nih.gov FU National Institute of Mental Health FX Support for and clearance of this report was provided by the National Institute of Mental Health. A condensed summary of this workshop, along with the agenda and participant list, can be found on the NIMH website at http://www.nimh.nih.gov/research-funding/scientific-meetings/meeting-sum maries.shtml. The views expressed do not necessarily represent the views of the NIMH, the National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 26 TC 7 Z9 7 U1 3 U2 15 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD MAR PY 2013 VL 2 IS 3 BP 217 EP 222 DI 10.5966/sctm.2012-0149 PG 6 WC Cell & Tissue Engineering SC Cell Biology GA 110FO UT WOS:000316428200015 PM 23408104 ER PT J AU Schweikart, K Guo, L Shuler, Z Abrams, R Chiao, ET Kolaja, KL Davis, M AF Schweikart, Karen Guo, Liang Shuler, Zachary Abrams, Rory Chiao, Eric T. Kolaja, Kyle L. Davis, Myrtle TI The effects of jaspamide on human cardiomyocyte function and cardiac ion channel activity SO TOXICOLOGY IN VITRO LA English DT Article DE Stem cell-derived cardiomyocytes; Jaspamide; Cyclodepsipeptide; In vitro alternatives; Predictive toxicology; Cardiotoxicity ID SPONGE JASPIS-SPLENDANS; CELL-DERIVED CARDIOMYOCYTES; F-ACTIN; PROSTATE CARCINOMA; NATURAL-PRODUCT; KV1.5; JASPLAKINOLIDE; BINDING; CYTOSKELETON; DERIVATIVES AB Jaspamide (jasplakinolide; NSC-613009) is a cyclodepsipeptide that has antitumor activity. A narrow margin of safety was observed between doses required for efficacy in mouse tumor models and doses that caused severe acute toxicity in rats and dogs. We explored the hypothesis that the observed toxicity was due to cardiotoxicity. Jaspamide was tested in a patch clamp assay to determine its effect on selected cardiac ion channels. Jaspamide (10 mu M) inhibited Kv1.5 activity by 98.5%. Jaspamide also inhibited other channels including Cav1.2, Cav3.2, and HCN2; however, the Kv11.1 (hERG) channel was minimally affected. Using spontaneously contracting human cardiomyocytes derived from induced pluripotent stem cells, effects on cardiomyocyte contraction and viability were also examined. Jaspamide (30 nM to 30 mu M) decreased cardiomyocyte cell indices and beat amplitude, putative measurements of cell viability and cardiac contractility, respectively. Concentration-dependent increases in rhythmic beating rate were noted at <= 6 h of treatment, followed by dose-dependent decreases after 6 and 72 h exposure. The toxic effects of jaspamide were compared with that of the known cardiotoxicant mitoxantrone, and confirmed by multiparameter fluorescence imaging analysis. These results support the hypothesis that the toxicity observed in rats and dogs is due to toxic effects of jaspamide on cardiomyocytes. Published by Elsevier Ltd. C1 [Schweikart, Karen; Davis, Myrtle] NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. [Guo, Liang; Shuler, Zachary; Abrams, Rory; Chiao, Eric T.; Kolaja, Kyle L.] Hoffmann La Roche Inc, Global Early & Investigat Safety, Nutley, NJ 07110 USA. RP Schweikart, K (reprint author), NCI, Dev Therapeut Program, Execut Plaza North Room 8038, Bethesda, MD 20892 USA. EM schweikk@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 26 TC 6 Z9 6 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD MAR PY 2013 VL 27 IS 2 BP 745 EP 751 DI 10.1016/j.tiv.2012.12.005 PG 7 WC Toxicology SC Toxicology GA 113CC UT WOS:000316642800027 PM 23261645 ER PT J AU Skolnick, P AF Skolnick, Phil TI Anxioselective anxiolytics: additional perspective Response SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Letter C1 NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. RP Skolnick, P (reprint author), NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, 6001 Execut Blvd,Suite 4123, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2013 VL 34 IS 3 BP 146 EP 146 DI 10.1016/j.tips.2013.01.007 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 115TD UT WOS:000316833900002 PM 23384390 ER PT J AU Simons-Morton, BG Cheon, K Guo, F Albert, P AF Simons-Morton, Bruce G. Cheon, Kyeongmi Guo, Feng Albert, Paul TI Trajectories of kinematic risky driving among novice teenagers SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Adolescence; Risk taking; Motor vehicle crashes; Naturalistic driving ID ADOLESCENT DRIVERS; CRASH; PERSPECTIVE; INVOLVEMENT; EXPERIENCE; CITATIONS; TRENDS AB Objectives: Elevated gravitational force event rates are associated with the likelihood of a crash or near crash and provide an objective measure of risky driving. The purpose of this research is to examine the patterns over time of kinematic measures of risky driving among novice teenage drivers. Methods: Driving data were collected from 42 newly licensed teenage drivers during the first 18 months of licensure. Data recording systems installed in participants' vehicles provided information on driving performance and driver characteristics. Latent class and logistic regression models were used to analyze trajectories of elevated gravitational-force (g-force) event rates, called kinematic risky driving, with respect to risk groups and associated factors. Results: Kinematic risky driving over the 18-month study period was best characterized as two classes, a higher-risk and a lower-risk class. The rate of kinematic risky driving during the first 6 months generally maintained over 18 months. Indeed, of those classified by latent class analysis as higher risk, 88.9%, 94.4% and 94.4% had average event rates above the median in the 1st, 2nd, and 3rd 6-month periods, respectively, indicating substantial tracking over time. Friends' risky driving, friends' risky behavior, self-reported risky driving, and perceptions about risky driving and driving privileges were associated with trip-level rates of kinematic risky driving. However, none of these factors was associated with trip-level rates after stratifying by overall risk in a latent class model, although friend's risky driving was marginally significant. Conclusion: Kinematic risky driving tended to track over time within the lower and higher risky driving groups. Self-reported risky driving and having risky friends were predictors of kinematic risky driving rates, but these variables did not explain the heterogeneity within higher and lower classes of risky drivers. Published by Elsevier Ltd. C1 [Simons-Morton, Bruce G.; Cheon, Kyeongmi; Albert, Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Guo, Feng] Virginia Tech Univ, VTTI, Blacksburg, VA USA. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. EM MortonB@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [Z01 HD001707-10, ZIA HD001707-14]; NICHD NIH HHS [N01-HD-5-3405] NR 31 TC 4 Z9 4 U1 0 U2 9 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 MAR PY 2013 VL 51 BP 27 EP 32 DI 10.1016/j.aap.2012.10.011 PG 6 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA 099JJ UT WOS:000315617000004 PM 23182780 ER PT J AU Gussin, HA Tomlinson, ID Cao, DC Qian, HH Rosenthal, SJ Pepperberg, DR AF Gussin, Helene A. Tomlinson, Ian D. Cao, Dingcai Qian, Haohua Rosenthal, Sandra J. Pepperberg, David R. TI Quantum Dot Conjugates of GABA and Muscimol: Binding to alpha 1 beta 2 gamma 2 and rho 1 GABA(A) Receptors SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE GABA receptor; ligand-gated ion channel; muscimol; GABA; quantum dot conjugate; nanocrystal ID GATED ION CHANNELS; WHITE PERCH RETINA; PHARMACOLOGY; ACID; ANTAGONIST; CELLS; NANOCRYSTALS; TRANSPORTER; MEMBRANE; SUBTYPES AB GABA(A) receptors are ligand-gated ion channels that mediate inhibitory synaptic signaling in the CNS. Fluorescent probes with the ability to target these receptors can provide insights into receptor location, distribution and g dynamics in live cells, while revealing abnormalities in their a distribution and dynamics that could occur in a variety of diseases. We have developed fluorescent probes of GABA(A) receptors that are composed of a CdSe/ZnS core-shell nanocrystal (quantum dot; qdot) conjugated to pegylated derivatives of the GABA receptor agonists GABA and muscimol (GABA-qdots and muscimol-qdots, respectively). Quantitative fluorescence imaging was used to analyze the binding activity of these conjugates to alpha 1 beta 2 gamma 2 GABA(A) and rho 1 GABA(A) receptors expressed in Xenopus oocytes. The selectivity of these conjugates for alpha 1 beta 2 gamma 2 GABA(A) and rho 1 GABA(A) receptors was determined by their ability to compete with the antagonists bicuculline and methyl-(1,2,3,6-tetrahydropyridin-4-yl)phosphinic acid (TPMPA). Both GABA- and muscimol-qdots exhibited robust binding to both alpha 1 beta 2 gamma 2 and rho 1 GABA(A) receptors. At alpha 1 beta 2 gamma 2 receptors, pretreatment with bicuculline reduced conjugate binding by >= 8-fold on average, an extent far exceeding the reduction produced by TPMPA (similar to 30%). Conversely, at rho 1 receptors, pretreatment with TPMPA inhibited binding by similar to 10-fold, an extent greatly exceeding the change produced by bicuculline (similar to 50% or less). These results indicate specific binding of muscimol-qdots and GABA-qdots to alpha 1 beta 2 gamma 2 GABA(A) and rho 1 GABA(A) receptors in a manner that preserves the respective pharmacological sensitivities of these receptors to TPMPA and bicuculline, and encourage the use of qdot-conjugated neurotransmitter analogs as labeling agents at GABA(A) receptors. C1 [Gussin, Helene A.; Cao, Dingcai; Qian, Haohua; Pepperberg, David R.] Univ Illinois, Dept Ophthalmol & Visual Sci, Lions Illinois Eye Res Inst, Chicago, IL 60612 USA. [Tomlinson, Ian D.; Rosenthal, Sandra J.] Vanderbilt Univ, Dept Chem, Nashville, TN 37235 USA. [Rosenthal, Sandra J.] Vanderbilt Univ, Dept Phys, Nashville, TN 37235 USA. [Rosenthal, Sandra J.] Vanderbilt Univ, Dept Chem & Biomol Engn, Nashville, TN 37235 USA. [Rosenthal, Sandra J.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37235 USA. [Qian, Haohua] NEI, NIH, Bethesda, MD 20892 USA. RP Pepperberg, DR (reprint author), Univ Illinois, Dept Ophthalmol & Visual Sci, 18S5 W Taylor St, Chicago, IL 60612 USA. EM davipepp@uic.edu FU NIH [EY016094, EY001792, EB003728, EM72048]; Daniel F. and Ada L. Rice Foundation (Skokie, IL); Macular Degeneration Research Program of the American Health Assistance Foundation (Clarksburg, MD); Hope for Vision (Washington, DC); Research to Prevent Blindness (New York, NY); Beckman Initiative for Macular Research (Los Angeles, CA); University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) [UL1RR029879]; Cless Family Foundation (Northbrook, IL); Intramural Program of the National Eye Institute FX This work was supported by NIH grants EY016094, EY001792, EB003728, and EM72048; by grants from the Daniel F. and Ada L. Rice Foundation (Skokie, IL); by the Macular Degeneration Research Program of the American Health Assistance Foundation (Clarksburg, MD); by Hope for Vision (Washington, DC), by Research to Prevent Blindness (New York, NY); by the Beckman Initiative for Macular Research (Los Angeles, CA); by award UL1RR029879 from the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS); by the Cless Family Foundation (Northbrook, IL); and by the Intramural Program of the National Eye Institute. NR 52 TC 5 Z9 5 U1 1 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2013 VL 4 IS 3 BP 435 EP 443 DI 10.1021/cn300144v PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 112LQ UT WOS:000316594100009 PM 23509979 ER PT J AU Zhang, CL AF Zhang, Cuilin TI Gestational diabetes: health consequences and determinants with focus on lifestyle and modifiable factors SO ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA LA English DT Meeting Abstract C1 [Zhang, Cuilin] NICHD, NIH, Div Epidemiol Stat & Prevent Res, Rockville, 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 0001-6349 J9 ACTA OBSTET GYN SCAN JI Acta Obstet. Gynecol. Scand. PD MAR PY 2013 VL 92 SU 160 SI SI BP 6 EP 6 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 108DP UT WOS:000316272000003 ER PT J AU Arnardottir, NY Koster, A Van Domelen, DR Brychta, RJ Caserotti, P Eiriksdottir, G Sverrisdottir, JE Launer, LJ Gudnason, V Johannsson, E Harris, TB Chen, KY Sveinsson, T AF Arnardottir, Nanna Yr Koster, Annemarie Van Domelen, Dane R. Brychta, Robert J. Caserotti, Paolo Eiriksdottir, Gudny Sverrisdottir, Johanna Eyrun Launer, Lenore J. Gudnason, Vilmundur Johannsson, Erlingur Harris, Tamara B. Chen, Kong Y. Sveinsson, Thorarinn TI Objective measurements of daily physical activity patterns and sedentary behaviour in older adults: Age, Gene/Environment Susceptibility-Reykjavik Study SO AGE AND AGEING LA English DT Article DE physical activity; accelerometry; sedentary behaviour; older adults; BMI; AGES-Reykjavik; older people ID UNITED-STATES; LIFE EXPECTANCY; HEALTH; ACCELEROMETER; PEOPLE; QUESTIONNAIRE; OPPORTUNITIES; RELIABILITY; CHALLENGES; LONGEVITY AB Background: objectively measured population physical activity (PA) data from older persons is lacking. The aim of this study was to describe free-living PA patterns and sedentary behaviours in Icelandic older men and women using accelerometer. Methods: from April 2009 to June 2010, 579 AGESII-study participants aged 73-98 years wore an accelerometer (Actigraph GT3X) at the right hip for one complete week in the free-living settings. Results: in all subjects, sedentary time was the largest component of the total wear time, 75%, followed by low-light PA, 21%. Moderate-vigorous PA (MVPA) was <1%. Men had slightly higher average total PA (counts x day(-1)) than women. The women spent more time in low-light PA but less time in sedentary PA and MVPA compared with men (P < 0.001). In persons <75 years of age, 60% of men and 34% of women had at least one bout >= 10 min of MVPA, which decreased with age, with only 25% of men and 9% of women 85 years and older reaching this. Conclusion: sedentary time is high in this Icelandic cohort, which has high life-expectancy and is living north of 60 northern latitude. C1 [Arnardottir, Nanna Yr; Sveinsson, Thorarinn] Univ Iceland, Res Ctr Movement Sci, IS-101 Reykjavik, Iceland. [Arnardottir, Nanna Yr; Eiriksdottir, Gudny; Sverrisdottir, Johanna Eyrun; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Koster, Annemarie; Van Domelen, Dane R.; Caserotti, Paolo; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, Maastricht, Netherlands. [Brychta, Robert J.; Chen, Kong Y.] NIDDKD, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. [Caserotti, Paolo] Univ So Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland. [Johannsson, Erlingur] Iceland Univ Educ, Ctr Sport & Hlth Sci, Laugarvatn, Iceland. RP Arnardottir, NY (reprint author), Univ Iceland, Res Ctr Movement Sci, Stapi 5 Hringbraut, IS-101 Reykjavik, Iceland. EM nya@hi.is RI Koster, Annemarie/E-7438-2010; Sveinsson, Thorarinn/F-7554-2010; Gudnason, Vilmundur/K-6885-2015; OI Sveinsson, Thorarinn/0000-0001-8989-5514; Gudnason, Vilmundur/0000-0001-5696-0084; Chen, Kong/0000-0002-0306-1904 FU NIH [N01-AG-1-2100]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Institutes of Health Intramural Research Program [Z01 DK071013, Z01 DK071014] FX This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). This study was also supported by National Institutes of Health Intramural Research Program, grant number: Z01 DK071013 and Z01 DK071014 to R.J.B. and K.Y.C. The researchers are indebted to the participants for their willingness to participate in the study NR 33 TC 33 Z9 36 U1 5 U2 38 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD MAR PY 2013 VL 42 IS 2 BP 222 EP 229 DI 10.1093/ageing/afs160 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 106PP UT WOS:000316157400016 PM 23117467 ER PT J AU Gaur, AH Cohen, RA Read, JS Hance, LF Dominguez, K Alarcon, JO Menezes, J Peixoto, MF Mussi-Pinhata, MM Coelho, DF Mitchell, C Siberry, GK AF Gaur, Aditya H. Cohen, Rachel A. Read, Jennifer S. Hance, Laura Freimanis Dominguez, Kenneth Alarcon, Jorge O. Menezes, Jacqueline Peixoto, Mario F. Mussi-Pinhata, Marisa M. Coelho, Debora F. Mitchell, Charles Siberry, George K. TI Prechewing and Prewarming Food for HIV-Exposed Children: A Prospective Cohort Experience from Latin America SO AIDS PATIENT CARE AND STDS LA English DT Editorial Material ID PREMASTICATION; TRANSMISSION; INFANTS; PROMOTE; HEALTH C1 [Gaur, Aditya H.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Cohen, Rachel A.; Hance, Laura Freimanis] Westat Corp, Rockville, MD USA. [Read, Jennifer S.; Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, DHHS, Bethesda, MD USA. [Dominguez, Kenneth] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Alarcon, Jorge O.] Univ San Marcos, Inst Med Trop Daniel Alcides Carrion, Seccion Epidemiol, Lima, Peru. [Menezes, Jacqueline] Hosp Fed Servidores Estado, Rio De Janeiro, Brazil. [Peixoto, Mario F.] Hosp Femina, Unidade Prevencao Transmissao Vertical, Porto Alegre, RS, Brazil. [Mussi-Pinhata, Marisa M.] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, Brazil. [Coelho, Debora F.] Santa Casa Misericordia Porto Alegre, Ctr Pesquisa Maternoinfantil Irmandade, Porto Alegre, RS, Brazil. [Mitchell, Charles] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. RP Gaur, AH (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, MS 600,262 Danny Thomas Pl, Memphis, TN 38105 USA. EM aditya.gaur@stjude.org OI Alarcon, Jorge/0000-0002-0800-2380 FU NICHD NIH HHS [N01-HD-8-0001, N01-HD-3-3345]; PHS HHS [HHSN267200800001C] NR 11 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD MAR PY 2013 VL 27 IS 3 BP 142 EP 145 DI 10.1089/apc.2012.0459 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 105EK UT WOS:000316048200002 PM 23477456 ER PT J AU Paz, C Samake, S Anderson, JM Faye, O Traore, P Tall, K Cisse, M Keita, S Valenzuela, JG Doumbia, S AF Paz, Carlos Samake, Sibiry Anderson, Jennifer M. Faye, Ousmane Traore, Pierre Tall, Koureishi Cisse, Moumine Keita, Somita Valenzuela, Jesus G. Doumbia, Seydou TI Short Report: Leishmania major, the Predominant Leishmania Species Responsible for Cutaneous Leishmaniasis in Mali SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID 2 NEIGHBORING VILLAGES; PCR; IDENTIFICATION; PREVALENCE; INFECTION; DIAGNOSIS; SLIDES AB Leishmania major is the only species of Leishmania known to cause cutaneous leishmanisis (CL) in Mali. We amplified Leishmania DNA stored on archived Giemsa-stained dermal scraping slides obtained from self-referral patients with clinically suspected CL seen in the Center National d'Appui A La Lutte Contre La Maladie (CNAM) in Bamako, Mali, to determine if any other Leishmania species were responsible for CL in Mali and evaluate its geographic distribution. Polymerase chain reaction (PCR) amplification was performed using a Leishmania species-specific primer pair that can amplify DNA from L. major, L. tropica, L. infantum, and L. donovani parasites, possible causative agents of CL in Mali. L. major was the only species detected in 41 microscopically confirmed cases of CL from five regions of Mali (Kayes, Koulikoro, Segou, Mopti, and Tombouctou). These results implicate L. major as the predominant, possibly exclusive species responsible for CL in Mali. C1 [Paz, Carlos] Univ Chicago, Dermatol Sect, Chicago, IL 60637 USA. [Samake, Sibiry; Doumbia, Seydou] Univ Sci Tech & Technol Bamako, Int Ctr Excellence Res ICER Mali, Bamako, Mali. [Samake, Sibiry; Doumbia, Seydou] Univ Sci Tech & Technol Bamako, Dept Publ Hlth, Fac Med, Bamako, Mali. [Anderson, Jennifer M.; Valenzuela, Jesus G.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Faye, Ousmane; Traore, Pierre; Tall, Koureishi; Cisse, Moumine; Keita, Somita] Natl Ctr Support Dis Control CNAM, Bamako, Mali. RP Doumbia, S (reprint author), Univ Sci Tech & Technol Bamako, Int Ctr Excellence Res ICER Mali, Bamako, Mali. EM Carlos.Paz@uchospitals.edu; ssam@icermali.org; jenanderson@niaid.nih.gov; faye_o@yahoo.fr; pierretraore@yahoo.fr; dibtall@yahoo.fr; moumine.cisse@gmail.com; somitak@yahoo.fr; jvalenzuela@niaid.nih.gov; sdoumbia@icermali.org FU Intramural Research Program of the National Institutes of Health; University of Bamako FX We would like to thank Bourama Traore, Ibrahim Sissoko, and Cheick Coulibaly from the Leishmaniasis Laboratory, International Center of Excellence in Research (ICER-Mali) for their technical assistance with this study. We also thank Drs. Shaden Kamhawi and Fabiano Oliveira for technical assistance and reviewing this manuscript. This research was supported in part by the Intramural Research Program of the National Institutes of Health and the University of Bamako. NR 14 TC 5 Z9 5 U1 0 U2 5 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAR PY 2013 VL 88 IS 3 BP 583 EP 585 DI 10.4269/ajtmh.12-0434 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 106QC UT WOS:000316158800032 PM 23324218 ER PT J AU Trinchieri, G AF Trinchieri, G. TI GUT COMMENSAL BACTERIA DETERMINE CANCER RESPONSE TO TREATMENT BY MODULATING SYSTEMIC INFLAMMATION SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 11th International Congress on Targeted Anticancer Therapies (TAT) CY MAR 04-06, 2013 CL Paris, FRANCE SP Natl Canc Inst, Ctr Canc Res, Novartis Pharma, AbbVie, Astex Pharmaceut, Boehringer Ingelheim Int, Roche, Servier, Pfizer Pharma, Sanofi-Aventis France C1 [Trinchieri, G.] NCI, Frederick, MD 21701 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2013 VL 24 SU 1 BP 12 EP 12 PG 1 WC Oncology SC Oncology GA 106EN UT WOS:000316125600024 ER PT J AU Rixe, O Qi, X Chu, Z Celerier, J Leconte, L Minet, N Pakradouni, J Kaur, B Cuttitta, F AF Rixe, O. Qi, X. Chu, Z. Celerier, J. Leconte, L. Minet, N. Pakradouni, J. Kaur, B. Cuttitta, F. TI NOV C-TER: A NOVEL VEGF-INDEPENDENT ANTI-ANGIOGENIC AGENT WITH A PROMISING PRECLINICAL ANTI-TUMOR EFFICACY SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 11th International Congress on Targeted Anticancer Therapies (TAT) CY MAR 04-06, 2013 CL Paris, FRANCE SP Natl Canc Inst, Ctr Canc Res, Novartis Pharma, AbbVie, Astex Pharmaceut, Boehringer Ingelheim Int, Roche, Servier, Pfizer Pharma, Sanofi-Aventis France C1 [Rixe, O.] GRU Canc Ctr, Augusta, GA USA. [Qi, X.; Chu, Z.] Univ Cincinnati, Inst Canc, Cincinnati, OH USA. [Celerier, J.; Leconte, L.; Minet, N.; Pakradouni, J.] Sisene Biotechnol, Paris, France. [Kaur, B.] Ohio State Univ, Columbus, OH 43210 USA. [Cuttitta, F.] NCI, Gaithersburg, MD USA. RI Cuttitta, Frank/B-4758-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2013 VL 24 SU 1 BP 14 EP 14 PG 1 WC Oncology SC Oncology GA 106EN UT WOS:000316125600032 ER PT J AU Carter, C Rajan, A Khozin, S Thomas, A Lopez-Chavez, A Brzezniak, C Doyle, L Keen, C Manu, M Raffeld, M Giaccone, G AF Carter, C. Rajan, A. Khozin, S. Thomas, A. Lopez-Chavez, A. Brzezniak, C. Doyle, L. Keen, C. Manu, M. Raffeld, M. Giaccone, G. TI THE EVALUATION OF SELUMETINIB A MEK-INHIBITOR WITH AND WITHOUT THE ADDITION OF ERLOTINIB IN KRAS MUTATED NON-SMALL CELL LUNG CANCER SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 11th International Congress on Targeted Anticancer Therapies (TAT) CY MAR 04-06, 2013 CL Paris, FRANCE SP Natl Canc Inst, Ctr Canc Res, Novartis Pharma, AbbVie, Astex Pharmaceut, Boehringer Ingelheim Int, Roche, Servier, Pfizer Pharma, Sanofi-Aventis France C1 [Carter, C.; Brzezniak, C.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Rajan, A.; Khozin, S.; Thomas, A.; Lopez-Chavez, A.; Keen, C.; Manu, M.; Raffeld, M.; Giaccone, G.] NCI, NIH, Bethesda, MD 20892 USA. [Doyle, L.] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. 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 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2013 VL 24 SU 1 BP 15 EP 15 PG 1 WC Oncology SC Oncology GA 106EN UT WOS:000316125600037 ER PT J AU Luo, J AF Luo, J. TI TARGETING RAF KINASES IN BRAF AND KRAS MUTANT CANCERS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 11th International Congress on Targeted Anticancer Therapies (TAT) CY MAR 04-06, 2013 CL Paris, FRANCE SP Natl Canc Inst, Ctr Canc Res, Novartis Pharma, AbbVie, Astex Pharmaceut, Boehringer Ingelheim Int, Roche, Servier, Pfizer Pharma, Sanofi-Aventis France C1 [Luo, J.] NCI, Bethesda, MD 20892 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 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2013 VL 24 SU 1 BP 15 EP 15 PG 1 WC Oncology SC Oncology GA 106EN UT WOS:000316125600036 ER PT J AU Thomas, A Rajan, A Lopez-Chavez, A Wang, Y Giaccone, G AF Thomas, A. Rajan, A. Lopez-Chavez, A. Wang, Y. Giaccone, G. TI From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma SO ANNALS OF ONCOLOGY LA English DT Review DE molecular profiling; next-generation sequencing; non-small-cell lung cancer; tumor heterogeneity ID ADAPTIVE SIGNATURE DESIGN; FACTOR-RECEPTOR MUTATIONS; LYMPH-NODE METASTASES; PHASE-III TRIAL; EGFR MUTATIONS; CLINICAL-PRACTICE; CANCER GENOMES; PRIMARY TUMORS; GENE STATUS; GEFITINIB AB Although tumor molecular-profile-directed therapy appears promising in early clinical studies, there are many practical challenges to its successful clinical application in non-small-cell lung cancer (NSCLC). These challenges may be broadly classified as those relating to tumor (heterogeneity), tissue (acquisition and processing), testing (assays for molecular profiling) and trials (clinical evaluation of molecular markers and drugs). Strategies to overcome these challenges include (i) understanding the biological basis of tumor heterogeneity and of carcinogenesis in the large subset of patients with no currently evident driver events; (ii) technological advances in minimally invasive acquisition of tumor and next-generation sequencing (NGS) which would enable single-platform analysis of molecular alterations in limited tissue at a reasonable turnaround time (TAT); (iii) deliberation in early stages of drug development as well as clinical trial design to identify, validate and assess the clinical utility of biomarkers in conjunction with drugs and (iv) collaboration to improve understanding of and accrual to trials enrolling patients with rare molecular alterations. C1 [Thomas, A.; Rajan, A.; Wang, Y.; Giaccone, G.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Lopez-Chavez, A.] Oregon Hlth & Sci Univ, Div Hematol Med Oncol, Portland, OR 97201 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural program, National Cancer Institute, National Institutes of Health. NR 62 TC 29 Z9 30 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2013 VL 24 IS 3 BP 577 EP 585 DI 10.1093/annonc/mds478 PG 9 WC Oncology SC Oncology GA 111ET UT WOS:000316504900002 PM 23131389 ER PT J AU Wadhawan, R Oh, W Vohr, BR Saha, S Das, A Bell, EF Laptook, A Shankaran, S Stoll, BJ Walsh, MC Higgins, R AF Wadhawan, Rajan Oh, William Vohr, Betty R. Saha, Shampa Das, Abhik Bell, Edward F. Laptook, Abbott Shankaran, Seetha Stoll, Barbara J. Walsh, Michele C. Higgins, Rose TI Spontaneous intestinal perforation in extremely low birth weight infants: association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age SO ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION LA English DT Article ID PATENT DUCTUS-ARTERIOSUS; NATIONAL DATA SET; NECROTIZING ENTEROCOLITIS; GASTROINTESTINAL PERFORATION; PREMATURE-INFANTS; PROPHYLAXIS; INSIGHTS; EXPOSURE; TRIAL; RISK AB Background Spontaneous intestinal perforation (SIP) is associated with the use of postnatal glucocorticoids and indometacin in extremely low birth weight (ELBW) infants. The authors hypothesised: 1) an association of SIP with the use of antenatal steroids (ANS) and indometacin either as prophylaxis for intraventricular hemorrhage (IVH) (P Indo) or for treatment of PDA (Indo/PDA) and 2) an increased risk of death or abnormal neurodevelopmental outcomes in infants with SIP at 18-22 months corrected age. Design/Methods The authors retrospectively identified ELBW infants with SIP in the Neonatal Research Network's generic database. Unadjusted analysis identified the differences in maternal, neonatal and clinical variables between infants with and without SIP. Logistic regression analysis identified the adjusted OR for SIP with reference to ANS, P Indo and Indo/PDA. Neurodevelopmental outcomes were assessed among survivors at 18-22 months corrected age. Results Indo/PDA was associated with an increased risk of SIP (adjusted OR 1.61; 95% CI 1.25 to 2.08), while P Indo and ANS were not. SIP was independently associated with an increased risk of death or neurodevelopmental impairment (NDI) (adjusted OR 1.85; 95% CI 1.32 to 2.60) and NDI among survivors (adjusted OR 1.75, 95% CI 1.20 to 2.55). Conclusion Indometacin used for IVH prophylaxis and ANS were not associated with the occurrence of SIP in ELBW infants. Indometacin used for treatment of symptomatic PDA was however associated with an increased risk of SIP. ELBW infants with SIP have an increased risk of poor neurodevelopmental outcomes. C1 [Wadhawan, Rajan] Univ S Florida, All Childrens Hosp, Div Neonatol, St Petersburg, FL 33701 USA. [Oh, William; Vohr, Betty R.; Laptook, Abbott] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Saha, Shampa] Res Triangle Inst, Dept Stat & Epidemiol, Res Triangle Pk, NC 27709 USA. [Das, Abhik] RTI Int, Rockville, MD USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Childrens Hosp Michigan, Detroit, MI 48202 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Walsh, Michele C.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Higgins, Rose] Eunice Kennedy Shiver Natl Inst Child Hlth & Huma, Bethesda, MD USA. RP Wadhawan, R (reprint author), Florida Hosp Children, Ctr Neonatal Care, Orlando, FL 32804 USA. EM Rajan.Wadhawan.MD@flhosp.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Child Health & Human Development; National Institutes of Health FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network. Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analysed the data for this study. On behalf of the NRN, Drs. Abhik Das (DCC Principal Investigator) and Shampa Saha (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. The authors are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study: NRN Steering Committee Chairs: Alan H. Jobe, MD PhD, University of Cincinnati (2003-2006); Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006-present). Brigham and Women's Hospital, Children's Hospital Boston, and Beth Israel Deaconess Medical Center (GCRC M01 RR2172, GCRC M01 RR2635, U10 HD34167) - Ann R. Stark, MD; Stacy Dow, RN; Colleen Driscoll; Kerri Fournier, RN; Kimberly Gronsman Lee, MD. Case Western Reserve University Rainbow Babies & Children's Hospital (GCRC M01 RR80, U10 HD21364) - Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Deanne E. Wilson-Costello, MD; Nancy S. Newman, BA RN; Harriet G. Friedman, MA; Bonnie S. Siner, RN. Cincinnati Children's Hospital Medical Center University of Cincinnati Hospital, and Good Samaritan Hospital (GCRC M01 RR8084, U10 HD27853) - Kurt Schibler, MD; Edward F. Donovan, MD; Kate Bridges, MD; Jean J. Steichen, MD; Kimberly Yolton, PhD; Barbara Alexander, RN; Teresa L. Gratton, PA; Cathy Grisby, BSN CCRC; Jody Hessling, RN; Holly L. Mincey, RN BSN; Marcia Worley Mersmann, RN CCRC. Duke University School of Medicine University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (GCRC M01 RR30, U10 HD40492) - Ronald N. Goldberg, MD; C. Michael Cotten, MD MHS; Ricki F. Goldstein, MD; Kathy J. Auten, MSHS; Kathryn E. Gustafson, PhD; Melody B. Lohmeyer, RN MSN. Emory University Children's Healthcare of Atlanta, Grady Memorial Hospital, and Emory Crawford Long Hospital (GCRC M01 RR39, U10 HD27851) - Ira Adams-Chapman, MD; Linda Black; Ann M. Blackwelder, RNC BS MS; Sheena Carter, PhD; Elisabeth Dinkins, PNP; Ellen C. Hale, RN BS CCRC; Judson Miller, MD; Maureen Mulligan LaRossa, RN; Irma Seabrook, RRT; Gloria V. Smikle, PNP MSN. Eunice Kennedy Shriver National Institute of Child Health and Human Development - Linda L. Wright, MD; Stephanie Wilson Archer, MA; Elizabeth M. McClure, MEd. Indiana University Indiana University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (GCRC M01 RR750, U10 HD27856) - Brenda B. Poindexter, MD MS; James A. Lemons, MD; Anna M. Dusick, MD FAAP; Diana D. Appel, RN BSN; Lon G. Bohnke; MS; Marilyn Bull; MD; Ann B. Cook, MS; Greg Eaken, PhD; Dianne E. Herron, RN; Darlene Kardatzke, MD; Carolyn Lytle, MD MPH; Lucy C. Miller, RN BSN CCRC; Heike M. Minnich, PsyD HSPP; Leslie Richard, RN; Leslie Dawn Wilson, BSN CCRC. RTI International (U01 HD36790) - W. Kenneth Poole, PhD; Betty K. Hastings; Elizabeth M. McClure, MEd; Jamie E. Newman, PhD MPH; Jeanette O'Donnell Auman, BS; Carolyn Petrie Huitema, MS; Scott E. Schaefer, MS; Kristin M. Zaterka-Baxter, RN BSN.; Stanford University California Pacific Medical Center, El Camino Hospital, and Lucile Packard Children's Hospital (GCRC M01 RR70, U10 HD27880) - Krisa P. Van Meurs, MD; David K. Stevenson, MD; Marian M. Adams, MD; Charles E. Ahlfors, MD; Monica Hajdena-Dawson, MD; Susan R. Hintz, MD MS; M. Bethany Ball, BS CCRC; Robert D. Stebbins, MD; Joan M. Baran, PhD; Lori E. Bond, PhD; Ginger K. Brudos, PhD; Anne M. DeBattista, RN PNP; Jean G. Kohn, MD MPH; Carol G. Kuelper, PhD; Julie C. Lee-Ancajas, PhD; Renee P. Pyle, PhD; Dharshi Sivakumar, MD MRCP; Nicholas H. St. John, PhD. University of Alabama at Birmingham Health System and Children's Hospital of Alabama (GCRC M01 RR32, U10 HD34216) - Waldemar A. Carlo, MD; Kirstin J. Bailey, PhD; Fred J. Biasini, PhD; Monica V. Collins, RN BSN MaEd; Stephanie A. Chopko, PhD; Shirley S. Cosby, RN BSN; Mary Beth Moses, PT MS PCS; Kathleen G. Nelson, MD; Myriam Peralta-Carcelen, MD MPH; Vivien A. Phillips, RN BSN; Julie Preskitt, MSOT MPH; Richard V. Rector, PhD; Sally Whitley, MA OTR-L FAOTA. University of California - San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461) - Neil N. Finer, MD; Paul R. Wozniak, MD; Maynard R. Rasmussen, MD; Yvonne E. Vaucher, MD MPH; Martha G. Fuller, RN MSN; Kathy Arnell, RNC; Rene Barbieri-Welge; Ayala Ben-Tall; Renee Bridge, RN; Clarence Demetrio, RN; Chris Henderson, RCP CRTT; Elaine Ito; Meghan Lukasik; Deborah Pontillo; Donna Posin, OTR/L MPA; Wade Rich, BSHS RRT; Cheryl Runyan; James Wilkes. University of Miami Holtz Children's Hospital (GCRC M01 RR16587, U10 HD21397) - Charles R. Bauer, MD; Shahnaz Duara, MD; Maria Calejo, RN; Alexis N. Diaz, BA; Ruth Everett-Thomas, RN MSN; Silvia M. Frade Eguaras, MA; Yamiley C. Gideon, BA; Sylvia Hiriart-Fajardo, MD; Amy Mur Worth, RN MS; Alexandra Stroerger. University of New Mexico Health Sciences Center (GCRC M01 RR997, U10 HD53089) - Lu-Ann Papile, MD; Conra Backstrom Lacy, RN; Ginny Laadt, PhD OTR; Debra V. Long, BSN; Jean Lowe, PhD; Rebecca Montman, RN. University of Rochester Medical Center Golisano Children's Hospital (GCRC M01 RR44, U10 HD40521) - Dale L. Phelps, MD; Gary J. Myers, MD; Linda J. Reubens, RN CCRC; Julie Babish Johnson, MSW; Erica Burnell, RN; Diane Hust, MS RN CS; Rosemary L. Jensen; Emily Kushner, MA; Joan Merzbach, LMSW; Mary Rowan, RN; Kelley Yost, PhD; Lauren Zwetsch, PNP. University of Tennessee (U10 HD21415) - Sheldon B. Korones, MD; Henrietta S. Bada, MD; Tina Hudson, RN BSN; Marilyn Williams, LCSW; Kimberly Yolton, PhD. University of Texas Southwestern Medical Center at Dallas Parkland Health & Hospital System and Children's Medical Center Dallas (GCRC M01 RR633, U10 HD40689) - Pablo J. Sanchez, MD; Abbot R. Laptook, MD; Charles R. Rosenfeld, MD; Wand A. Salhab, MD; R. Sue Broyles, MD; Roy J. Heyne, MD; Sally S. Adams, MS RN CPNP; Cristin Dooley, PhD LSSP; Alicia Guzman; Gaynelle Hensley, RN; Jackie F. Hickman, RN; Elizabeth Heyne, PA; Christine Lupino, MS; Linda A. Madden, BSN RN CPNP; Susie Madison, RN; Nancy A. Miller, RN; Janet S. Morgan, RN; Catherine Twell Boatman, MS. University of Texas Health Science Center at Houston Medical School, Children's Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373) -Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Pamela J. Bradt, MD MPH; Patricia W. Evans, MD; Beverly Foley Harris, RN BSN; Tern Major-Kincade, MD MPH; Brenda H. Morris, MD; Laura L. Whitely, MD; Esther G. Akpa, RN BSN; Nora I. Alaniz, BS; Magda Cedillo; Patty A.; Cluff, RN; Susan Dieterich, PhD; Claudia I. Franco, RNC MSN; Anna E. Lis, RN BSN; Sarah Martin, RN BSN; Georgia E. McDavid, RN; Maegan C. Simmons, RN; Patti Pierce Tate, RCP; Stacey Reddoch, BA; Sharon L. Wright, MT. Wake Forest University Baptist Medical Center, Forsyth Medical Center, and Brenner Children's Hospital (GCRC M01 RR7122, U10 HD40498) - T. Michael O'Shea, MD MPH; Robert G. Dillard, MD; Lisa K. Washburn, MD; Cherrie D. Welch, MD MPH; Deborah Evans Allred, MA LPA; Donald J. Goldstein, PhD; Barbara G. Jackson, RN BSN; Nancy J. Peters, RN CCRP; Carroll Peterson, MA; Ellen L. Waldrep, MS; Melissa Whalen Morris, MA; Gail Wiley Hounshell, PhD. Wayne State University Hutzel Women's Hospital and Children's Hospital of Michigan (U10 HD21385) - Virginia Delaney-Black, MD MPH; Athina Pappas, MD; Rebecca Bara, RN BSN; Debra Driscoll, RN BSN; Laura Goldston, MA; Yvette R. Johnson, MD MPH; Deborah Kennedy, RN BSN; Geraldine Muran, RN BSN. Women & Infants' Hospital of Rhode Island (U10 HD27904) - Regina A. Gargus, MD FAAP; James R. Moore, MD; Bonnie E. Stephens, MD; Rachel V. Walden, MD; Barbara Alksninis, PNP; Angelita M. Hensman, RN BSN; Shabnam Lainwala, MD; Theresa M. Leach, MEd CAES; Martha R. Leonard, BA BS; Lucy Noel; Victoria E. Watson, MS CAS. Yale University Yale-New Haven Children's Hospital (CTSA UL1 RR24139, GCRC M01 RR125, GCRC M01 RR6022, U10 HD27871) - Richard A. Ehrenkranz, MD; Patricia Gettner, RN; Monica Konstantino, RN BSN; Linda Mayes, MD; JoAnn Poulsen, RN; Elaine Romano, MSN; Janet Taft, RN BSN; Joanne Williams, RN BSN.; National Institute of Child Health & Human Development. NR 24 TC 13 Z9 14 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1359-2998 J9 ARCH DIS CHILD-FETAL JI Arch. Dis. Child.-Fetal Neonatal Ed. PD MAR PY 2013 VL 98 IS 2 BP F127 EP F132 DI 10.1136/archdischild-2011-300659 PG 6 WC Pediatrics SC Pediatrics GA 105RT UT WOS:000316090800009 PM 22684157 ER PT J AU Arimbasseri, AG Rijal, K Maraia, RJ AF Arimbasseri, Aneeshkumar G. Rijal, Keshab Maraia, Richard J. TI Transcription termination by the eukaryotic RNA polymerase III SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE RPC11; RPC53; RPC37; RPC2; Intrinsic transcript cleavage; RNA:DNA hybrid ID YEAST LA PROTEIN; LUPUS ANTIGEN-LA; 5S RIBOSOMAL-RNA; U6 SNRNA GENE; SACCHAROMYCES-CEREVISIAE; STRUCTURAL BASIS; ALPHA-AMANITIN; ELONGATION COMPLEX; BINDING PROTEIN; DNA HYBRID AB RNA polymerase (pol) III transcribes a multitude of tRNA and 5S rRNA genes as well as other small RNA genes distributed through the genome. By being sequence-specific, precise and efficient, transcription termination by pol III not only defines the 3' end of the nascent RNA which directs subsequent association with the stabilizing La protein, it also prevents transcription into downstream DNA and promotes efficient recycling. Each of the RNA polymerases appears to have evolved unique mechanisms to initiate the process of termination in response to different types of termination signals. However, in eukaryotes much less is known about the final stage of termination, destabilization of the elongation complex with release of the RNA and DNA from the polymerase active center. By comparison to pols I and II, pol III exhibits the most direct coupling of the initial and final stages of termination, both of which occur at a short oligo(dT) tract on the non-template strand (dA on the template) of the DNA. While pol III termination is autonomous involving the core subunits C2 and probably Cl, it also involves subunits Cl 1, 07 and C53, which act on the pol III catalytic center and exhibit homology to the pol II elongation factor TFIIS and TFIIF alpha/beta respectively. Here we compile knowledge of pol III termination and associate mutations that affect this process with structural elements of the polymerase that illustrate the importance of C53/37 both at its docking site on the pol III lobe and in the active center. The models suggest that some of these features may apply to the other eukaryotic pols. This article is part of a Special Issue entitled: Transcription by Odd Pols. Published by Elsevier B.V. C1 [Arimbasseri, Aneeshkumar G.; Rijal, Keshab; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Differentiat, NIH, Bethesda, MD USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Rockville, MD USA. RP Maraia, RJ (reprint author), 31 Ctr Dr,Rm 2A25, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov OI Arimbasseri, Gopalakrishnan Aneeshkumar/0000-0001-5266-2688 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 165 TC 19 Z9 19 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAR-APR PY 2013 VL 1829 IS 3-4 SI SI BP 318 EP 330 DI 10.1016/j.bbagrm.2012.10.006 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 111LG UT WOS:000316522200009 PM 23099421 ER PT J AU Persson, EC Schwartz, LM Park, Y Trabert, B Hollenbeck, AR Graubard, BI Freedman, ND McGlynn, KA AF Persson, E. Christina Schwartz, Lauren M. Park, Yikyung Trabert, Britton Hollenbeck, Albert R. Graubard, Barry I. Freedman, Neal D. McGlynn, Katherine A. TI Alcohol Consumption, Folate Intake, Hepatocellular Carcinoma, and Liver Disease Mortality SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; UNITED-STATES; RISK-FACTORS; PLASMA HOMOCYSTEINE; NATIONAL-INSTITUTES; C677T POLYMORPHISM; PROSPECTIVE COHORT; HEPATITIS-C; CANCER AB Background: Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH-American Association of Retired Persons Diet and Health Study. Methods: The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazards ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index, and diabetes. HCC incidence (n = 435) was determined through 2006 via linkage with cancer registries, and liver disease mortality (n = 789) was determined through 2008 via linkage to the U.S. Social Security Administration Death Master File and the National Death Index Plus by the National Center for Health Statistics. Results: Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.42-2.60) and liver disease mortality (HR: 5.84; 95%CI: 4.81-7.10), whereas folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (P-interaction = 0.03), but had no effect on the relationship between alcohol and liver disease mortality (P-interaction = 0.54). Conclusions: These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC. Impact: Folate intake may be beneficial in the prevention of alcohol-associated HCC. Cancer Epidemiol Biomarkers Prev; 22(3); 415-21. (c) 2013 AACR. C1 [Persson, E. Christina; Schwartz, Lauren M.; Trabert, Britton; McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Park, Yikyung; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Persson, EC (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS Suite 550 Room 5008, Bethesda, MD 20852 USA. EM christina.persson@nih.gov RI Freedman, Neal/B-9741-2015; Trabert, Britton/F-8051-2015; OI Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of NIH (National Cancer Institute) FX This study was supported by the Intramural Research Program of NIH (National Cancer Institute). NR 40 TC 17 Z9 18 U1 2 U2 13 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 MAR PY 2013 VL 22 IS 3 BP 415 EP 421 DI 10.1158/1055-9965.EPI-12-1169 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 105EE UT WOS:000316047600011 PM 23307533 ER PT J AU Poole, EM Merritt, MA Jordan, SJ Yang, HP Hankinson, SE Park, Y Rosner, B Webb, PM Cramer, DW Wentzensen, N Terry, KL Tworoger, SS AF Poole, Elizabeth M. Merritt, Melissa A. Jordan, Susan J. Yang, Hannah P. Hankinson, Susan E. Park, Yikung Rosner, Bernard Webb, Penelope M. Cramer, Daniel W. Wentzensen, Nicolas Terry, Kathryn L. Tworoger, Shelley S. TI Hormonal and Reproductive Risk Factors for Epithelial Ovarian Cancer by Tumor Aggressiveness SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SURVIVAL; WOMEN; PROGESTERONE; SURGERY; HEALTH; COHORT AB Background: Approximately half of epithelial ovarian cancers are fatal within 3 years; however, roughly 35% of women survive for at least 10 years. In the Nurses' Health Study, New England Case-Control Study, Australian Ovarian Cancer Study, and NIH-AARP Diet and Health Study, we investigated potential differences in the associations with ovarian cancer risk factors by tumor aggressiveness, defined on the basis of time from diagnosis until death. Methods: We calculated relative risks (RR) and 95% confidence intervals (CI) for associations of known or suspected ovarian cancer risk factors with rapidly fatal (death within 3 years of diagnosis) and less aggressive tumors (all others) using Cox proportional hazards competing risks analysis (NHS and AARP) or polytomous logistic regression (NECC, AOCS). Results were combined using random effects meta-analysis. Results: Increasing age was associated with greater risk of rapidly fatal versus less aggressive disease (RR, 5-year increase: 1.39; 95% CI, 1.29-1.49 vs. RR, 1.09; 95% CI, 1.03-1.16, respectively; P-diff < 0.0001). Oral contraceptive use was associated with a greater decreased risk of rapidly fatal (RR, 5-year increase: 0.69; 95% CI, 0.58-0.82) versus less aggressive disease (RR, 0.81; 95% CI, 0.74-0.89; P-diff, 0.002). Conversely, increasing parity was associated only with less aggressive disease (RR per child, 0.87; 95% CI, 0.81-0.93). Conclusion: In this analysis of 4,342 cases, there were clear differences in risk factors for rapidly fatal versus less aggressive ovarian tumors. Impact: Differences in risk factor associations by tumor aggressiveness suggests the developmental pathways through which the tumors develop and may be important for developing primary preventive strategies for the most aggressive cancers. Cancer Epidemiol Biomarkers Prev; 22(3); 429-36. (c) 2013 AACR. C1 [Poole, Elizabeth M.; Hankinson, Susan E.; Rosner, Bernard; Tworoger, Shelley S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med,Epidemiol Ctr, Boston, MA 02115 USA. [Merritt, Melissa A.; Cramer, Daniel W.; Terry, Kathryn L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol,Epidemiol Ctr, Boston, MA 02115 USA. [Poole, Elizabeth M.; Merritt, Melissa A.; Hankinson, Susan E.; Rosner, Bernard; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Yang, Hannah P.; Park, Yikung; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Jordan, Susan J.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Jordan, Susan J.; Webb, Penelope M.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Merritt, Melissa A.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. RP Poole, EM (reprint author), Channing Labs, 181 Longwood Ave,3rd Floor, Boston, MA 02115 USA. EM nhlip@channing.harvard.edu OI Merritt, Melissa A./0000-0002-5067-6119; Tworoger, Shelley/0000-0002-6986-7046; Webb, Penelope/0000-0003-0733-5930; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute [P01 CA87969, R03 CA143928, T32 CA009001, R01 CA54419, P50 CA105009, R25 CA098566]; Intramural Research Program of the National Institutes of Health; US Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of New South Wales; Cancer Council of Queensland; Cancer Council of South Australia; Cancer Council of Tasmania; Cancer Council of Victoria; Cancer Foundation of Western Australia; National Health and Medical Research Council of Australia [199600, 400413]; Department of Defense [W81XWH-10-1-0280] FX NHS: The Nurses' Health Study (NHS) was financially supported by the National Cancer Institute grants P01 CA87969 and R03 CA143928; Dr. E.M. Poole was supported by the National Cancer Institute grant T32 CA009001. In the NIH-AARP study,; AARP: H.P. Yang, Y. Park, and N. Wentzensen were supported by the Intramural Research Program of the National Institutes of Health.; AOCS: The Australian Ovarian Cancer Study (AOCS) was supported financially by the US Army Medical Research and Materiel Command DAMD17-01-1-0729, the Cancer Councils of New South Wales, Queensland, South Australia, Tasmania, and Victoria, the Cancer Foundation of Western Australia, and grants No. 199600 and 400413 from the National Health and Medical Research Council of Australia. S.J. Jordan and P.M. Webb were financially supported by fellowships from the National Health and Medical Research Council of Australia.; NECC: The New England Case-Control (NECC) study received funding from the National Cancer Institute via grants R01 CA54419, P50 CA105009, and the Department of Defense grant W81XWH-10-1-0280; M.A. Merritt was supported by National Cancer Institute grant R25 CA098566. NR 27 TC 22 Z9 22 U1 0 U2 7 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 MAR PY 2013 VL 22 IS 3 BP 429 EP 436 DI 10.1158/1055-9965.EPI-12-1183-T PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 105EE UT WOS:000316047600013 PM 23307531 ER PT J AU Slager, SL Achenbach, SJ Asmann, YW Camp, NJ Rabe, KG Goldin, LR Call, TG Shanafelt, TD Kay, NE Cunningham, JM Wang, AH Weinberg, JB Norman, AD Link, BK Leis, JF Vachon, CM Lanasa, MC Caporaso, NE Novak, AJ Cerhan, JR AF Slager, Susan L. Achenbach, Sara J. Asmann, Yan W. Camp, Nicola J. Rabe, Kari G. Goldin, Lynn R. Call, Timothy G. Shanafelt, Tait D. Kay, Neil E. Cunningham, Julie M. Wang, Alice H. Weinberg, J. Brice Norman, Aaron D. Link, Brian K. Leis, Jose F. Vachon, Celine M. Lanasa, Mark C. Caporaso, Neil E. Novak, Anne J. Cerhan, James R. TI Mapping of the IRF8 Gene Identifies a 3 ' UTR Variant Associated with Risk of Chronic Lymphocytic Leukemia but not Other Common Non-Hodgkin Lymphoma Subtypes SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POLYMORPHISMS AB Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3' untranslated region (UTR) of IRF8 (rs1044873, log additive OR = 0.7, P = 1.81 x 10(-6)). This SNP was not associated with the other NHL subtypes (all P > 0.05). Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. Impact: These data provide support that a functional variant within the 3'UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk. Cancer Epidemiol Biomarkers Prev; 22(3); 461-6. (c) 2013 AACR. C1 [Slager, Susan L.; Achenbach, Sara J.; Asmann, Yan W.; Rabe, Kari G.; Call, Timothy G.; Shanafelt, Tait D.; Kay, Neil E.; Cunningham, Julie M.; Wang, Alice H.; Norman, Aaron D.; Leis, Jose F.; Vachon, Celine M.; Novak, Anne J.; Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN 55905 USA. [Camp, Nicola J.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Goldin, Lynn R.; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Weinberg, J. Brice; Lanasa, Mark C.] Duke Univ, Med Ctr, Durham, NC USA. [Weinberg, J. Brice] Durham VA Med Ctr, Durham, NC USA. [Link, Brian K.] Univ Iowa, Coll Med, Iowa City, IA USA. RP Slager, SL (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM slager@mayo.edu OI Cerhan, James/0000-0002-7482-178X FU Celgene; Gilead; NIH [CA118444, CA148690, CA97274, CA92153, CA134919]; Veterans Affairs Research Service; [CA15083] FX N.E. Kay has commercial research support from Celgene and Gilead. No potential conflicts of interest were disclosed by the other authors.; In the GEC Consortium and Mayo Clinic SPORE Lymphoma case-control study, the work was supported in part by NIH grants CA118444 (S. L. Slager), CA148690 (S.L. Slager), CA97274 (J.R. Cerhan) and CA92153 (J.R. Cerhan). The genotyping at the Mayo Clinic Genotyping Core is supported, in part, by CA15083 (J.M. Cunningham). Support was also obtained by the Veterans Affairs Research Service, and by NIH CA134919 (M.C. Lanasa). NR 17 TC 4 Z9 4 U1 0 U2 2 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 MAR PY 2013 VL 22 IS 3 BP 461 EP 466 DI 10.1158/1055-9965.EPI-12-1217 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 105EE UT WOS:000316047600017 PM 23307532 ER PT J AU Gara, N Zhao, XC Kleiner, DE Liang, TJ Hoofnagle, JH Ghany, MG AF Gara, Naveen Zhao, Xiongce Kleiner, David E. Liang, T. Jake Hoofnagle, Jay H. Ghany, Marc G. TI Discordance Among Transient Elastography, Aspartate Aminotransferase to Platelet Ratio Index, and Histologic Assessments of Liver Fibrosis in Patients With Chronic Hepatitis C SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE HCV; Liver Disease; Cancer Risk; AUROC ID SIGNIFICANT PORTAL-HYPERTENSION; STIFFNESS MEASUREMENT; XL PROBE; HEPATOCELLULAR-CARCINOMA; RISK-ASSESSMENT; OBESE-PATIENTS; BIOPSY; CIRRHOSIS; DIAGNOSIS; DISEASE AB BACKGROUND & AIMS: Liver biopsy is the standard for assessing hepatic fibrosis. Ultrasound transient elastography (TE) and the aspartate aminotransferase to platelet ratio index (APRI) are validated, noninvasive tests for identifying patients with cirrhosis. We evaluated discordance among TE, APRI, and histology diagnoses of cirrhosis. METHODS: We analyzed findings from 109 patients with chronic hepatitis C who underwent TE within 6 months of liver biopsy at the US National Institutes of Health from 2006 to 2011. Fibrosis was scored using the Ishak scale (0-6). APRI scores were calculated using data collected on the day of the biopsy. Area under receiver operator characteristic curves for TE and APRI were calculated to distinguish patients with cirrhosis (Ishak scores, 5-6) from those without cirrhosis (Ishak scores, 0-4). The best cut-off value and corresponding positive predictive value (PPV) and negative predictive value (NPV) were selected. RESULTS: Based on biopsy analysis, 18% of the patients had no fibrosis, 52% had mild fibrosis, 17% had bridging fibrosis, and 13% had cirrhosis. A TE cut-off value of 13.1 kPa identified patients with cirrhosis with the highest level of accuracy (100% sensitivity, 89% specificity, 58% PPV, 100% NPV), as did an APRI cut-off value of 1.0 (79% sensitivity, 78% specificity, 34% PPV, 96% NPV). Results from TE and APRI were discordant for 28% of cases. TE identified all cases of cirrhosis and an additional 10 patients who were not found to have cirrhosis based on histology analysis; 7 of these patients had clinical or radiologic evidence of cirrhosis, indicating that the biopsy sample was not staged correctly. CONCLUSIONS: TE increases the accuracies of biopsy and APRI analyses in identifying patients with cirrhosis. TE also might be used to screen patients for cirrhosis and identify those who should be followed up for development of hepatocellular carcinoma and varices. C1 [Gara, Naveen; Liang, T. Jake; Hoofnagle, Jay H.; Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Gara, N (reprint author), NIDDK, Liver Dis Branch, NIH, CRC 4-5722,10 Ctr Dr, Bethesda, MD 20892 USA. EM naveen.gara@nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Intramural Divisions of the National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute of the National Institutes of Health FX Supported by the Intramural Divisions of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute of the National Institutes of Health. NR 33 TC 14 Z9 15 U1 1 U2 6 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 MAR PY 2013 VL 11 IS 3 BP 303 EP + DI 10.1016/j.cgh.2012.10.044 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 107ZI UT WOS:000316259500021 PM 23142332 ER PT J AU Yang, JC AF Yang, James C. TI The adoptive transfer of cultured T cells for patients with metastatic melanoma SO CLINICS IN DERMATOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; HIGH-DOSE INTERLEUKIN-2; CANCER REGRESSION; COMPLETE RESPONSES; AUTOLOGOUS TUMOR; TRANSFER THERAPY; ANTIGEN; IMMUNOTHERAPY; LYMPHODEPLETION; DIFFERENTIATION AB T cells have been shown to be capable of rejecting a patient's tumor. Weak responses to current vaccines and the toxicity of exogenously administered cytokines limit the intensity of the T-cell response that can be actively generated in vivo. Adoptive T-cell transfer enhances an intrinsically weak immune response to cancer by activating and expanding tumor reactive T cells in vitro and manipulating the environment of the host at the time of transfer. One can frequently find tumor-reactive T cells in metastatic lesions in patients with melanoma, and expand them in vitro for readministration. When successful, this adoptive cellular immunotherapy has resulted in sustainable curative outcomes. Subsequently, the applicability of adoptive T-cell transfer has been greatly expanded by the development of methods to genetically engineer open-repertoire human T-cells to confer tumor reactivity. This re-direction of T-cell specificity can be achieved by introducing a variety of receptors that ligate tumor-associated antigens and then trigger the normal activation mechanism of T cells. Future T-cell engineering will add a new dimension by reprogramming T-cell functions for optimal tumor rejection. The antigens recognized by T cells, the techniques to procure and grow tumor reactive T cells, the conditioning of the recipient to optimize efficacy, and the results of clinical protocols are reviewed herein. Published by Elsevier Inc. C1 NCI, Surg Branch, Clin Res Ctr, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, Clin Res Ctr, Bldg 10A,Rm 3-5952, Bethesda, MD 20892 USA. EM james_yang@nih.gov NR 44 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0738-081X J9 CLIN DERMATOL JI Clin. Dermatol. PD MAR-APR PY 2013 VL 31 IS 2 BP 209 EP 219 DI 10.1016/j.clindermatol.2012.08.019 PG 11 WC Dermatology SC Dermatology GA 105SY UT WOS:000316094000009 ER PT J AU Raju, R Jian, BX Hooks, JJ Nagineni, CN AF Raju, Raghavan Jian, Bixi Hooks, John J. Nagineni, Chandrasekharam N. TI Transforming growth factor-beta regulates the expression of anosmin (KAL-1) in human retinal pigment epithelial cells SO CYTOKINE LA English DT Article DE Anosmin; KAL-1; TGF-beta; Adhesion proteins; Retinal pigment epithelium ID TGF-BETA; DEGENERATION; DEFICIENCY AB In a microarray analysis of human retinal pigment epithelial cells (HRPE) treated with TGF-beta, in addition to the alteration of a number of known Extracellular matrix (ECM)-related genes regulated by TGF-beta, we found a significant increase in the expression of Kallmann Syndrome (KAL)-1 gene, that codes for the protein anosmin-1. Enhanced expression of KAL-1 by TGF-beta was validated by real-time PCR analysis. In in vitro experiments, TGF-beta receptor inhibitor abolished TGF-beta-induced expression of KAL-1. Immunofluorescence staining showed increased presence of anosmin-1 in TGF-beta treated HRPE cells, with distinct localization at the intercellular junctions. Treatment of HRPE cells with TGF-beta enhanced secretion of anosmin-1 and the release of anosmin-1 was further augmented by heparin sulfate. Enhanced secretion of anosmin-1 in the presence of TGF-beta and heparin was also observed in other ocular cells such as corneal epithelial and corneal fibroblast cultures. The role of anosmin-1, a protein with adhesion functions, in retinal structure, function and pathology has not been known and remains to be investigated. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Raju, Raghavan; Jian, Bixi] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Raju, Raghavan] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Hooks, John J.; Nagineni, Chandrasekharam N.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Raju, R (reprint author), Univ Alabama Birmingham, Dept Surg, VH G094,1670 Univ Blvd, Birmingham, AL 35294 USA. EM RRaju@uab.edu FU HSF-GEF scholar award from UAB; NEI, NIH FX This work was supported in part by an HSF-GEF scholar award from UAB (RR) and intramural research support from NEI, NIH. NR 15 TC 4 Z9 4 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 MAR PY 2013 VL 61 IS 3 BP 724 EP 727 DI 10.1016/j.cyto.2012.12.019 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 112FM UT WOS:000316577900006 PM 23357298 ER PT J AU Phang, JM Liu, W Hancock, C AF Phang, James M. Liu, Wei Hancock, Chad TI Bridging epigenetics and metabolism Role of non-essential amino acids SO EPIGENETICS LA English DT Article DE metabolism and cancer; epigenetics; redox regulation; reactive oxygen species; non-essential amino acids; proline metabolism ID L-PROLINE CATABOLISM; EXTENDS LIFE-SPAN; CELL-GROWTH; SACCHAROMYCES-CEREVISIAE; GLUTAMINE-METABOLISM; ENERGY-METABOLISM; TUMOR-SUPPRESSOR; GENE-EXPRESSION; CANCER CELLS; ACETYL-COA AB Recent research suggests that chromatin-modifying enzymes are metabolic sensors regulating gene expression. Epigenetics is linked to metabolomics in response to the cellular microenvironment. Specific metabolites involved in this sensing mechanism include S-adenosylmethionine, acetyl-CoA, alphaketoglutarate and NAD(+). Although the core metabolic pathways involving glucose have been emphasized as the source of these metabolites, the reprogramming of pathways involving nonessential amino acids may also play an important role, especially in cancer. Examples include metabolic pathways for glutamine, serine and glycine. The coupling of these pathways to the intermediates affecting epigenetic regulation occurs by "parametabolic" mechanisms. The metabolism of proline may play a special role in this parametabolic linkage between metabolism and epigenetics. Both proline degradation and biosynthesis are robustly affected by oncogenes or suppressor genes, and they can modulate intermediates involved in epigenetic regulation. A number of mechanisms in a variety of animal species have been described by our laboratory and by others. The challenge we now face is to identify the specific chromatin-modifying enzymes involved in coupling of proline metabolism to altered reprogramming of gene expression. C1 [Phang, James M.; Liu, Wei; Hancock, Chad] NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Phang, JM (reprint author), NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM phangj@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN27612080001] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project also has been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN27612080001. The content of this review 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. We gratefully acknowledge Gregory Borchert and Dr. Kyle Christian for their helpful discussions and Meredith Harman for reading the manuscript. NR 73 TC 21 Z9 22 U1 4 U2 22 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 J9 EPIGENETICS-US JI Epigenetics PD MAR PY 2013 VL 8 IS 3 BP 231 EP 236 DI 10.4161/epi.24042 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 103NE UT WOS:000315923300001 PM 23422013 ER PT J AU Boghossian, NS Yeung, EH Mumford, SL Zhang, C Gaskins, AJ Wactawski-Wende, J Schisterman, EF AF Boghossian, N. S. Yeung, E. H. Mumford, S. L. Zhang, C. Gaskins, A. J. Wactawski-Wende, J. Schisterman, E. F. CA BioCycle Study Grp TI Adherence to the Mediterranean diet and body fat distribution in reproductive aged women SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE Mediterranean diet; body fat; trunk fat; regional adiposity; obesity; DXA ID TO-HIP RATIO; MASS INDEX; WAIST CIRCUMFERENCE; PLASMA-CONCENTRATIONS; OXIDATIVE STRESS; WEIGHT CHANGE; MEAT INTAKE; SUN COHORT; OBESITY; PATTERNS AB BACKGROUND/OBJECTIVES: Adherence to the Mediterranean diet (MD), high in fruits, vegetables and monounsaturated fats, has been associated with lower body mass index. Associations with measured body fat, including regional adiposity, have not been previously investigated. We examined the associations between the alternate Mediterranean diet score (aMED), anthropometry and measured adiposity by dual-energy x-ray absorptiometry (DXA). SUBJECTS/METHODS: This study included 248 healthy females, aged 18-44 years from the BioCycle Study. Each woman's aMED (range 0-9) was calculated from up to eight 24-h dietary recalls over 1-2 menstrual cycles (>97% had >= 7 recalls). Multiple linear regression was used to determine whether aMED and its specific components were associated with total and regional adiposity after adjusting for age, race, education, physical activity and energy intake. RESULTS: Participants had an average (s.d.) aMED of 4.2 (1.7) and percent body fat of 29.5 (6.0)%. Significant inverse associations were found between aMED and all the examined adiposity measures except waist-to-hip ratio. Among the DXA measures, a 1-unit increment in aMED was associated with a 0.06 (95% confidence interval (CI): -0.09, -0.02) lower trunk-to-leg fat ratio (T/L), a measure of upper to lower body fat. In an analysis examining T/L as an outcome with the separate components of the aMED, T/L was lower with increased legume consumption (beta = -0.280, 95% CI: -0.550, -0.010) but was higher with increased consumption of red and processed meat (beta = 0.060, 95% CI: 0.002, 0.117). CONCLUSIONS: Adherence to the aMED was associated with lower total and regional adiposity, adding to the mounting evidence of the health benefits of the MD. European Journal of Clinical Nutrition (2013) 67, 289-294; doi:10.1038/ejcn.2013.4; published online 6 February 2013 C1 [Boghossian, N. S.; Yeung, E. H.; Mumford, S. L.; Zhang, C.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Gaskins, A. J.] Harvard Univ, Dept Nutr, Boston, MA 02115 USA. [Gaskins, A. J.] Harvard Univ, Dept Epidemiol, Boston, MA 02115 USA. [Wactawski-Wende, J.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Yeung, EH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM yeungedw@mail.nih.gov RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [HHSN275200403394C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract no. HHSN275200403394C). The authors thank the BioCycle working group for comments and feedback on this work. NR 40 TC 8 Z9 8 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD MAR PY 2013 VL 67 IS 3 BP 289 EP 294 DI 10.1038/ejcn.2013.4 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 104FX UT WOS:000315978400011 PM 23388669 ER PT J AU Mohanty, JG Nagababu, E Friedman, JS Rifkind, JM AF Mohanty, Joy G. Nagababu, Enika Friedman, Jeffrey S. Rifkind, Joseph M. TI SOD2 deficiency in hematopoietic cells in mice results in reduced red blood cell deformability and increased heme degradation SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; OXIDATIVE-STRESS; SIDEROBLASTIC ANEMIA; MICROARRAY EXPERIMENTS; HEMOLYTIC-ANEMIA; MUTANT MICE; IRON; ERYTHROCYTE; THALASSEMIA; DISEASE AB Among the three types of super oxide dismutases (SODs) known, SOD2 deficiency is lethal in neonatal mice owing to cardiomyopathy caused by severe oxidative damage. SOD2 is found in red blood cell (RBC) precursors, but not in mature RBCs. To investigate the potential damage to mature RBCs resulting from SOD2 deficiency in precursor cells, we studied RBCs from mice in which fetal liver stem cells deficient in SOD2 were capable of efficiently rescuing lethally irradiated host animals. These transplanted animals lack SOD2 only in hematopoietically generated cells and live longer than SOD2 knockouts. In these mice, approximately 2.8% of their total RBCs in circulation are iron-laden reticulocytes, with numerous siderocytic granules and increased protein oxidation similar to that seen in sideroblastic anemia. We have studied the RBC deformability and oxidative stress in these animals and the control group by measuring them with a microfluidic ektacytometer and assaying fluorescent heme degradation products with a fluorimeter, respectively. In addition, the rate of hemoglobin oxidation in RBCs from these mice and the control group were measured spectrophotometrically. The results show that RBCs from these SOD2-deficient mice have reduced deformability, increased heme degradation products, and an increased rate of hemoglobin oxidation compared with control animals, indicative of increased RBC oxidative stress. (C) 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. C1 [Mohanty, Joy G.; Nagababu, Enika; Rifkind, Joseph M.] NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. [Friedman, Jeffrey S.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. RP Mohanty, JG (reprint author), NIA, NIH, Mol Dynam Sect, 251 Bayview Blvd,Suite 100,05B131, Baltimore, MD 21224 USA. EM mohantyj@mail.nih.gov FU National Institutes of Health, National Institute on Aging; The Scripps Research Institute, La Jolla, California FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging and The Scripps Research Institute, La Jolla, California. NR 40 TC 10 Z9 10 U1 1 U2 12 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 MAR PY 2013 VL 41 IS 3 BP 316 EP 321 DI 10.1016/j.exphem.2012.10.017 PG 6 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 112JX UT WOS:000316589600010 PM 23142655 ER PT J AU Resnik, DB AF Resnik, David B. TI H5N1 Avian Flu Research and the Ethics of Knowledge SO HASTINGS CENTER REPORT LA English DT Article ID LIFE SCIENCES; INFLUENZA; VIRUS; CONTROVERSY; EXPRESSION; TRANSMISSION; FREEDOM C1 NIEHS, NIH, Bethesda, MD 20892 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA ES102646-04, ZIA ES102646-05] NR 49 TC 7 Z9 7 U1 0 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR-APR PY 2013 VL 43 IS 2 BP 22 EP 33 DI 10.1002/hast.143 PG 12 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 108EI UT WOS:000316274100013 PM 23390001 ER PT J AU Mandava, A Milum, J AF Mandava, Amulya Milum, Joseph TI Manipulation in the Enrollment of Research Participants SO HASTINGS CENTER REPORT LA English DT Article C1 [Mandava, Amulya] Harvard Univ, Sch Divin, Cambridge, MA 02138 USA. [Mandava, Amulya] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Milum, Joseph] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Milum, Joseph] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Mandava, A (reprint author), Harvard Univ, Sch Divin, Cambridge, MA 02138 USA. FU Intramural NIH HHS [Z99 CL999999] NR 27 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR-APR PY 2013 VL 43 IS 2 BP 38 EP 47 DI 10.1002/hast.144 PG 10 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 108EI UT WOS:000316274100016 PM 23390007 ER PT J AU Hoofnagle, JH Serrano, J Knoben, JE Navarro, VJ AF Hoofnagle, Jay H. Serrano, Jose Knoben, James E. Navarro, Victor J. TI LiverTox: A website on drug-induced liver injury SO HEPATOLOGY LA English DT Editorial Material C1 [Hoofnagle, Jay H.; Serrano, Jose] NIDDKD, Liver Dis Res Branch, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Knoben, James E.] NIH, Div Specialized Informat Serv, Natl Lib Med, Bethesda, MD 20892 USA. [Navarro, Victor J.] Einstein Healthcare Network, Div Hepatol & Liver Transplantat, Philadelphia, PA USA. RP Hoofnagle, JH (reprint author), NIH, Bldg 31,Rm 9A27,31 Ctr Dr, Bethesda, MD 20892 USA. EM HoofnagleJ@extra.niddk.nih.gov FU Intramural NIH HHS [Z99 LM999999, Z99 DK999999]; NIDDK NIH HHS [U01 DK083027] NR 0 TC 38 Z9 43 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAR PY 2013 VL 57 IS 3 BP 873 EP 874 DI 10.1002/hep.26175 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 099TG UT WOS:000315644200004 PM 23456678 ER PT J AU Duffy, A Wilkerson, J Greten, TF AF Duffy, Austin Wilkerson, Julia Greten, Tim F. TI Hemorrhagic events in hepatocellular carcinoma patients treated with antiangiogenic therapies SO HEPATOLOGY LA English DT Article ID PHASE-II TRIAL; RENAL-CELL CARCINOMA; VARICEAL HEMORRHAGE; OPEN-LABEL; SYSTEMIC CHEMOTHERAPY; ESOPHAGEAL-VARICES; CIRRHOTIC-PATIENTS; NATURAL-HISTORY; CLINICAL-TRIALS; SORAFENIB AB The presence of cirrhosis increases the potential risk of hemorrhage for patients with hepatocellular carcinoma (HCC). We evaluated the relative risk for hemorrhage in patients with HCC treated with antiangiogenic agents. We performed a systematic review and meta-analysis of antiangiogenic studies in HCC from 1995 to 2011. For nonrandomized studies we compared bleeding risk with other HCC single-arm studies that did not include an antiangiogenic agent. To separate disease-specific factors we also performed a comparison analysis with renal cell cancer (RCC)) studies that evaluated sorafenib. Sorafenib was associated with increased bleeding risk compared to control for all grade bleeding events (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.04, 3.0) but not grade 3-5 events in both HCC and RCC (OR 1.46; 95% CI 0.9, 2.36; P = 0.45). When comparing the risk of bleeding in single-arm phase 2 studies evaluating antiangiogenic agents, this risk for all events (OR 4.34; 95% CI 2.16, 8.73) was increased compared to control. Conclusion: This analysis of both randomized and nonrandomized studies evaluating an antiangiogenic agent in HCC showed that whereas the use of sorafenib was associated with an increased risk of bleeding in HCC, this was primarily for lower-grade events and similar in magnitude to the risk encountered in RCC. (HEPATOLOGY 2013) C1 [Duffy, Austin; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Wilkerson, Julia] NCI, Expt Therapeut Sect, Med Oncol Branch, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, 9000 Rockville Pike,10-12N224, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015; OI Greten, Tim/0000-0002-0806-2535; Wilkerson, Julia/0000-0002-6965-0867 FU NIH, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 63 TC 7 Z9 8 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAR PY 2013 VL 57 IS 3 BP 1068 EP 1077 DI 10.1002/hep.26120 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 099TG UT WOS:000315644200027 PM 23112096 ER PT J AU Song, LH Carlson, JH Whitmire, WM Kari, L Virtaneva, K Sturdevant, DE Watkins, H Zhou, B Sturdevant, GL Porcella, SF McClarty, G Caldwell, HD AF Song, Lihua Carlson, John H. Whitmire, William M. Kari, Laszlo Virtaneva, Kimmo Sturdevant, Daniel E. Watkins, Heather Zhou, Bing Sturdevant, Gail L. Porcella, Stephen F. McClarty, Grant Caldwell, Harlan D. TI Chlamydia trachomatis Plasmid-Encoded Pgp4 Is a Transcriptional Regulator of Virulence-Associated Genes SO INFECTION AND IMMUNITY LA English DT Article ID LYMPHOGRANULOMA-VENEREUM; DNA-REPLICATION; GENOME SEQUENCE; 7.5-KB PLASMID; PROTEIN PGP3; INFECTION; IMMUNIZATION; EXPRESSION; VACCINE; GROWTH AB Chlamydia trachomatis causes chronic inflammatory diseases of the eye and genital tract and has global medical importance. The chlamydial plasmid plays an important role in the pathophysiology of these diseases, as plasmid-deficient organisms are highly attenuated. The cryptic plasmid carries noncoding RNAs and eight conserved open reading frames (ORFs). To understand plasmid gene function, we generated plasmid shuttle vectors with deletions in each of the eight ORFs. The individual deletion mutants were used to transform chlamydiae and the transformants were characterized phenotypically and at the transcriptional level. We show that pgp1, -2, -6, and -8 are essential for plasmid maintenance, while the other ORFs can be deleted and the plasmid stably maintained. We further show that a pgp4 knockout mutant exhibits an in vitro phenotype similar to its isogenic plasmidless strain, in terms of abnormal inclusion morphology and lack of glycogen accumulation. Microarray and qRT-PCR analysis revealed that Pgp4 is a transcriptional regulator of plasmid-encoded pgp3 and multiple chromosomal genes, including the glycogen synthase gene glgA, that are likely important in chlamydial virulence. Our findings have major implications for understanding the plasmid's role in chlamydial pathogenesis at the molecular level. C1 [Song, Lihua; Carlson, John H.; Whitmire, William M.; Kari, Laszlo; Watkins, Heather; Zhou, Bing; Sturdevant, Gail L.; Caldwell, Harlan D.] NIAID, Lab Intracellular Parasites, NIH, Hamilton, MT USA. [Virtaneva, Kimmo; Sturdevant, Daniel E.; Porcella, Stephen F.] NIAID, Genom Unit Res Technol Sect, NIH, Hamilton, MT USA. [McClarty, Grant] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Caldwell, HD (reprint author), NIAID, Lab Intracellular Parasites, NIH, Hamilton, MT USA. EM hcaldwell@niaid.nih.gov OI Watkins, Hugh/0000-0002-5287-9016 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 53 TC 68 Z9 70 U1 0 U2 15 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 MAR PY 2013 VL 81 IS 3 BP 636 EP 644 DI 10.1128/IAI.01305-12 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RH UT WOS:000316313200004 PM 23319558 ER PT J AU Qiu, J Olszewski, MA Williamson, PR AF Qiu, Jin Olszewski, Michal A. Williamson, Peter R. TI Cryptococcus neoformans Growth and Protection from Innate Immunity Are Dependent on Expression of a Virulence-Associated DEAD-Box Protein, Vad1 SO INFECTION AND IMMUNITY LA English DT Article ID ALLERGIC BRONCHOPULMONARY MYCOSIS; NECROSIS-FACTOR-ALPHA; PULMONARY INFECTION; T-CELLS; ALVEOLAR MACROPHAGES; DENDRITIC CELLS; HOST-DEFENSE; RESISTANCE; LUNG; DISSEMINATION AB The fungus Cryptococcus neoformans has emerged as a major cause of meningoencephalitis worldwide. Host response to the fungus involves both innate and adaptive immunity, but fungal genes that modulate these processes are poorly understood. Previous studies demonstrated attenuated virulence of a mutant of a virulence-associated DEAD-box protein (VAD1) in mice, despite normal growth at host temperatures, suggesting modulation of the immune response. In the present study, the Delta vad1 mutant demonstrated progressive clearance from lung and was unable to induce pathological lesions or to cause extrapulmonary disease, despite retaining its ability to grow in mouse serum and a J774.16 macrophage cell line. Pulmonary clearance occurred with a minimal cellular infiltrate, marked by reduced CD4 cells, CD11b(+) Ly6C(high) monocytes, and F4/80(+) macrophages, but the mutant strain retained recruitment of CD8 cells, compared to infections with wild-type fungi. Adaptive cytokine responses were reduced, including Th1, Th2, and Th17 cytokines; however, early gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) responses were retained while nonprotective interleukin 4 (IL-4) and IL-5 were diminished. Furthermore, the Delta vad1 mutant was controlled in lungs despite CD4/CD8 cell depletion. These data, along with improved phagocytosis by macrophages and increases in early/innate IL-1 alpha, IFN-gamma, and chemokines elicited in the lungs within 3 days of infection with the Delta vad1 mutant, indicate that VAD1 expression reduces innate recognition of C. neoformans, rendering the yeast resistant to elimination by the innate mechanisms of host defense. Thus, our studies define a novel role of the cryptococcal Vad1 protein as a central regulator of cryptococcal virulence and illustrate that Vad1 promotes microbe resistance to innate host defenses. C1 [Qiu, Jin; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Olszewski, Michal A.] VA Med Ctr, Ann Arbor, MI USA. [Olszewski, Michal A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Williamson, Peter R.] Univ Illinois, Coll Med, Sect Infect Dis Immunol & Int Med, Chicago, IL USA. RP Williamson, PR (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU United States Public Health Service [NIH-AI45995, AI49371]; Veterans Administration Merit Award [1I01BX000656]; Intramural Research Program of the NIH, NIAID FX This work was supported, in part, by United States Public Health Service grant NIH-AI45995 and AI49371 (P.R.W.) and Veterans Administration Merit Award 1I01BX000656. This research was also supported, in part, by the Intramural Research Program of the NIH, NIAID. NR 47 TC 9 Z9 10 U1 0 U2 0 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 MAR PY 2013 VL 81 IS 3 BP 777 EP 788 DI 10.1128/IAI.00821-12 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RH UT WOS:000316313200019 PM 23264050 ER PT J AU Kastenmuller, K Espinosa, DA Trager, L Stoyanov, C Salazar, AM Pokalwar, S Singh, S Dutta, S Ockenhouse, CF Zavala, F Seder, RA AF Kastenmueller, Kathrin Espinosa, Diego A. Trager, Lauren Stoyanov, Cristina Salazar, Andres M. Pokalwar, Santosh Singh, Sanjay Dutta, Sheetij Ockenhouse, Christian F. Zavala, Fidel Seder, Robert A. TI Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I.C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4(+) T Cell Immunity and Protection in Mice SO INFECTION AND IMMUNITY LA English DT Article ID MALARIA VACCINE RTS,S/AS02A; STRANDED-RNA POLY(I-C); MURINE MALARIA; SPOROZOITE VACCINE; CONFERS PROTECTION; GAMMA-INTERFERON; STAGE MALARIA; PHASE-3 TRIAL; CUTTING EDGE; NAIVE ADULTS AB The Plasmodium falciparum circumsporozoite (CS) protein (CSP) is a major vaccine target for preventing malaria infection. Thus, developing strong and durable antibody and T cell responses against CSP with novel immunogens and potent adjuvants may improve upon the success of current approaches. Here, we compare four distinct full-length P. falciparum CS proteins expressed in Escherichia coli or Pichia pastoris for their ability to induce immunity and protection in mice when administered with long-chain poly(I.C) [poly(I.C) LC] as an adjuvant. CS proteins expressed in E. coli induced high-titer antibody responses against the NANP repeat region and potent CSP-specific CD4(+) T cell responses. Moreover, E. coli-derived CS proteins in combination with poly(I.C) LC induced potent multifunctional (interleukin 2-positive [IL-2(+)], tumor necrosis factor alpha-positive [TNF-alpha(+)], gamma interferon-positive [IFN-gamma(+)]) CD4(+) effector T cell responses in blood, in spleen, and particularly in liver. Using transgenic Plasmodium berghei expressing the repeat region of P. falciparum CSP [Pb-CS(Pf)], we showed that there was a 1- to 4-log decrease in malaria rRNA in the liver following a high-dose challenge and similar to 50% sterilizing protection with a low-dose challenge compared to control levels. Protection was directly correlated with high-level antibody titers but not CD4(+) T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4(+) T cell immunity that was significantly less potent than that with poly(I.C) LC. Overall, these data suggest that full-length CS proteins and poly(I.C) LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection. C1 [Kastenmueller, Kathrin; Trager, Lauren; Stoyanov, Cristina; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kastenmueller, Kathrin; Trager, Lauren; Stoyanov, Cristina; Seder, Robert A.] NIAID, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. [Espinosa, Diego A.; Stoyanov, Cristina; Zavala, Fidel] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Salazar, Andres M.] Oncovir, Washington, DC USA. [Pokalwar, Santosh; Singh, Sanjay] Gennova Biopharmaceut Ltd, Pune, Maharashtra, India. [Dutta, Sheetij; Ockenhouse, Christian F.] Walter Reed Army Inst Res, Div Malaria Vaccine Dev, Silver Spring, MD USA. [Trager, Lauren] Virginia Polytech Inst & State Univ, Virginia Maryland Reg Coll Vet Med, Blacksburg, VA 24061 USA. RP Seder, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov FU MVI FX We thank MVI for funding and facilitating this comparative study by identifying and accessing the proteins and ensuring agreement of all partners on the final study design. We thank Gennova Biopharmaceuticals and WRAIR for providing the proteins CSP1 and CSP2, respectively. NR 71 TC 14 Z9 15 U1 0 U2 17 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 MAR PY 2013 VL 81 IS 3 BP 789 EP 800 DI 10.1128/IAI.01108-12 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RH UT WOS:000316313200020 PM 23275094 ER PT J AU Gerling, M Nousiainen, K Hautaniemi, S Kruger, S Fritzsche, B Homann, N Bruch, HP Auer, G Roblick, UJ Ried, T Habermann, JK AF Gerling, Marco Nousiainen, Kari Hautaniemi, Sampsa Krueger, Stefan Fritzsche, Britta Homann, Nils Bruch, Hans-Peter Auer, Gert Roblick, Uwe J. Ried, Thomas Habermann, Jens K. TI Aneuploidy-Associated Gene Expression Signatures Characterize Malignant Transformation in Ulcerative Colitis SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE ulcerative colitis; colorectal carcinoma; aneuploidy; gene expression; microarrays ID INFLAMMATORY-BOWEL-DISEASE; TIME RT-PCR; COLORECTAL-CANCER; GENOMIC INSTABILITY; COLON-CANCER; MICROARRAY DATA; DNA-DAMAGE; CELLS; PROTEIN; CARCINOGENESIS AB Background: Malignant transformation in ulcerative colitis (UC) is associated with pronounced chromosomal instability, reflected by aneuploidy. Although aneuploidy can precede primary cancer diagnosis in UC for more than a decade, little is known of its cellular consequences. Methods: Whole-genome gene expression analysis was applied to noninflamed colon mucosa, mucosal biopsies of patients with UC, and UC-associated carcinomas (UCCs). DNA image cytometry was used to stratify samples into ploidy types. Differentially expressed genes (DEGs) were analyzed by Ingenuity Pathway Analysis and validated by real-time quantitative PCR. Results: Gene expression changes were more pronounced between normal mucosa and UC (2587 DEGs) than between UC and UCC (827 DEGs). Cytometry identified colitis patients with euploid or aneuploid mucosa biopsies, whereas all UCCs were aneuploid. However, 1749 DEGs distinguished euploid UC and UCCs, whereas only 15 DEGs differentiated aneuploid UC and UCCs. A total of 16 genes were differentially expressed throughout the whole sequence from normal controls to UCCs. Particularly, genes pivotal for chromosome segregation (e. g., SMC3 and NUF2) were differentially regulated along aneuploidy development. Conclusions: The high number of DEGs between normal mucosa and colitis is dominated by inflammatory-associated genes. Subsequent acquisition of aneuploidy leads to subtle but distinct transcriptional alterations, revealing novel target genes that drive genomic instability and thus carcinogenesis. The gene expression signature of malignant phenotypes in aneuploid UC suggests that these lesions might need to be considered as severe as high-grade dysplasia. (Inflamm Bowel Dis 2013;19:691-703) C1 [Gerling, Marco; Fritzsche, Britta; Habermann, Jens K.] Med Univ Lubeck, Dept Surg, Surg Res Lab, D-23538 Lubeck, Germany. [Gerling, Marco; Ried, Thomas; Habermann, Jens K.] NCI, Dept Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nousiainen, Kari; Hautaniemi, Sampsa] Univ Helsinki, Biomedicum Helsinki, Inst Biomed & Genome Scale Biol Res, Computat Syst Biol Lab, Helsinki, Finland. [Homann, Nils] Hosp Wolfsburg, Med Clin 2, Wolfsburg, Germany. [Bruch, Hans-Peter] Med Univ Lubeck, Dept Surg, D-23538 Lubeck, Germany. [Auer, Gert] Karolinska Inst, Karolinska Biom Ctr, Stockholm, Sweden. [Roblick, Uwe J.] Hosp Wolfsburg, Dept Surg, Wolfsburg, Germany. RP Habermann, JK (reprint author), Med Univ Lubeck, Dept Surg, Surg Res Lab, Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM jens.habermann@chirurgie.uni-luebeck.de RI Hautaniemi, Sampsa/A-3122-2009; Habermann, Jens/E-2968-2010; OI Hautaniemi, Sampsa/0000-0002-7749-2694; Gerling, Marco/0000-0002-1810-0662 FU Werner and Klara Kreitz Foundation, Germany; Academy of Finland; University of Lubeck; German Academic Exchange Service (DAAD) FX This project was supported by the Werner and Klara Kreitz Foundation, Germany, and the Academy of Finland. M. Gerling received a doctoral stipend of excellence by the University of Lubeck and a travel grant by the German Academic Exchange Service (DAAD). NR 50 TC 6 Z9 6 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR-APR PY 2013 VL 19 IS 4 BP 691 EP 703 DI 10.1097/MIB.0b013e31827eeaa4 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 110NT UT WOS:000316451600013 PM 23455720 ER PT J AU Edwards, E Belard, JL Glowa, J Khalsa, P Weber, W Huntley, K AF Edwards, Emmeline Belard, Jean Louis Glowa, John Khalsa, Partap Weber, Wendy Huntley, Kristen TI DoD-NCCAM/NIH Workshop on Acupuncture for Treatment of Acute Pain SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID DOUBLE-BLINDED TRIAL; RANDOMIZED CONTROLLED-TRIAL; PREHOSPITAL ANALGESIA; ACUPRESSURE; COMPLEMENTARY; MEDICINE; TRAUMA; CARE; TOOL AB The Department of Defense (DoD) and the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) cosponsored a workshop that explored the possible benefits of acupuncture treatment for acute pain. One goal of the workshop was to establish a roadmap to building an evidence base on that would indicate whether acupuncture is helpful for treating active-duty military personnel experiencing acute pain. The workshop highlighted brief presentations on the most current research on acupuncture and acute pain mechanisms. The impact of various modifiers (stress, genetics, population, phenotypes, etc.) on acute pain pathways and response to acupuncture treatment was discussed. Additional presentations focused on common neural mechanisms, an overview of real-world experience with using acupuncture to treat traumatic acute pain, and best tools and methods specific for acupuncture studies. Three breakout groups addressed the gaps, opportunities, and barriers to acupuncture use for acute pain in military and trauma settings. Different models of effectiveness research and optimal research designs for conducting trials in acute traumatic pain were also discussed. C1 [Edwards, Emmeline; Glowa, John; Khalsa, Partap; Weber, Wendy; Huntley, Kristen] NCCAM, Div Extramural Res, Bethesda, MD 20892 USA. [Belard, Jean Louis] USA, Henry M Jackson Fdn, Telemed & Adv Technol Res Ctr, MCMR TT,Med Res & Mat Command, Ft Detrick, MD USA. RP Edwards, E (reprint author), NCCAM, Div Extramural Res, Courier Serv 20817, 6707 Democracy Blvd 2,Suite 401, Bethesda, MD 20892 USA. EM edwardse@mail.nih.gov NR 36 TC 1 Z9 2 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD MAR PY 2013 VL 19 IS 3 BP 266 EP 279 DI 10.1089/acm.2012.9229.dod PG 14 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 110RW UT WOS:000316464200014 PM 23020611 ER PT J AU Deschamps, JR Saavedra, JE Cao, Z Keefer, LK Chakrapani, H AF Deschamps, Jeffrey R. Saavedra, Joseph E. Cao, Zhao Keefer, Larry K. Chakrapani, Harinath TI Stereochemical Origins of Chromophore Extension in O-2-Substituted Diazeniumdiolates, Prodrugs of Nitric Oxide SO JOURNAL OF CHEMICAL CRYSTALLOGRAPHY LA English DT Article DE Nitric oxide; Diazeniumdiolate; Crystallography; Ultraviolet spectrophotometry ID IN-VITRO; CHEMISTRY; RELEASE; FAMILY; IONS; NO AB Ultraviolet spectral data for nitric oxide prodrugs of structure R2NN(O)=NOR' tend to fall into two classes: those in which R2N is pyrrolidinyl have lambda(max) near 255 nm when R' is a simple alkyl substituent, while those in which R2N is not pyrrolidinyl display lambda(max) around 230 nm. To test the hypothesis that this spectral difference might reflect an electronic interaction large enough to affect key bond lengths and the configuration at the R2N nitrogen, we have compared the crystal structures of two compounds in which R' was beta-d-glucopyranosyl tetraacetate and R2N was pyrrolidinyl versus diethylamino. The X-ray studies revealed a pyramidyl R2N nitrogen for the diethylamino derivative while the pyrrolidine derivative's R2N approached planarity, consistent with substantial electronic interaction between the N(O)=NOR' chromophore and pyrrolidine's (but not diethylamine's) nitrogen atom. Compensatory changes in key bond lengths were also seen. These findings indicate that overlap between the pyrrolidine nitrogen's p orbital and the N(O)=NOR' chromophore can be an important determinant of structure and electron distribution in the diazeniumdiolate series. Ultraviolet spectral data for nitric oxide prodrugs of structure R2NN(O)=NOR' tend to fall into two classes and the wavelength of the ultraviolet absorbance maximum is a convenient and rather sensitive indicator of the tetrahedral versus planar steric arrangement at the R2N3 nitrogen. C1 [Deschamps, Jeffrey R.] USN, Ctr Biomol Sci & Engn, Res Lab, Washington, DC 20375 USA. [Saavedra, Joseph E.; Cao, Zhao] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Keefer, Larry K.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Chakrapani, Harinath] Indian Inst Sci Educ & Res, Pune 411008, Maharashtra, India. RP Deschamps, JR (reprint author), USN, Ctr Biomol Sci & Engn, Res Lab, Code 6930,4555 Overlook Ave, Washington, DC 20375 USA. EM deschamps@nrl.navy.mil RI G, Neela/H-3016-2014; Keefer, Larry/N-3247-2014; OI Keefer, Larry/0000-0001-7489-9555; Deschamps, Jeffrey/0000-0001-5845-0010 FU National Institute on Drug Abuse (NIDA) [Y1-DA1101]; Naval Research Laboratory; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute [HHSN261200800001E] FX Crystallographic studies presented in the paper were supported in part by the National Institute on Drug Abuse (NIDA) under contract Y1-DA1101 and by the Naval Research Laboratory. Support was also provided by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and with federal funds from the National Cancer Institute under Contract HHSN261200800001E. NR 12 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1074-1542 J9 J CHEM CRYSTALLOGR JI J. Chem. Crystallogr. PD MAR PY 2013 VL 43 IS 3 BP 123 EP 126 DI 10.1007/s10870-013-0394-1 PG 4 WC Crystallography; Spectroscopy SC Crystallography; Spectroscopy GA 108KW UT WOS:000316292900002 ER PT J AU De Sancho, D Mittal, J Best, RB AF De Sancho, David Mittal, Jeetain Best, Robert B. TI Folding Kinetics and Unfolded State Dynamics of the GB1 Hairpin from Molecular Simulation SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID FREE-ENERGY LANDSCAPE; BETA-HAIRPIN; FORCE-FIELDS; HIDDEN COMPLEXITY; EXPLICIT WATER; SPEED LIMIT; SIDE-CHAIN; TIME-SCALE; PROTEIN L; PEPTIDE AB The C-terminal beta-hairpin of protein G is a 16-residue peptide that folds in a two-state fashion akin to many larger proteins. However, with an experimental folding time of similar to 6 mu s, it remains a challenging system for all-atom, explicitly solvated, molecular dynamics simulations. Here, we use a large simulation data set (0.7 ms total) of the hairpin at 300 and 350 K to interpret its folding via a master equation approach. We find a separation of over an order of magnitude between the longest and second longest relaxation times, with the slowest relaxation corresponding to folding. However, in spite of this apparent two-state dynamics, the folding rate determined based on a first-passage time analysis depends on the initial conditions chosen, with a nonexponential distribution of first passage times being obtained in some cases. Using the master equation model, we are now able to account quantitatively for the observed distribution of first passage times. The deviation from the expected exponential distribution for a two-state system arises from slow dynamics in the unfolded state, associated with formation and melting of helical structures. Our results help to reconcile recent findings of slow dynamics in unfolded proteins with observed two-state folding kinetics. At the same time, they indicate that care is required in estimating folding kinetics from many short folding simulations. Last, we are able to use the master equation model to obtain details of the folding mechanism and folding transition state, which appear consistent with the "zipper" mechanism inferred from the experiment. C1 [De Sancho, David] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Mittal, Jeetain] Lehigh Univ, Dept Chem Engn, Bethlehem, PA 18015 USA. [Best, Robert B.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI De Sancho, David/C-4995-2009; Best, Robert/H-7588-2016 OI De Sancho, David/0000-0002-8985-2685; Best, Robert/0000-0002-7893-3543 FU FEBS Long Term Post Doctoral Fellowship; Royal Society University Research Fellowship; National Science Foundation [MCB-120014] FX D.D.S was supported by a FEBS Long Term Post Doctoral Fellowship and R.B.B. by a Royal Society University Research Fellowship. The authors acknowledge Prof. Victor Munoz for granting access to computing resources. This work used the Extreme Science and Engineering Discovery Environment, which is supported by National Science Foundation grant no. MCB-120014. NR 72 TC 17 Z9 17 U1 0 U2 34 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD MAR PY 2013 VL 9 IS 3 BP 1743 EP 1753 DI 10.1021/ct301033r PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 106TX UT WOS:000316168700044 PM 26587632 ER PT J AU Findling, RL Kafantaris, V Pavuluri, M McNamara, NK Frazier, JA Sikich, L Kowatch, R Rowles, BM Clemons, TE Taylor-Zapata, P AF Findling, Robert L. Kafantaris, Vivian Pavuluri, Mani McNamara, Nora K. Frazier, Jean A. Sikich, Linmarie Kowatch, Robert Rowles, Brieana M. Clemons, Traci E. Taylor-Zapata, Perdita TI Post-Acute Effectiveness of Lithium in Pediatric Bipolar I Disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID TREATMENT ENHANCEMENT PROGRAM; CONTROLLED 18-MONTH TRIAL; PLACEBO-CONTROLLED TRIAL; DIVALPROEX SODIUM; DOUBLE-BLIND; MAINTENANCE TREATMENT; RATING-SCALE; STEP-BD; ADOLESCENTS; CHILDREN AB Objective: This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions. Methods: Outpatients, ages 7-17 years, meeting American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnostic criteria for bipolar disorder I (BP-I) (manic or mixed) who demonstrated at least a partial response to 8 weeks of open-label treatment with lithium (Phase I) were eligible to receive open-label lithium for an additional 16 weeks (Phase II). Up to two adjunctive medications could be prescribed to patients experiencing residual symptoms of mania or comorbid psychiatric conditions, following a standardized algorithm. Results: Forty-one patients received continued open-label long-term treatment with lithium for a mean of 14.9 (3.0) weeks during Phase II. The mean weight-adjusted total daily dose at end of Phase II was 27.8 (6.7) mg/kg/day, with an average lithium concentration of 1.0 (0.3) mEq/L. Twenty-five of the 41 patients (60.9%) were prescribed adjunctive psychotropic medications for residual symptoms. The most frequent indications for adjunctive medications were refractory mania (n = 13; 31.7%) and attention-deficit/hyperactivity disorder (ADHD) (n = 15; 36.6%). At the end of this phase 28 (68.3%) patients met a priori criteria for response (>= 50% reduction from Phase I baseline in Young Mania Rating Scale [YMRS] summary score and a Clinical Global Impressions-Improvement [CGI-I] score of 1 or 2), with 22 (53.7%) considered to be in remission (YMRS summary score <= 12 and CGI-Severity score of 1 or 2). These data suggest that patients who initially responded to lithium maintained mood stabilization during continuation treatment, but partial responders did not experience further improvement during Phase II, despite the opportunity to receive adjunctive medications. The most commonly reported (>= 20%) adverse events associated with lithium treatment were vomiting, headache, abdominal pain, and tremor. Conclusions: Lithium may be a safe and effective longer-term treatment for patients with pediatric bipolar disorder who respond to acute treatment with lithium. Partial responders to acute lithium did not appear to experience substantial symptom improvement during the continuation phase, despite the possibility that adjunctive medications could be prescribed. C1 [Findling, Robert L.] Johns Hopkins Univ, Baltimore, MD USA. [Findling, Robert L.] Kennedy Krieger Inst, Baltimore, MD USA. [Kafantaris, Vivian] Zucker Hillside Hosp, Glen Oaks, NY USA. [Kafantaris, Vivian] Long Isl Jewish Hlth Syst, Feinstein Inst Med Res North Shore, Glen Oaks, NY USA. [Pavuluri, Mani] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [McNamara, Nora K.; Rowles, Brieana M.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Frazier, Jean A.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Sikich, Linmarie] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Kowatch, Robert] Nationwide Childrens Hosp, Ctr Innovat Pediat Practice, Cincinnati, OH USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Taylor-Zapata, Perdita] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Findling, RL (reprint author), Johns Hopkins Univ Hosp, Div Child & Adolescent Psychiat, 1800 Orleans St, Baltimore, MD 21287 USA. EM RFindlil@jhmi.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [HHSN275200503406C] FX This project was funded by 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. HHSN275200503406C. NR 49 TC 9 Z9 9 U1 2 U2 15 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD MAR PY 2013 VL 23 IS 2 BP 80 EP 90 DI 10.1089/cap.2012.0063 PG 11 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 109YO UT WOS:000316407700003 PM 23510444 ER PT J AU Maher, KN Tan, M Tossell, JW Weisinger, B Gochman, P Miller, R Greenstein, D Overman, GP Rapoport, JL Gogtay, N AF Maher, Kristin N. Tan, Marcus Tossell, Julia W. Weisinger, Brian Gochman, Peter Miller, Rachel Greenstein, Deanna Overman, Gerald P. Rapoport, Judith L. Gogtay, Nitin TI Risk Factors for Neutropenia in Clozapine-Treated Children and Adolescents with Childhood-Onset Schizophrenia SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID BENIGN ETHNIC NEUTROPENIA; OLANZAPINE-INDUCED NEUTROPENIA; INDUCED AGRANULOCYTOSIS; DOUBLE-BLIND; HISTORY; AGE; EFFICACY; IRELAND; SEX; UK AB Objective: The purpose of this study was to retrospectively analyze rates of neutropenia and risk factors for neutropenia in hospitalized children and adolescents treated with clozapine. Methods: A retrospective chart review was conducted for all patients who received clozapine at any time during a hospitalization at the National Institute of Mental Health (NIMH) between 1990 and 2011. All patients satisfied screening criteria for the NIMH childhood-onset schizophrenia study, including onset of psychosis before the age of 13 years. Absolute neutrophil count (ANC) values recorded during inpatient hospitalization were extracted for 87 eligible patients with a mean age of 13.35 +/- 2.46 years at hospitalization and a mean length of stay of 117 +/- 43 days. Results: Mild neutropenia only (lowest ANC < 2000/mm(3) but >1500/mm(3)) was observed in 27 (31%) patients and moderate neutropenia (any ANC < 1500/mm(3)) was observed in 17 (20%) patients. There were no cases of agranulocytosis or severe infection. Significant risk factors for mild neutropenia compared with no hematologic adverse effects (HAEs) were male gender (p = 0.012) and younger age (p < 0.001). Male gender was also a significant risk factor for moderate neutropenia compared with no HAEs (p = 0.003). If a child of African American ethnicity developed neutropenia during hospitalization at all that child was significantly more likely to develop moderate neutropenia than mild neutropenia only (p = 0.017). African American boys had the highest rate of moderate neutropenia at 47%. Sixteen of the 17 patients exhibiting moderate neutropenia were successfully treated with clozapine by the time of discharge; 8 of these 16 required adjunctive lithium carbonate administration to maintain ANC >2000/mm(3). Conclusions: Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine. C1 [Maher, Kristin N.; Tan, Marcus; Tossell, Julia W.; Weisinger, Brian; Gochman, Peter; Miller, Rachel; Greenstein, Deanna; Overman, Gerald P.; Rapoport, Judith L.; Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Rm 3N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM gogtayn@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 42 TC 9 Z9 9 U1 2 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD MAR PY 2013 VL 23 IS 2 BP 110 EP 116 DI 10.1089/cap.2011.0136 PG 7 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 109YO UT WOS:000316407700006 PM 23510445 ER PT J AU Wong, TB Rowell, JC Waldhausen, JHT Parisi, MA Jonmarker, C AF Wong, Tina B. Rowell, Jonathan C. Waldhausen, John H. T. Parisi, Melissa A. Jonmarker, Christer TI Anesthesia in a 12 year old boy with somatic overgrowth secondary to pericentric inversion of chromosome 12 SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Editorial Material DE Chromosome 12 inversion; Gigantism; Pediatric anesthesia; Pediatrics; Somatic overgrowth; Splenectomy ID DIFFICULT TRACHEAL INTUBATION AB The management of a splenectomy in a boy with an unusual form of somatic overgrowth is presented. Except for a moderately difficult airway, no unusual reactions to anesthesia and surgery were encountered. Possible anesthetic implications of different somatic overgrowth syndromes in children are presented. (C) 2013 Published by Elsevier Inc. C1 [Wong, Tina B.; Rowell, Jonathan C.; Jonmarker, Christer] Seattle Childrens Hosp, Dept Anesthesiol & Pain Med, Seattle, WA 98105 USA. [Waldhausen, John H. T.] Seattle Childrens Hosp, Dept Surg, Seattle, WA 98105 USA. [Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intellectual & Dev Disabil Branch, Bethesda, MD 20892 USA. RP Jonmarker, C (reprint author), Seattle Childrens Hosp, Dept Anesthesiol & Pain Med, 4800 Sand Point Way NE, Seattle, WA 98105 USA. EM christer.jonmarker@seattlechildrens.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD MAR PY 2013 VL 25 IS 2 BP 135 EP 137 DI 10.1016/j.jclinane.2012.06.014 PG 3 WC Anesthesiology SC Anesthesiology GA 109NK UT WOS:000316375100009 PM 23274076 ER PT J AU Christophi, CA Resnick, HE Ratner, RE Temprosa, M Fowler, S Knowler, WC Shamoon, H Barrett-Connor, E Kahn, SE AF Christophi, C. A. Resnick, H. E. Ratner, R. E. Temprosa, M. Fowler, S. Knowler, W. C. Shamoon, H. Barrett-Connor, E. Kahn, S. E. CA Diabet Prevention Program Res Grp TI Confirming Glycemic Status in the Diabetes Prevention Program: Implications for Diagnosing Diabetes in High Risk Adults SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Diabetes mellitus; Screening; Epidemiology ID IMPAIRED GLUCOSE-TOLERANCE; NUTRITION EXAMINATION SURVEY; CAUCASIAN POPULATION; FASTING GLUCOSE; PREVALENCE; HEALTH; HOORN AB Aims: To examine the ability of fasting plasma glucose (FPG) and/or 2-h glucose to confirm diabetes and to determine the proportion of participants with HbA1c >= 6.5%. Methods: Diabetes confirmation rates were calculated after a single elevated FPG and/or 2-h glucose on an oral glucose tolerance test (OGTT) using a confirmatory OGTT performed within 6 weeks. Results: 772 (24%) participants had elevated FPG or 2-h glucose on an OGTT that triggered a confirmation visit. There were 101 triggers on FPG alone, 574 on 2-h glucose alone, and 97 on both. Only 47% of participants who triggered had confirmed diabetes. While the confirmation rate for FPG was higher than that for 2-h glucose, the larger number of 2-h glucose triggers resulted in 87% of confirmed cases triggering on 2-h glucose. Confirmation rates increased to 75% among persons with FPG >= 126 mg/dl and HbA1c >= 6.5%. Conclusions: Only half of the persons with elevated FPG and IGT were subsequently confirmed to have diabetes. At current diagnostic levels, more persons trigger on 2-h glucose than on FPG, but fewer of these persons have their diagnoses confirmed. In individuals with FPG >= 126 mg/dl and HbA1c >= 6.5%, the confirmation rate was increased. (C) 2013 Elsevier Inc. All rights reserved. C1 [Christophi, C. A.; Temprosa, M.; Fowler, S.] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. [Resnick, H. E.] Amer Assoc Homes & Serv Aging, Inst Future Aging Serv, Washington, DC USA. [Resnick, H. E.] Georgetown Univ, Washington, DC USA. [Ratner, R. E.] MedStar Res Inst, Hyattsville, MD USA. [Knowler, W. C.] NIDDKD, Phoenix, AZ USA. [Shamoon, H.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Barrett-Connor, E.] Univ Calif San Diego, San Diego, CA 92103 USA. [Kahn, S. E.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Kahn, S. E.] Univ Washington, Seattle, WA 98195 USA. RP Christophi, CA (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, Rockville, MD 20852 USA. EM dppmail@bsc.gwu.edu RI Altshuler, David/A-4476-2009; de Bakker, Paul/B-8730-2009; Uwaifo, Gabriel/M-2361-2016; OI Altshuler, David/0000-0002-7250-4107; de Bakker, Paul/0000-0001-7735-7858; Uwaifo, Gabriel/0000-0002-6962-9304; Shamoon, Harry/0000-0002-5014-5211; 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; Department of Veterans Affairs; American Diabetes Association; intramural research program of the NIDDK; McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation; Coordinating Center FX The Investigators gratefully acknowledge the commitment and dedication of the participants of the DPP. 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. 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 and Department of Veteran Affairs 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 Department of Veterans Affairs and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of Centers, investigators, and staff can be found in Appendix 1. NR 20 TC 5 Z9 5 U1 0 U2 21 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 MAR-APR PY 2013 VL 27 IS 2 BP 150 EP 157 DI 10.1016/j.jdiacomp.2012.09.012 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109NG UT WOS:000316374700008 PM 23140912 ER PT J AU Gonzalez, JM Romero, R Girardi, G AF Gonzalez, Juan M. Romero, Roberto Girardi, Guillermina TI Comparison of the mechanisms responsible for cervical remodeling in preterm and term labor SO JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article; Proceedings Paper CT Joint Meeting of the European-Society-for-Reproductive-Immunology (ESRI) and the American-Society-for-Reproductive-Immunology (ASRI) CY MAY 31-JUN 02, 2012 CL Hamburg, GERMANY SP European Soc Reprod Immunol (ESRI), Amer Soc Reprod Immunol (ASRI) DE Mouse model; Inflammation; Preterm labor; Cervical remodeling; Complement activation; Pregnancy ID PLACEBO-CONTROLLED TRIAL; COMPLEMENT ACTIVATION; MEDROXYPROGESTERONE ACETATE; VAGINAL PROGESTERONE; ALTERNATIVE PATHWAY; RIPENING PROCESS; DOUBLE-BLIND; PARTURITION; BIRTH; PREGNANCY AB Understanding the mechanisms of term and preterm cervical remodeling is essential to prevent prematurity. Is preterm cervical remodeling caused by the same mechanisms that cause cervical remodeling at term, and are these changes accelerated in time? This question has been pondered by obstetricians seeking strategies to prevent preterm labor for many years. Mice represent an informative model of preterm birth. Thus, in this review we discuss the recent findings from mouse models that identify and characterize the initiators and cellular effectors of cervical remodeling at term and preterm labor/delivery. These studies suggest that similarities and differences exist between term and preterm cervical remodeling. Complement is an initiator or mediator in preterm labor/delivery, but is not involved in the physiological process that leads to term delivery. Therefore, complememt constitutes a specific and selective target for potentially preventing preterm delivery, thus improving neonatal health. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Gonzalez, Juan M.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Detroit, MD USA. [Girardi, Guillermina] Univ Edinburgh, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. RP Girardi, G (reprint author), Univ Edinburgh, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. EM guillerminagirardi@gmail.com FU Intramural NIH HHS [ZIA HD002401-17] NR 54 TC 16 Z9 17 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-0378 J9 J REPROD IMMUNOL JI J. Reprod. Immunol. PD MAR PY 2013 VL 97 IS 1 SI SI BP 112 EP 119 DI 10.1016/j.jri.2012.07.008 PG 8 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 110HV UT WOS:000316434100014 PM 23312455 ER PT J AU Buicel, MA Chow, CC AF Buicel, Michael A. Chow, Carson C. TI Beyond mean field theory: statistical field theory for neural networks SO JOURNAL OF STATISTICAL MECHANICS-THEORY AND EXPERIMENT LA English DT Article DE finite-size scaling; dynamics (theory); neuronal networks (theory); Boltzmann equation ID POPULATION-DENSITY APPROACH; COUPLED OSCILLATORS; FIRE NEURONS; ASYNCHRONOUS STATES; PATTERN-FORMATION; SPIKING NEURONS; KURAMOTO MODEL; VISUAL-CORTEX; LOCKED STATE; DYNAMICS AB Mean field theories have been a stalwart for studying the dynamics of networks of coupled neurons. They are convenient because they are relatively simple and possible to analyze. However, classical mean field theory neglects the effects of fluctuations and correlations due to single neuron effects. Here, we consider various possible approaches for going beyond mean field theory and incorporating correlation effects. Statistical field theory methods, in particular the Doi-Peliti-Janssen formalism, are particularly useful in this regard. C1 [Buicel, Michael A.] Univ Texas Austin, Ctr Learning & Memory, Austin, TX 78712 USA. [Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Buicel, MA (reprint author), Univ Texas Austin, Ctr Learning & Memory, Austin, TX 78712 USA. EM mabuice@mail.elm.utexas.edu; carsonc@niddk.nih.gov FU Intramural Research Program of NIH/NIDDK FX This research was supported by the Intramural Research Program of NIH/NIDDK. NR 61 TC 8 Z9 9 U1 1 U2 8 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1742-5468 J9 J STAT MECH-THEORY E JI J. Stat. Mech.-Theory Exp. PD MAR PY 2013 AR P03003 DI 10.1088/1742-5468/2013/03/P03003 PG 21 WC Mechanics; Physics, Mathematical SC Mechanics; Physics GA 105HI UT WOS:000316056900003 PM 25243014 ER PT J AU Thigpen, JE Setchell, KDR Kissling, GE Locklear, J Caviness, GF Whiteside, T Belcher, SM Brown, NM Collins, BJ Lih, FB Tomer, KB Padilla-Banks, E Camacho, L Adsit, FG Grant, M AF Thigpen, Julius E. Setchell, Kenneth D. R. Kissling, Grace E. Locklear, Jacqueline Caviness, Gordon F. Whiteside, Tanya Belcher, Scott M. Brown, Nadine M. Collins, Bradley J. Lih, Fred B. Tomer, Kenneth B. Padilla-Banks, Elizabeth Camacho, Luisa Adsit, Floyd G. Grant, Mary TI The Estrogenic Content of Rodent Diets, Bedding, Cages, and Water Bottles and Its Effect on Bisphenol A Studies SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID SPRAGUE-DAWLEY RATS; IMMATURE CD-1 MICE; ZEARALENONE SIGNIFICANTLY ADVANCES; ENDOCRINE-DISRUPTING CHEMICALS; REPRODUCTIVE ORGAN DEVELOPMENT; APPROPRIATE POSITIVE CONTROLS; EXPERIMENTAL-DESIGN REVEALS; GOOD LABORATORY PRACTICES; EXPOSED IN-UTERO; ETHINYL ESTRADIOL AB The lowest observed adverse effect level for bisphenol A (BPA) in mice and rats is currently poorly defined due to inconsistent study designs and results in published studies. The objectives of the current study were to (1) compare the estrogenic content of rodent diets, bedding, cages, and water bottles to evaluate their impact on the estrogenic activity of BPA and (2) review the literature on BPA to determine the most frequently reported diets, beddings, cages, and water bottles used in animal studies. Our literature review indicated that low-dose BPA animal studies have inconsistent results and that factors contributing to this inconsistency are the uses of high-phytoestrogen diets and the different routes of exposure. In 44% (76 of 172) of all reports, rodents were exposed to BPA via the subcutaneous route. Our literature review further indicated that the type of diet, bedding, caging, and water bottles used in BPA studies were not always reported. Only 37% (64 of 172) of the reports described the diet used. In light of these findings, we recommend the use of a diet containing low levels of phytoestrogen (less than 20 mu g/g diet) and metabolizable energy (approximately 3.1 kcal/g diet) and estrogen-free bedding, cages, and water bottles for studies evaluating the estrogenic activity of endocrine-disrupting compounds such as BPA. The oral route of BPA exposure should be used when results are to be extrapolated to humans. C1 [Thigpen, Julius E.; Locklear, Jacqueline; Caviness, Gordon F.; Whiteside, Tanya; Adsit, Floyd G.; Grant, Mary] NIEHS, Comparat Med Branch, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Collins, Bradley J.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Lih, Fred B.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Padilla-Banks, Elizabeth] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Setchell, Kenneth D. R.; Brown, Nadine M.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Belcher, Scott M.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Camacho, Luisa] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Thigpen, JE (reprint author), NIEHS, Comparat Med Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM thigpen@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 NR 100 TC 19 Z9 19 U1 1 U2 36 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAR PY 2013 VL 52 IS 2 BP 130 EP 141 PG 12 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 106QL UT WOS:000316159700002 PM 23562095 ER PT J AU Schonberg, MA Breslau, ES McCarthy, EP AF Schonberg, Mara A. Breslau, Erica S. McCarthy, Ellen P. TI Targeting of Mammography Screening According to Life Expectancy in Women Aged 75 and Older SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE mammography screening; older women; life expectancy ID SERVICES TASK-FORCE; BREAST-CANCER; HEALTH-STATUS; DIAGNOSIS; PROGNOSIS; SURVIVAL; ADULTS AB Objectives To examine receipt of mammography screening according to life expectancy in women aged 75 and older. Design Population-based survey. Setting United States. Participants Community dwelling U.S. women aged 75 and older who participated in the 2008 or 2010 National Health Interview Survey. Measurements Using a previously developed and validated index, women were categorized according to life expectancy (>9, 59, <5years). Receipt of mammography screening in the past 2years was examined according to life expectancy, adjusting for sociodemographic characteristics, access to care, preventive orientation (e.g., receipt of influenza vaccination), and receipt of a clinician recommendation for screening. Results Of 2,266 respondents, 27.1% had a life expectancy of greater than 9years, 53.4% had a life expectancy of 5 to 9years, and 19.5% had a life expectancy of less than 5years. Overall, 55.7% reported receiving mammography screening in the past 2years. Life expectancy was strongly associated with receipt of screening (P<.001), yet 36.1% of women with less than 5years life expectancy were screened, and 29.2% of women with more than 9years life expectancy were not screened. A clinician recommendation for screening was the strongest predictor of screening independent of life expectancy. Higher educational attainment, age, receipt of influenza vaccination, and history of benign breast biopsy were also independently associated with being screened. Conclusion Despite uncertainty of benefit, many women aged 75 and older are screened with mammography. Life expectancy is strongly associated with receipt of screening, which may reflect clinicians and patients appropriately considering life expectancy in screening decisions, but 36% of women with short life expectancies are still screened, suggesting that new interventions are needed to further improve targeting of screening according to life expectancy. Decision aids and guidelines encouraging clinicians to consider patient life expectancy in screening decisions may improve care. C1 [Schonberg, Mara A.; McCarthy, Ellen P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gen Med & Primary Care,Dept Med, Boston, MA 02215 USA. [Breslau, Erica S.] NCI, Proc Care Res Branch, Behav Res Program, NIH, Bethesda, MD 20892 USA. RP Schonberg, MA (reprint author), Beth Israel Deaconess Med Ctr, 1309 Beacon St,Off 202, Brookline, MA 02446 USA. EM mschonbe@bidmc.harvard.edu FU National Institute on Aging [K23AG028584]; John A. Hartford Foundation; Atlantic Philanthropies; Starr Foundation; American Federation for Aging Research; American Cancer Society [RSGT-10-080-CPHSPS] FX This research was conducted while Dr. Mara Schonberg was supported by a Paul B. Beeson Career Development Award in Aging from the National Institute on Aging (K23AG028584), The John A. Hartford Foundation, The Atlantic Philanthropies, The Starr Foundation, and The American Federation for Aging Research. Dr. McCarthy was supported by the American Cancer Society (RSGT-10-080-CPHSPS). NR 30 TC 14 Z9 14 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2013 VL 61 IS 3 BP 388 EP 395 DI 10.1111/jgs.12123 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 108ZM UT WOS:000316334900010 PM 23414437 ER PT J AU Palmer, SAP Armstrong, A AF Palmer, Sheallah A. P. Armstrong, Alicia TI Intimate Partner Violence and the Role of Legislation SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Palmer, Sheallah A. P.; Armstrong, Alicia] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2013 VL 22 IS 3 MA P93 BP 37 EP 37 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 105IU UT WOS:000316061700094 ER PT J AU Gould, HN Bakalov, VK Tankersley, C Bondy, CA AF Gould, Harley N. Bakalov, Vladimir K. Tankersley, Carolyn Bondy, Carolyn A. TI High Levels of Education and Employment Among Women with Turner Syndrome SO JOURNAL OF WOMENS HEALTH LA English DT Article ID PREMATURE OVARIAN FAILURE; ADULT WOMEN; COGNITIVE FUNCTION; GROWTH-HORMONE; X-CHROMOSOME; PREVALENCE; PROFILE; AUTISM; ADHD AB Background: Turner Syndrome (TS) is due to X chromosome monosomy and affects similar to 1 per 2500 females at birth. The major features are short stature and primary ovarian failure. Short stature and monosomy for a maternal X chromosome have been implicated in impaired functionality in adult life; however, data on adult outcomes in TS are limited. In this study we evaluated the influence of adult height and parental origin of the single X chromosome on education, employment, and marital outcomes among women with TS. Methods: This was a cross-sectional study of 240 women (25-67 years old) with TS participating in an intramural National Institutes of Health (NIH) study. Parental origin of the single X chromosome was determined by genotyping proband and parental genomic DNA. Information on education, employment, and family status was self reported. Normative data was obtained from the U. S. Bureaus of Census and Labor and Statistics. Results: Seventy percent of the TS group had a baccalaureate degree or higher, compared with 30% of U. S. women (p < 0.0001). Eighty percent of the TS group was employed compared with 70% of the U. S. female population. Approximately 50% of the TS group had ever married, compared with 78% of the general female population (p < 0.0001). Height and parental origin of the single normal X chromosome had no association with education, employment, or marital status. Conclusion: Women with TS currently achieve education and employment levels higher than the female U. S. population but are less likely to marry. Neither adult height nor parental origin of the single X chromosome influenced outcomes in education, employment, or marriage. C1 [Gould, Harley N.; Bakalov, Vladimir K.; Tankersley, Carolyn; Bondy, Carolyn A.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHHD, Program Dev Endocrinolgy & Genet, NIH, 10 Ctr Dr,Room 1-3330, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov FU NICHD, NIH FX We are grateful to the women with TS who participated in our study. This work was entirely supported by the intramural research program of the NICHD, NIH. NR 22 TC 7 Z9 7 U1 0 U2 14 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2013 VL 22 IS 3 BP 230 EP 235 DI 10.1089/jwh.2012.3931 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 105IU UT WOS:000316061700129 PM 23421579 ER PT J AU Fwu, CW Eggers, PW Kimmel, PL Kusek, JW Kirkali, Z AF Fwu, Chyng-Wen Eggers, Paul W. Kimmel, Paul L. Kusek, John W. Kirkali, Ziya TI Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States SO KIDNEY INTERNATIONAL LA English DT Article DE computed tomography; NHAMCS; radiation ID KIDNEY-STONES; RADIATION-EXPOSURE; GEOGRAPHIC VARIABILITY; UROLOGIC DISEASES; NATIONAL TRENDS; AMERICA PROJECT; PREVALENCE; RISK; CT; POPULATION AB The occurrence of urolithiasis in the United States has increased; however, information on long-term trends, including recurrence rates, is lacking. Here we describe national trends in rates of emergency department visits, use of imaging, and drug treatment, primarily using the National Hospital Ambulatory Medical Care Survey to describe trends and the National Health and Nutrition Examination Survey to determine the frequency of lifetime passage of kidney stones. Emergency department visit rates for urolithiasis increased from 178 to 340 visits per 100,000 individuals from 1992 to 2009. Increases in visit rates were greater in women, Caucasians, and in those aged 25-44 years. The use of computed tomography in urolithiasis patients more than tripled, from 21 to 71%. Medical expulsive therapy was used in 14% of the patients with a urolithiasis diagnosis in 2007-2009. Among National Health and Nutrition Examination Survey participants who reported a history of kidney stones, 22.4% had passed three or more stones. Hence, emergency department urolithiasis visit rates have increased significantly, as has the use of computed tomography in the United States. Further research is necessary to determine whether recurrent stone formers receive unnecessary radiation exposure during diagnostic evaluation in the emergency department and allow development of corresponding evidence-based guidelines. Kidney International (2013) 83, 479-486; doi:10.1038/ki.2012.419; published online 2 January 2013 C1 [Fwu, Chyng-Wen] Social & Sci Syst, Silver Spring, MD USA. [Eggers, Paul W.; Kimmel, Paul L.; Kusek, John W.; Kirkali, Ziya] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Kirkali, Z (reprint author), NIDDK, Div Kidney Urol & Hematol Dis, NIH, 6707 Democracy Blvd,Room 627, Bethesda, MD 20892 USA. EM ziya.kirkali@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [HHSN267200700001G] FX CWF is supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN267200700001G). NR 55 TC 47 Z9 47 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2013 VL 83 IS 3 BP 479 EP 486 DI 10.1038/ki.2012.419 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 106PD UT WOS:000316156100020 PM 23283137 ER PT J AU Cornwell, BR Overstreet, C Krimsky, M Grillon, C AF Cornwell, Brian R. Overstreet, Cassie Krimsky, Marissa Grillon, Christian TI Passive avoidance is linked to impaired fear extinction in humans SO LEARNING & MEMORY LA English DT Article ID VIRTUAL-REALITY ENVIRONMENT; POTENTIATED STARTLE; ANXIETY DISORDERS; HUMAN HIPPOCAMPAL; EXPOSURE THERAPY; AWARENESS; CONTEXT; MECHANISMS; BEHAVIOR; THETA AB Conventional wisdom dictates we must face our fears to conquer them. This idea is embodied in exposure-based treatments for anxiety disorders, where the intent of exposure is to reverse a history of avoidant behavior that is thought to fuel a patient's irrational fears. We tested in humans the relationship between fear and avoidance by combining Pavlovian differential fear conditioning with a novel task for quantifying spontaneous passive avoidant behavior. During self-guided navigation in virtual reality following de novo fear conditioning, we observed participants keeping their distance from the feared object. At the individual level, passive avoidant behavior was highly associated with maladaptive fear expression (fear-potentiated startle) during late extinction training, indicating that extinction learning was impaired following a brief episode of avoidance. Avoidant behavior, however, was not related to initial acquired fear, raising doubt about a straightforward link between physiological fear and behavioral avoidance. We conclude that a deeper understanding of what motivates avoidance may offer a target for early intervention, before fears transition from the rational to the irrational. C1 [Cornwell, Brian R.; Overstreet, Cassie; Krimsky, Marissa; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Cornwell, Brian R.] Swinburne Univ Technol, Fac Life & Social Sci, Hawthorn, Vic 3122, Australia. RP Cornwell, BR (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. EM bcornwell@swin.edu.au FU Intramural Research Program of the National Institute of Mental Health FX We thank Daniel Pine, Katherine Vytal, and Oliver Robinson for helpful comments on an earlier draft of the manuscript. This work was funded by the Intramural Research Program of the National Institute of Mental Health. NR 33 TC 2 Z9 2 U1 2 U2 16 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD MAR PY 2013 VL 20 IS 3 BP 164 EP 169 DI 10.1101/lm.028902.112 PG 6 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 108VN UT WOS:000316324400007 PM 23427168 ER PT J AU Zimmerman, MA Baker, T Goodrich, NP Freise, C Hong, JC Kumer, S Abt, P Cotterell, AH Samstein, B Everhart, JE Merion, RM AF Zimmerman, Michael A. Baker, Talia Goodrich, Nathan P. Freise, Chris Hong, Johnny C. Kumer, Sean Abt, Peter Cotterell, Adrian H. Samstein, Benjamin Everhart, James E. Merion, Robert M. TI Development, management, and resolution of biliary complications after living and deceased donor liver transplantation: A report from the adult-to-adult living donor liver transplantation cohort study consortium SO LIVER TRANSPLANTATION LA English DT Article ID STRICTURES; LOBE AB Adult recipients of living donor liver transplantation (LDLT) have a higher incidence of biliary complications than recipients of deceased donor liver transplantation (DDLT). Our objective was to define the intensity of the interventions and the time to resolution after the diagnosis of biliary complications after liver transplantation. We analyzed the management and resolution of posttransplant biliary complications and investigated the comparative effectiveness of interventions in LDLT and DDLT recipients. For the analysis of biliary complications (leaks or strictures), we used a retrospective cohort of patients who underwent liver transplantation at 8 centers between 1998 and 2006 (median follow-up from onset=4.7 years). The numbers, procedure types, and times to resolution were compared for LDLT and DDLT recipients. Posttransplant biliary complications occurred in 47 of the 189 DDLT recipients (25%) and in 141 of the 356 LDLT recipients (40%). Biliary leaks constituted 38% of the post-DDLT biliary complications (n=18) and 65% of the post-LDLT biliary complications (n=91). The median times to first biliary complications were similar for DDLT and LDLT (11 versus 14 days for leaks, P=0.63; 69 versus 107 days for strictures, P=0.34). Overall, 1225 diagnostic and therapeutic procedures, including reoperation and retransplantation, were performed (6.5 +/- 5.4 per recipient; 5.5 +/- 3.6 for DDLT versus 6.8 +/- 5.8 for LDLT, P=0.52). The median number of months to the resolution of a biliary complication (i.e., a tube-, stent-, and drain-free status) did not significantly differ between the DDLT and LDLT groups for leaks (2.3 versus 1.3 months, P=0.29) or strictures (4.9 versus 2.3 months, P=0.61). Although the incidence of biliary complications is higher after LDLT versus DDLT, the treatment requirements and the time to resolution after the development of a biliary complication are similar for LDLT and DDLT recipients. Liver Transpl 19:259267, 2013. (c) 2013 AASLD. C1 [Zimmerman, Michael A.] Univ Colorado, Div Transplant Surg, Denver, CO 80202 USA. [Baker, Talia] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Goodrich, Nathan P.; Merion, Robert M.] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Freise, Chris] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Hong, Johnny C.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Kumer, Sean] Univ Virginia, Dept Surg, Charlottesville, VA USA. [Abt, Peter] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Cotterell, Adrian H.] Virginia Commonwealth Univ, Dept Surg, Richmond, VA USA. [Samstein, Benjamin] Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA. [Everhart, James E.] NIDDK, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. [Merion, Robert M.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. RP Zimmerman, MA (reprint author), Univ Colorado Denver, Div Transplant Surg, 1635 Aurora Court,7th Floor,Mail Stop C318, Aurora, CO 80045 USA. EM michael.zimmerman@ucdenver.edu OI Goodrich, Nathan/0000-0003-0392-7146 FU Columbia University Health Sciences, New York, NY [DK62483]; Northwestern University, Chicago, IL [DK62467]; University of Pennsylvania Health System, Philadelphia, PA [DK62494]; University of Colorado Health Sciences Center, Denver, CO [DK62536]; University of California Los Angeles, Los Angeles, CA [DK62496]; University of California San Francisco, San Francisco, CA [DK62444]; University of Michigan Medical Center, Ann Arbor, MI [DK62498]; University of North Carolina, Chapel Hill, NC [DK62505]; University of Virginia, Charlottesville, VA [DK62484] FX The following individuals were instrumental in the planning, conduct, and/or care of the patients enrolled in this study at each of the participating institutions: Jean C. Emond, M. D. (principal investigator), Robert S. Brown Jr, M. D., M. P. H. (co-principal investigator), and Scott Heese, B. A., and Taruna Chawla, M. D. (study coordinators), Columbia University Health Sciences, New York, NY (DK62483); Michael M. I. Abecassis, M. D., M. B. A. (principal investigator), Laura M. Kulik, M. D. (co-principal investigator), and Patrice Al-Saden, R.N., C. C. R. C. (study coordinator), Northwestern University, Chicago, IL (DK62467); Abraham Shaked, M. D., Ph.D. (principal investigator), Kim M. Olthoff, M. D. (co-principal investigator), and Brian Conboy, P. A., M. B. A., and Mary Shaw, R.N., B. B. A. (study coordinators), University of Pennsylvania Health System, Philadelphia, PA (DK62494); Gregory T. Everson, M. D. (principal investigator), Igal Kam, M. D. (co-principal investigator), and Andrea Herman, R.N. (study coordinator), University of Colorado Health Sciences Center, Denver, CO (DK62536); Johnny C. Hong, M. D. (principal investigator), Ronald W. Busuttil, M. D., Ph.D. (co-principal investigator), Janet Mooney, R.N., B.S.N. (study coordinator), and Sammy Saab, M. D. (principal investigator for low accelerating dose regimen [LADR]), University of California Los Angeles, Los Angeles, CA (DK62496); Chris E. Freise, M. D., F. A. C. S. (principal investigator), Norah A. Terrault, M. D. (co-principal investigator), and Dulce MacLeod, R.N. (study coordinator), University of California San Francisco, San Francisco, CA (DK62444); Robert M. Merion, M. D. (principal investigator), and Anna S. F. Lok, M. D., Akinlolu O. Ojo, M. D., Ph.D., Brenda W. Gillespie, Ph.D., Margaret Hill-Callahan, B. S., L. S. W., Terese Howell, B. S., C. C. R. C., Lisa Holloway, B. S., C. C. R. C., Monique Lowe, M. S., Abby Smith, B. A., and Abby Brithinee, B. A. (data coordinating center staff), University of Michigan Medical Center, Ann Arbor, MI (DK62498); Paul H. Hayashi, M. D., M. P. H. (principal investigator), and Tracy Russell, M. A. (study coordinator), University of North Carolina, Chapel Hill, NC (DK62505); Carl L. Berg, M. D. (principal investigator), Jaye Davis, R. N., and Colleen Green, P. A. (study coordinators), and Abdullah M. S. Al-Osaimi, M. D. (principal investigator for low accelerating dose regimen (LADR)), University of Virginia, Charlottesville, VA (DK62484); Robert A. Fisher, M. D., F. A. C. S. (principal investigator), R. Todd Stravitz, M. D. (co-principal investigator), April Ashworth, R. N., Andrea Lassiter, B. S., and Charlotte Hoffman, R. N. (study coordinators), and Mitchell Shiffman, M. D. (principal investigator for LADR), Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, VA (DK62531); and James E. Everhart, M. D., M. P. H., Averell Sherker, M. D., and Jay H. Hoofnagle, M. D., Division of Diges-tive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. NR 15 TC 29 Z9 33 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD MAR PY 2013 VL 19 IS 3 BP 259 EP 267 DI 10.1002/lt.23595 PG 9 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 107JG UT WOS:000316212000005 PM 23495079 ER PT J AU Everson, GT Hoefs, JC Niemann, CU Olthoff, KM Dupuis, R Lauriski, S Herman, A Milne, N Gillespie, BW Goodrich, NP Everhart, JE AF Everson, Gregory T. Hoefs, John C. Niemann, Claus U. Olthoff, Kim M. Dupuis, Robert Lauriski, Shannon Herman, Andrea Milne, Norah Gillespie, Brenda W. Goodrich, Nathan P. Everhart, James E. TI Functional elements associated with hepatic regeneration in living donors after right hepatic lobectomy SO LIVER TRANSPLANTATION LA English DT Article ID ERYTHROMYCIN BREATH TEST; LIVER-TRANSPLANTATION; RIGHT HEPATECTOMY; SPLEEN VOLUME; DONATION; RATS; RECIPIENTS; CLEARANCE; CIRRHOSIS; RECOVERY AB We quantified the rates of hepatic regeneration and functional recovery for 6 months after right hepatic lobectomy in living donors for liver transplantation. Twelve donors were studied pre-donation (baseline); 8 were retested at a mean +/- SD of 11 +/- 3 days after donation (T1), 10 were retested at a mean of 91 +/- 9 days after donation (T2), and 10 were retested at a mean of 185 +/- 17 days after donation (T3). Liver and spleen volumes were measured with computed tomography (CT) and single-photon emission computed tomography (SPECT). Hepatic metabolism was assessed with caffeine and erythromycin, and hepatic blood flow (HBF) was assessed with cholates, galactose, and the perfused hepatic mass (PHM) by SPECT. The regeneration rates (mL kg1 of body weight day1) by CT were 0.60 +/- 0.22 mL from the baseline to T1, 0.05 +/- 0.02 mL from T1 to T2, and 0.01 +/- 0.01 from T2 to T3; by SPECT they were 0.54 +/- 0.20, 0.04 +/- 0.01, and 0.01 +/- 0.02, respectively. At T3, the liver volumes were 84%+/- 7% of the baseline according to CT and 92%+/- 13% of the baseline according to SPECT. Changes in the hepatic metabolism did not achieve statistical significance. At T1, the unadjusted clearance ratios with respect to the baseline were 0.75 +/- 0.07 for intravenous cholate (P<0.001), 0.88 +/- 0.15 for galactose (P=0.07), 0.84 +/- 0.08 for PHM (P=0.002), and 0.83 +/- 0.19 for the estimated HBF (P=0.06). At T1, these ratios adjusted per liter of liver were up to 50% greater than the baseline values, suggesting recruitment of HBF by the regenerating liver. Increased cholate shunt, increased spleen volume, and decreased platelet count, were consistent with an altered portal circulation. In conclusion, initial hepatic regeneration is rapid, accounts for nearly two-thirds of total regeneration, and is associated with increases in HBF and cholate uptake. Right lobe donation alters the portal circulation of living donors, but the long-term clinical consequences, if there are any, are unknown. Liver Transpl 19:292304, 2013. (c) 2013 AASLD. C1 [Everson, Gregory T.; Lauriski, Shannon; Herman, Andrea] Univ Colorado Denver, Sect Hepatol, Div Gastroenterol & Hepatol, Aurora, CO 80045 USA. [Hoefs, John C.; Milne, Norah] Univ Calif Irvine, Div Radiol Sci, Irvine, CA USA. [Niemann, Claus U.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Niemann, Claus U.] Univ Calif San Francisco, Dept Surg, Div Transplantat, San Francisco, CA USA. [Olthoff, Kim M.] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Dupuis, Robert] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Gillespie, Brenda W.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Goodrich, Nathan P.] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Everhart, James E.] NIDDK, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Everson, GT (reprint author), Univ Colorado Denver, Sect Hepatol, Div Gastroenterol & Hepatol, 1635 Aurora Court,B-154, Aurora, CO 80045 USA. EM greg.everson@ucdenver.edu OI Goodrich, Nathan/0000-0003-0392-7146 FU Columbia University Health Sciences, New York, NY [DK62483]; Northwestern University, Chicago, IL [DK62467]; University of Pennsylvania Health System, Philadelphia, PA [DK62494]; University of Colorado Health Sciences Center, Denver, CO [DK62536]; University of California Los Angeles, Los Angeles, CA [DK62496]; University of California San Francisco, San Francisco, CA [DK62444]; University of Michigan Medical Center, Ann Arbor, MI [DK62498] FX The following individuals were instrumental in the planning, conduct, and/or care of the patients enrolled in this study at each of the participating institutions: Jean C. Emond, M. D. (principal investigator), Robert S. Brown Jr, M. D., M. P. H. (co-principal investigator), and Scott Heese, B. A., and Jonah S. Zaretsky, B. A. (study coordinators), Columbia University Health Sciences, New York, NY (DK62483); Michael M. I. Abecassis, M. D., M. B. A. (principal investigator), Laura M. Kulik, M. D. (co-principal investigator), and Patrice AlSaden, R. N., C. C. R. C. (study coordinator), Northwestern University, Chicago, IL (DK62467); Abraham Shaked, M. D., Ph. D. (principal investigator), Kim M. Olthoff, M. D. (co-principal investigator), and Brian Conboy, P. A., M. B. A., and Mary Shaw, R. N., B. B. A. (study coordinators), University of Pennsylvania Health System, Philadelphia, PA (DK62494); Gregory T. Everson, M. D. (principal investigator), Igal Kam, M. D. (co-principal investigator), and Carlos Garcia, B. S., and Anastasia Krajec, R. N. (study coordinators), University of Colorado Health Sciences Center, Denver, CO (DK62536); Johnny C. Hong, M. D. (principal investigator), Ronald W. Busuttil, M. D., Ph. D. (coprincipal investigator), and Janet Mooney, R. N., B. S. N. (study coordinator), University of California Los Angeles, Los Angeles, CA (DK62496); Chris E. Freise, M. D., F. A. C. S. (principal investigator), Norah A. Terrault, M. D. (co-principal investigator), and Dulce MacLeod, R. N. (study coordinator), University of California San Francisco, San Francisco, CA (DK62444); Robert M. Merion, M. D. (principal investigator), and Anna S. F. Lok, M. D., Akinlolu O. Ojo, M. D., Ph.D., Brenda W. Gillespie, Ph. D., Margaret Hill-Callahan, B. S., L. S. W., Terese Howell, B. S., A. C. R. P., Lisa Holloway, B. S., A. C. R. P., Monique Lowe, B. S., Abby Smith, B. A., and Abby Brithinee, B. A. (data coordinating center staff), University of Michigan Medical Center, Ann Arbor, MI (DK62498); Paul H. Hayashi, M. D., M. P. H. (principal investigator), and Tracy Russell, M. A. (study coordinator), University of North Carolina, Chapel Hill, NC (DK62505); Carl L. Berg, M. D. (principal investigator), and Jaye Davis, R.N. (study coordinator), University of Virginia, Charlottesville, VA (DK62484); Robert A. Fisher, M. D., F. A. C. S. (principal investigator), R. Todd Stravitz, M. D. (co-principal investigator), and April Ashworth, R.N., and Andrea Lassiter, B. S. (study coordinators), Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, VA (DK62531); and James E. Everhart, M. D., M. P. H., Averell Sherker, M. D., and Jay H. Hoofnagle, M. D., Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. NR 29 TC 9 Z9 9 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 EI 1527-6473 J9 LIVER TRANSPLANT JI Liver Transplant. PD MAR PY 2013 VL 19 IS 3 BP 292 EP 304 DI 10.1002/lt.23592 PG 13 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 107JG UT WOS:000316212000009 PM 23239552 ER PT J AU Faranesh, AZ Kellman, P Ratnayaka, K Lederman, RJ AF Faranesh, Anthony Z. Kellman, Peter Ratnayaka, Kanishka Lederman, Robert J. TI Integration of cardiac and respiratory motion into MRI roadmaps fused with x-ray SO MEDICAL PHYSICS LA English DT Article DE x-ray; MRI; fusion; motion ID ATRIAL-FIBRILLATION; MAGNETIC-RESONANCE; IMAGE INTEGRATION; REGISTRATION; ABLATION; RECONSTRUCTION; INTERVENTIONS; TRACKING; HEART AB Purpose: Volumetric roadmaps overlaid on live x-ray fluoroscopy may be used to enhance image guidance during interventional procedures. These roadmaps are often static and do not reflect cardiac or respiratory motion. In this work, the authors present a method for integrating cardiac and respiratory motion into magnetic resonance imaging (MRI)-derived roadmaps to fuse with live x-ray fluoroscopy images, and this method was tested in large animals. Methods: Real-time MR images were used to capture cardiac and respiratory motion. Nonrigid registration was used to calculate motion fields to deform a reference end-expiration, end-diastolic image to different cardiac and respiratory phases. These motion fields were fit to separate affine motion models for the aorta and proximal right coronary artery. Under x-ray fluoroscopy, an image-based navigator and ECG signal were used as inputs to deform the roadmap for live overlay. The in vivo accuracy of motion correction was measured in four swine as the ventilator tidal volume was varied. Results: Motion correction reduced the root-mean-square error between the roadmaps and manually drawn centerlines, even under high tidal volume conditions. For the aorta, the error was reduced from 2.4 +/- 1.5 mm to 2.2 +/- 1.5 mm (p < 0.05). For the proximal right coronary artery, the error was reduced from 8.8 +/- 16.2 mm to 4.3 +/- 5.2 mm (p < 0.001). Using real-time MRI and an affine motion model it is feasible to incorporate physiological cardiac and respiratory motion into MRI-derived roadmaps to provide enhanced image guidance for interventional procedures. Conclusions: A method has been presented for creating dynamic 3D roadrnaps that incorporate cardiac and respiratory motion. These roadmaps can be overlaid on live X-ray fluoroscopy to enhance image guidance for cardiac interventions. (C) 2013 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4789919] C1 [Faranesh, Anthony Z.; Ratnayaka, Kanishka; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Kellman, Peter] NHLBI, Cardiac Energet Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Faranesh, AZ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM faranesa@mail.nih.gov OI lederman, robert/0000-0003-1202-6673 FU National Institutes of Health (NIH), NHLBI FX The authors thank Victor Wright, Bill Schenke, Katherine Lucas, and Joni Taylor for their assistance with the animal experiments. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NHLBI. NR 26 TC 8 Z9 8 U1 0 U2 4 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAR PY 2013 VL 40 IS 3 AR 032302 DI 10.1118/1.4789919 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 109LG UT WOS:000316369400042 PM 23464334 ER PT J AU Metlay, G AF Metlay, Grischa TI Federalizing Medical Campaigns against Alcoholism and Drug Abuse SO MILBANK QUARTERLY LA English DT Article DE alcoholism; drug abuse; substance abuse; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Special Action Office for Drug Abuse Prevention; policy history ID CONTROLLED SUBSTANCES ACT; HEROIN-ADDICTION; CIVIL COMMITMENT; EPIDEMIC; PROGRAM AB Context The formation of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Special Action Office for Drug Abuse Prevention (SAODAP) in the early 1970s dramatically expanded scientific and medical efforts to control alcoholism and drug abuse in the United States. Methods Drawing on a variety of primary, secondary, and archival sources, this article describes the creation and early years of these agencies. Findings I show that while the agencies appeared at roughly the same time, their creation involved separate sets of issues and actors. In addition, I show that SAODAP received more money and resources, even though advocates for alcoholics mobilized a stronger lobbying campaign. Conclusions Two factors explain this discrepancy in money and resources: (1) alcoholism was framed as a public health problem, whereas drug abuse was drawn into broader debates about crime and social decline; and (2) alcohol programs relied on congressional support, whereas drug programs found champions at high levels of the Nixon administration. These political and cultural factors help explain why current programs for illegal drugs receive more federal support, despite alcohol's greater public health burden. C1 [Metlay, Grischa] NIH, Off NIH Hist, Bethesda, MD 20814 USA. RP Metlay, G (reprint author), NIH, Bldg 60,Room 262,1 Cloister Ct, Bethesda, MD 20814 USA. EM grischa.metlay@nih.gov FU National Institute on Alcohol Abuse and Alcoholism FX Caroline Acker, Eva Ahrens, Richard Bonnie, Allan Brandt, David Cantor, David Courtwright, Judith Friedman, Sheila Jasanoff, Robert Martensen, Sejal Patel, Ron Roizen, Steven Shapin, and Richard Wyatt provided invaluable guidance during the research process and offered insightful comments on previous drafts of this article. This research was supported by a training grant from the National Institute on Alcohol Abuse and Alcoholism, which was overseen by the Office of NIH History. Opinions expressed in this article do not reflect the official position of the Office of NIH History, the NIAAA, or the National Institutes of Health. NR 85 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-378X J9 MILBANK Q JI Milbank Q. PD MAR PY 2013 VL 91 IS 1 BP 123 EP 162 DI 10.1111/milq.12004 PG 40 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 108IT UT WOS:000316286900005 PM 23488713 ER PT J AU Mullard, A Austin, C AF Mullard, Asher Austin, Chris TI AN AUDIENCE WITH ... SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Austin, Chris] NIH, Therapeut Rare & Neglected Dis TRND Programme, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD MAR PY 2013 VL 12 IS 3 BP 182 EP 183 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 105BT UT WOS:000316041300012 ER PT J AU Young, RM Staudt, LM AF Young, Ryan M. Staudt, Louis M. TI Targeting pathological B cell receptor signalling in lymphoid malignancies SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; TYROSINE KINASE INHIBITOR; NON-HODGKIN-LYMPHOMA; HUMAN FOLLICULAR LYMPHOMA; TRANSGENIC MOUSE MODEL; C-BETA INHIBITOR; PHASE-II TRIAL; ANTIGEN RECEPTOR; THERAPEUTIC TARGET AB Signalling through the B cell receptor (BCR) is central to the development and maintenance of B cells. In light of the numerous proliferative and survival pathways activated downstream of the BCR, it comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. However, direct evidence for BCR signalling in human lymphoma has only come to light recently. Roles for antigen-dependent and antigen-independent, or tonic, BCR signalling have now been described for several different lymphoma subtypes. Furthermore, correlative data implicate antigen-dependent BCR signalling in many other forms of lymphoma. A host of therapeutic agents targeting effectors of the BCR signalling pathway are now in clinical trials and have shown initial success against multiple forms of lymphoma. C1 [Young, Ryan M.; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 151 TC 155 Z9 156 U1 2 U2 34 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 MAR PY 2013 VL 12 IS 3 BP 229 EP 243 DI 10.1038/nrd3937 PG 15 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 105BT UT WOS:000316041300022 PM 23449308 ER PT J AU O'Shea, JJ Laurence, A McInnes, IB AF O'Shea, John J. Laurence, Arian McInnes, Iain B. TI Back to the future: oral targeted therapy for RA and other autoimmune diseases SO NATURE REVIEWS RHEUMATOLOGY LA English DT Review ID MODIFYING ANTIRHEUMATIC DRUGS; CELL ANTIGEN RECEPTOR; ACTIVE RHEUMATOID-ARTHRITIS; JANUS KINASE INHIBITOR; PLACEBO-CONTROLLED TRIAL; SPLEEN TYROSINE KINASE; TEC FAMILY KINASES; MICE LACKING JAK3; TOFACITINIB CP-690,550; SIGNAL-TRANSDUCTION AB The molecular biology revolution coupled with the development of monoclonal antibody technology enabled remarkable progress in rheumatology therapy, comprising an array of highly effective biologic agents. With advances in understanding of the molecular nature of immune cell receptors came elucidation of intracellular signalling pathways downstream of these receptors. These discoveries raise the question of whether selective targeting of key intracellular factors with small molecules would add to the rheumatologic armamentarium. In this Review, we discuss several examples of this therapeutic strategy that seem to be successful, and consider their implications for the future of immune-targeted treatments. We focus on kinase inhibitors, primarily those targeting Janus kinase family members and spleen tyrosine kinase, given their advanced status in clinical development and application. We also summarize other targets involved in signalling pathways that might offer promise for therapeutic intervention in the future. O'Shea, J. J. etal. Nat. Rev. Rheumatol. 9, 173-182 (2013); published online 19 February 2013; doi:10.1038/nrrheum.2013.7 C1 [O'Shea, John J.; Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [McInnes, Iain B.] Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Rm 13C103C,10 Ctr Dr, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009; OI Laurence, Arian/0000-0003-0942-8292; McInnes, Iain/0000-0002-6462-4280 FU Intramural NIH HHS [ZIA AR041106-17] NR 103 TC 32 Z9 34 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD MAR PY 2013 VL 9 IS 3 BP 173 EP 182 DI 10.1038/nrrheum.2013.7 PG 10 WC Rheumatology SC Rheumatology GA 107RZ UT WOS:000316239800006 PM 23419429 ER PT J AU Fuller, RL Van Winkle, EP Anderson, KE Gruber-Baldini, AL Hill, T Zampieri, C Weiner, WJ Shulman, LM AF Fuller, Rebecca L. Van Winkle, Elizabeth P. Anderson, Karen E. Gruber-Baldini, Ann L. Hill, Terra Zampieri, Cris Weiner, William J. Shulman, Lisa M. TI Dual task performance in Parkinson's disease: A sensitive predictor of impairment and disability SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Dual task; Cognition; Word generation; Gait speed; Disability and impairment ID EXECUTIVE FUNCTION; COGNITIVE IMPAIRMENT; GAIT; MOTOR; ATTENTION; WALKING; PEOPLE; INTERFERENCE; MAINTENANCE; COMMUNITY AB Background: Dual task (DT) performance assesses the ability to perform two tasks simultaneously. Difficulty with DT performance may be a sensitive indicator of early Parkinson's disease (PD) impairment. The objective of this study was to assess what elements of a DT performance (cognition or gait) are most associated with impairment and disability in PD. Methods: Performance in single and DT conditions was examined in 154 PD patients. The single task assessments included the time required to walk 50 feet (gait speed) and the number of words generated in a verbal fluency task (word generation). The DT comprised simultaneous performance of the single tasks. Impairment and disability were measured with the Unified Parkinson's Disease Rating Scale, Hoehn &Yahr, Berg Balance Scale, and Older Americans Resource and Services Scale. Age, education, and gender were control variables. Standardized residuals from regressions of DT upon single task performance were computed separately for word and gait, indicating the extent that the individual performed proportionally better/worse than predicted in DT considering their single task performance. Results: Multiple regressions revealed that individuals who performed worse than expected in DT-word had greater impairment and disability. Dual task-gait was not significant in any model. Verbal fluency during DT performance is more closely associated with PD-related impairment and disability than gait speed during DT. Conclusion: This suggests that subjects prioritize gait performance at the expense of cognitive performance, and that DT word generation may be a sensitive indicator of early PD impairment and disability. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Fuller, Rebecca L.; Van Winkle, Elizabeth P.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Anderson, Karen E.; Hill, Terra; Weiner, William J.; Shulman, Lisa M.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Anderson, Karen E.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Gruber-Baldini, Ann L.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Zampieri, Cris] NIH, Bethesda, MD 20892 USA. RP Fuller, RL (reprint author), Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. EM fuller@cua.edu NR 32 TC 17 Z9 18 U1 0 U2 30 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD MAR PY 2013 VL 19 IS 3 BP 325 EP 328 DI 10.1016/j.parkreldis.2012.11.011 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 111GY UT WOS:000316511000010 PM 23265679 ER PT J AU Wanczyk, H Barker, T Rood, D Zapata, DI Howell, AR Richardson, SK Zinckgraf, J Marusov, GP Lynes, MA Silbart, LK AF Wanczyk, Heather Barker, Tolga Rood, Debra Zapata, Daniel I. Howell, Amy R. Richardson, Stewart K. Zinckgraf, John Marusov, Gregory P. Lynes, Michael A. Silbart, Lawrence K. TI Cloning and Characterization of a Hybridoma Secreting a 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-Specific Monoclonal Antibody and Recombinant F(ab) SO TOXINS LA English DT Article DE TSNAs; F(ab); NNK; monoclonal antibody; 2A cleavage ID TOBACCO-DERIVED NITROSAMINES; NICOTINIC RECEPTOR; SMOKELESS TOBACCO; CLEAVAGE ACTIVITIES; LUNG-CANCER; DRUG-ABUSE; EXPRESSION; IMMUNIZATION; CARCINOGEN; REDUCTION AB Smokeless tobacco products have been associated with increased risks of oro-pharyngeal cancers, due in part to the presence of tobacco-specific nitrosamines (TSNAs) such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These potent carcinogens are formed during tobacco curing and as a result of direct nitrosation reactions that occur in the oral cavity. In the current work we describe the isolation and characterization of a hybridoma secreting a high-affinity, NNK-specific monoclonal antibody. A structurally-related benzoyl derivative was synthesized to facilitate coupling to NNK-carrier proteins, which were characterized for the presence of the N-nitroso group using the Griess reaction, and used to immunize BALB/c mice. Splenocytes from mice bearing NNK-specific antibodies were used to create hybridomas. Out of four, one was selected for subcloning and characterization. Approximately 99% of the monoclonal antibodies from this clone were competitively displaced from plate-bound NNKB conjugates in the presence of free NNK. The affinity of the monoclonal antibody to the NNKB conjugates was K-d = 2.93 nM as determined by surface plasmon resonance. Free nicotine was a poor competitor for the NNKB binding site. The heavy and light chain antibody F(ab) fragments were cloned, sequenced and inserted in tandem into an expression vector, with an FMDV Furin 2A cleavage site between them. Expression in HEK 293 cells revealed a functional F(ab) with similar binding features to that of the parent hybridoma. This study lays the groundwork for synthesizing transgenic tobacco that expresses carcinogen-sequestration properties, thereby rendering it less harmful to consumers. C1 [Wanczyk, Heather; Rood, Debra] Univ Connecticut, Dept Anim Sci, Storrs, CT 06268 USA. [Barker, Tolga] NIAID, NIH, Bethesda, MD 20892 USA. [Zapata, Daniel I.] New York Med Coll, New York, NY 10162 USA. [Howell, Amy R.; Richardson, Stewart K.] Univ Connecticut, Dept Chem, Storrs, CT 06268 USA. [Zinckgraf, John] Immucell, Portland, ME 04101 USA. [Marusov, Gregory P.; Lynes, Michael A.] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06268 USA. [Silbart, Lawrence K.] Univ Connecticut, CANR, Dept Allied Hlth Sci, Storrs, CT 06269 USA. RP Silbart, LK (reprint author), Univ Connecticut, CANR, Dept Allied Hlth Sci, 358 Mansfield Rd, Storrs, CT 06269 USA. EM heather.wanczyk@uconn.edu; barkertt@niaid.nih.gov; debra.rood@uconn.edu; dzapata84@gmail.com; amy.howell@uconn.edu; stewart.richardson@uconn.edu; jzinckgra@yahoo.com; gregmarusov@gmail.com; michael.lynes@uconn.edu; lawrence.silbart@uconn.edu FU UCONN UCRF faculty large grant program; UCONN Center for Environmental Health and Health Promotion FX We thank Andrew Hayhurst (Texas Biomedical Research Institute) for productive discussions/suggestions, and Richard C. Johnson for synthesizing the initial lot of NNKB used in this study. We thank Dong Chen from Creative Biolabs for helpful discussions, synthesis and cloning of the F(ab) insert. We acknowledge funding from the UCONN UCRF faculty large grant program and the UCONN Center for Environmental Health and Health Promotion. NR 52 TC 1 Z9 2 U1 0 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD MAR PY 2013 VL 5 IS 3 BP 568 EP 589 DI 10.3390/toxins5030568 PG 22 WC Toxicology SC Toxicology GA 112SJ UT WOS:000316613300007 PM 23518474 ER PT J AU Park, JW Piknova, B Kurtz, J Seetharaman, S Wagner, SJ Schechter, AN AF Park, Ji Won Piknova, Barbora Kurtz, James Seetharaman, Shalini Wagner, Stephen J. Schechter, Alan N. TI Effect of storage on levels of nitric oxide metabolites in platelet preparations SO TRANSFUSION LA English DT Article ID DIETARY NITRATE; RELAXING FACTOR; XANTHINE OXIDOREDUCTASE; DEPENDENT INHIBITION; THROMBUS FORMATION; HYPOXIC CONDITIONS; L-ARGININE; IN-VIVO; AGGREGATION; REDUCTION AB BACKGROUND: Nitric oxide (NO), a potent signaling molecule, is known to inhibit platelet (PLT) function in vivo. We investigated how the levels of NO and its metabolites change during routine PLT storage. We also tested whether the material of PLT storage containers affects nitrite content since many plastic materials are known to contain and release nitrite. STUDY DESIGN AND METHODS: For nitrite and nitrate measurement, leukoreduced apheresis PLTs and concurrent plasma (CP) were collected from healthy donors using a cell separator. Sixty-milliliter aliquots of PLT or CP were stored in CLX or PL120 Teflon containers at 20 to 24 degrees C with agitation and daily samples were processed to yield PLT pellet and supernatant. In a separate experiment, PLTs were stored in PL120 Teflon to measure NO generation using electron paramagnetic resonance (EPR). RESULTS: Nitrite level increased markedly in both PLT supernatant and CP stored in CLX containers at a rate of 58 and 31nmol/L/day, respectively. However, there was a decrease in nitrite level in PLTs stored in PL120 Teflon containers. Nitrite was found to leach from CLX containers and this appears to compensate for nitrite consumption in these preparations. Nitrate level did not significantly change during storage. CONCLUSION: PLTs stored at 20 to 24 degrees C maintain measurable levels of nitrite and nitrate. The nitrite decline in nonleachable Teflon containers in contrast to increases in CLX containers that leach nitrite suggests that it is consumed by PLTs, residual white blood cells, or red blood cells. These results suggest NO-related metabolic changes occur in PLT units during storage. C1 [Schechter, Alan N.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Holland Lab, Blood Components Dept, Rockville, MD USA. RP Schechter, AN (reprint author), NIDDKD, Mol Med Branch, NIH, 10 Ctr Dr,9N314, Bethesda, MD 20892 USA. EM alans@intra.niddk.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 FU Molecular Medicine Branch, NIDDK, NIH; Blood Components Department, American Red Cross FX Research support was received from Molecular Medicine Branch, NIDDK, NIH, and Blood Components Department, American Red Cross. NR 52 TC 4 Z9 4 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAR PY 2013 VL 53 IS 3 BP 637 EP 644 DI 10.1111/j.1537-2995.2012.03777.x PG 8 WC Hematology SC Hematology GA 104DF UT WOS:000315969500023 PM 22804724 ER PT J AU Revollo, JR Li, XL AF Revollo, Javier R. Li, Xiaoling TI The ways and means that fine tune Sirt1 activity SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review DE Sirt1; energy metabolism; aging; nutrients; metabolic sensor ID DEACETYLASE ACTIVITY; REGULATES SIRT1; CALORIE RESTRICTION; SKELETAL-MUSCLE; TRANSCRIPTION FACTORS; HEPATIC STEATOSIS; NAD(+) METABOLISM; CELLULAR-RESPONSE; GENOTOXIC STRESS; FEEDBACK LOOP AB Sirt1 is the most evolutionarily conserved mammalian sirtuin. It plays a vital role in the regulation of metabolism, stress responses, genome stability, and ultimately aging. Although much attention has focused on the identification of the cellular targets and functional networks controlled by Sirt1, the mechanisms that regulate Sirt1 activity by biological stimuli have only recently begun to emerge. As an enzyme, the activity of Sirt1 can be controlled by the availability of its substrates, post-translational modifications, interactions with other proteins, or changes in its expression levels. In this review, we briefly discuss the ways and means by which the activity of Sirt1 is fine-tuned under different conditions. C1 [Revollo, Javier R.; Li, Xiaoling] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Revollo, JR (reprint author), NIEHS, Lab Signal Transduct, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Javier.Revollo@fda.hhs.gov; lix3@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01 ES102205] FX We thank Drs John Cidlowski, Aaron Jetten, Brant Hamel, and members of the Li laboratory for critical reading of the manuscript. The work related to this article was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to X.L. (Z01 ES102205). NR 83 TC 37 Z9 37 U1 2 U2 40 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2013 VL 38 IS 3 BP 160 EP 167 DI 10.1016/j.tibs.2012.12.004 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 107TJ UT WOS:000316243400006 PM 23394938 ER PT J AU Busillo, JM Cidlowski, JA AF Busillo, John M. Cidlowski, John A. TI The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID NF-KAPPA-B; INNATE IMMUNE-SYSTEM; INDUCED THYMIC ATROPHY; RECEPTOR-BINDING; T-CELLS; CHROMATIN ACCESSIBILITY; DEHYDROGENASE TYPE-1; ADAPTIVE IMMUNITY; GENE-EXPRESSION; JNK PATHWAY AB Glucocorticoids are essential for maintaining homeostasis and regulate a wide variety of physiological processes. Therapeutically, synthetic glucocorticoids are widely prescribed for the treatment of inflammation, autoimmune disorders, and malignancies of lymphoid origin. In this review we examine emerging evidence highlighting both proinflammatory and anti-inflammatory actions of glucocorticoids on both the innate and adaptive immune systems. We incorporate these findings into the more traditional anti-inflammatory role attributed to glucocorticoids, and propose how the two seemingly disparate processes seamlessly work together to resolve cellular responses to inflammatory stimuli. These ideas provide a framework by which glucocorticoids ready and reinforce the innate immune system, and repress the adaptive immune system, to help to resolve inflammation and restore homeostasis. C1 [Busillo, John M.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural NIH HHS [ZIA ES090057-17] NR 92 TC 66 Z9 67 U1 1 U2 21 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD MAR PY 2013 VL 24 IS 3 BP 109 EP 119 DI 10.1016/j.tem.2012.11.005 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109LS UT WOS:000316370700001 PM 23312823 ER PT J AU Goldspiel, JT Goldspiel, BR Grimes, GJ Yuan, P Potti, G AF Goldspiel, Justin T. Goldspiel, Barry R. Grimes, George J. Yuan, Peng Potti, Gopal TI Stability of alemtuzumab solutions at room temperature SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article AB Purpose. The 24-hour stability of alemtuzumab solutions prepared at concentrations not included in the product label and stored in glass or polyolefin containers at room temperature was evaluated. Methods. Triplicate solutions of alemtuzumab (6.67, 40, and 120 mu g/mL) in 0.9% sodium chloride were prepared in either glass bottles or polyolefin containers and stored at room temperature under normal fluorescent lighting conditions. The solutions were analyzed by a validated stability-indicating high-performance liquid chromatography (HPLC) assay at time zero and 8, 14, and 24 hours after preparation; solution pH values were measured and the containers visually inspected at all time points. Stability was defined as the retention of >= 90% of the initial alemtuzumab concentration. Results. HPLC analysis indicated that the percentage of the initial alemtuzumab concentration retained was >90% for all solutions evaluated, with no significant changes over the study period. The most dilute alemtuzumab solution (6.67 mu g/mL) showed some degradation (91% of the initial concentration retained at hour 24), whereas the retained concentration was >99% for all other preparations throughout the study period. Solution pH values varied by drug concentration but did not change significantly over 24 hours. No evidence of particle formation was detected in any solution by visual inspection at any time during the study. Conclusion. Solutions of alemtuzumab 6.67 mu g/mL stored in glass bottles and solutions of 40 and 120 mu g/mL stored in polyolefin containers were stable for at least 24 hours at room temperature. Am J Health-Syst Pharm. 2013; 70:439-42 C1 [Goldspiel, Justin T.] NIH, Pharmaceut Dev Serv, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Goldspiel, Barry R.] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Potti, Gopal] NIH, Dept Pharm, Ctr Clin, Pharmaceut Dev Serv,Analyt Unit, Bethesda, MD 20892 USA. RP Goldspiel, BR (reprint author), NIH, Dept Pharm, Ctr Clin, Bldg 10,Room 1C240,MSC 1196, Bethesda, MD 20892 USA. EM bgoldspiel@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 9 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD MAR 1 PY 2013 VL 70 IS 5 BP 439 EP 442 DI 10.2146/ajhp110632 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 099HO UT WOS:000315612300012 PM 23413168 ER PT J AU Andres, RL Zhao, Y Klebanoff, MA Hauth, JC Caritis, SN Carey, JC Wapner, RJ Iams, JD Leveno, KJ Miodovnik, M Sibai, B Van Dorsten, JP Dombrowski, MP O'Sullivan, MJ Langer, O AF Andres, Robert L. Zhao, Yuan Klebanoff, Mark A. Hauth, John C. Caritis, Steve N. Carey, J. Christopher Wapner, Ronald J. Iams, Jay D. Leveno, Kenneth J. Miodovnik, Menachem Sibai, Baha Van Dorsten, J. Peter Dombrowski, Mitchell P. O'Sullivan, Mary J. Langer, Oded CA Eunice Kennedy Shriver Natl Inst TI The Impact of Tobacco Use on Preterm Premature Rupture of the Membranes SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE tobacco; premature rupture of the membranes ID FETAL MEMBRANES; PREGNANT-WOMEN; BACTERIAL VAGINOSIS; RISK-FACTORS; SMOKING; DELIVERY; BIRTH; METRONIDAZOLE AB Objective To determine if tobacco use increases the incidence of preterm premature rupture of the membranes (pPROM) or alters perinatal outcomes after pPROM. Study Design This is a secondary analysis of the databases of three completed Eunice Kennedy Shriver National Institute of Child Health and Human Development supported Maternal Fetal Medicine Units Network studies. Self-reported tobacco exposure data was obtained. Its relationship with the incidence of pPROM and associated neonatal outcome measures were assessed. Results There was no difference in the incidence of pPROM when comparing nonsmokers to those using tobacco. Although a trend was seen between the incidence of pPROM and the amount smoked, this did not reach statistical significance. Among the patients with pPROM, the use of tobacco was not associated with an increase in perinatal morbidity. Conclusion Our data do not support a significant relationship between tobacco use and pPROM. C1 [Andres, Robert L.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Zhao, Yuan] George Washington Univ, Dept Obstet & Gynecol, Ctr Biostat, Washington, DC USA. [Klebanoff, Mark A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Hauth, John C.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Caritis, Steve N.] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Carey, J. Christopher] Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. [Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Miodovnik, Menachem] Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH USA. [Sibai, Baha] Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. [Van Dorsten, J. Peter] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC USA. [Dombrowski, Mitchell P.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [O'Sullivan, Mary J.] Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. [Langer, Oded] Univ Texas San Antonio, Dept Obstet & Gynecol, San Antonio, TX USA. RP Andres, RL (reprint author), Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, 30 North 1900 East, Salt Lake City, UT 84132 USA. EM Robert.Andres@imail.org OI caritis, steve/0000-0002-2169-0712 FU NIAID NIH HHS [AI 38514, U19 AI038514]; NICHD NIH HHS [HD34136, HD21410, HD21414, HD27860, HD27861, HD27869, HD27889, HD27915, HD27917, HD34116, HD34208, HD34210, HD36801, U01 HD019897, U01 HD036801, U10 HD021410, U10 HD027860, U10 HD027869, U10 HD027883, U10 HD027905, U10 HD027915, U10 HD027917, U10 HD034116, U10 HD034122, U10 HD034136, U10 HD034208, U10 HD036801, U10 HD040485, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208] NR 21 TC 0 Z9 0 U1 0 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD MAR PY 2013 VL 30 IS 3 BP 185 EP 189 DI 10.1055/s-0032-1322517 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 100LY UT WOS:000315703900005 PM 22930157 ER PT J AU Wu, T Hallett, M AF Wu, Tao Hallett, Mark TI The cerebellum in Parkinson's disease SO BRAIN LA English DT Review DE Parkinson's disease; cerebellum; compensation; pathological changes ID POSITRON-EMISSION-TOMOGRAPHY; SUBTHALAMIC NUCLEUS STIMULATION; LEVODOPA-INDUCED DYSKINESIAS; SYNUCLEIN MESSENGER-RNA; CEREBRAL-BLOOD-FLOW; EXTERNALLY TRIGGERED MOVEMENTS; DEEP BRAIN-STIMULATION; METABOLIC NETWORK ACTIVITY; HIGH-FREQUENCY STIMULATION; BASAL GANGLIA AB Parkinson's disease is a chronic progressive neurodegenerative disorder characterized by resting tremor, slowness of movements, rigidity, gait disturbance and postural instability. Most investigations on Parkinson's disease focused on the basal ganglia, whereas the cerebellum has often been overlooked. However, increasing evidence suggests that the cerebellum may have certain roles in the pathophysiology of Parkinson's disease. Anatomical studies identified reciprocal connections between the basal ganglia and cerebellum. There are Parkinson's disease-related pathological changes in the cerebellum. Functional or morphological modulations in the cerebellum were detected related to akinesia/rigidity, tremor, gait disturbance, dyskinesia and some non-motor symptoms. It is likely that the major roles of the cerebellum in Parkinson's disease include pathological and compensatory effects. Pathological changes in the cerebellum might be induced by dopaminergic degeneration, abnormal drives from the basal ganglia and dopaminergic treatment, and may account for some clinical symptoms in Parkinson's disease. The compensatory effect may help maintain better motor and non-motor functions. The cerebellum is also a potential target for some parkinsonian symptoms. Our knowledge about the roles of the cerebellum in Parkinson's disease remains limited, and further attention to the cerebellum is warranted. C1 [Wu, Tao] Capital Med Univ, Dept Neurobiol, Key Lab Neurodegenerat Disorders, Minist Educ,Beijing Inst Geriatr,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, Dept Neurobiol, Key Lab Neurodegenerat Disorders, Minist Educ,Beijing Inst Geriatr,Xuanwu Hosp, Beijing 100053, Peoples R China. EM wutao69@gmail.com FU National Science Foundation of China [30870693, 81071012, 81271429] FX This work was supported by grants from the National Science Foundation of China [30870693, 81071012 and 81271429, to T.W.]. NR 170 TC 138 Z9 140 U1 9 U2 98 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAR PY 2013 VL 136 BP 696 EP 709 DI 10.1093/brain/aws360 PN 3 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 099MD UT WOS:000315624700004 PM 23404337 ER PT J AU Hirsch, D Kemmerling, R Davis, S Camps, J Meltzer, PS Ried, T Gaiser, T AF Hirsch, Daniela Kemmerling, Ralf Davis, Sean Camps, Jordi Meltzer, Paul S. Ried, Thomas Gaiser, Timo TI Chromothripsis and Focal Copy Number Alterations Determine Poor Outcome in Malignant Melanoma SO CANCER RESEARCH LA English DT Article ID COLORECTAL-CANCER; GENOME; REARRANGEMENTS; MUTATIONS AB Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study showed that in 2% to 3% of all cancers a single catastrophic event, termed chromothripsis, can lead to massive genomic rearrangements confined to one or a few chromosomes. To explore whether the degree of genomic instability and chromothripsis influences prognosis in cancer, we retrospectively applied array-comparative genomic hybridization (aCGH) to 20 malignant melanomas that showed, despite comparable conventional clinical and pathologic parameters, a profoundly different clinical course. We compared 10 patients who died of malignant melanoma 3.7 years (median, range 0.9-7.6 years) after diagnosis with 10 patients who survived malignant melanoma and had a median disease-free survival of 14.8 years (range 12.5-16.7 years; P = 0.00001). We observed a striking association between the degree of chromosomal instability, both numerical and structural, and outcome. Malignant melanomas associated with good prognosis showed only few chromosomal imbalances (mean 1.6 alterations per case), predominantly whole chromosome or chromosome arm gains and losses, whereas malignant melanomas with poor prognosis harbored significantly more chromosomal aberrations (13.9 per case; P = 0.008). Array-based CGH showed that these aberrations were mostly focal events, culminating in two cases in a pattern consistent with the phenomenon of chromothripsis, which was confirmed by paired-end sequencing. This is the first description of chromothripsis in primary malignant melanomas. Our study therefore links focal copy number alterations and chromothripsis with poor outcome in patients with malignant melanomas (P = 0.0002) and provides a genetic approach to predict outcome in malignant melanomas. Cancer Res; 73(5); 1454-9. (C) 2012 AACR. C1 [Hirsch, Daniela; Davis, Sean; Camps, Jordi; Meltzer, Paul S.; Ried, Thomas; Gaiser, Timo] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kemmerling, Ralf] Paracelsus Med Univ, Inst Pathol, Salzburg, Austria. [Gaiser, Timo] Heidelberg Univ, Med Fac Mannheim, Inst Pathol, D-68167 Mannheim, Germany. RP Ried, T (reprint author), NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res,NIH, 50 South Dr,Bldg 50,Room 1408, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov; timo.gaiser@umm.de OI Davis, Sean/0000-0002-8991-6458 FU NIH, National Cancer Institute; RISE program of the German Academic Exchange Service FX The study was supported by the Intramural Research Program of the NIH, National Cancer Institute. D. Hirsch was supported by the RISE program of the German Academic Exchange Service. NR 19 TC 28 Z9 28 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2013 VL 73 IS 5 BP 1454 EP 1459 DI 10.1158/0008-5472.CAN-12-0928 PG 6 WC Oncology SC Oncology GA 100YM UT WOS:000315741500002 PM 23271725 ER PT J AU Izhak, L Ambrosino, E Kato, S Parish, ST O'Konek, JJ Weber, H Xia, Z Venzon, D Berzofsky, JA Terabe, M AF Izhak, Liat Ambrosino, Elena Kato, Shingo Parish, Stanley T. O'Konek, Jessica J. Weber, Hannah Xia, Zheng Venzon, David Berzofsky, Jay A. Terabe, Masaki TI Delicate Balance among Three Types of T Cells in Concurrent Regulation of Tumor Immunity SO CANCER RESEARCH LA English DT Article ID NKT CELLS; IMMUNOREGULATORY AXIS; IN-VIVO; CANCER-IMMUNOTHERAPY; MONOCLONAL-ANTIBODY; PARTIAL REDUCTION; IMMUNOSURVEILLANCE; IMMUNOTOXIN; REJECTION; ACTIVATION AB The nature of the regulatory cell types that dominate in any given tumor is not understood at present. Here, we addressed this question for regulatory T cells (Treg) and type II natural killer T (NKT) cells in syngeneic models of colorectal and renal cancer. In mice with both type I and II NKT cells, or in mice with neither type of NKT cell, Treg depletion was sufficient to protect against tumor outgrowth. Surprisingly, in mice lacking only type I NKT cells, Treg blockade was insufficient for protection. Thus, we hypothesized that type II NKT cells may be neutralized by type I NKT cells, leaving Tregs as the primary suppressor, whereas in mice lacking type I NKT cells, unopposed type II NKT cells could suppress tumor immunity even when Tregs were blocked. We confirmed this hypothesis in 3 ways by reconstituting type I NKT cells as well as selectively blocking or activating type II NKT cells with antibody or the agonist sulfatide, respectively. In this manner, we showed that blockade of both type II NKT cells and Tregs is necessary to abrogate suppression of tumor immunity, but a third cell, the type I NKT cell, determines the balance between these regulatory mechanisms. As patients with cancer often have deficient type I NKT cell function, managing this delicate balance among 3 T-cell subsets may be critical for the success of immunotherapy for human cancer. Cancer Res; 73(5); 1514-23. (C) 2012 AACR. C1 [Izhak, Liat; Ambrosino, Elena; Kato, Shingo; Parish, Stanley T.; O'Konek, Jessica J.; Weber, Hannah; Xia, Zheng; Berzofsky, Jay A.; Terabe, Masaki] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bldg 41 Rm D702D,41 Medlars Dr, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov; Terabe@mail.nih.gov FU NCI; NIH; Gui Foundation FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH, and the Gui Foundation. NR 37 TC 22 Z9 23 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2013 VL 73 IS 5 BP 1514 EP 1523 DI 10.1158/0008-5472.CAN-12-2567 PG 10 WC Oncology SC Oncology GA 100YM UT WOS:000315741500008 PM 23319803 ER PT J AU Orentas, RJ AF Orentas, Rimas J. TI Reading the Tea Leaves of Tumor-Mediated Immunosuppression SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID SUPPRESSOR-CELLS; PROSTATE-CANCER; T-CELLS; NEUROBLASTOMA AB Polyphenol E, available as Polyphenon E, is a green tea extract whose activity can be benchmarked to the presence of specific catechins such as epigallocatechin 3-gallate (EGCG). Herein, Polyphenon E is shown to reverse myeloid-derived suppressor cell activity, linking the activity of a natural product extract to cell-mediated immunity. Clin Cancer Res; 19(5); 955-7. (C) 2012 AACR. C1 NCI, Pediat Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Orentas, RJ (reprint author), NCI, Pediat Oncol Branch, CCR, NIH, 1W3840 10 Ctr Dr, Bethesda, MD 20892 USA. EM Rimas.Orentas@nih.gov FU Intramural Research Program of the NIH, CCR, NCI FX This work was supported by the Intramural Research Program of the NIH, CCR, NCI. NR 12 TC 1 Z9 1 U1 1 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2013 VL 19 IS 5 BP 955 EP 957 DI 10.1158/1078-0432.CCR-12-3792 PG 3 WC Oncology SC Oncology GA 100YB UT WOS:000315740200001 PM 23430024 ER PT J AU Do, K Chen, AP AF Do, Khanh Chen, Alice P. TI Molecular Pathways: Targeting PARP in Cancer Treatment SO CLINICAL CANCER RESEARCH LA English DT Article ID ADP-RIBOSE POLYMERASE; REFRACTORY SOLID TUMORS; NEGATIVE BREAST-CANCER; ANEMIA-BRCA PATHWAY; POLY(ADP-RIBOSE) POLYMERASE; DNA-DAMAGE; PHASE-I; PROMOTER HYPERMETHYLATION; SPORADIC BREAST; OVARIAN-CANCER AB Poly (ADP-ribose) polymerases (PARP) are a family of nuclear protein enzymes involved in the DNA damage response. The role of PARP-1 in base excisional repair has been extensively characterized. More recent in vitro studies additionally implicate a role for PARP-1 in facilitating homologous recombination and nonhomologous end-joining. The more faithful process of homologous recombination repair of double-stranded DNA breaks involves localization of BRCA-1 and BRCA-2 to sites of DNA damage, resection of the double-stranded break, and gap-filling DNA synthesis using the homologous sister chromatid as a template. Simultaneous dysfunction of both DNA repair pathways decreases the ability of cells to compensate, and forms the basis for the concept of synthetic lethality. Treatment strategies, thus far, have focused on two main principles: (i) exploitation of the concept of synthetic lethality in homologous recombination-deficient tumors, primarily in breast and ovarian cancer patients with BRCA mutation, and (ii) as radiosensitizers and chemosensitizers. BRCA deficiency accounts for only a fraction of dysfunction in homologous recombination repair. Epigenetic alterations of BRCA function and defects within the Fanconi anemia pathway also result in defective DNA repair. Rational therapeutic combinations exploiting alternate mechanisms of defective DNA repair, abrogation of cell-cycle checkpoints, and additional functions of PARP-1 present novel opportunities for further clinical development of PARP inhibitors. On the basis of the results of clinical studies of PARP inhibitors thus far, it is imperative that future development of PARP inhibitors take a more refined approach, identifying the unique subset of patients that would most benefit from these agents, determining the optimal time for use, and identifying the optimal combination partner in any particular setting. Clin Cancer Res; 19(5); 977-84. (C) 2012 AACR. C1 [Do, Khanh] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20852 USA. [Chen, Alice P.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20852 USA. RP Chen, AP (reprint author), NCI, 6130 Executive Blvd,Suite 7130, Bethesda, MD 20852 USA. EM chenali@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 61 TC 30 Z9 30 U1 2 U2 33 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 MAR 1 PY 2013 VL 19 IS 5 BP 977 EP 984 DI 10.1158/1078-0432.CCR-12-0163 PG 8 WC Oncology SC Oncology GA 100YB UT WOS:000315740200005 PM 23269547 ER PT J AU Bates, SE AF Bates, Susan E. TI Waking the Immune System at Last SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 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 MAR 1 PY 2013 VL 19 IS 5 BP 996 EP 996 DI 10.1158/1078-0432.CCR-13-0274 PG 1 WC Oncology SC Oncology GA 100YB UT WOS:000315740200007 PM 23460530 ER PT J AU Campbell, CT Gulley, JL Oyelaran, O Hodge, JW Schlom, J Gildersleeve, JC AF Campbell, Christopher T. Gulley, James L. Oyelaran, Oyindasola Hodge, James W. Schlom, Jeffrey Gildersleeve, Jeffrey C. TI Serum Antibodies to Blood Group A Predict Survival on PROSTVAC-VF SO CLINICAL CANCER RESEARCH LA English DT Article ID RESISTANT PROSTATE-CANCER; NATURAL ANTIBODIES; CLINICAL-RELEVANCE; TUMOR-CELLS; ANTI-A; VACCINE; IMMUNOTHERAPY; CARBOHYDRATE; MICROARRAY; RESPONSES AB Purpose: There is evidence that therapeutic cancer vaccines can lengthen survival for some patients with cancer, but responses vary widely from one person to another. Methods to predict clinical outcomes will advance the field and provide new insights into critical determinants of in vivo efficacy. Experimental Design: This retrospective study included 141 subjects from phase II trials of PROSTVAC-VF, a poxvirus-based cancer vaccine currently in phase III clinical trials for advanced prostate cancer. A glycan microarray was used to profile prevaccination antiglycan antibody populations in sera as potential biomarkers for PROSTVAC-VF. The screen for predictive biomarkers identified antiglycan antibodies that consistently stratified subjects into groups with different Kaplan-Meier survival estimates. Because of the potential for overfitting, a permutation test was used to estimate the false discovery rate. Results: Prevaccination antibody levels to blood group A trisaccharide (BG-A(tri)) were found to have a statistically significant correlation with survival. Long-term survival was approximately doubled in subjects with abundant anti-BG-A(tri) immunoglobulinM(IgM) relative to subjects with little or no preexisting IgM for BG-A(tri). This survival correlation was specific to vaccine treatment, as no correlation was observed in control patients immunized with wild-type poxviruses lacking the key tumor antigen, prostate-specific antigen (PSA). Moreover, anti-BG-A(tri) IgM levels were not correlated with general measures of disease severity, such as PSA levels, Gleason score, or Halabi predicted survival. Conclusion: In addition to reporting a new potentially predictive biomarker for PROSTVAC-VF, this study highlights the use of glycan microarray technology for improving our understanding of vaccine immunology. Clin Cancer Res; 19(5); 1290-9. (C) 2012 AACR. C1 [Campbell, Christopher T.; Oyelaran, Oyindasola; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. [Gulley, James L.; Hodge, James W.; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gildersleeve, JC (reprint author), NCI, NIH, 376 Boyles St,Room 208, Frederick, MD 21702 USA. EM gildersj@mail.nih.gov RI Gildersleeve, Jeffrey/N-3392-2014; Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Intramural Research Program of the NIH; National Cancer Institute; PRAT Program of the National Institute of General Medical Sciences (NIGMS) FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. C.T. Campbell received fellowship funding from the PRAT Program of the National Institute of General Medical Sciences (NIGMS). NR 56 TC 18 Z9 18 U1 1 U2 15 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 MAR 1 PY 2013 VL 19 IS 5 BP 1290 EP 1299 DI 10.1158/1078-0432.CCR-12-2478 PG 10 WC Oncology SC Oncology GA 100YB UT WOS:000315740200036 PM 23362327 ER PT J AU Komlodi-Pasztor, E Sackett, DL Fojo, T AF Komlodi-Pasztor, Edina Sackett, Dan L. Fojo, Tito TI Tales of How Great Drugs Were Brought Down by a Flawed Rationale-Response SO CLINICAL CANCER RESEARCH LA English DT Letter C1 [Komlodi-Pasztor, Edina; Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Fojo, T (reprint author), NCI, 10 Ctr Dr,MSC 1906,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 2 TC 1 Z9 1 U1 2 U2 4 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 MAR 1 PY 2013 VL 19 IS 5 BP 1304 EP 1304 DI 10.1158/1078-0432.CCR-12-2058 PG 1 WC Oncology SC Oncology GA 100YB UT WOS:000315740200041 PM 23393076 ER PT J AU Falvey, CM Rosano, C Simonsick, EM Harris, T Strotmeyer, ES Satterfield, S Yaffe, K AF Falvey, Cherie M. Rosano, Caterina Simonsick, Eleanor M. Harris, Tamara Strotmeyer, Elsa S. Satterfield, Suzanne Yaffe, Kristine CA Hlth ABC Study TI Macro- and Microstructural Magnetic Resonance Imaging Indices Associated With Diabetes Among Community-Dwelling Older Adults SO DIABETES CARE LA English DT Article ID DIFFUSION TENSOR MRI; WHITE-MATTER; COGNITIVE DECLINE; SPATIAL STATISTICS; ALZHEIMERS-DISEASE; HUMAN BRAIN; TYPE-2; MELLITUS; ATROPHY; ABNORMALITIES AB OBJECTIVE-To better understand the association between diabetes and cognitive impairment, we evaluated macro- and microstructural brain MRI measures for the total brain and regions of interest (RO1s) in a group of community-dwelling elders with and without diabetes. RESEARCH DESIGN AND METHODS-MRI measures were obtained on 308 elders (mean age 83.3 years; n = 85 with diabetes) from the Health ABC Healthy Brain Substudy. We performed a series of linear regressions and used standardized beta values to estimate the cross-sectional association between diabetes and macrostructural (gray matter volume [GMV] and white matter hyperintensities [WMHs]) and microstructural (mean diffusivity [MD] and fractional anisotropy [FA]) measures for the total brain and ROIs. Models were adjusted for age, race, and sex; GMV values for ROIs were also adjusted for total brain volume (TBV). RESULTS-In multivariate-adjusted models, diabetes was associated with lower total GMV (P = 0.0006), GMV in the putamen (P = 0.02 for left and right), and TBV (P = 0.04) and greater cerebral atrophy (P = 0.02). There was no association with WMHs. On microstructural measures, diabetes was associated with reduced FA for total white matter (P = 0.006) and greater MD for the hippocampus (P = 0.006 left; P = 0.01 right), dorsolateral prefrontal cortex (P = 0.0007, left; P = 0.002, right), left posterior cingulate (P = 0.02), and right putamen (P = 0.02). Further adjustment for stroke, hypertension, and myocardial infarction produced similar results. CONCLUSIONS-In this cross-sectional study, elders with diabetes compared with those without had greater brain atrophy and early signs of neurodegeneration. Further studies are needed to determine whether these structural changes associated with diabetes predict risk of cognitive decline. Diabetes Care 36:677-682,2013 C1 [Falvey, Cherie M.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Falvey, Cherie M.; Yaffe, Kristine] San Francisco Vet Adm Med Ctr, San Francisco, CA USA. [Rosano, Caterina; Strotmeyer, Elsa S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Falvey, CM (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM cherie.falvey@ucsf.edu RI Strotmeyer, Elsa/F-3015-2014; OI Rosano, Caterina/0000-0002-0909-1506; Strotmeyer, Elsa/0000-0002-4093-6036; Rosano, Caterina/0000-0002-4271-6010 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR012459]; National Institutes of Health (NIH), NIA; American Health Assistance Foundation [A201-0029]; NIA [K24AG031155]; NIH (NIA, National Institute of Diabetes and Digestive and Kidney Diseases, and NIMH); Department of Defense; American Health Assistance Foundation; Anonymous Foundation; Alzheimer's Association; NIH/NIA; NIH FX This work was supported by National Institute on Aging (NIA) grants N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, and R01-AG028050 and National Institute of Nursing Research Grant R01-NR012459. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), NIA, and American Health Assistance Foundation Grant A201-0029. K.Y. is supported in part by NIA Grant K24AG031155. K.Y. has served on data safety-monitoring boards for the NIH (National Institute of Mental Health [NIMH] and NIA trials) and has received research support from the NIH (NIA, National Institute of Diabetes and Digestive and Kidney Diseases, and NIMH), Department of Defense, American Health Assistance Foundation, Anonymous Foundation, and Alzheimer's Association. S.S. receives research support from the NIH/NIA. T.H. receives research support from the NIH. NR 40 TC 33 Z9 38 U1 1 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 MAR PY 2013 VL 36 IS 3 BP 677 EP 682 DI 10.2337/dc12-0814 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 103OU UT WOS:000315928700040 PM 23160721 ER PT J AU Ikram, MK Cheung, CY Lorenzi, M Klein, R Jones, TLZ Wong, TY AF Ikram, M. Kamran Cheung, Carol Y. Lorenzi, Mara Klein, Ronald Jones, Teresa L. Z. Wong, Tien Yin CA NIH JDRF Workshop Retinal TI Retinal Vascular Caliber as a Biomarker for Diabetes Microvascular Complications SO DIABETES CARE LA English DT Review ID PREDICTS INCIDENT RETINOPATHY; BLOOD-FLOW; VESSEL DIAMETERS; PERIPHERAL NEUROPATHY; ATHEROSCLEROSIS RISK; FLICKER STIMULATION; FRACTAL ANALYSIS; HEART-DISEASE; PROGRESSION; MELLITUS C1 [Ikram, M. Kamran; Cheung, Carol Y.; Wong, Tien Yin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Ikram, M. Kamran; Cheung, Carol Y.; Wong, Tien Yin] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Ikram, M. Kamran] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Kamran] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Ikram, M. Kamran; Cheung, Carol Y.; Wong, Tien Yin] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Lorenzi, Mara] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. [Lorenzi, Mara] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Jones, Teresa L. Z.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Wong, Tien Yin] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. RP Wong, TY (reprint author), Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. EM ophwty@nus.edu.sg RI Cheung, Carol/G-7895-2016; OI Klein, Ronald/0000-0002-4428-6237; Ikram, Mohammad Kamran/0000-0003-0173-9571 NR 61 TC 33 Z9 34 U1 0 U2 16 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 MAR PY 2013 VL 36 IS 3 BP 750 EP 759 DI 10.2337/dc12-1554 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 103OU UT WOS:000315928700052 PM 23431093 ER PT J AU Zorrilla, EP Heilig, M de Wit, H Shaham, Y AF Zorrilla, Eric P. Heilig, Markus de Wit, Harriet Shaham, Yavin TI Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE Corticotropin-releasing factor or hormone receptor antagonist; CRF or CRH; Anxiety disorder; Major depression; Alcohol or ethanol; Drug addiction or alcoholism or alcohol dependence or alcohol use disorder or binge drinking; Acute or protracted withdrawal or abstinence; Treatment or clinical trial; Stress-induced relapse or reinstatement or craving ID CORTICOTROPIN-RELEASING-FACTOR; ANXIETY-LIKE BEHAVIOR; FACTOR TYPE-1 RECEPTOR; ETHANOL-DEPENDENT RATS; STRESS-INDUCED RELAPSE; WITHDRAWAL-INDUCED ANXIETY; PLACEBO-CONTROLLED TRIAL; PREFERRING MSP RATS; INDUCED INCREASES; MAJOR DEPRESSION AB Background: Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry "Translational Research in Addiction" symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods: We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results: The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions: Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence. (c) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Zorrilla, Eric P.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [de Wit, Harriet] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Zorrilla, EP (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, 10550 North Torrey Pines Rd,SP30-2400, La Jolla, CA 92037 USA. EM ezorrilla@scripps.edu RI shaham, yavin/G-1306-2014; OI Heilig, Markus/0000-0003-2706-2482; de Wit, Harriet/0000-0002-7211-8994 FU National Institutes of Health [AA006420, DA02812, DK026741, DK070118]; National Institute on Drug Abuse [R13DA029347]; Intramural Research Program of NIDA; Intramural Research Program of NIAAA FX The research was supported by National Institutes of Health grants AA006420, DA02812, DK026741 and DK070118 as well as travel support from the Behavior, Biology and Chemistry: Translational Research in Addiction 2012 symposium. Funding for the BBC conference was made possible, in part, by R13DA029347 from the National Institute on Drug Abuse. The research of YS and MH is supported by the Intramural Research Programs of NIDA and NIAAA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Health and Human Services, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse or the University of Texas at San Antonio Health Sciences Center. Mention of trade names, commercial practices, or organization does not imply endorsement by the U.S. Government. The funding sources had no role in writing the review or in the decision to submit the review for publication. NR 169 TC 34 Z9 34 U1 3 U2 37 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 MAR 1 PY 2013 VL 128 IS 3 BP 175 EP 186 DI 10.1016/j.drugalcdep.2012.12.017 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 101DY UT WOS:000315756600001 PM 23294766 ER PT J AU Zilbermint, MF Wisniewski, AB Xu, XQ Selnes, OA Dobs, AS AF Zilbermint, Mihail F. Wisniewski, Amy B. Xu, Xiaoqiang Selnes, Ola A. Dobs, Adrian S. TI Relationship between sex hormones and cognitive performance in men with substance use SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Testosterone; Estradiol; Sex hormones; Cognitive function; Illicit drug users; Substance use ID PITUITARY-GONADAL-FUNCTION; ELDERLY-MEN; TESTOSTERONE LEVELS; DRUG-USERS; OLDER MEN; FOLLOW-UP; AGING MEN; NEUROPSYCHOLOGICAL IMPAIRMENT; STEROID-HORMONES; PROSTATE-CANCER AB Background: Hypogonadism is common with opiate-like drug use and may contribute to cognitive abnormalities. With the increasing epidemic of HIV and substance use (SU) worldwide, it is important to understand the impact of these conditions on cognition, which may affect quality of life and possibly decrease adherence to treatment. We hypothesized that men with SU, by virtue of hypogonadism secondary to HIV and/or SU, may demonstrate impaired cognition. Methods: We recruited men aged 18-50 from a population of low income, inner-city individuals. Details of HIV and SU status, serum blood levels of total testosterone (TT), free testosterone (FT) and estradiol (E2) were assessed. All subjects were administered ten neuropsychological tests. Results: Our sample consisted of 68 men (mean age: 43.2 years (SD 5.8), African Americans: 86.6%). The recruited population was primarily from low socioeconomic status and unemployed. The mean level of TT was 553.9 ng/dL (SD 262.0), the mean level of FT was 69.5 pg/mL (SD 34.8), mean E2 was 3.2 pg/mL (SD 4.4). We found that 30.9% were hypogonadal and it was associated with higher SU. We observed some relationships between sex hormones and cognitive domains, however, after adjustment for age, drug use category, education, depression, HIV, there was no statistically significant correlation between cognitive performance and sex hormone levels. Conclusions: In this cross-sectional study of men with a high prevalence of SU and hypogonadism, endogenous levels of TT, FT or E2 were not related to cognitive performance. Other factors need to be identified which may contribute to poor cognitive function in the setting of SU. Published by Elsevier Ireland Ltd. C1 [Zilbermint, Mihail F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Wisniewski, Amy B.] Univ Oklahoma, Hlth Sci Ctr, Dept Urol, Oklahoma City, OK 73104 USA. [Xu, Xiaoqiang] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Selnes, Ola A.] Johns Hopkins Univ, Sch Med, Cognit Neurosci Div, Dept Neurol, Baltimore, MD 21287 USA. [Dobs, Adrian S.] Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Johns Hopkins Clin Res Network, Baltimore, MD 21287 USA. RP Dobs, AS (reprint author), Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Johns Hopkins Clin Res Network, 1830 Monument St,Suite 328, Baltimore, MD 21287 USA. EM adobs@jhmi.edu FU Johns Hopkins University; National Institute on Drug Abuse, National Institutes of Health [1R01DA014098-01A2, 5R01DA014098-02, 3R01DA014098-03S1, 5R01DA014098-03, 5R01DA014098-04, 5R01DA014098-05] FX This research was supported in part by the Johns Hopkins University and by the National Institute on Drug Abuse, National Institutes of Health (grants: 1R01DA014098-01A2, 5R01DA014098-02, 3R01DA014098-03S1, 5R01DA014098-03, 5R01DA014098-04, 5R01DA014098-05). These organizations had no further role in 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. ClinicalTrials.gov identifier: NCT00245531. NR 77 TC 0 Z9 0 U1 0 U2 6 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 MAR 1 PY 2013 VL 128 IS 3 BP 250 EP 254 DI 10.1016/j.drugalcdep.2012.08.024 PG 5 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 101DY UT WOS:000315756600011 PM 23021515 ER PT J AU Sommers, R Miller, FG AF Sommers, Roseanna Miller, Franklin G. TI Forgoing Debriefing in Deceptive Research: Is It Ever Ethical? SO ETHICS & BEHAVIOR LA English DT Article DE debriefing (experimental); deception; informed consent ID PSYCHOLOGICAL EXPERIMENTS; FIELD EXPERIMENT; SELF; DISCRIMINATION; ALTRUISM; INTERNET; BEHAVIOR; MADNESS; AROUSAL; LOST AB The use of deception in research is generally permitted so long as participants are debriefed at the conclusion of their participation. Several authoritative research ethics guidelines allow investigators to omit debriefing under certain circumstances, however. Here we examine various justifications for forgoing debriefing in deceptive research, including concerns about subject pool contamination, the risk that revealing the deception will be harmful or distressing to participants, and issues of practicability. We conclude that, contrary to current practice, omitting debriefing is ethically acceptable only when debriefing is impracticable, the deception is innocuous, and no reasonable person would object to involvement in the research. C1 [Sommers, Roseanna; Miller, Franklin G.] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 52 TC 3 Z9 3 U1 6 U2 38 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1050-8422 J9 ETHICS BEHAV JI Ethics Behav. PD MAR 1 PY 2013 VL 23 IS 2 BP 98 EP 116 DI 10.1080/10508422.2012.732505 PG 19 WC Ethics; Psychology, Multidisciplinary SC Social Sciences - Other Topics; Psychology GA 097QK UT WOS:000315488400002 ER PT J AU Facio, FM Eidem, H Fisher, T Brooks, S Linn, A Kaphingst, KA Biesecker, LG Biesecker, BB AF Facio, Flavia M. Eidem, Haley Fisher, Tyler Brooks, Stephanie Linn, Amy Kaphingst, Kimberly A. Biesecker, Leslie G. Biesecker, Barbara B. TI Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE whole-genome sequencing; individual results; attitudes and intentions ID MANAGING INCIDENTAL FINDINGS; CLINICAL-PRACTICE; WORKING GROUP; RETURN; RECOMMENDATIONS; PREFERENCES; PROJECT AB Genome sequencing has been rapidly integrated into clinical research and is currently marketed to health-care practitioners and consumers alike. The volume of sequencing data generated for a single individual and the wide range of findings from whole-genome sequencing raise critical questions about the return of results and their potential value for end-users. We conducted a mixed-methods study of 311 sequential participants in the NIH ClinSeq study to assess general preferences and specific attitudes toward learning results. We tested how these variables predicted intentions to receive results within four categories of findings ranging from medically actionable to variants of unknown significance. Two hundred and ninety-four participants indicated a preference to learn their genome sequencing results. Most often, participants cited disease prevention as their reason, including intention to change their lifestyle behaviors. Participants held positive attitudes, strongly perceived social norms and strong intentions to learn results, although there were significant mean differences among four categories of findings (P<0.01). Attitudes and social norms for medically actionable and carrier results were most similar and rated the highest. Participants distinguished among the types and quality of information they may receive, despite strong intentions to learn all results presented. These intentions were motivated by confidence in their ability to use the information to prevent future disease and a belief in the value of even uninterpretable information. It behooves investigators to facilitate participants' desire to learn a range of information from genomic sequencing while promoting realistic expectations for its clinical and personal utility. European Journal of Human Genetics (2013) 21, 261-265; doi:10.1038/ejhg.2012.179; published online 15 August 2012 C1 [Facio, Flavia M.; Eidem, Haley; Fisher, Tyler; Brooks, Stephanie; Linn, Amy; Biesecker, Leslie G.; Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Kaphingst, Kimberly A.] Washington Univ, Dept Surg, Div Publ Hlth Sci, St Louis, MO USA. RP Biesecker, BB (reprint author), NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,Room B1B36, Bethesda, MD 20892 USA. EM barbarab@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute. NR 28 TC 47 Z9 47 U1 3 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAR PY 2013 VL 21 IS 3 BP 261 EP 265 DI 10.1038/ejhg.2012.179 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 101DG UT WOS:000315754800005 PM 22892536 ER PT J AU Kummar, S Doroshow, JH AF Kummar, Shivaani Doroshow, James H. TI Molecular targets in cancer therapy SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review ID RESISTANT PROSTATE-CANCER; CIRCULATING TUMOR-CELLS; BREAST-CANCER; EGFR; ACTIVATION; SURVIVAL; DRUGS AB The EORTC-NCI-AACR Symposium is an annual meeting, jointly hosted by the European Organization for Research and Treatment of Cancer, the US National Cancer Institute and the American Association for Cancer Research, to encourage exchange of information, dialogue and collaboration between investigators from the US, Europe and the world over regarding the development of novel cancer therapeutics. This meeting is hosted on alternate years in the US and Europe. This year's symposium, held in Dublin, Ireland, focused on the identification of novel targets, strategies for biomarker development and trial designs to expedite development of new therapies and improve patient selection. With over 30 oral presentations, more than 600 poster presentations and over 2000 participants, the meeting covered all the major aspects of oncology drug development, including the integration of newer platforms for the development of biomarkers. C1 [Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kummar, S (reprint author), NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov NR 11 TC 0 Z9 0 U1 0 U2 10 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD MAR PY 2013 VL 13 IS 3 BP 267 EP 269 DI 10.1586/ERA.12.170 PG 3 WC Oncology SC Oncology GA 105FH UT WOS:000316051100009 PM 23477512 ER PT J AU Aagaard, K Petrosino, J Keitel, W Watson, M Katancik, J Garcia, N Patel, S Cutting, M Madden, T Hamilton, H Harris, E Gevers, D Simone, G McInnes, P Versalovic, J AF Aagaard, Kjersti Petrosino, Joseph Keitel, Wendy Watson, Mark Katancik, James Garcia, Nathalia Patel, Shital Cutting, Mary Madden, Tessa Hamilton, Holli Harris, Emily Gevers, Dirk Simone, Gina McInnes, Pamela Versalovic, James TI The Human Microbiome Project strategy for comprehensive sampling of the human microbiome and why it matters SO FASEB JOURNAL LA English DT Article DE metagenomics; HMP clinical data; clinical metadata; clinical research studies; metagenomic medicine ID CORE GUT MICROBIOME; INTESTINAL MICROBIOTA; HUMAN SKIN; MOLECULAR ANALYSIS; BODY HABITATS; DIVERSITY; COMMUNITIES; OBESITY; FLORA; EVOLUTION AB The Human Microbiome Project used rigorous good clinical practice standards to complete comprehensive body site sampling in healthy 18- to 40-yr-old adults, creating an unparalleled reference set of microbiome specimens. To ensure that specimens represented minimally perturbed microbiomes, we first screened potential participants using exclusion criteria based on health history, including the presence of systemic diseases (e.g., hypertension, cancer, or immunodeficiency or autoimmune disorders), use of potential immunomodulators, and recent use of antibiotics or probiotics. Subsequent physical examinations excluded individuals based on body mass index (BMI), cutaneous lesions, and oral health. We screened 554 individuals to enroll 300 (149 men and 151 women, mean age 26 yr, mean BMI 24 kg/m(2), 20.0% racial minority, and 10.7% Hispanic). We obtained specimens from the oral cavity, nares, skin, gastrointestinal tract, and vagina (15 specimens from men and 18 from women). The study evaluated longitudinal changes in an individual's microbiome by sampling 279 participants twice (mean 212 d after the first sampling; range 30-359 d) and 100 individuals 3 times (mean 72 d after the second sampling; range 30-224 d). This sampling strategy yielded 11,174 primary specimens, from which 12,479 DNA samples were submitted to 4 centers for metagenomic sequencing. Our clinical design and well-defined reference cohort has laid a foundation for microbiome research.-Aagaard, K., Petrosino, J., Keitel, W., Watson, M., Katancik, J., Garcia, N., Patel, S., Cutting, M., Madden, T., Hamilton, H., Harris, E., Gevers, D., Simone, G., McInnes, P., Versalovic, J. The Human Microbiome Project strategy for comprehensive sampling of the human microbiome and why it matters. FASEB J. 27, 1012-1022 (2013). www.fasebj.org C1 [Aagaard, Kjersti; Petrosino, Joseph; Keitel, Wendy; Patel, Shital; Versalovic, James] Baylor Coll Med, Houston, TX 77030 USA. [Watson, Mark; Madden, Tessa] Washington Univ, St Louis, MO USA. [Katancik, James] Univ Texas Hlth Sci Ctr, Houston, TX USA. [Garcia, Nathalia] St Louis Univ, St Louis, MO 63103 USA. [Cutting, Mary; Hamilton, Holli; Harris, Emily; McInnes, Pamela] NIH, Bethesda, MD 20892 USA. [Gevers, Dirk] MIT, Broad Inst, Cambridge, MA 02139 USA. [Simone, Gina] EMMES Corp, Rockville, MD USA. [Versalovic, James] Texas Childrens Hosp, Houston, TX 77030 USA. RP Aagaard, K (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. EM aagaardt@bcm.edu OI Garcia, M. Nathalia/0000-0003-3685-027X FU U.S. National Instiutes of Health (NIH); National Human Genome Research Institute at NIH [U54HG004973, U54HG004968] FX The authors thank the staff directly involved in clinical evaluation of subjects, human body sampling, and specimen processing. At Baylor College of Medicine (BCM), the staff included Chanei Henry, Michelle Rubio-Gonzales, Janet Wells, V. A. Mancha, Joanna Allaire, Kavitha Parthasarathy, Jayne McWherter, Antone Opekun, Coni Cheesman, Shannon Hawkins, Matthew Ross, Tulin Ayvaz, Bonnie Youmans, and Yue Shang. At Washington University in St. Louis (WUSTL), the staff included Sally Anderson, Shea Roesel, Linda Ventimiglia, Debra Kemp, Teresa Arb, Arlyn Pittler, Cindy Neske, Laura Granderson, Beth Reagan, Amy Brink, Nicole Gaudin, Emily Rozycki, and Amanda Alyatim. At St Louis University, the staff included Mary Signorino and Diane Collier. The authors are grateful to Dr. Sarah Highlander (BCM) for assisting with protocol development for DNA isolation and sample processing, and to Dr. Curtis Huttenhower (Harvard School of Public Health) for generating essential data used in Fig. 2. The authors gratefully acknowledge the support of the Human Microbiome Project funded through the U.S. National Instiutes of Health (NIH) Director's Common Fund (as part of NIH RoadMap 1.5). The genome centers participating in this study were funded by direct support from the National Human Genome Research Institute at NIH (U54HG004973, BCM; and U54HG004968, WUSTL). NR 45 TC 68 Z9 70 U1 9 U2 125 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2013 VL 27 IS 3 BP 1012 EP 1022 DI 10.1096/fj.12-220806 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 098YO UT WOS:000315585200016 PM 23165986 ER PT J AU Wang, XQ Cabrera, RM Li, Y Miller, DS Finnell, RH AF Wang, Xueqian Cabrera, Robert M. Li, Yue Miller, David S. Finnell, Richard H. TI Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice SO FASEB JOURNAL LA English DT Article DE ABC transporters; valproic acid; brain capillaries ID CONSTITUTIVE ANDROSTANE RECEPTOR; MULTIDRUG-RESISTANCE PROTEINS; XENOBIOTIC EFFLUX TRANSPORTERS; MEDIATED UP-REGULATION; FOLIC-ACID; ANTIFOLATE RESISTANCE; EXPRESSION; HOMEOSTASIS; DEFICIENCY; DISEASES AB Folate deficiency has been associated with many adverse clinical manifestations. The blood-brain barrier (BBB), formed by brain capillary endothelial cells, protects the brain from exposure to neurotoxicants. The function of BBB is modulated by multiple ABC transporters, particularly P-glycoprotein. A proton-coupled folate transporter (PCFT)-deficient mouse has been previously described as a model for systemic folate deficiency. Herein, we demonstrate that exposing mouse brain capillaries to the antiepileptic drug, valproic acid (VPA; 5 mu M), significantly increased P-glycoprotein transport function in the wild-type animals. A ligand to the aryl hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produced a similar induction of P-glycoprotein, which tightened the BBB, thereby increasing the neuroprotection. However, VPA- or TCDD-induced P-glycoprotein transport was blocked in the PCFT-nullizygous mice, indicating that multiple neuroprotective mechanisms are compromised under folate-deficient conditions. Brain capillaries from S-folinic acid (SFA; 40 mg/kg)-treated PCFT-nullizygous mice exhibited increased P-glycoprotein transport following VPA exposure. This suggests that SFA supplementation restored the normal BBB function. In addition, we show that tight-junction proteins are disintegrated in the PCFT mutant mice. Taken together, these findings strongly suggest that folate deficiency disrupts the BBB function by targeting the transporter and tight junctions, which may contribute to the development of neurological disorders.-Wang, X., Cabrera, R. M., Li, Y., Miller, D. S., Finnell, R. H. Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice. FASEB J. 27, 1167-1175 (2013). www.fasebj.org C1 [Wang, Xueqian; Cabrera, Robert M.; Finnell, Richard H.] Univ Texas Austin, Dell Pediat Res Inst, Dept Nutr Sci, Austin, TX 78723 USA. [Li, Yue] Univ Texas Austin, Dell Pediat Res Inst, Confocal Microscopy Core, Austin, TX 78723 USA. [Finnell, Richard H.] Univ Texas Austin, Dept Chem & Biochem, Austin, TX 78723 USA. [Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Finnell, RH (reprint author), Univ Texas Austin, Dell Pediat Res Inst, Dept Nutr Sci, Austin, TX 78723 USA. EM rfinnell@austin.utexas.edu FU U.S. National Institutes of Health (NIH) [HD067244, HD072251]; National Institute of Environmental Health Sciences, NIH FX This work was supported in part by funds from the U.S. National Institutes of Health (NIH; HD067244 and HD072251). Additional support was provided by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. Although the research described in this article has been funded in part by the NIH, it does not necessarily reflect the views of the NIH, and no official endorsement should be inferred. The authors are indebted to Krystal Ogle for the care and well being of the mouse colony. NR 42 TC 8 Z9 8 U1 0 U2 9 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2013 VL 27 IS 3 BP 1167 EP 1175 DI 10.1096/fj.12-218495 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 098YO UT WOS:000315585200029 PM 23212123 ER PT J AU Wolff, EF Sun, LP Hediger, ML Sundaram, R Peterson, CM Chen, Z Louis, GMB AF Wolff, Erin Foran Sun, Liping Hediger, Mary L. Sundaram, Rajeshwari Peterson, C. Matthew Chen, Zhen Louis, Germaine M. Buck TI In utero exposures and endometriosis: the Endometriosis, Natural History, Disease, Outcome (ENDO) Study SO FERTILITY AND STERILITY LA English DT Article DE Endometriosis; epidemiology; in utero; ovarian dysgenesis hypothesis ID BODY-SIZE; POPULATION; ORIGINS; HEALTH AB Objective: To assess in utero exposures and the odds of an endometriosis diagnosis. Design: Matched cohort design. Setting: Fourteen participating clinical centers in geographically defined areas in Utah and California. Patient(s): Operative cohort comprised 473 women undergoing laparoscopy/laparotomy, and an age- and residence-matched population cohort comprising 127 women undergoing pelvic magnetic resonance imaging (MRI), 2007-2009. Intervention(s): None. Main Outcome Measure(s): Women completed standardized interviews before surgery or MRI regarding in utero exposures: mothers' lifestyle during the index pregnancy, and the index woman's gestation and birth size. Endometriosis was defined as visually confirmed disease in the operative cohort, and MRI visualized disease in the population cohort. The odds of an endometriosis diagnosis and corresponding 95% confidence intervals (CI) were estimated for each exposure by cohort using logistic regression and adjusting for current smoking, age at menarche, body mass index, and study site. Result(s): Endometriosis was diagnosed in 41% and 11% of women in the operative and population cohorts, respectively. In the primary analysis, adjust odds ratios (AORs) were elevated for maternal vitamin usage (1.27; 95% CI, 0.85-1.91), maternal cigarette smoking (1.16; 95% CI = 0.61-2.24), and low birth weight (1.1; 95% CI, 0.92-1.32). Reduced odds were observed for maternal usage of caffeine (0.99; 95% CI, 0.64-1.54), alcohol (0.82; 95% CI, 0.35-1.94), paternal cigarette smoking (0.72; 95% CI, 0.43-1.19), and preterm delivery (0.98; 95% CI, 0.47-2.03). Sensitivity analyses mostly upheld the primary results except for a decreased AOR for preterm birth (0.41; 95% CI, 0.18-0.94) when restricting to visualized and histologically confirmed endometriosis in the operative cohort. Conclusion(s): In utero exposures were not statistically significantly associated with the odds of an endometriosis diagnosis in either cohort. (Fertil Steril (R) 2013;99:790-5. (C) 2013 by American Society for Reproductive Medicine.) C1 [Wolff, Erin Foran] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Reprod Regenerat Med, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Sun, Liping; Hediger, Mary L.; Sundaram, Rajeshwari; Chen, Zhen; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Peterson, C. Matthew] Univ Utah, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Salt Lake City, UT USA. RP Wolff, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Reprod Regenerat Med, Program Reprod & Adult Endocrinol, Bldg 10,CRC Room 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM erin.wolff@nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02]; Program in Reproductive and Adult Endocrinology FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts # NO1-DK-6-3428; NO1-DK-6-3427; 10001406-02; 10001406-02) and in part by the Program in Reproductive and Adult Endocrinology. NR 15 TC 13 Z9 13 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD MAR PY 2013 VL 99 IS 3 BP 790 EP 795 DI 10.1016/j.fertnstert.2012.11.013 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 098ZZ UT WOS:000315589300032 PM 23211710 ER PT J AU Barbash, IM Cecchini, S Faranesh, AZ Virag, T Li, L Yang, Y Hoyt, RF Kornegay, JN Bogan, JR Garcia, L Lederman, RJ Kotin, RM AF Barbash, I. M. Cecchini, S. Faranesh, A. Z. Virag, T. Li, L. Yang, Y. Hoyt, R. F. Kornegay, J. N. Bogan, J. R. Garcia, L. Lederman, R. J. Kotin, R. M. TI MRI roadmap-guided transendocardial delivery of exon-skipping recombinant adeno-associated virus restores dystrophin expression in a canine model of Duchenne muscular dystrophy SO GENE THERAPY LA English DT Article DE Duchenne muscular dystrophy; rAAV; exon-skipping; cardiomyopathy ID MYOCARDIAL GENE-TRANSFER; MAGNETIC-RESONANCE; MUSCLE-CELLS; RESTORATION; HEART; CARDIOMYOPATHY; BLOCKADE; HOMOLOG; FAILURE; PRO051 AB Duchenne muscular dystrophy (DMD) cardiomyopathy patients currently have no therapeutic options. We evaluated catheter-based transendocardial delivery of a recombinant adeno-associated virus (rAAV) expressing a small nuclear U7 RNA (U7smOPT) complementary to specific cis-acting splicing signals. Eliminating specific exons restores the open reading frame resulting in translation of truncated dystrophin protein. To test this approach in a clinically relevant DMD model, golden retriever muscular dystrophy (GRMD) dogs received serotype 6 rAAV-U7smOPT via the intracoronary or transendocardial route. Transendocardial injections were administered with an injection-tipped catheter and fluoroscopic guidance using X-ray fused with magnetic resonance imaging (XFM) roadmaps. Three months after treatment, tissues were analyzed for DNA, RNA, dystrophin protein, and histology. Whereas intracoronary delivery did not result in effective transduction, transendocardial injections, XFM guidance, enabled 30 +/- 10 non-overlapping injections per animal. Vector DNA was detectable in all samples tested and ranged from <1 to >3000 vector genome copies per cell. RNA analysis, western blot analysis, and immunohistology demonstrated extensive expression of skipped RNA and dystrophin protein in the treated myocardium. Left ventricular function remained unchanged over a 3-month follow-up. These results demonstrated that effective transendocardial delivery of rAAV-U7smOPT was achieved using XFM. This approach restores an open reading frame for dystrophin in affected dogs and has potential clinical utility. Gene Therapy (2013) 20, 274-282; doi:10.1038/gt.2012.38; published online 3 May 2012 C1 [Barbash, I. M.; Faranesh, A. Z.; Lederman, R. J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Cecchini, S.; Virag, T.; Li, L.; Yang, Y.; Kotin, R. M.] NHLBI, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Hoyt, R. F.] NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. [Kornegay, J. N.; Bogan, J. R.] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Kornegay, J. N.; Bogan, J. R.] Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27599 USA. [Kornegay, J. N.; Bogan, J. R.] Univ N Carolina, Sch Med, Gene Therapy Ctr, Chapel Hill, NC USA. [Garcia, L.] UPMC UM76, CNRS UMR7215, Inst Myol, Paris, France. RP Kotin, RM (reprint author), NHLBI, Lab Mol Virol & Gene Therapy, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM kotinr@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, Division of Intramural Research; International Collaborative Effort (ICE) for Duchenne Muscular Dystrophy FX We are grateful to the NHLBI Laboratory of Animal Medicine and Surgery technologists for assistance with animal experiments, and the veterinarians and technicians of the Division of Veterinary Research and Victor Wright for assistance with MRI scans. We appreciate the professional skills and advice of the Dr Christian Combs, NHLBI Light Microscopy Core, and Dr Xu-Zi Yu, NHLBI Pathology Core. Dr Victoria Joan Hoffman of Diagnostic & Research Services Branch, Division of Veterinary Resources, NIH, provided essential support and advice. Dr H Lee Sweeney provided helpful comments and discussion. We thank Boston Scientific for providing the injection catheters. Funding was provided by the National Heart, Lung, and Blood Institute, Division of Intramural Research, and the International Collaborative Effort (ICE) for Duchenne Muscular Dystrophy. The ICE consists of the Duchenne Parent Project France and the Association Monagasque Contra les Myopathies. NR 44 TC 14 Z9 14 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD MAR PY 2013 VL 20 IS 3 BP 274 EP 282 DI 10.1038/gt.2012.38 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 104FU UT WOS:000315978100005 PM 22551778 ER PT J AU Hwang, YS Lee, HS Kamata, T Mood, K Cho, HJ Winterbottom, E Ji, YJ Singh, A Daar, IO AF Hwang, Yoo-Seok Lee, Hyun-Shik Kamata, Teddy Mood, Kathleen Cho, Hee Jun Winterbottom, Emily Ji, Yon Ju Singh, Arvinder Daar, Ira O. TI The Smurf ubiquitin ligases regulate tissue separation via antagonistic interactions with ephrinB1 SO GENES & DEVELOPMENT LA English DT Article DE Smurf; cell adhesion; ephrinB1; tissue boundaries ID PLANAR CELL POLARITY; BREAST-CANCER CELLS; TGF-BETA; C2 DOMAIN; PARAXIAL PROTOCADHERIN; DEPENDENT DEGRADATION; CONVERGENT EXTENSION; XENOPUS EMBRYOS; I RECEPTOR; EYE FIELD AB The formation of tissue boundaries is dependent on the cell-cell adhesion/repulsion system that is required for normal morphogenetic processes during development. The Smad ubiquitin regulatory factors (Smurfs) are E3 ubiquitin ligases with established roles in cell growth and differentiation, but whose roles in regulating cell adhesion and migration are just beginning to emerge. Here, we demonstrate that the Smurfs regulate tissue separation at mesoderm/ectoderm boundaries through antagonistic interactions with ephrinB1, an Eph receptor ligand that has a key role in regulating the separation of embryonic germlayers. EphrinB1 is targeted by Smurf2 for degradation; however, a Smurf1 interaction with ephrinB1 prevents the association with Smurf2 and precludes ephrinB1 from ubiquitination and degradation, since it is a substantially weaker substrate for Smurf1. Inhibition of Smurf1 expression in embryonic mesoderm results in loss of ephrinB1-mediated separation of this tissue from the ectoderm, which can be rescued by the coincident inhibition of Smurf2 expression. This system of differential interactions between Smurfs and ephrinB1 regulates the maintenance of tissue boundaries through the control of ephrinB protein levels. C1 [Hwang, Yoo-Seok; Lee, Hyun-Shik; Kamata, Teddy; Mood, Kathleen; Cho, Hee Jun; Winterbottom, Emily; Ji, Yon Ju; Singh, Arvinder; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Lee, Hyun-Shik] Kyungpook Natl Univ, Sch Life Sci, Coll Nat Sci, ABRC,CMRI, Taegu 702701, South Korea. RP Daar, IO (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM daar@ncifcrf.gov RI Lee, Hyun-Shik/G-3555-2011; OI Daar, Ira/0000-0003-2657-526X FU NIH, National Cancer Institute; Ministry for Health, Welfare, and Family Affairs, Republic of Korea [A100335] FX We thank Dr. Robert Grosse for H10GFP-RBD and the H10GFP-spacer-MCS construct, Dr. Ken W. Cho for the Rho N19 construct, Dr. Gerald Thomsen for the HA-Smurf1 construct, and Dr. John Wallingford for the H2B-mRFP construct. We also thank Dr. Robert Stephens for generating the Xenopus database, Dr. Ming Zhou and Dr. Tim Veenstra for mass spectrometric analysis, Dr. Robert Leighty for statistical analysis, and the Cancer Genetics and Signaling Group for helpful suggestions and discussions. Also, we thank Dr. Renping Zhou, Dr. Jairaj Acharya, and Dr. Shyam Sharan for critical reading of this manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, and a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea (A100335). H. L., Y.H., and I. D. designed the experiments, analyzed the data, and wrote the manuscript. H. L., Y.H., K. M., H. C., E. W., and T. K. performed the experiments. A. S. and Y.J. assisted in the design of the experiments. NR 56 TC 11 Z9 11 U1 0 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 0890-9369 J9 GENE DEV JI Genes Dev. PD MAR 1 PY 2013 VL 27 IS 5 BP 491 EP 503 DI 10.1101/gad.208355.112 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 103YE UT WOS:000315954600003 PM 23475958 ER PT J AU Cyert, MS Philpott, CC AF Cyert, Martha S. Philpott, Caroline C. TI Regulation of Cation Balance in Saccharomyces cerevisiae SO GENETICS LA English DT Article ID CYTOCHROME-C-OXIDASE; IRON-SULFUR CLUSTER; MEMBRANE H+-ATPASE; ZAP1 TRANSCRIPTIONAL ACTIVATOR; DNA-BINDING DOMAIN; UBIQUITIN-DEPENDENT TRAFFICKING; MITOCHONDRIAL CALCIUM UNIPORTER; MAJOR FACILITATOR SUPERFAMILY; ENDOPLASMIC-RETICULUM STRESS; THIOLATE POLYNUCLEAR CLUSTER AB All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish the electrochemical gradients across membranes that drive cellular processes such as transport and ATP synthesis. Metal ions serve as essential enzyme cofactors and perform both structural and signaling roles within cells. However, because these ions can also be toxic, cells have developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Studies in Saccharomyces cerevisiae have characterized many of the gene products and processes responsible for acquiring, utilizing, storing, and regulating levels of these ions. Findings in this model organism have often allowed the corresponding machinery in humans to be identified and have provided insights into diseases that result from defects in ion homeostasis. This review summarizes our current understanding of how cation balance is achieved and modulated in baker's yeast. Control of intracellular pH is discussed, as well as uptake, storage, and efflux mechanisms for the alkali metal cations, Na+ and K+, the divalent cations, Ca2+ and Mg2+, and the trace metal ions, Fe2+, Zn2+, Cu2+, and Mn2+. Signal transduction pathways that are regulated by pH and Ca2+ are reviewed, as well as the mechanisms that allow cells to maintain appropriate intracellular cation concentrations when challenged by extreme conditions, i.e., either limited availability or toxic levels in the environment. C1 [Cyert, Martha S.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [Philpott, Caroline C.] NIDDKD, Genet & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Cyert, MS (reprint author), Stanford Univ, Dept Biol, Stanford, CA 94305 USA. EM mcyert@stanford.edu FU National Institutes of Health (NIH) from the National Institute of General Medicine [R01GM48729]; NIH Intramural Research Program of the National Institue of Diabetes and Digestive and Kidney Disease FX The authors would like to thank the anonymous reviewers for their helpful comments. M.S.C. is funded the National Institutes of Health (NIH) grant R01GM48729 from the National Institute of General Medicine. C.C.P. is supported by the NIH Intramural Research Program of the National Institue of Diabetes and Digestive and Kidney Disease. NR 423 TC 66 Z9 66 U1 8 U2 74 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAR PY 2013 VL 193 IS 3 BP 677 EP 713 DI 10.1534/genetics.112.147207 PG 37 WC Genetics & Heredity SC Genetics & Heredity GA 103MD UT WOS:000315920000003 PM 23463800 ER PT J AU Gaur, NA Hasek, J Brickner, DG Qiu, HF Zhang, F Wong, CM Malcova, I Vasicova, P Brickner, JH Hinnebusch, AG AF Gaur, Naseem A. Hasek, Jiri Brickner, Donna Garvey Qiu, Hongfang Zhang, Fan Wong, Chi-Ming Malcova, Ivana Vasicova, Pavla Brickner, Jason H. Hinnebusch, Alan G. TI Vps Factors Are Required for Efficient Transcription Elongation in Budding Yeast SO GENETICS LA English DT Article ID RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE GENOME; ELL-ASSOCIATED PROTEINS; NUCLEAR-PORE COMPLEX; IN-VIVO; PHOSPHATIDYLINOSITOL 3-KINASE; MOLECULAR EVIDENCE; INDEPENDENT RECRUITMENT; ESCRT MACHINERY; BINDING PROTEIN AB There is increasing evidence that certain Vacuolar protein sorting (Vps) proteins, factors that mediate vesicular protein trafficking, have additional roles in regulating transcription factors at the endosome. We found that yeast mutants lacking the phosphatidylinositol 3-phosphate [PI(3) P] kinase Vps34 or its associated protein kinase Vps15 display multiple phenotypes indicating impaired transcription elongation. These phenotypes include reduced mRNA production from long or G+C-rich coding sequences (CDS) without affecting the associated GAL1 promoter activity, and a reduced rate of RNA polymerase II (Pol II) progression through lacZ CDS in vivo. Consistent with reported genetic interactions with mutations affecting the histone acetyltransferase complex NuA4, vps15 Delta and vps34 Delta mutations reduce NuA4 occupancy in certain transcribed CDS. vps15D and vps34D mutants also exhibit impaired localization of the induced GAL1 gene to the nuclear periphery. We found unexpectedly that, similar to known transcription elongation factors, these and several other Vps factors can be cross-linked to the CDS of genes induced by Gcn4 or Gal4 in a manner dependent on transcriptional induction and stimulated by Cdk7/Kin28-dependent phosphorylation of the Pol II C-terminal domain (CTD). We also observed colocalization of a fraction of Vps15-GFP and Vps34-GFP with nuclear pores at nucleus-vacuole (NV) junctions in live cells. These findings suggest that Vps factors enhance the efficiency of transcription elongation in a manner involving their physical proximity to nuclear pores and transcribed chromatin. C1 [Gaur, Naseem A.; Qiu, Hongfang; Zhang, Fan; Wong, Chi-Ming; Hinnebusch, Alan G.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Hasek, Jiri; Malcova, Ivana; Vasicova, Pavla] Acad Sci Czech Republic, Inst Microbiol, Lab Cell Reprod, CR-14220 Prague, Czech Republic. [Brickner, Donna Garvey; Brickner, Jason H.] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA. RP Hinnebusch, AG (reprint author), Eunice K Shriver Natl Inst Child Hlth & Human Dev, NIH, Bldg 6A,Room B1A13, Bethesda, MD 20874 USA. EM ahinnebusch@nih.gov RI Malcova, Ivana/H-2439-2014; Hasek, Jiri/H-2427-2014; Vasicova, Pavla/I-2010-2014; OI Wong, Chi-Ming/0000-0002-0025-7135; Gaur, Naseem/0000-0002-1224-8789 FU Intramural Research Program of the National Institutes of Health; W. M. Keck Young Scholars in Medical Research Award; [P305/12/0480]; [RVO61388971] FX We thank Sebastian Chavez, Andres Aguilera, Henrik Dohlman, Steven Hahn, Kristine Willis, Roger Tsien, and the Yeast Resource Center at the University of Washington for gifts of plasmids, and Thomas Dever for useful suggestions. This work was supported in part by the Intramural Research Program of the National Institutes of Health. J.H. was supported by P305/12/0480 and RVO61388971, and D.G.B. and J.H.B. were supported by a W. M. Keck Young Scholars in Medical Research Award. NR 73 TC 9 Z9 9 U1 2 U2 19 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAR PY 2013 VL 193 IS 3 BP 829 EP U284 DI 10.1534/genetics.112.146308 PG 29 WC Genetics & Heredity SC Genetics & Heredity GA 103MD UT WOS:000315920000012 PM 23335340 ER PT J AU Hakim, O Sung, MH Nakayamada, S Voss, TC Baek, S Hager, GL AF Hakim, Ofir Sung, Myong-Hee Nakayamada, Shingo Voss, Ty C. Baek, Songjoon Hager, Gordon L. TI Spatial congregation of STAT binding directs selective nuclear architecture during T-cell functional differentiation SO GENOME RESEARCH LA English DT Article ID HELPER TYPE-1 CELLS; INTERFERON-GAMMA; REGULATORY ELEMENTS; BET EXPRESSION; TARGET GENES; IFNG LOCUS; STEM-CELLS; TRANSCRIPTION; ORGANIZATION; GENOME AB Higher-order genome organization shows tissue-specific patterns. However, functional relevance and the mechanisms shaping the genome architecture are poorly understood. Here we report a profound shift from promiscuous to highly selective genome organization that accompanies the effector lineage choice of differentiating T cells. As multipotent naive cells receive antigenic signals and commit to a T helper (Th) pathway, the genome-wide contacts of a lineage-specific cytokine locus are preferentially enriched for functionally relevant genes. Despite the establishment of divergent inter-actomes and global reprogramming of transcription in Th1 versus Th2, the overall expression status of the contact genes is surprisingly similar between the two lineages. Importantly, during differentiation, the genomic contacts are retained and strengthened precisely at DNA binding sites of the specific lineage-determining STAT transcription factor. In cells from the specific STAT knock-out mouse, the signature cytokine locus is unable to shed the promiscuous contacts established in the naive T cells, indicating the importance of genomic STAT binding. Altogether, the global aggregation of STAT binding loci from genic and nongenic regions highlights a new role for differentiation-promoting transcription factors in direct specification of higher-order nuclear architecture through interacting with regulatory regions. Such subnuclear environments have significant implications for efficient functioning of the mature effector lymphocytes. C1 [Hakim, Ofir; Sung, Myong-Hee; Voss, Ty C.; Baek, Songjoon; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Nakayamada, Shingo] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Hakim, O (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Inst Nanotechnol & Adv Mat, IL-52900 Ramat Gan, Israel. EM Ofir.Hakim@biu.ac.il; hagerg@exchange.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank John J. O'Shea and Yuka Kanno for their advice throughout the project and critical reading of the manuscript; Anindya Indrawan for technical help; Daoud Meerzaman and Robert L. Walker for help with the microarray scanner; Tatiana Karpova for help with microscopy; and Karen Meaburn for critical comments on the manuscript. Fluorescence imaging was performed at the National Cancer Institute Fluorescence Imaging Facility. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 65 TC 16 Z9 17 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAR PY 2013 VL 23 IS 3 BP 462 EP 472 DI 10.1101/gr.147652.112 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 101XD UT WOS:000315806800006 PM 23212947 ER PT J AU Agenor, M Collins, PY AF Agenor, Madina Collins, Pamela Y. TI Preventing HIV Among U.S. Women of Color With Severe Mental Illness: Perceptions of Mental Health Care Providers Working in Urban Community Clinics SO HEALTH CARE FOR WOMEN INTERNATIONAL LA English DT Article ID SEXUAL RISK BEHAVIOR; SUBSTANCE USE DISORDER; TREATMENT PROGRAMS; HIV/AIDS CARE; NEW-YORK; ADULTS; PEOPLE; SEROPREVALENCE; PREVALENCE; INFECTION AB Given their knowledge of the behavioral issues related to psychiatric illness, mental health care providers are in a unique position to help prevent HIV among women with severe mental illness (SMI). We conducted in-depth interviews with providers at two New York City community clinics. We identified three major, interrelated themes pertaining to HIV prevention among women of color with SMI. Interventions that address the barriers that clinicians face in discussing sex, sexuality, and HIV with patients and train providers in the cultural considerations of cross-cultural mental health care are needed to help prevent HIV among women of color with SMI. C1 [Agenor, Madina] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Collins, Pamela Y.] NIMH, Off Res Dispar & Global Mental Hlth, Bethesda, MD 20892 USA. RP Agenor, M (reprint author), Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 677 Huntington Ave,7th Floor, Boston, MA 02115 USA. EM magenor@mail.harvard.edu FU NIMH NIH HHS [K01 MH01691, K01 MH001691] NR 52 TC 2 Z9 2 U1 1 U2 13 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0739-9332 J9 HEALTH CARE WOMEN IN JI Health Care Women Int. PD MAR 1 PY 2013 VL 34 IS 3-4 BP 281 EP 302 DI 10.1080/07399332.2012.755983 PG 22 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 100DB UT WOS:000315674900007 PM 23394326 ER PT J AU Deo, R Nalls, MA Avery, CL Smith, JG Evans, DS Keller, MF Butler, AM Buxbaum, SG Li, G Quibrera, PM Smith, EN Tanaka, T Akylbekova, EL Alonso, A Arking, DE Benjamin, EJ Berenson, GS Bis, JC Chen, LY Chen, W Cummings, SR Ellinor, PT Evans, MK Ferrucci, L Fox, ER Heckbert, SR Heiss, G Hsueh, WC Kerr, KF Limacher, MC Liu, Y Lubitz, SA Magnani, JW Mehra, R Marcus, GM Murray, SS Newman, AB Njajou, O North, KE Paltoo, DN Psaty, BM Redline, SS Reiner, AP Robinson, JG Rotter, JI Samdarshi, TE Schnabel, RB Schork, NJ Singleton, AB Siscovick, D Soliman, EZ Sotoodehnia, N Srinivasan, SR Taylor, HA Trevisan, M Zhang, Z Zonderman, AB Newton-Cheh, C Whitsel, EA AF Deo, R. Nalls, M. A. Avery, C. L. Smith, J. G. Evans, D. S. Keller, M. F. Butler, A. M. Buxbaum, S. G. Li, G. Quibrera, P. Miguel Smith, E. N. Tanaka, T. Akylbekova, E. L. Alonso, A. Arking, D. E. Benjamin, E. J. Berenson, G. S. Bis, J. C. Chen, L. Y. Chen, W. Cummings, S. R. Ellinor, P. T. Evans, M. K. Ferrucci, L. Fox, E. R. Heckbert, S. R. Heiss, G. Hsueh, W. C. Kerr, K. F. Limacher, M. C. Liu, Y. Lubitz, S. A. Magnani, J. W. Mehra, R. Marcus, G. M. Murray, S. S. Newman, A. B. Njajou, O. North, K. E. Paltoo, D. N. Psaty, B. M. Redline, S. S. Reiner, A. P. Robinson, J. G. Rotter, J. I. Samdarshi, T. E. Schnabel, R. B. Schork, N. J. Singleton, A. B. Siscovick, D. Soliman, E. Z. Sotoodehnia, N. Srinivasan, S. R. Taylor, H. A. Trevisan, M. Zhang, Z. Zonderman, A. B. Newton-Cheh, C. Whitsel, E. A. TI Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants SO HEART RHYTHM LA English DT Article DE African Americans; Heart rate; Singe nucleotide polymorphisms; Meta-analysis ID SICK SINUS SYNDROME; MIDDLE-AGED MEN; RISK-FACTOR; FOLLOW-UP; POPULATIONS; MORTALITY; DISEASE; CONDUCTION; VARIANTS; MICE AB BACKGROUND Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. OBJECTIVE To identify novel genetic variants associated with resting heart rate in African Americans. METHODS Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of singe nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P <= 2.5 x 10(-8)). RESULTS Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98 x 10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. CONCLUSIONS An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin. C1 [Deo, R.] Univ Penn, Div Cardiol, Electrophysiol Sect, Philadelphia, PA 19104 USA. [Nalls, M. A.; Keller, M. F.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Avery, C. L.; Whitsel, E. A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Smith, J. G.] Lund Univ, Fac Med, Dept Cardiol, Lund, Sweden. [Smith, J. G.; Newton-Cheh, C.] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA. [Evans, D. S.; Cummings, S. R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Keller, M. F.] Temple Univ, Dept Biol Anthropol, Philadelphia, PA 19122 USA. [Butler, A. M.; Quibrera, P. Miguel; Heiss, G.; North, K. E.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Buxbaum, S. G.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Buxbaum, S. G.] Jackson State Univ, Sch Hlth Sci, Dept Epidemiol & Biostat, Jackson, MS USA. [Li, G.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Smith, E. N.] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Smith, E. N.] Univ Calif San Diego, Sch Med, Radys Childrens Hosp, La Jolla, CA 92093 USA. [Tanaka, T.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Akylbekova, E. L.; Fox, E. R.; Taylor, H. A.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Alonso, A.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Arking, D. E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Benjamin, E. J.] NHLBI, Framingham Study, Framingham, MA USA. [Benjamin, E. J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, E. J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, E. J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, E. J.] Boton Univ, Evans Mem Whitaker Cardiovasc Inst, Boston, MA USA. [Berenson, G. S.; Chen, W.; Srinivasan, S. R.] Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Bis, J. C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Chen, L. Y.] Univ Minnesota, Sch Med, Div Cardiovasc, Cardiac Arrhythmia Ctr, Minneapolis, MN 55455 USA. [Ellinor, P. T.; Lubitz, S. A.; Newton-Cheh, C.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ellinor, P. T.; Lubitz, S. A.; Newton-Cheh, C.] Harvard Univ, Sch Med, Boston, MA USA. [Ellinor, P. T.; Newton-Cheh, C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Evans, M. K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Ferrucci, L.] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Heckbert, S. R.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Hsueh, W. C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kerr, K. F.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Limacher, M. C.] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA. [Liu, Y.] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Magnani, J. W.] Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Magnani, J. W.] NHLBI, Framingham, MA USA. [Magnani, J. W.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Mehra, R.] Case Western Sch Med, Dept Med, Cleveland, OH USA. [Marcus, G. M.] Univ Calif San Francisco, Div Cardiol, Electrophysiol Sect, San Francisco, CA USA. [Murray, S. S.; Schork, N. J.] Scripps Translat Sci Inst, La Jolla, CA USA. [Murray, S. S.; Schork, N. J.] Scripps Res Inst, La Jolla, CA 92037 USA. [Newman, A. B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Njajou, O.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [North, K. E.] Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Paltoo, D. N.] NIH, Off Sci Policy, Off Director, Bethesda, MD 20892 USA. [Psaty, B. M.; Siscovick, D.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, B. M.; Siscovick, D.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, B. M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, B. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Redline, S. S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Sleep Med,Dept Hlth, Boston, MA 02115 USA. [Reiner, A. P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Robinson, J. G.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Rotter, J. I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Samdarshi, T. E.] Univ Mississippi, Sch Med, Jackson, MS 39216 USA. [Schnabel, R. B.] Univ Heart Ctr, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Singleton, A. B.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Soliman, E. Z.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Sotoodehnia, N.] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Taylor, H. A.] Univ Mississippi, Med Ctr, Dept Epidemiol, Jackson, MS 39216 USA. [Taylor, H. A.] Univ Mississippi, Med Ctr, Dept Prevent Med, Jackson, MS 39216 USA. [Trevisan, M.] CUNY City Coll, Sophie Davis Sch Biomed Educ, New York, NY USA. [Zhang, Z.] Wake Forest Sch Med, Epidemiol Cardiol Ctr EPICARE, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Zonderman, A. B.] NIA, Bethesda, MD 20892 USA. [Zonderman, A. B.] NIH Biomed Res Ctr, NIH Intramural Res Program, Baltimore, MD USA. [Whitsel, E. A.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. RP Deo, R (reprint author), Univ Penn, Div Cardiol, Electrophysiol Sect, 3400 Spruce St, Philadelphia, PA 19104 USA. EM Rajat.Deo@uphs.upenn.edu RI Singleton, Andrew/C-3010-2009; Alonso, Alvaro/A-4917-2010; Schnabel, Renate/F-6527-2014; Newman, Anne/C-6408-2013; Kerr, Kathleen/A-2893-2013; Buxbaum, Sarah/E-1970-2013; OI Zonderman, Alan B/0000-0002-6523-4778; Alonso, Alvaro/0000-0002-2225-8323; Newman, Anne/0000-0002-0106-1150; Buxbaum, Sarah/0000-0002-4886-3564; Mehra, Reena/0000-0002-6222-2675; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015]; 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]; University of North Carolina, Forsyth County [N01-HC-55018]; National Institutes of Health (NIB), National Institute on Aging (NIA); MedStar Research Institute; NIH/National Center for Research Resources (NCRR) [UL1 RR025774]; Scripps Genomic Medicine; National Institute of Child Health and Human Development [HD-061437, HD-062783]; NIA [AG-16592, AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; 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, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756, HL085251, N02-HL-64278]; National Institute of Neurological Disorders and Stroke (NINDS); National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NIH [HHSN268200782096C, K23DK089118]; NIH, NIA; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; NIH by the NHLIB [N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Center for Minority Health and Health Disparities; NHLBI, 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]; NIH/NIEHS [1-R01-ES017794]; NIH/NCI [N01-WH-2-2110]; NHLBI/NIH [R00HL098458]; Swedish Heart-Lung Foundation; [NIB HL 46380]; [M01RR00080]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95168]; [N01-HC95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95169]; [R01-HL-071205] FX The first 5 authors should be regarded as first authors. Atherosclerosis Risk in Communities (ARIC): The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts to the University of North Carolina at Chapel Hill (N01-HC-55015), 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), and University of North Carolina, Forsyth County (N01-HC-55018). Baltimore Longitudinal Study of Aging (BLSA): The BLSA was supported in part by the Intramural Research Program of the National Institutes of Health (NIB), National Institute on Aging (NIA). A portion of that support was through an R&D contract with MedStar Research Institute. Bogalusa Heart Study (BHS): Dr Smith, Dr Murray, and Dr Schork were supported in part by NIH/National Center for Research Resources (NCRR) grant number UL1 RR025774 and Scripps Genomic Medicine. The BHS was supported by grants HD-061437 and HD-062783 from the National Institute of Child Health and Human Development and AG-16592 from the NIA. Cleveland Family Study (CFS): This study was supported by grant to Case Western Reserve University (NIB HL 46380, M01RR00080). Cardiovascular Health Study (CHS): This 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, and HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, and HL085251 with additional contribution from National Institute of Neurological Disorders and Stroke (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 were 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. The Health, Aging, and Body Composition (Health ABC) study: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 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 NIH to Johns Hopkins University (contract number HHSN268200782096C). This research was supported in part by the Intramural Research Program of the NIH, NIA. The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study: This HANDLS study was supported by the Intramural Research Program of the NIH, NIA, and the National Center on Minority Health and Health Disparities (contract number Z01-AG000513 and human subjects protocol number 2009-149). Data analyses for the HANDLS study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov). Jackson Heart Study (JHS): This JHS was supported by NIH contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 provided by the NHLIB and the National Center for Minority Health and Health Disparities.; Multi-Ethnic Study of Atherosclerosis (MESA): This study was supported by grants to the University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC95163), 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), and University of Virginia (subcontract to R01-HL-071205). Women's Health Initiative (WHI): The WHI program is funded by the NHLBI, NIH, 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. This article was prepared in collaboration with the investigators of WHI and has been reviewed and/or approved by WHI. WHI investigators are listed at http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf. Funding for WHI SHARe genotyping was provided by NHLBI contract N02-HL-64278. Analyses in WHI were funded by the NIH/NIEHS (1-R01-ES017794, Whitsel) and the NIH/NCI (N01-WH-2-2110, North). Dr Deo was supported by K23DK089118 from the NIH. Dr Avery was partially supported by NHLBI/NIH grant R00HL098458. Dr Smith was supported by the Swedish Heart-Lung Foundation. Address reprint requests and correspondence: Dr Rajat Deo, Division of Cardiology, Electrophysiology Section, University of Pennsylvania, 3400 Spruce St, 9 Founders Cardiology, Philadelphia, PA 19104. E-mail address: Rajat.Deo@uphs.upenn.edu. NR 35 TC 10 Z9 10 U1 0 U2 13 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 MAR PY 2013 VL 10 IS 3 BP 401 EP 408 DI 10.1016/j.hrthm.2012.11.014 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 101KD UT WOS:000315773000017 PM 23183192 ER PT J AU Ajenifuja, KO Gage, JC Adepiti, AC Wentzensen, N Eklund, C Reilly, M Hutchinson, M Burk, RD Schiffman, M AF Ajenifuja, Kayode Olusegun Gage, Julia C. Adepiti, Akinfolarin C. Wentzensen, Nicolas Eklund, Claire Reilly, Mary Hutchinson, Martha Burk, Robert D. Schiffman, Mark TI A Population-Based Study of Visual Inspection With Acetic Acid (VIA) for Cervical Screening in Rural Nigeria SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Cervical cancer; VIA; Liquid-based cytology; HPV DNA; health workers ID GOLD STANDARD; CANCER; ACCURACY; INDIA AB Objective: Cervical cancer is the most common gynecological cancer in developing countries. Visual inspection with acetic acid (VIA) was introduced to screen for cervical premalignant lesions in developing countries owing to the inability of many countries to implement high-quality cytologic services. We sought to compare VIA performance among different health workers in Nigeria. Methods: In a population-based project, 7 health workers who had been screening women with VIA for approximately 2 years at local government health centers in rural Nigeria were retrained in a 2-week program using the International Agency for Research on Cancer training manual. Women from a rural village who had never had cervical cancer screening were recruited into the study. Each woman had cervical cancer screening by VIA, liquid-based cytologic test, and oncogenic human papillomavirus (HPV) DNA test. Results: Despite similar participant characteristics, across all age groups, providers had wide ranges of VIA results; 0% to 21% suspect cancer and 0% to 25% were VIA positive. Visual inspection with acetic acid was insensitive compared to a combination of cytologic and HPV tests. Conclusion: In our study, VIA was not reproducible, nor was it sensitive compared to cytologic and HPV tests. C1 [Ajenifuja, Kayode Olusegun; Adepiti, Akinfolarin C.] Obafemi Awolowo Univ, Dept Obstet Gynecol & Perinatol, Ife, Osun State, Nigeria. [Gage, Julia C.; Wentzensen, Nicolas; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Eklund, Claire; Reilly, Mary; Hutchinson, Martha] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Burk, Robert D.] Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Burk, Robert D.] Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Pediat, Bronx, NY 10461 USA. [Burk, Robert D.] Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Obstet, Bronx, NY 10461 USA. [Burk, Robert D.] Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Gynecol, Bronx, NY 10461 USA. [Burk, Robert D.] Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Womens Hlth & Epidemiol & Populat Hlth, Bronx, NY 10461 USA. RP Ajenifuja, KO (reprint author), Obafemi Awolowo Univ, Dept Obstet Gynecol & Perinatol, PMB 5538, Ife, Osun State, Nigeria. EM ajenifujako@yahoo.com FU Intramural NIH HHS [ZIA CP010206-01]; NCI NIH HHS [R01 CA078527, U01 CA078527] NR 25 TC 6 Z9 6 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD MAR PY 2013 VL 23 IS 3 BP 507 EP 512 DI 10.1097/IGC.0b013e318280f395 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 099EF UT WOS:000315602200018 PM 23354369 ER PT J AU Baker, SG Kramer, BS AF Baker, Stuart G. Kramer, Barnett S. TI Surrogate Endpoint Analysis: An Exercise in Extrapolation SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ADVANCED COLORECTAL-CANCER; RANDOMIZED CLINICAL-TRIALS; COMPARING 2 PROBABILITIES; FREE SURVIVAL; MIXED MODELS; VALIDATION; METAANALYSIS; BIOMARKERS; INFERENCE; CRITERIA AB Surrogate endpoints offer the hope of smaller or shorter cancer trials. It is, however, important to realize they come at the cost of an unverifiable extrapolation that could lead to misleading conclusions. With cancer prevention, the focus is on hypothesis testing in small surrogate endpoint trials before deciding whether to proceed to a large prevention trial. However, it is not generally appreciated that a small surrogate endpoint trial is highly sensitive to a deviation from the key Prentice criterion needed for the hypothesis-testing extrapolation. With cancer treatment, the focus is on estimation using historical trials with both surrogate and true endpoints to predict treatment effect based on the surrogate endpoint in a new trial. Successively leaving out one historical trial and computing the predicted treatment effect in the left-out trial yields a standard error multiplier that summarizes the increased uncertainty in estimation extrapolation. If this increased uncertainty is acceptable, three additional extrapolation issues (biological mechanism, treatment following observation of the surrogate endpoint, and side effects following observation of the surrogate endpoint) need to be considered. In summary, when using surrogate endpoint analyses, an appreciation of the problems of extrapolation is crucial. J Natl Cancer Inst; 2013;105:316-320 C1 [Baker, Stuart G.; Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 43 TC 9 Z9 9 U1 0 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 MAR PY 2013 VL 105 IS 5 BP 316 EP 320 DI 10.1093/jnci/djs527 PG 5 WC Oncology SC Oncology GA 103RV UT WOS:000315937500003 PM 23264679 ER PT J AU Arem, H Park, Y Pelser, C Ballard-Barbash, R Irwin, ML Hollenbeck, A Gierach, GL Brinton, LA Pfeiffer, RM Matthews, CE AF Arem, Hannah Park, Yikyung Pelser, Colleen Ballard-Barbash, Rachel Irwin, Melinda L. Hollenbeck, Albert Gierach, Gretchen L. Brinton, Louise A. Pfeiffer, Ruth M. Matthews, Charles E. TI Prediagnosis Body Mass Index, Physical Activity, and Mortality in Endometrial Cancer Patients SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; NIH-AARP DIET; SEDENTARY BEHAVIOR; DIABETES-MELLITUS; PROGNOSTIC-FACTOR; OBESITY; SURVIVAL; DISEASE; HEALTH; RISK AB Background Higher body mass index (BMI) and inactivity have been associated with a higher risk of developing endometrial cancer, but the impact on endometrial cancer survival is unclear. Methods Among incident endometrial cancer case subjects in the National Institutes of Health-AARP Diet and Health Study, we examined associations of prediagnosis BMI (n = 1400) and physical activity (n = 875) with overall and diseasespecific 5- and 10-year mortality. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for tumor characteristics, treatment, and other risk factors. All statistical tests were two-sided. Results Compared with women with a BMI in the range of 18.5 to less than 25 kg/m(2), the hazard ratios for 5-year all-cause mortality were 1.74 (95% CI = 1.13 to 2.66) for BMI in the range of 25 to less than 30 kg/m2, 1.84 (95% CI = 1.17 to 2.88) for BMI in the range of 30 to less than 35 kg/m(2), and 2.35 (95% CI = 1.48 to 3.73) for BMI greater than or equal to 35 kg/m(2) (P-trend < .001). Higher BMI was also statistically significantly associated with poorer endometrial cancer-specific but not cardiovascular disease 5-year mortality. Hazard ratio estimates for 10-year all-cause and endometrial cancer-specific mortality as related to BMI were similar to 5-year hazard ratio estimates, whereas 10-year cardiovascular disease mortality became statistically significant (HR = 4.08; 95% CI = 1.56 to 10.71 comparing extreme BMI groups). More physical activity was related to lower all-cause 5-year mortality (HR = 0.57, 95% CI = 0.33 to 0.98 for >7 hours/week vs never/rarely), but the association was attenuated after adjustment for BMI (HR = 0.64, 95% CI = 0.37 to 1.12). No association was observed between physical activity and disease-specific mortality. Conclusions Our findings suggest that higher prediagnosis BMI increases risk of overall and disease-specific mortality among women diagnosed with endometrial cancer, whereas physical activity lowers risk. Intervention studies of the effect of these modifiable lifestyle factors on mortality are needed. J Natl Cancer Inst; 2013;105:342-349 C1 [Arem, Hannah; Irwin, Melinda L.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Irwin, Melinda L.] Yale Canc Ctr, New Haven, CT USA. [Arem, Hannah; Park, Yikyung; Pelser, Colleen; Gierach, Gretchen L.; Brinton, Louise A.; Pfeiffer, Ruth M.; Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Arem, H (reprint author), 6120 Execut Blvd,EPS 3029, Rockville, MD 20852 USA. EM aremhe2@mail.nih.gov RI matthews, Charles/E-8073-2015; Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016; OI matthews, Charles/0000-0001-8037-3103; Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522; Park, Yikyung/0000-0002-6281-489X FU Yale-National Cancer Institute [T32 CA105666]; National Cancer Institute at the National Institutes of Health; Florida Department of Health FX This work was supported in part by a Yale-National Cancer Institute predoctoral training grant (T32 CA105666). This research was also supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health.; Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract with the Florida Department of Health. The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or the Department of Health. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Center for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. NR 35 TC 32 Z9 32 U1 0 U2 14 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 MAR PY 2013 VL 105 IS 5 BP 342 EP 349 DI 10.1093/jnci/djs530 PG 8 WC Oncology SC Oncology GA 103RV UT WOS:000315937500006 PM 23297041 ER PT J AU Silverberg, MJ Leyden, W Warton, EM Quesenberry, CP Engels, EA Asgari, MM AF Silverberg, Michael J. Leyden, Wendy Warton, E. Margaret Quesenberry, Charles P., Jr. Engels, Eric A. Asgari, Maryam M. TI HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ORGAN TRANSPLANT RECIPIENTS; ACTIVE ANTIRETROVIRAL THERAPY; AIDS-DEFINING CANCERS; HUMAN-PAPILLOMAVIRUS; IMMUNOCOMPETENT INDIVIDUALS; POSITIVE INDIVIDUALS; UNITED-STATES; RISK-FACTORS; PHOTOSENSITIVITY AB Background The incidence of non-melanoma skin cancers (NMSCs), including basal cell (BCC) or squamous cell carcinoma (SCC), is not well documented among HIV-positive (HIV+) individuals. Methods We identified 6560 HIV+ and 36 821 HIV(-)negative (HIV-) non-Hispanic white adults who were enrolled and followed up in Kaiser Permanente Northern California from 1996 to 2008. The first biopsy-proven NMSCs diagnosed during follow-up were identified from pathology records. Poisson models estimated rate ratios that compared HIV+ (overall and stratified by recent CD4 T-cell counts and serum HIV RNA levels) with HIV(-)subjects and were adjusted for age, sex, smoking history, obesity diagnosis history, and census-based household income. Sensitivity analyses were adjusted for outpatient visits (ie, a proxy for screening). All statistical tests were two-sided. Results The NMSC incidence rate was 1426 and 766 per 100 000 person-years for HIV+ and HIV- individuals, respectively, which corresponds with an adjusted rate ratio of 2.1 (95% confidence interval [CI] = 1.9 to 2.3). Similarly, the adjusted rate ratio for HIV+ vs HIV- subjects was 2.6 (95% CI = 2.1 to 3.2) for SCCs, and it was 2.1 (95% CI = 1.8 to 2.3) for BCCs. There was a statistically significant trend of higher rate ratios with lower recent CD4 counts among HIV+ subjects compared with HIV- subjects for SCCs (P-trend < .001). Adjustment for number of outpatient visits did not affect the results. Conclusion HIV+ subjects had a twofold higher incidence rate of NMSCs compared with HIV(-)subjects. SCCs but not BCCs were associated with immunodeficiency. J Natl Cancer Inst; 2013;105:350-360 C1 [Silverberg, Michael J.; Leyden, Wendy; Warton, E. Margaret; Quesenberry, Charles P., Jr.; Asgari, Maryam M.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Silverberg, MJ (reprint author), Kaiser Permanente, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM michael.j.silverberg@kp.org RI Asgari, Maryam/O-4947-2016 FU Pfizer Inc.; Kaiser Permanente Northern California Community; National Institute of Allergy and Infectious Diseases at the National Institutes of Health [K01AI071725]; National Cancer Institute; Pfizer; Merck FX This work was supported by research grants from Pfizer Inc. and Kaiser Permanente Northern California Community benefits. MJS was supported by a grant from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (K01AI071725). EAE was supported by the Intramural Research Program of the National Cancer Institute.; Study authors have received research funding from Pfizer (M. J. Silverberg, W. Leyden, C. P. Quesenberry) and Merck (M. J. Silverberg, C. P. Quesenberry). NR 54 TC 42 Z9 44 U1 0 U2 6 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 MAR PY 2013 VL 105 IS 5 BP 350 EP 360 DI 10.1093/jnci/djs529 PG 11 WC Oncology SC Oncology GA 103RV UT WOS:000315937500007 PM 23291375 ER PT J AU Mizesko, MC Banerjee, PP Monaco-Shawver, L Mace, EM Bernal, WE Sawalle-Belohradsky, J Belohradsky, BH Heinz, V Freeman, AF Sullivan, KE Holland, SM Torgerson, TR Al-Herz, W Chou, J Hanson, IC Albert, MH Geha, RS Renner, ED Orange, JS AF Mizesko, Melissa C. Banerjee, Pinaki P. Monaco-Shawver, Linda Mace, Emily M. Bernal, William E. Sawalle-Belohradsky, Julie Belohradsky, Bernd H. Heinz, Valerie Freeman, Alexandra F. Sullivan, Kathleen E. Holland, Steven M. Torgerson, Troy R. Al-Herz, Waleed Chou, Janet Hanson, Imelda C. Albert, Michael H. Geha, Raif S. Renner, Ellen D. Orange, Jordan S. TI Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE DOCK8 deficiency; natural killer cells; actin; cytotoxicity; immunologic synapse ID HYPER-IGE SYNDROME; IMMUNOLOGICAL SYNAPSE; DOCK8 DEFICIENCY; LYTIC GRANULES; F-ACTIN; CYTOTOXICITY; CDC42; POLARIZATION; MUTATIONS; TRANSPLANTATION AB Background: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. Objectives: We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. Methods: A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. Results: DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. Conclusions: DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy. (J Allergy Clin Immunol 2013; 131:840-8.) C1 [Mizesko, Melissa C.; Banerjee, Pinaki P.; Mace, Emily M.; Hanson, Imelda C.; Orange, Jordan S.] Baylor Coll Med, Houston, TX 77030 USA. [Mizesko, Melissa C.; Banerjee, Pinaki P.; Mace, Emily M.; Hanson, Imelda C.; Orange, Jordan S.] Texas Childrens Hosp, Houston, TX 77030 USA. [Monaco-Shawver, Linda; Bernal, William E.; Sullivan, Kathleen E.] Childrens Hosp Philadelphia, Res Inst, Philadelphia, PA USA. [Sawalle-Belohradsky, Julie; Belohradsky, Bernd H.; Heinz, Valerie; Albert, Michael H.; Renner, Ellen D.] Univ Munich, Univ Childrens Hosp, Munich, Germany. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, NIH, Bethesda, MD 20892 USA. [Torgerson, Troy R.] Univ Washington, Seattle, WA 98195 USA. [Torgerson, Troy R.] Seattle Childrens Hosp, Seattle, WA USA. [Al-Herz, Waleed] Kuwait Univ, Dept Pediat, Fac Med, Kuwait, Kuwait. [Chou, Janet; Geha, Raif S.] Boston Childrens Hosp, Boston, MA USA. RP Orange, JS (reprint author), Texas Childrens Hosp, Baylor Coll Med, 1102 Bates Ave,Suite 330, Houston, TX 77030 USA. EM orange@bcm.edu OI Sullivan, Kathleen/0000-0003-4018-1646; orange, jordan/0000-0001-7117-7725 FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases [R01067946]; German Research Foundation [DFG RE2799/3-1]; Fritz-Thyssen research foundation [Az. 10.07.1.159]; Dubai-Harvard Foundation of Medical Research; Jeffrey Modell Foundation; National Institutes of Health (NIH); Fritz-Thyssen Foundation; [5P01AI076210-04]; [5R03AI094017-02] FX Supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grant R01067946 (to J.S.O.), the German Research Foundation (DFG RE2799/3-1) and a Fritz-Thyssen research foundation grant (Az. 10.07.1.159; to E. D. R.); and the Dubai-Harvard Foundation of Medical Research, the Jeffrey Modell Foundation, "Role of TACI Mutations in CVID," 5P01AI076210-04, NIH, and "Combined SNP analysis and whole genome sequencing to discover immunodeficiency genes," 5R03AI094017-02, NIH (to R.S.G.).; Disclosure of potential conflict of interest: M. C. Mizesko has received grants from the National Institutes of Health (NIH). L. Monaco-Shawver has received grants from the NIH. T. R. Torgerson has consulted for Baxter Biosciences; has grants/grants pending from Baxter Biosciences and CSL Behring; has received payment for lectures, including service on speakers' bureaus for Baxter Biosciences; has received royalties from New England Biolabs; and has received payment for development of Educational Presentations from Baxter Biosciences. J. Chou is employed by Boston Children's Hospital and has grants/grants pending from the NIH. R. S. Geha has received grants from the NIH. E. D. Renner has received grant money from DFG and the Fritz-Thyssen Foundation. J. S. Orange has received grants from the NIH; has consulted for Baxter Biosciences on lg therapies, CSL Bhering on lg therapies, Grifols on lg therapies, Octapharma USA on the Grants Review Committee, Cangene on lg therapy, and IBT reference laboratories on immunology; has received payment for lectures, including service on speakers' bureaus for Baxter Healthcare; has received royalties from Unimed Publishers for a book on immunoglobulins; and has received payment for development of educational presentations from CSL Bhering for a presentation on lg therapy. The rest of the authors declare that they have no relevant conflicts of interest. NR 38 TC 45 Z9 45 U1 0 U2 4 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 MAR PY 2013 VL 131 IS 3 BP 840 EP 848 DI 10.1016/j.jaci.2012.12.1568 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 098ZM UT WOS:000315587800028 PM 23380217 ER PT J AU Theis, T Mishra, B von der Ohe, M Loers, G Prondzynski, M Pless, O Blackshear, PJ Schachner, M Kleene, R AF Theis, Thomas Mishra, Bibhudatta von der Ohe, Maren Loers, Gabriele Prondzynski, Maksymilian Pless, Ole Blackshear, Perry J. Schachner, Melitta Kleene, Ralf TI Functional Role of the Interaction between Polysialic Acid and Myristoylated Alanine-rich C Kinase Substrate at the Plasma Membrane SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-ADHESION MOLECULE; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; MICE DEFICIENT; PSA-NCAM; PHOSPHOLIPID-MEMBRANES; CALMODULIN-BINDING; NEURITE OUTGROWTH; MARCKS DEFICIENCY; MUTANT MICE AB Polysialic acid (PSA) is a homopolymeric glycan that plays crucial roles in the developing and adult nervous system. So far only a few PSA-binding proteins have been identified. Here, we identify myristoylated alanine-rich C kinase substrate (MARCKS) as novel PSA binding partner. Binding assays showed a direct interaction between PSA and a peptide comprising the effector domain of MARCKS (MARCKS-ED). Co-immunoprecipitation of PSA-carrying neural cell adhesion molecule (PSA-NCAM) with MARCKS and co-immunostaining of MARCKS and PSA at the cell membrane of hippocampal neurons confirm the interaction between PSA and MARCKS. Co-localization and an intimate interaction of PSA and MARCKS at the cell surface was seen by confocal microscopy and fluorescence resonance energy transfer (FRET) analysis after the addition of fluorescently labeled PSA or PSA-NCAM to live CHO cells or hippocampal neurons expressing MARCKS as a fusion protein with green fluorescent protein (GFP). Cross-linking experiments showed that extracellularly applied PSA or PSA-NCAM and intracellularly expressed MARCKS-GFP are in close contact, suggesting that PSA and MARCKS interact with each other at the plasma membrane from opposite sides. Insertion of PSA and MARCKS-ED peptide into lipid bilayers from opposite sides alters the electric properties of the bilayer confirming the notion that PSA and the effector domain of MARCKS interact at and/or within the plane of the membrane. The MARCKS-ED peptide abolished PSA-induced enhancement of neurite outgrowth from cultured hippocampal neurons indicating an important functional role for the interaction between MARCKS and PSA in the developing and adult nervous system. C1 [Theis, Thomas; Mishra, Bibhudatta; von der Ohe, Maren; Loers, Gabriele; Schachner, Melitta; Kleene, Ralf] Univ Klinikum Hamburg Eppendorf, Zentrum Mol Neurobiol, D-20246 Hamburg, Germany. [Schachner, Melitta] Rutgers State Univ, Keck Ctr Collaborat Neurosci, Piscataway, NJ 08854 USA. [Schachner, Melitta] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA. [Schachner, Melitta] Shantou Univ, Ctr Neurosci, Coll Med, Shantou 515041, Peoples R China. [Blackshear, Perry J.] Duke Univ, Dept Med, Durham, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Dept Biochem, Durham, NC 27709 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Prondzynski, Maksymilian; Pless, Ole] European Screening Port GmbH, D-22525 Hamburg, Germany. RP Schachner, M (reprint author), Shantou Univ, Ctr Neurosci, Coll Med, 22 Xin Ling Rd, Shantou 515041, Peoples R China. EM schachner@stu.edu.cn RI Pless, Ole/E-8348-2016 OI Pless, Ole/0000-0002-1468-316X FU New Jersey Commission for Spinal Cord Research FX Supported by the New Jersey Commission for Spinal Cord Research and a consultant at the Center for Neuroscience at Shantou University Medical College, China. To whom correspondence should be addressed: Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou 515041, China. Tel.: 86-754-88900276; Fax: 86 754 88900236; E-mail: schachner@stu.edu.cn. NR 72 TC 14 Z9 16 U1 4 U2 21 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 1 PY 2013 VL 288 IS 9 BP 6726 EP 6742 DI 10.1074/jbc.M112.444034 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 102CJ UT WOS:000315820700070 PM 23329829 ER PT J AU Jalah, R Rosati, M Ganneru, B Pilkington, GR Valentin, A Kulkarni, V Bergamaschi, C Chowdhury, B Zhang, GM Beach, RK Alicea, C Broderick, KE Sardesai, NY Pavlakis, GN Felber, BK AF Jalah, Rashmi Rosati, Margherita Ganneru, Brunda Pilkington, Guy R. Valentin, Antonio Kulkarni, Viraj Bergamaschi, Cristina Chowdhury, Bhabadeb Zhang, Gen-Mu Beach, Rachel Kelly Alicea, Candido Broderick, Kate E. Sardesai, Niranjan Y. Pavlakis, George N. Felber, Barbara K. TI The p40 Subunit of Interleukin (IL)-12 Promotes Stabilization and Export of the p35 Subunit IMPLICATIONS FOR IMPROVED IL-12 CYTOKINE PRODUCTION SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL STIMULATORY FACTOR; PLASMID DNA VACCINE; HUMORAL IMMUNE-RESPONSES; IN-VIVO; RECEPTOR-ALPHA; GENE-THERAPY; IL-12 FAMILY; INTRATUMORAL INJECTION; SOLUBLE IL-15R-ALPHA AB IL-12 is a 70-kDa heterodimeric cytokine composed of the p35 and p40 subunits. To maximize cytokine production from plasmid DNA, molecular steps controlling IL-12p70 biosynthesis at the posttranscriptional and posttranslational levels were investigated. We show that the combination of RNA/codon-optimized gene sequences and fine-tuning of the relative expression levels of the two subunits within a cell resulted in increased production of the IL-12p70 heterodimer. We found that the p40 subunit plays a critical role in enhancing the stability, intracellular trafficking, and export of the p35 subunit. This posttranslational regulation mediated by the p40 subunit is conserved in mammals. Based on these findings, dual gene expression vectors were generated, producing an optimal ratio of the two subunits, resulting in a similar to 1 log increase in human, rhesus, and murine IL-12p70 production compared with vectors expressing the wild type sequences. Such optimized DNA plasmids also produced significantly higher levels of systemic bioactive IL-12 upon in vivo DNA delivery in mice compared with plasmids expressing the wild type sequences. A single therapeutic injection of an optimized murine IL-12 DNA plasmid showed significantly more potent control of tumor development in the B16 melanoma cancer model in mice. Therefore, the improved IL-12p70 DNA vectors have promising potential for in vivo use as molecular vaccine adjuvants and in cancer immunotherapy. C1 [Zhang, Gen-Mu; Beach, Rachel Kelly; Alicea, Candido; Felber, Barbara K.] Frederick Natl Lab Canc Res, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Rosati, Margherita; Ganneru, Brunda; Valentin, Antonio; Bergamaschi, Cristina; Chowdhury, Bhabadeb; Zhang, Gen-Mu; Beach, Rachel Kelly; Pavlakis, George N.] Frederick Natl Lab Canc Res, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Broderick, Kate E.; Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA 19422 USA. RP Felber, BK (reprint author), Frederick Natl Lab Canc Res, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. EM felberb@mail.nih.gov RI bebarta, vikhyat/K-3476-2015 FU National Institutes of Health, NCI, Intramural Research Program FX This work was supported, in whole or in part, by the National Institutes of Health, NCI, Intramural Research Program. NR 68 TC 26 Z9 27 U1 0 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 1 PY 2013 VL 288 IS 9 BP 6763 EP 6776 DI 10.1074/jbc.M112.436675 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 102CJ UT WOS:000315820700073 PM 23297419 ER PT J AU Xi, SC Xu, H Shan, JG Tao, YG Hong, JA Inchauste, S Zhang, M Kunst, TF Mercedes, L Schrump, DS AF Xi, Sichuan Xu, Hong Shan, Jigui Tao, Yongguang Hong, Julie A. Inchauste, Suzanne Zhang, Mary Kunst, Tricia F. Mercedes, Leandro Schrump, David S. TI Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CELL LUNG-CANCER; TRANSFORMING GROWTH-FACTOR-BETA-1 LEVEL; DNA METHYLATION; GENE-EXPRESSION; PROGNOSTIC MARKER; STEM-CELLS; MICRORNA; CHROMATIN; GENOME; SEQUENCES AB MicroRNAs are critical mediators of stem cell pluripotency, differentiation, and malignancy. Limited information exists regarding microRNA alterations that facilitate initiation and progression of human lung cancers. In this study, array techniques were used to evaluate microRNA expression in normal human respiratory epithelia and lung cancer cells cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly repressed miR-487b. Subsequent experiments demonstrated that miR-487b directly targeted SUZ12, BMI1, WNT5A, MYC, and KRAS. Repression of miR-487b correlated with overexpression of these targets in primary lung cancers and coincided with DNA methylation, de novo nucleosome occupancy, and decreased H2AZ and TCF1 levels within the miR-487b genomic locus. Deoxyazacytidine derepressed miR-487b and attenuated CSC-mediated silencing of miR-487b. Constitutive expression of miR-487b abrogated Wnt signaling, inhibited in vitro proliferation and invasion of lung cancer cells mediated by CSC or overexpression of miR-487b targets, and decreased growth and metastatic potential of lung cancer cells in vivo. Collectively, these findings indicate that miR-487b is a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis and suggest that DNA demethylating agents may be useful for activating miR-487b for lung cancer therapy. C1 [Xi, Sichuan; Hong, Julie A.; Inchauste, Suzanne; Zhang, Mary; Kunst, Tricia F.; Mercedes, Leandro; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Xu, Hong; Tao, Yongguang] NCI, Lab Canc Prevent, Frederick, MD 21701 USA. [Shan, Jigui] NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD 21701 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, 10 Ctr Dr,Room 4-3942, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov FU NCI Intramural grants [ZIA BC 011122, ZIA BC 011418]; Steven J. Solarz Memorial Fund FX The authors express their gratitude to Jan Pappas for assistance regarding manuscript preparation. This work was supported by NCI Intramural grants ZIA BC 011122 (to D.S. Schrump) and ZIA BC 011418 (to D.S. Schrump) as well as the Steven J. Solarz Memorial Fund. NR 69 TC 38 Z9 41 U1 0 U2 18 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 MAR PY 2013 VL 123 IS 3 BP 1241 EP 1261 DI 10.1172/JCI61271 PG 21 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 101BE UT WOS:000315749400035 PM 23426183 ER PT J AU Zoon, KC AF Zoon, Kathryn C. TI Ernest (Pete) Knight Jr. (1932-2013) A Remembrance to a Great Interferon Scientist and Colleague IN MEMORIAM SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Biographical-Item C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 1 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 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD MAR PY 2013 VL 33 IS 3 BP 97 EP 98 DI 10.1089/jir.2013.1500 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 105FM UT WOS:000316051700001 PM 23477599 ER PT J AU Cecere, MC Vazquez-Prokopec, GM Ceballos, LA Boragno, S Zarate, JE Kitron, U Gurtler, RE AF Carla Cecere, Maria Vazquez-Prokopec, Gonzalo M. Ceballos, Leonardo A. Boragno, Silvana Zarate, Joaquin E. Kitron, Uriel Guertler, Ricardo E. TI Improved Chemical Control of Chagas Disease Vectors in the Dry Chaco Region SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE vector control; Chaco; pyrethroid; insecticide; Chagas disease ID RURAL NORTHWESTERN ARGENTINA; TRIATOMA-INFESTANS HEMIPTERA; PERIDOMESTIC POPULATIONS; PYRETHROID INSECTICIDES; DOMESTIC REINFESTATION; GRAN CHACO; REDUVIIDAE; COMMUNITY; HOUSES; DELTAMETHRIN AB The effectiveness of two doses of suspension concentrate (SC) pyrethroid insecticides in suppressing peridomestic populations of Triatoma infestans (Klug) was evaluated in 28 rural communities located in Santiago del Estero province, northwestern Argentina, including 388 houses and 1,516 identified sites. Four treatments were randomly assigned to peridomiciles within each community: 5% SC beta-cypermethrin at standard (S, 50 mg active ingredient [AI]/m(2)) and double dose (2S), and 2.5% SC deltamethrin at standard (D, 25 mg [AI]/m(2)) and double dose (2D). Simultaneously, we assessed the effects of both pyrethroids applied at standard doses against domestic infestations. Bug infestation at the site level was assessed by timed manual collections with a dislodging agent at baseline, 13 and 21 mo postspraying (MPS). In domiciles, D and S nearly suppressed all T. infestans infestations up to 21 MPS. In peridomestic sites infested before interventions, multiple logistic regression analysis showed that site-level reinfestation at 13 MPS was significantly lower for treatment 2D (1%) than for other treatments, whereas 2S (6%), D (5%), and S (14%) did not differ significantly between them. The risk of reinfestation after spraying was significantly greater in goat or pig corrals than in other peridomestic ecotopes (in which treatments did not differ significantly), and in sites infested before interventions than in uninfested sites. The application of SC deltamethrin at double dose in goat or pig corrals may suppress T. infestans foci and achieve more sustained effects in the dry Chaco. C1 [Carla Cecere, Maria; Ceballos, Leonardo A.; Boragno, Silvana; Guertler, Ricardo E.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Ecol Genet & Evoluc, Lab Ecoepidemiol, Buenos Aires, DF, Argentina. [Vazquez-Prokopec, Gonzalo M.; Kitron, Uriel] Emory Univ, Dept Environm Studies, Math & Sci Ctr, Atlanta, GA 30322 USA. [Vazquez-Prokopec, Gonzalo M.; Kitron, Uriel] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Zarate, Joaquin E.] Programa Nacl Control Vectores, RA-1971 San Miguel De Tucuman, Tucuman, Argentina. RP Cecere, MC (reprint author), Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Ecol Genet & Evoluc, Lab Ecoepidemiol, Intendente Guiraldes 2160,Ciudad Univ,C1428EGA, Buenos Aires, DF, Argentina. EM carla@ege.fcen.uba.ar FU Fundacion Bunge y Born (Argentina); National Institutes of Health/National Science Foundation Ecology of Infectious Disease program award [R01TW05836]; Fogarty International Center; National Institute of Environmental Health Sciences; University of Buenos Aires; United Nations Development Programme/World Bank/World Health Organization/Training in Tropical Diseases [A70596]; International Development Research Centre [103696-009] FX In memory of Joaquin Zarate. We thank the staff of the National Vector Control Program at Tucuman and Cordoba, Diego Glaser, Leonardo Lanati, Silvana Ferreyra, and Mariana Carro for providing active support during fieldwork and data entry; residents of the communities for their participation; Padre Sergio, Sara, and Tuki families of Bandera Bajada, Moyano and Citati families of Amama, and the families from Libertad for field accommodation. This study was supported by awards from Fundacion Bunge y Born (Argentina) to M.C.C., the National Institutes of Health/National Science Foundation Ecology of Infectious Disease program award R01TW05836 funded by the Fogarty International Center and the National Institute of Environmental Health Sciences to U.K. and R.E.G, and the University of Buenos Aires to R.E.G. The participation of R.E.G. was also supported by United Nations Development Programme/World Bank/World Health Organization/Training in Tropical Diseases (grant A70596) and International Development Research Centre (grant 103696-009). M.C.C. and R.E.G. are members of Consejo Nacional de Investigaciones Cientificas Y Tecnicas (CONICET) Researcher's Career. NR 40 TC 13 Z9 13 U1 2 U2 10 PU ENTOMOLOGICAL SOC AMER PI LANHAM PA 10001 DEREKWOOD LANE, STE 100, LANHAM, MD 20706-4876 USA SN 0022-2585 EI 1938-2928 J9 J MED ENTOMOL JI J. Med. Entomol. PD MAR PY 2013 VL 50 IS 2 BP 394 EP 403 DI 10.1603/ME12109 PG 10 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 104MK UT WOS:000315997300025 PM 23540129 ER PT J AU Smith, DH Hicks, R Povlishock, JT AF Smith, Douglas H. Hicks, Ramona Povlishock, John T. TI Therapy Development for Diffuse Axonal Injury SO JOURNAL OF NEUROTRAUMA LA English DT Review DE animal models of injury; axonal injury; non-invasive detection methods; therapeutic targeting; traumatic brain injury ID TRAUMATIC BRAIN-INJURY; ALPHA-II-SPECTRIN; PIG OPTIC-NERVE; COMMON DATA ELEMENTS; CONTROLLED CORTICAL IMPACT; AMYLOID PRECURSOR PROTEIN; C-TERMINAL HYDROLASE; IN-VIVO MODEL; CALPAIN INHIBITOR MDL-28170; FLUID-PERCUSSION MODEL AB Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled. C1 [Smith, Douglas H.] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Hicks, Ramona] NINDS, NIH, Bethesda, MD 20892 USA. [Povlishock, John T.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Coll Med, Richmond, VA 23298 USA. RP Povlishock, JT (reprint author), Virginia Commonwealth Univ, Med Ctr, Dept Anat & Neurobiol, POB 980709, Richmond, VA 23298 USA. EM jtpovlis@vcu.edu FU National Institute of Neurological Disorders and Stroke FX We gratefully acknowledge the contributions that were made by all participants during the workshop discussion. Special thanks are extended to Drs. Elizabeth Wilde, Kevin Wang, and Roger Siman, for their critical input into some of the sections focusing on the noninvasive detection of DAI. Lastly, additional thanks are extended to Dr. Carole Christman for her critical review and editing of the manuscript and her preparation of Figures 2 and 3. Support for this workshop was provided by the National Institute of Neurological Disorders and Stroke. NR 194 TC 36 Z9 42 U1 0 U2 35 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR PY 2013 VL 30 IS 5 BP 307 EP 323 DI 10.1089/neu.2012.2825 PG 17 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 103CI UT WOS:000315891600001 PM 23252624 ER PT J AU Johnson, KA Minoshima, S Bohnen, NI Donohoe, KJ Foster, NL Herscovitch, P Karlawish, JH Rowe, CC Carrillo, MC Hartley, DM Hedrick, S Pappas, V Thies, WH AF Johnson, Keith A. Minoshima, Satoshi Bohnen, Nicolaas I. Donohoe, Kevin J. Foster, Norman L. Herscovitch, Peter Karlawish, Jason H. Rowe, Christopher C. Carrillo, Maria C. Hartley, Dean M. Hedrick, Saima Pappas, Virginia Thies, William H. TI Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE guidelines; AUC; imaging; amyloid; MCI; Alzheimer's; PET; florbetapir; biomarker; beta-amyloid; dementia; radiopharmaceutical ID PITTSBURGH COMPOUND-B; POSITRON-EMISSION-TOMOGRAPHY; MILD COGNITIVE IMPAIRMENT; NATIONAL INSTITUTE; FDG-PET; A-BETA; NEUROPATHOLOGIC ASSESSMENT; DIFFERENTIAL-DIAGNOSIS; VASCULAR DEMENTIA; C-11-PIB PET AB Positron emission tomography (PET) of brain amyloid b is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. To provide guidance to dementia care practitioners, patients, and caregivers, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be used appropriately. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific appropriate use criteria (AUC) were agreed on that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated, and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes. C1 [Johnson, Keith A.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Johnson, Keith A.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Minoshima, Satoshi] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Bohnen, Nicolaas I.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Bohnen, Nicolaas I.] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Bohnen, Nicolaas I.] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Donohoe, Kevin J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Foster, Norman L.] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Herscovitch, Peter] NIH, PET Dept, NIH Clin Ctr, Bethesda, MD 20892 USA. [Karlawish, Jason H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Rowe, Christopher C.] Austin Hlth, Dept Nucl Med, Heidelberg, Vic, Australia. [Rowe, Christopher C.] Austin Hlth, Ctr PET, Heidelberg, Vic, Australia. [Carrillo, Maria C.; Hartley, Dean M.; Thies, William H.] Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60601 USA. [Hedrick, Saima; Pappas, Virginia] Soc Nucl Med & Mol Imaging, Reston, VA USA. RP Carrillo, MC (reprint author), Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60601 USA. EM maria.carrillo@alz.org NR 80 TC 68 Z9 70 U1 1 U2 35 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAR 1 PY 2013 VL 54 IS 3 BP 476 EP 490 DI 10.2967/jnumed.113.120618 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 099PA UT WOS:000315632500045 PM 23359661 ER PT J AU Calzone, KA Jenkins, J Nicol, N Skirton, H Feero, WG Green, ED AF Calzone, Kathleen A. Jenkins, Jean Nicol, Nick Skirton, Heather Feero, W. Gregory Green, Eric D. TI Relevance of Genomics to Healthcare and Nursing Practice SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Editorial Material ID MEDICINE C1 [Calzone, Kathleen A.] NCI, NIH, Bethesda, MD 20892 USA. [Jenkins, Jean; Feero, W. Gregory; Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Nicol, Nick] Univ Coll Learning, Palmerston North, New Zealand. [Skirton, Heather] Univ Plymouth, Taunton, Somerset, England. RP Calzone, KA (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM calzonek@mail.nih.gov OI Skirton, Heather/0000-0002-3639-5265 NR 9 TC 14 Z9 14 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD MAR PY 2013 VL 45 IS 1 BP 1 EP 2 DI 10.1111/j.1547-5069.2012.01464.x PG 2 WC Nursing SC Nursing GA 099RV UT WOS:000315639800001 PM 23368676 ER PT J AU Conley, YP Biesecker, LG Gonsalves, S Merkle, CJ Kirk, M Aouizerat, BE AF Conley, Yvette P. Biesecker, Leslie G. Gonsalves, Stephen Merkle, Carrie J. Kirk, Maggie Aouizerat, Bradley E. TI Current and Emerging Technology Approaches in Genomics SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Genetics; genomics; next generation sequencing; genome-wide association studies; epigenomics; gene expression; nursing ID GENE-EXPRESSION; CLINICAL-APPLICATIONS; CLINSEQ PROJECT; BREAST-CANCER; WHOLE EXOME; MEDICINE; DIAGNOSTICS; PHENOTYPES AB Purpose: To introduce current and emerging approaches that are being utilized in the field of genomics so the reader can conceptually evaluate the literature and appreciate how these approaches are advancing our understanding of health-related issues. Organizing Construct: Each approach is described and includes information related to how it is advancing research, its potential clinical utility, exemplars of current uses, challenges related to technologies used for these approaches, and when appropriate information related to understanding the evidence base for clinical utilization of each approach is provided. Web-based resources are included for the reader who would like more in-depth information and to provide opportunity to stay up to date with these approaches and their utility. Conclusions: The chosen approachesgenome sequencing, genome-wide association studies, epigenomics, and gene expressionare extremely valuable approaches for collecting research data to help us better understand the pathophysiology of a variety of health-related conditions, but they are also gaining in utility for clinical assessment and testing purposes. Clinical Relevance: Our increased understanding of the molecular underpinnings of disease will assist with better development of screening tests, diagnostic tests, tests that allow us to prognosticate, tests that allow for individualized treatments, and tests to facilitate post-treatment surveillance. C1 [Conley, Yvette P.] Univ Pittsburgh, Pittsburgh, PA 15261 USA. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Gonsalves, Stephen] NHGRI, NIH, Bethesda, MD 20892 USA. [Merkle, Carrie J.] Univ Arizona, Tucson, AZ USA. [Kirk, Maggie] Univ Glamorgan, NHS Natl Genet Educ & Dev Ctr, Pontypridd CF37 1DL, M Glam, Wales. [Aouizerat, Bradley E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Conley, YP (reprint author), Univ Pittsburgh, 3500 Victoria St,440 Victoria Bldg, Pittsburgh, PA 15261 USA. EM yconley@pitt.edu RI Kirk, Maggie/G-9333-2012 OI Kirk, Maggie/0000-0003-1745-7106 FU Intramural NIH HHS [ZIA HG200359-05]; NIDDK NIH HHS [P30 DK026743] NR 43 TC 12 Z9 12 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD MAR PY 2013 VL 45 IS 1 BP 5 EP 14 DI 10.1111/jnu.12001 PG 10 WC Nursing SC Nursing GA 099RV UT WOS:000315639800003 PM 23294727 ER PT J AU Calzone, KA Jenkins, J Bakos, AD Cashion, AK Donaldson, N Feero, WG Feetham, S Grady, PA Hinshaw, AS Knebel, AR Robinson, N Ropka, ME Seibert, D Stevens, KR Tully, LA Webb, JA AF Calzone, Kathleen A. Jenkins, Jean Bakos, Alexis D. Cashion, Ann K. Donaldson, Nancy Feero, W. Gregory Feetham, Suzanne Grady, Patricia A. Hinshaw, Ada Sue Knebel, Ann R. Robinson, Nellie Ropka, Mary E. Seibert, Diane Stevens, Kathleen R. Tully, Lois A. Webb, Jo Ann CA Genomic Nursing State Sci Advisory TI A Blueprint for Genomic Nursing Science SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Nurses; nursing; genetics; genomics; nursing research ID HEALTH-CARE; GENETICS; INTEGRATION; COMPETENCES; CURRICULA; NURSES AB Purpose: This article reports on recommendations arising from an invitational workshop series held at the National Institutes of Health for the purposes of identifying critical genomics problems important to the health of the public that can be addressed through nursing science. The overall purpose of the Genomic Nursing State of the Science Initiative is to establish a nursing research blueprint based on gaps in the evidence and expert evaluation of the current state of the science and through public comment. Organizing Constructs: A Genomic Nursing State of the Science Advisory Panel was convened in 2012 to develop the nursing research blueprint. The Advisory Panel, which met via two webinars and two in-person meetings, considered existing evidence from evidence reviews, testimony from key stakeholder groups, presentations from experts in research synthesis, and public comment. Findings: The genomic nursing science blueprint arising from the Genomic Nursing State of Science Advisory Panel focuses on biologic plausibility studies as well as interventions likely to improve a variety of outcomes (e.g., clinical, economic, environmental). It also includes all care settings and diverse populations. The focus is on (a) the client, defined as person, family, community, or population; (b) the context, targeting informatics support systems, capacity building, education, and environmental influences; and (c) cross-cutting themes. It was agreed that building capacity to measure the impact of nursing actions on costs, quality, and outcomes of patient care is a strategic and scientific priority if findings are to be synthesized and aggregated to inform practice and policy. Conclusions: The genomic nursing science blueprint provides the framework for furthering genomic nursing science to improve health outcomes. This blueprint is an independent recommendation of the Advisory Panel with input from the public and is not a policy statement of the National Institutes of Health or the federal government. Clinical Relevance: This genomic nursing science blueprint targets research to build the evidence base to inform integration of genomics into nursing practice and regulation (such as nursing licensure requirements, institutional accreditation, and academic nursing school accreditation). C1 [Calzone, Kathleen A.] NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Jenkins, Jean] NHGRI, NIH, Bethesda, MD 20892 USA. [Bakos, Alexis D.] US Hlth Resources & Serv Adm, Div Nursing, Bur Hlth Profess, Rockville, MD 20857 USA. [Cashion, Ann K.] NINR, NINR Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Donaldson, Nancy] UCSF Sch Nursing, Dept Physiol Nursing, San Francisco, CA USA. [Feero, W. Gregory] NHGRI, Genom Healthcare Branch, Bethesda, MD 20892 USA. [Feetham, Suzanne] Childrens Natl Med Ctr, Bethesda, MD USA. [Grady, Patricia A.; Knebel, Ann R.] NINR, NIH, Bethesda, MD 20892 USA. [Hinshaw, Ada Sue] Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Bethesda, MD 20814 USA. [Robinson, Nellie] Patient Care Serv, Washington, DC USA. [Robinson, Nellie] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Ropka, Mary E.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Seibert, Diane] Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Family Nurse Practitioner Program, Bethesda, MD 20814 USA. [Stevens, Kathleen R.] Univ Texas Hlth Sci Ctr San Antonio, Acad Ctr Evidence Based Practice, San Antonio, TX 78229 USA. [Tully, Lois A.] NINR, Div Extramural Activ, Bethesda, MD 20892 USA. [Webb, Jo Ann] Amer Org Nurse Execut, Fed Relat & Policy, Washington, DC USA. RP Calzone, KA (reprint author), NCI, Ctr Canc Res, Genet Branch, 41 Medlars Dr,Bldg 41,RM B622,MSC 5055, Bethesda, MD 20892 USA. EM calzonek@mail.nih.gov FU Intramural Research Program of the United States National Institutes of Health; National Cancer Institute; National Human Genome Research Institute; National Institute of Nursing Research FX This project was supported by the Intramural Research Program of the United States National Institutes of Health, including support from the National Cancer Institute, the National Human Genome Research Institute, and the National Institute of Nursing Research. NR 22 TC 23 Z9 25 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD MAR PY 2013 VL 45 IS 1 BP 96 EP 104 DI 10.1111/jnu.12007 PG 9 WC Nursing SC Nursing GA 099RV UT WOS:000315639800013 ER PT J AU Tana, MM Heller, T AF Tana, Michele M. Heller, Theo TI Autoantibodies in Hepatitis C: Red Flag or Bystander Effect? SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Editorial Material C1 [Tana, Michele M.; Heller, Theo] NIDDK, Liver Dis Branch, Div Intramural Res, NIH, Bethesda, MD USA. RP Heller, T (reprint author), NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM TheoH@intra.niddk.nih.gov FU Intramural NIH HHS [ZIA DK054514-06] NR 5 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD MAR PY 2013 VL 56 IS 3 BP 243 EP 243 DI 10.1097/MPG.0b013e3182774b04 PG 1 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 097GG UT WOS:000315461400007 PM 23443062 ER PT J AU Suskind, DL Wahbeh, G Burpee, T Cohen, M Christie, D Weber, W AF Suskind, David L. Wahbeh, Ghassan Burpee, Tyler Cohen, Morty Christie, Dennis Weber, Wendy TI Tolerability of Curcumin in Pediatric Inflammatory Bowel Disease: A Forced-Dose Titration Study SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE complementary alternative medicine; Crohn disease; curcumin; inflammatory bowel disease; pediatrics; turmeric; ulcerative colitis ID PROSPECTIVE MULTICENTER; DIFERULOYL METHANE; ULCERATIVE-COLITIS; ACTIVITY INDEX; INHIBITION; COMPLEMENTARY; THERAPY; TRIAL; LONGA AB Background: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation in the absence of a recognized etiology. The primary therapies are medications that possess anti-inflammatory or immunosuppressive effects. Given the high use of complementary alternative medicines in pediatric IBD, a prospective tolerability study of curcumin, an herbal therapy with known anti-inflammatory effects, was conducted to assess possible dosage in children with IBD. Methods: Prospectively, patients with Crohn disease or ulcerative colitis in remission or with mild disease (Pediatric Crohn's Disease Activity Index [PCDAI] <30 or Pediatric Ulcerative Colitis Activity Index [PUCAI] score <34) were enrolled in a tolerability study. All patients received curcumin in addition to their standard therapy. Patients initially received 500 mg twice per day for 3 weeks. Using the forced-dose titration design, doses were increased up to 1 g twice per day at week 3 for a total of 3 weeks and then titrated again to 2 g twice per day at week 6 for 3 weeks. Validated measures of disease activity, using the PUCAI and PCDAI, and the Monitoring of Side Effect System score were obtained at weeks 3, 6, and 9. Results: All patients tolerated curcumin well, with the only symptom that was consistently reported during all 3 visits being an increase in gassiness, which occurred in only 2 patients. Three patients saw improvement in PUCAI/PCDAI score. Conclusions: This pilot study suggests that curcumin may be used as an adjunctive therapy for individuals seeking a combination of conventional medicine and alternative medicine. C1 [Suskind, David L.; Wahbeh, Ghassan; Burpee, Tyler; Christie, Dennis] Seattle Childrens Hosp, Dept Pediat, Seattle, WA 98105 USA. [Suskind, David L.; Wahbeh, Ghassan; Burpee, Tyler; Christie, Dennis] Univ Washington, Seattle, WA 98195 USA. [Weber, Wendy] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Cohen, Morty] Seattle Childrens, Dept Pharm, Seattle, WA USA. RP Suskind, DL (reprint author), Seattle Childrens Hosp, 4800 Sandpoint Way NE, Seattle, WA 98105 USA. EM David.Suskind@seattlechildrens.org FU Institute of Translational Health Sciences (ITHS) at the University of Washington; NIH National Center for Research Resources [UL1 RR025014, KL2 RR025015, TL1 RR025016] FX This work was supported by grants from the Institute of Translational Health Sciences (ITHS) at the University of Washington. The institute is supported by grants UL1 RR025014, KL2 RR025015, and TL1 RR025016 from the NIH National Center for Research Resources. NR 16 TC 17 Z9 17 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD MAR PY 2013 VL 56 IS 3 BP 277 EP 279 DI 10.1097/MPG.0b013e318276977d PG 3 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 097GG UT WOS:000315461400013 PM 23059643 ER PT J AU Kaltman, JR Burns, KM Pearson, GD AF Kaltman, Jonathan R. Burns, Kristin M. Pearson, Gail D. TI Screening in Pediatrics-More Questions than Answers? SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID SUDDEN CARDIAC DEATH; CONGENITAL HEART-DISEASE; PULSE OXIMETRY; CARDIOVASCULAR EVENTS; CHILDREN; RISK; ADOLESCENTS; CHILDHOOD; TRIALS C1 [Kaltman, Jonathan R.; Burns, Kristin M.; Pearson, Gail D.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Kaltman, JR (reprint author), NHLBI, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8104, Bethesda, MD 20892 USA. EM kaltmanj@nhlbi.nih.gov NR 23 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2013 VL 162 IS 3 BP 454 EP 456 DI 10.1016/j.jpeds.2012.10.020 PG 3 WC Pediatrics SC Pediatrics GA 101QS UT WOS:000315790100005 PM 23164312 ER PT J AU Thezenas, ML Huang, HL Njie, M Ramaprasad, A Nwakanma, DC Fischer, R Digleria, K Walther, M Conway, DJ Kessler, BM Casals-Pascual, C AF Thezenas, Marie L. Huang, Honglei Njie, Madi Ramaprasad, Abhinay Nwakanma, Davis C. Fischer, Roman Digleria, Katalin Walther, Michael Conway, David J. Kessler, Benedikt M. Casals-Pascual, Climent TI PfHPRT: A New Biomarker Candidate of Acute Plasmodium falciparum Infection SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Plasmodium falciparum; malaria; biomarker; hypoxanthine phosphoribosyltransferase; pHPRT; shotgun proteomics; SRM ID MASS-SPECTROMETRY; MALARIA; ENRICHMENT; PROTEOME; SEQUENCE AB Plasmodium falciparum is a protozoan parasite that causes human malaria. This parasitic infection accounts for approximately 655 000 deaths each year worldwide. Most deaths could be prevented by diagnosing and treating malaria promptly. To date, few parasite proteins have been developed into rapid diagnostic tools. We have combined a shotgun and a targeted proteomic strategy to characterize the plasma proteome of Gambian children with severe malaria (SM), mild malaria, and convalescent controls in search of new candidate biomarkers. Here we report four P. falciparum proteins with a high level of confidence in SM patients, namely, PF10_0121 (hypoxanthine phosphoribosyltransferase, pHPRT), PF11_0208 (phosphoglycerate mutase, pPGM), PF13_0141 (lactate dehydrogenase, pLDH), and PF14_0425 (fructose bisphosphate aldolase, pFBPA). We have optimized selected reaction monitoring (SRM) assays to quantify these proteins in individual patients. All P. falciparum proteins were higher in SM compared with mild cases or control subjects. SRM-based measurements correlated markedly with clinical anemia (low blood hemoglobin concentration), and pLDH and pFBPA were significantly correlated with higher P. falciparum parasitemia. These findings suggest that pHPRT is a promising biomarker to diagnose P. falciparum malaria infection. The diagnostic performance of this marker should be validated prospectively. C1 [Thezenas, Marie L.; Huang, Honglei; Ramaprasad, Abhinay; Fischer, Roman; Kessler, Benedikt M.; Casals-Pascual, Climent] Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet & Henry Wellcome B, Oxford OX3 7BN, England. [Njie, Madi; Nwakanma, Davis C.] MRC Unit, Malaria Programme, Banjul, Gambia. [Ramaprasad, Abhinay] King Abdulla Univ Sci & Technol, Jeddah, Saudi Arabia. [Digleria, Katalin] Univ Oxford, Nuffield Dept Med, Weatherall Inst Mol Med, Oxford OX3 7BN, England. [Walther, Michael] NIAID, NIH, Rockville, MD USA. [Conway, David J.] London Sch Hyg & Trop Med, London WC1, England. RP Casals-Pascual, C (reprint author), Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet & Henry Wellcome B, Oxford OX3 7BN, England. EM ccasals@well.ox.ac.uk RI Ramaprasad, Abhinay/D-1181-2013; OI Ramaprasad, Abhinay/0000-0001-9372-5526; Conway, David/0000-0002-8711-3037; Fischer, Roman/0000-0002-9715-5951; Kessler, Benedikt/0000-0002-8160-2446 FU Wellcome Trust [075491/Z/04]; Medical Research Council U.K. [G0701885] FX The MRC Unit (The Gambia), field workers, nurses, laboratory staff, data staff, drivers and administrative staff, the staff at the MRC Hospital Fajara, and the government health staff at Royal Victoria Teaching Hospital (RVTH) are acknowledged. This work was supported by the Wellcome Trust [Grant No. 075491/Z/04]. C.C.-P. is supported by the Medical Research Council U.K. (Clinician Scientist Fellowship: G0701885). NR 29 TC 7 Z9 7 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD MAR PY 2013 VL 12 IS 3 BP 1211 EP 1222 DI 10.1021/pr300858g PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 100NN UT WOS:000315708000014 PM 23339668 ER PT J AU Strader, MB Hervey, WJ Costantino, N Fujigaki, S Chen, CY Akal-Strader, A Ihunnah, CA Makusky, AJ Court, DL Markey, SP Kowalak, JA AF Strader, Michael Brad Hervey, William Judson Costantino, Nina Fujigaki, Suwako Chen, Cai Yun Akal-Strader, Ayca Ihunnah, Chibueze A. Makusky, Anthony J. Court, Donald L. Markey, Sanford P. Kowalak, Jeffrey A. TI A Coordinated Proteomic Approach for Identifying Proteins that Interact with the E. coli Ribosomal Protein S12 SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE affinity pull-down protein purification; peptide affinity pull-downs; PTM: post-translational modification; SPA: sequence peptide affinity; SPA-S12: SPA tagged ribosomal protein S12; 1D-LC-MS/MS: one-dimensional liquid chromatography tandem mass spectrometry; FDR: false positive discovery rate; metabolic labeling; relative quantification ID ESCHERICHIA-COLI; TRANSFER-RNA; POSTTRANSLATIONAL MODIFICATION; MASS-SPECTROMETRY; CRYSTAL-STRUCTURE; 70S RIBOSOME; MIAB PROTEIN; IDENTIFICATION; METHYLTRANSFERASE; ENZYME AB The bacterial ribosomal protein S12 contains a universally conserved D88 residue on a loop region thought to be critically involved in translation due to its proximal location to the A site of the 30S subunit. While D88 mutants are lethal this residue has been found to be post-translationally modified to beta-methylthioaspartic acid, a post-translational modification (PTM) identified in S12 orthologs from several phylogenetically distinct bacteria. In a previous report focused on characterizing this PTM, our results provided evidence that this conserved loop region might be involved in forming multiple proteins-protein interactions (Strader, M. B.; Costantino, N.; Elkins, C. A.; Chen, C. Y.; Patel, I.; Makusky, A. J.; Choy, J. S.; Court, D. L.; Markey, S. P.; Kowalak, J. A. A proteomic and transcriptomic approach reveals new insight into betamethylthiolation of Escherichia colt ribosomal protein S12. Mol. Cell. Proteomics 2011, 10, M110 005199). To follow-up on this study, the D88 containing loop was probed to identify candidate binders employing a two-step complementary affinity purification strategy. The first involved an endogenously expressed S12 protein containing a C-terminal tag for capturing S12 binding partners The second strategy utilized a synthetic biotinylated peptide representing the D88 conserved loop region for capturing S12 loop interaction partners. Captured proteins from both approaches were detected by utilizing SDS-PAGE and one-dimensional liquid chromatography-tandem mass spectrometry. The results presented in this report revealed proteins that form direct interactions with the 30S subunit and elucidated which are likely to interact with S12. In addition, we provide evidence that two proteins involved in regulating ribosome and/or mRNA transcript levels under stress conditions, RNase R and Hfq, form direct interactions with the S12 conserved loop, suggesting that it is likely part of a protein binding interface. C1 [Strader, Michael Brad; Fujigaki, Suwako; Chen, Cai Yun; Makusky, Anthony J.; Markey, Sanford P.; Kowalak, Jeffrey A.] NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. [Costantino, Nina; Court, Donald L.] NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. [Akal-Strader, Ayca] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Ihunnah, Chibueze A.] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15206 USA. RP Strader, MB (reprint author), US FDA, Labs Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM Michael.Strader@fda.hhs.gov FU National Institute of Mental Health [1ZIAMH000274] FX We would like to thank Jack Greenblatt (University of Toronto, Canada) for generously providing the SPA cassette used for generating SPA tagged genes. We would like to thank Mikhail Bunenko for his valuable comments and suggestions (National Cancer Institute/Frederick Cancer Research and Development Center, Frederick, MD). We would like to thank Chongle Pan for assistance in using ProRata software. We would like to thank Todd L. Mollan (CBER/FDA), Adele Bladder (NCI/NIMH) and Christopher Crutchfield (NICHD/NIH) for assistance with reading and/or editing this manuscript. This work was supported by the Intramural Research Program of the National Institute of Mental Health (1ZIAMH000274). NR 47 TC 5 Z9 5 U1 0 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD MAR PY 2013 VL 12 IS 3 BP 1289 EP 1299 DI 10.1021/pr3009435 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 100NN UT WOS:000315708000021 PM 23305560 ER PT J AU Li, F Pang, XY Krausz, KW Jiang, CT Chen, C Cook, JA Krishna, MC Mitchell, JB Gonzalez, FJ Patterson, AD AF Li, Fei Pang, Xiaoyan Krausz, Kristopher W. Jiang, Changtao Chen, Chi Cook, John A. Krishna, Murali C. Mitchell, James B. Gonzalez, Frank J. Patterson, Andrew D. TI Stable Isotope- and Mass Spectrometry-based Metabolomics as Tools in Drug Metabolism: A Study Expanding Tempol Pharmacology SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE tempol; stable isotope; metabolomics; mass spectrometry; drug metabolism ID FATTY-ACID OXIDATION; ACTIVATED RECEPTOR-ALPHA; BETA-OXIDATION; IN-VITRO; REVEALS; MICE; IDENTIFICATION; GLUCURONIDE; SUPEROXIDE; EXPRESSION AB The application of mass spectrometry-based metabolomics in the field of drug metabolism has yielded important insights not only into the metabolic routes of drugs but has provided unbiased, global perspectives of the endogenous metabolome that can be useful for identifying biomarkers associated with mechanism of action, efficacy, and toxicity. In this report, a stable isotope- and mass spectrometry-based metabolomics approach that captures both drug metabolism and changes in the endogenous metabolome in a single experiment is described. Here the antioxidant drug tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) was chosen because its mechanism of action is not completely understood and its metabolic fate has not been studied extensively. Furthermore, its small size (MW = 172.2) and chemical composition (C9H18NO2) make it challenging to distinguish from endogenous metabolites. In this study, mice were dosed with tempol or deuterated tempol (C9D17HNO2) and their urine was profiled using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Principal component analysis of the urinary metabolomics data generated a Y-shaped scatter plot containing drug metabolites (protonated and deuterated) that were clearly distinct from the endogenous metabolites. Ten tempol drug metabolites, including eight novel metabolites, were identified. Phase II metabolism was the major metabolic pathway of tempol in vivo, including glucuronidation and glucosidation. Urinary endogenous metabolites significantly elevated by tempol treatment included 2,8-dihydroxyquinoline (8.0-fold, P < 0.05) and 2,8-dihydroxyquinoline-beta-D-glucuronide (6.8-fold, P < 0.05). Urinary endogenous metabolites significantly attenuated by tempol treatment including pantothenic acid (1.3-fold, P < 0.05) and isobutrylcarnitine (5.3-fold, P < 0.01). This study underscores the power of a stable isotope- and mass spectrometry-based metabolomics in expanding the view of drug pharmacology. C1 [Li, Fei; Pang, Xiaoyan; Krausz, Kristopher W.; Jiang, Changtao; Chen, Chi; Gonzalez, Frank J.; Patterson, Andrew D.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Chi] Univ Minnesota, Dept Food Sci & Nutr, St Paul, MN 55108 USA. [Cook, John A.; Krishna, Murali C.; 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 Patterson, AD (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM adp117@psu.edu RI Li, Fei/F-6849-2013; Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; [ES022186] FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (F.J.G. and J.B.M.) and ES022186 (A.D.P.). NR 47 TC 15 Z9 15 U1 0 U2 43 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR PY 2013 VL 12 IS 3 BP 1369 EP 1376 DI 10.1021/pr301023x PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 100NN UT WOS:000315708000027 PM 23301521 ER PT J AU Pagura, J Stein, MB Bolton, JM Cox, BJ Grant, B Sareen, J AF Pagura, Jina Stein, Murray B. Bolton, James M. Cox, Brian J. Grant, Bridget Sareen, Jitender TI Comorbidity of borderline personality disorder and posttraumatic stress disorder in the U.S. population (vol 44, pg 1190, 2010) SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Correction C1 [Pagura, Jina; Bolton, James M.; Cox, Brian J.; Sareen, Jitender] Univ Manitoba, Dept Psychol, Winnipeg, MB R3E 3N4, Canada. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Pagura, Jina; Bolton, James M.; Cox, Brian J.; Sareen, Jitender] Univ Manitoba, Dept Psychiat, Winnipeg, MB R3E 3N4, Canada. [Cox, Brian J.; Sareen, Jitender] Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3E 3N4, Canada. [Grant, Bridget] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Sareen, J (reprint author), Univ Manitoba, Dept Psychiat, PZ 430 771 Bannatyne Ave, Winnipeg, MB R3E 3N4, Canada. EM sareen@cc.umanitoba.ca NR 1 TC 1 Z9 1 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAR PY 2013 VL 47 IS 3 BP 423 EP 423 DI 10.1016/j.jpsychires.2012.11.014 PG 1 WC Psychiatry SC Psychiatry GA 098HG UT WOS:000315539200020 ER PT J AU Powell-Wiley, TM Banks-Richard, K Williams-King, E Tong, LY Ayers, CR de Lemos, JA Gimpel, N Lee, JJ DeHaven, MJ AF Powell-Wiley, Tiffany M. Banks-Richard, Kamakki Williams-King, Elicia Tong, Liyue Ayers, Colby R. de Lemos, James A. Gimpel, Nora Lee, Jenny J. DeHaven, Mark J. TI Churches as targets for cardiovascular disease prevention: comparison of genes, nutrition, exercise, wellness and spiritual growth (GoodNEWS) and Dallas County populations SO JOURNAL OF PUBLIC HEALTH LA English DT Article DE AfricanAmericans; cardiovascular risk factors; community-based participatory research; obesity ID AMERICAN-HEART-ASSOCIATION; WEIGHT-LOSS PROGRAM; PHYSICAL-ACTIVITY; SCIENTIFIC STATEMENT; HEALTH; RISK; COMMITTEE; OBESITY; WOMEN; INTERVENTIONS AB We compared cardiovascular (CV) risk factors (CVRFs) of community-based participatory research (CBPR) participants with the community population to better understand how CBPR participants relate to the population as a whole. GoodNEWS participants in 20 African-American churches in Dallas, Texas were compared with age/sex-matched African-Americans in the Dallas Heart Study (DHS), a probability-based sample of Dallas County residents. DHS characteristics were sample-weight adjusted to represent the Dallas County population. Despite having more education (college education: 75 versus 51, P 0.0001), GoodNEWS participants were more obese (mean body mass index: 34 versus 31 kg/m(2), P 0.001) and had more diabetes (23 versus 12, P 0.001) and hyperlipidemia (53 versus 14, P 0.001) compared with African-Americans in Dallas County. GoodNEWS participants had higher rates of treatment and control of most CVRFs (treated hyperlipidemia: 95 versus 64, P 0.001; controlled diabetes: 95 versus 21, P 0.001; controlled hypertension: 70 versus 52, P 0.003), were more physically active (233 versus 177 metabolic equivalent units-min/week, P 0.0001) and less likely to smoke (10 versus 30, P 0.001). Compared with African-Americans in Dallas County, CBPR participants in church congregations were more educated, physically active and had more treatment and control of most CVRFs. Surprisingly, this motivated population had a greater obesity burden, identifying them as a prime target for CBPR-focused obesity treatment. C1 [Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Banks-Richard, Kamakki; Ayers, Colby R.; de Lemos, James A.] Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA. [Williams-King, Elicia] Univ Utah, Dept Internal Med, Salt Lake City, UT 84132 USA. [Tong, Liyue] Dept Clin Sci, Dallas, TX 75390 USA. [Gimpel, Nora] Univ Texas SW Med Ctr Dallas, Dept Family Med, Dallas, TX 75390 USA. [Lee, Jenny J.] Univ North Texas Hlth Sci Ctr, Dept Social & Behav Sci, Ft Worth, TX 76107 USA. [DeHaven, Mark J.] Univ North Texas Hlth Sci Ctr, Texas Prevent Inst, Ft Worth, TX 76107 USA. RP Powell-Wiley, TM (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tiffany.powell@nih.gov RI Kattelmann, Kendra/E-8225-2013 FU National Heart, Lung and Blood Institute, National Institutes of Health [RO1 HL087768]; Donald W. Reynolds Foundation (Las Vegas, NV); United States Public Health Service General Clinical Research Center grant from the National Institutes of Health/National Center Research Resources-Clinical Research [MO1-RR00633]; Ruth Kirschstein National Research Service Award from the National Institutes of Health [2-T32-HL007360-31]; Division of Intramural Research (DIR) of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health FX This work was supported by the National Heart, Lung and Blood Institute, National Institutes of Health [RO1 HL087768]. Funding support for the Dallas Heart Study was provided by the Donald W. Reynolds Foundation (Las Vegas, NV) and the United States Public Health Service General Clinical Research Center grant [#MO1-RR00633] from the National Institutes of Health/National Center Research Resources-Clinical Research. Funding support for Dr Powell-Wiley and Dr Banks-Richard was provided by the Ruth Kirschstein National Research Service Award from the National Institutes of Health [#2-T32-HL007360-31]. Dr Powell-Wiley is currently funded by the Division of Intramural Research (DIR) of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health. NR 29 TC 2 Z9 3 U1 5 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-3842 J9 J PUBLIC HEALTH-UK JI J. Public Health PD MAR PY 2013 VL 35 IS 1 BP 99 EP 106 DI 10.1093/pubmed/fds060 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 099TR UT WOS:000315645600017 PM 22811446 ER PT J AU Molina, BSG Hinshaw, SP Arnold, LE Swanson, JM Swanson, JM Pelham, WE Hechtman, L Hoza, B Epstein, JN Wigal, T Abikoff, HB Greenhill, LL Jensen, PS Wells, KC Vitiello, B Gibbons, RD Howard, A Houck, PR Hur, K Lu, B Marcus, S AF Molina, Brooke S. G. Hinshaw, Stephen P. Arnold, L. Eugene Swanson, James M. Swanson, James M. Pelham, William E. Hechtman, Lily Hoza, Betsy Epstein, Jeffery N. Wigal, Timothy Abikoff, Howard B. Greenhill, Laurence L. Jensen, Peter S. Wells, Karen C. Vitiello, Benedetto Gibbons, Robert D. Howard, Andrea Houck, Patricia R. Hur, Kwan Lu, Bo Marcus, Sue CA MTA Cooperative Grp TI Adolescent Substance Use in the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (ADHD) (MTA) as a Function of Childhood ADHD, Random Assignment to Childhood Treatments, and Subsequent Medication SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE attention-deficit/hyperactivity disorder (ADHD); substance use ID PROSPECTIVE FOLLOW-UP; LONG-TERM OUTCOMES; CIGARETTE-SMOKING; DRUG-USE; STIMULANT MEDICATION; TREATMENT STRATEGIES; CANNABIS USE; ALCOHOL-USE; EMERGING ADULTHOOD; CONDUCT DISORDER AB Objective: To determine long-term effects on substance use and substance use disorder (SUD), up to 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA; n = 436); to test whether medication at follow-up, cumulative psychostimulant treatment over time, or both relate to substance use/SUD; and to compare substance use/SUD in the ADHD sample to the non-ADHD childhood classmate comparison group (n = 261). Method: Mixed-effects regression models with planned contrasts were used for all tests except the important cumulative stimulant treatment question, for which propensity score matching analysis was used. Results: The originally randomized treatment groups did not differ significantly on substance use/SUD by the 8-year follow-up or earlier (mean age = 17 years). Neither medication at follow-up (mostly stimulants) nor cumulative stimulant treatment was associated with adolescent substance use/SUD. Substance use at all time points, including use of two or more substances and SUD, were each greater in the ADHD than in the non-ADHD samples, regardless of sex. Conclusions: Medication for ADHD did not protect from, or contribute to, visible risk of substance use or SLID by adolescence, whether analyzed as randomized treatment assignment in childhood, as medication at follow-up, or as cumulative stimulant treatment over an 8-year follow-up from childhood. These results suggest the need to identify alternative or adjunctive adolescent-focused approaches to substance abuse prevention and treatment for boys and girls with ADHD, especially given their increased risk for use and abuse of multiple substances that is not improved with stimulant medication. Clinical trial registration information Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://clinical trials.gov/; NCT00000388. J. Am. Acad. Child Adolesc. Psychiatry; 2013;52(3):250-263. C1 [Molina, Brooke S. G.] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Hinshaw, Stephen P.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Arnold, L. Eugene; Lu, Bo] Ohio State Univ, Columbus, OH 43210 USA. [Swanson, James M.; Wigal, Timothy] Univ Calif Irvine, Irvine, CA 92717 USA. [Pelham, William E.] Florida Int Univ, Miami, FL 33199 USA. [Hechtman, Lily] McGill Univ, Montreal, PQ H3A 2T5, Canada. [Hoza, Betsy] Univ Vermont, Burlington, VT 05405 USA. [Epstein, Jeffery N.] Univ Cincinnati, Cincinnati, OH 45221 USA. [Abikoff, Howard B.] NYU, New York, NY 10003 USA. [Greenhill, Laurence L.; Marcus, Sue] Columbia Univ, New York, NY 10027 USA. [Jensen, Peter S.] REsource Adv Childrens Hlth REACH Inst, New York, NY USA. [Jensen, Peter S.] Mayo Clin, Rochester, MN USA. [Wells, Karen C.] Duke Univ, Durham, NC 27706 USA. [Vitiello, Benedetto] NIMH, Rockville, MD USA. [Gibbons, Robert D.] Univ Chicago, Chicago, IL 60637 USA. [Howard, Andrea] Univ N Carolina, Chapel Hill, NC 27515 USA. [Houck, Patricia R.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. [Hur, Kwan] Vet Affairs Edward Hines Jr Hosp, Hines, IL USA. [Hur, Kwan] Univ Illinois, Chicago, IL 60680 USA. RP Molina, BSG (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. OI Jensen, Peter/0000-0003-2387-0650; Newcorn, Jeffrey /0000-0001-8993-9337 FU NIMH; National Institute on Drug Abuse (NIDA) [U01 MH50461, N01MH12009, HHSN271200800005-C, DA-8-5550, U01 MH50477, N01MH12012, HHSN271200800009-C, DA-8-5554]; Office of Special Education Programs of the U.S. Department of Education; Office of Juvenile Justice and Delinquency Prevention of the Justice Department; NIDA; Curemark; Eli Lilly and Co.; Shire; Noven Pharmaceuticals; Eli Lilly and Co; Janssen; Ortho; Purdue; Noven; Rhodes; Otsuka; National Institute on Drug Abuse (NIDA). [U01 MH50440, N01MH 12011, HHSN271200800006-C, DA-8-5551, U01 MH50467, N01 MH12007, HHSN271200800007-C, DA-8-5552, U01 MH50453, N01MH 12004, HHSN271200800004-C, DA-8-5549, N01 MH 12010, HHSN271200800008-C, DA-8-5553, N01MH12008, HHSN271200800003-C, DA-8-5548] FX The work reported was supported by cooperative agreement grants and contracts from NIMH and the National Institute on Drug Abuse (NIDA) to the following: University of California-Berkeley: U01 MH50461, N01MH12009, and HHSN271200800005-C; DA-8-5550; Duke University: U01 MH50477, N01MH12012, and HHSN271200800009-C; DA-8-5554; University of California-Irvine: U01 MH50440, N01MH 12011, and HHSN271200800006-C; DA-8-5551; Research Foundation for Mental Hygiene (New York State Psychiatric Institute/Columbia University): U01 MH50467, N01 MH12007, and HHSN271200800007-C; DA-8-5552; Long Island Jewish Medical Center U01 MH50453; New York University: N01MH 12004, and HHSN271200800004-C; DA-8-5549; University of Pittsburgh: U01 MH50467, N01 MH 12010, and HHSN271200800008-C; DA-8-5553; and McGill University N01MH12008, and HHSN271200800003-C; DA-8-5548. The Office of Special Education Programs of the U.S. Department of Education, the Office of Juvenile Justice and Delinquency Prevention of the Justice Department, and NIDA also participated in funding.; Dr. Hinshaw has received an honorarium from the American Psychological Association for his editorship of Psychological Bulletin. Dr. Arnold has received research funding from Curemark, Eli Lilly and Co., and Shire; advisory board honoraria from Biomarin, Noven, Seaside Therapeutics, and Shire; and travel support from Noven. Dr. Swanson has served on the advisory board of Noven Pharmaceuticals, and has received travel support from Shire and Jannsen to attend separate, professional meetings. Dr. Pelham has received a research grant from and has served on the advisory board of Noven Pharmaceuticals Dr. Hechtman has received research funds from and has served On the advisory boards and speakers' bureaus for Eli Lilly and Co, Janssen, Ortho, Purdue, and Shire. Dr Wigal has received research support and consulting honoraria from, and has served on the speakers bureau for Eli Lilly and Co, Noven, Rhodes, Otsuka, and Shire Dr Abikoff has received royalties from Multi-Health Systems regarding: the Children's Organizational Skills Scale: Dr. Greenhill has received grant support from Shire and Rhodes, and has served as a member of the Scientific Advisory Board of BioBDX LLC. Dr Jensen has received honoraria for three keynote addresses given at European conferences on attention-deficit/hyperactivity disorder treatment outcomes (two from Shire and one from Janssen-Cilag), and has received a charitable donation from Shire. Dr, Wells has received royalties from Multi-Health Systems, the publisher of Conners' Rating Scales. Drs. Molina, Hoza, Epstein, Vitiello, Gibbons, Howard, Hur, Lu, and Marcus, and Ms. Houck report no biomedical financial interests or potential conflicts of interest. NR 88 TC 69 Z9 69 U1 13 U2 58 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2013 VL 52 IS 3 BP 250 EP 263 DI 10.1016/j.jaac.2012.12.014 PG 14 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 099YA UT WOS:000315660700008 PM 23452682 ER PT J AU Riddle, MA Yershova, K Lazzaretto, D Paykina, N Yenokyan, G Greenhill, L Abikoff, H Vitiello, B Wigal, T McCracken, JT Kollins, SH Murray, DW Wigal, S Kastelic, E McGough, JJ dosReis, S Bauzo-Rosario, A Stehli, A Posner, K AF Riddle, Mark A. Yershova, Kseniya Lazzaretto, Deborah Paykina, Natalya Yenokyan, Gayane Greenhill, Laurence Abikoff, Howard Vitiello, Benedetto Wigal, Tim McCracken, James T. Kollins, Scott H. Murray, Desiree W. Wigal, Sharon Kastelic, Elizabeth McGough, James J. dosReis, Susan Bauzo-Rosario, Audrey Stehli, Annamarie Posner, Kelly TI The Preschool Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS) 6-Year Follow-Up SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE attention-deficit/hyperactivity disorder (ADHD); follow-up; development ID DEFICIT-HYPERACTIVITY DISORDER; ADOLESCENTS-PARENT INTERVIEW; AGE-DEPENDENT DECLINE; PSYCHIATRIC STATUS; CONDUCT PROBLEMS; PSYCHOTROPIC MEDICATIONS; PREDICTIVE-VALIDITY; CRITERION VALIDITY; UNITED-STATES; MISSING DATA AB Objective: To describe the clinical course of attention-deficit/hyperactivity disorder (ADHD) symptom severity and diagnosis from ages 3 to 5 up to 9 to 12 years during a 6-year follow-up after the original Preschool ADHD Treatment Study (PATS). Method: A total of 207 participants (75% male) from the original PATS, assessed at baseline (mean age, 4.4 years, when all met criteria for ADHD) and 3 months later (before medication treatment), were re-evaluated in three follow-up assessment visits (year 3, mean age 7.4 years; year 4, 8.3 years; and year 6, 10.4 years). Parents and teachers rated symptom severity, and clinicians established psychiatric diagnoses. Analyses examined longitudinal changes in symptom severity and ADHD diagnosis. Results: Parent- and teacher-rated symptom severity decreased from baseline to year 3 but remained relatively stable and in the moderate-to-severe clinical range through year 6. Girls showed generally steeper decreases in symptom T-scores. At year 6, 89% (160/180) of remaining participants met ADHD symptom and impairment diagnostic criteria. Comorbidity of oppositional defiant disorder and/or conduct disorder was associated with a 30% higher risk of having an ADHD diagnosis at year 6 in the multiple logistic model. Medication status during follow-up, on versus off, did not predict symptom severity change from year 3 to year 6 after adjustment for other variables. Conclusions: ADHD in preschoolers is a relatively stable diagnosis over a 6-year period. The course is generally chronic, with high symptom severity and impairment, in very young children with moderate-to-severe ADHD, despite treatment with medication. Development of more effective ADHD intervention strategies is needed for this age group. J. Am. Acad. Child Adolesc. Psychiatry; 2013;52(3):264-278. C1 [Riddle, Mark A.; Kastelic, Elizabeth] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Yershova, Kseniya; Lazzaretto, Deborah; Paykina, Natalya; Greenhill, Laurence; Posner, Kelly] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Yershova, Kseniya; Lazzaretto, Deborah; Paykina, Natalya; Greenhill, Laurence; Posner, Kelly] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Yenokyan, Gayane] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Abikoff, Howard] NYU, Sch Med, New York, NY 10003 USA. [Vitiello, Benedetto] NIMH, Rockville, MD USA. [Wigal, Tim; Wigal, Sharon; Stehli, Annamarie] Univ Calif Irvine, Irvine, CA 92717 USA. [McCracken, James T.; McGough, James J.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Kollins, Scott H.; Murray, Desiree W.] Duke Univ, Sch Med, Durham, NC 27706 USA. [dosReis, Susan] Univ Maryland, Sch Pharm, College Pk, MD 20742 USA. [Bauzo-Rosario, Audrey] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. RP Riddle, MA (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Child & Adolescent Psychiat, 1800 Orleans St, Baltimore, MD 21287 USA. EM mriddle@jhmi.edu OI Yenokyan, Gayane/0000-0003-1482-5612 FU NIMH; Duke University Medical Center [U01MH60848]; Johns Hopkins University [U01 MH60642]; New York University Child Study Center [U01 MH60943]; NYSPI/Columbia University [U01 MH60903]; University of California-Irvine [U01 MH60833]; UCLA [U01 H60900]; NIH; Maryland Mental Hygiene Administration; Eunice Kennedy Shriven National Institute of Child Health and Human Development (NICHD); Research Foundation for Mental Hygiene at the New York State Institute; Research Foundation for Mental Hygiene, Inc., at NYSPI from National Institute on Drug Abuse (NIDA); NYSPI via the New York State Office of Mental Health; NIDA; Shire Pharmaceuticals; BioBehavioral Diagnostics; American Physician Institute for Advanced Professional Studies; Shire; Noven; Forest; Seaside Therapeutics; Roche; Otsuka; Addrenex; Rhodes; NIH/Center for Scientific Review; Institute of Educational Sciences; Incredible Years, Inc.; Forest Addrenex; Eli Lilly and Co.,; McNeil; NextWave; NICHD; Psychogenics; Quintiles; Shionogi Pharma; Centers for Medicare and Medicaid Services (CMS); Research Foundation for Mental Hygiene (RFMH); Abbott; Albany Molecular Research; Alfresa; Alkermes; Amgen; AstraZeneca Pharmaceuticals; Biodelivery Sciences, Intl.; Biomarin; Bristol-Myers Squibb; Canam; Cato Research; Cephalon; Cetero Research; Covance; CRI Worldwide; Depomed; Douglas Pharmaceuticals; Eisai; Euthymics; Forest Laboratories; GlaxoSmithKline; GW Pharma; Human Genome Sciences; i3 Research; ICON; IntelGenx Corp.; Intracellular Therapies; Johnson and Johnson; Kendle Early Stage; Lilly USA; Lundbeck A/S; Lundbeck USA; MedImmune; Medtronic; Merck and Co., Inc.; Neurosearch; Next Wave Pharmaceuticals; Novartis; Novo-Nordisk; Orexigen; Parexel; Pfizer; PGx Health; PPDI; Psyadon; QED; Reckitt Benckiser; Sanofi-Aventis; Schering-Plough Corporation; SCOPE International; Sepracor, Inc./Sunovion; Siena Biotech; Supernus; Synosia Therapeutics; Takeda-Pharmaceutical Company; Theravance; Upsher Smith; Valeant Pharmaceuticals; Vivus, Inc.; World Wide Clinical Trials; Wyeth Research; electronic Columbia Suicide Severity Rating Scale (e-CSSRS) FX This research was supported by a cooperative agreement between NIMH and the following institution's: Duke University Medical Center (U01MH60848), Johns Hopkins University (U01 MH60642), New York University Child Study Center (U01 MH60943), NYSPI/Columbia University (U01 MH60903), University of California-Irvine (U01 MH60833), and UCLA (U01 H60900).; Dr. Riddle has received research support from NIH and the Maryland Mental Hygiene Administration, consultation fees from the Eunice Kennedy Shriven National Institute of Child Health and Human Development (NICHD), and has received aripiprazole from Bristol Myers Squibb for an NIMH-sponsored study. Dr. Yershova has received salary from the Research Foundation for Mental Hygiene at the New York State Institute. Ms. Paykina has received support through her employer, Research Foundation for Mental Hygiene, Inc., at NYSPI from National Institute on Drug Abuse (NIDA). Dr. Yenokyan has received research funding from NIH. Dr. Greenhill has received salary support from NYSPI via the New York State Office of Mental Health, and has received research support from NIDA as well as from Shire Pharmaceuticals and BioBehavioral Diagnostics. Dr. Abikoff has received research support from NIMH and NIDA, and royalties from Multi-Health Systems and Premier/School Specialty. Dr. Vitiello has received income from medical private practice and consultation fees from the American Physician Institute for Advanced Professional Studies. Dr. T. Wigal has received research support from NIDA, Shire, Noven, and Forest, and has served as a consultant for Purdue Pharmaceuticals. Dr. McCracken has received research support from NIH, Seaside Therapeutics, Roche, and Otsuka; consultant income from Novartis, BioMarin, PharmaNet, and Novena speaker's honoraria from the burette Syndrome Association; and research study drug supply from Shire. Dr. Kollins has received research support from Addrenex, NIDA, Otsuka, Rhodes, and Shire. He has received consulting fees from Addrenex, NIH/Center for Scientific Review, Otsuka, Rhodes, and Shire. Dr Murray has received funding from the Institute of Educational Sciences, NIDA, and Incredible Years, Inc. Dr S. Wigal has received research support from Forest Addrenex, Eli Lilly and Co., McNeil, NextWave, NICHD, Noven, Psychogenics, Quintiles, Rhodes, Shionogi Pharma, Otsuka, and Shire She has served as a consultant for Eli Lilly and Co., McNeil, Next Wave, NIH, NuTec, Shire, Noven, and TAISHO; and on the speakers' bureaus of Shionogi and Noven. Dr. McGough has received consulting honoraria from Alexza Pharmaceuticals, MedImmune, Shionogi, Sunovion, Theravance, and Targacept, and research support from NIH, NeuroSigma Inc., Shionogi, Shire, and Supernus Pharmaceuticals. Dr. dosReis has received research support from NIH and the Centers for Medicare and Medicaid Services (CMS). Ms. Stehli has received funding Support from NICHD and NIDA. Dr. Posner has received salary support from the Research Foundation for Mental Hygiene (RFMH). She has served as the director of the Center for Suicide Risk Assessment which, as part of an effort to help execute the Food and Drug Administration (FDA) suicidality classification mandates, and has received support from Abbott, Albany Molecular Research, Alfresa, Alkermes, Amgen, AstraZeneca Pharmaceuticals, Biodelivery Sciences, Intl., Biomarin, Bristol-Myers Squibb, Canam, Cato Research, Cephalon, Cetero Research, Covance, CRI Worldwide, Depomed, Douglas Pharmaceuticals, Eisai, Euthymics, Forest Laboratories, GlaxoSmithKline, GW Pharma, Human Genome Sciences, i3 Research, ICON, IntelGenx Corp., Intracellular Therapies, Johnson and Johnson, Kendle Early Stage, Lilly USA, Lundbeck A/S, Lundbeck USA, MedImmune, Medtronic, Merck and Co., Inc.; , Neurosearch, Next Wave Pharmaceuticals, Novartis, Noven, Novo-Nordisk, Orexigen, Otsuka, Parexel, Pfizer, PGx Health, PPDI, Psyadon; QED, Quintiles, Reckitt Benckiser, Roche, Sanofi-Aventis, Schering-Plough Corporation, SCOPE International, Sepracor, Inc./Sunovion, Shire, Siena Biotech, Supernus, Synosia Therapeutics, Takeda-Pharmaceutical Company, Theravance, Upsher Smith, Valeant Pharmaceuticals, Vivus, Inc.,World Wide Clinical Trials, and Wyeth Research. Dr. Posner has received royalty payments from the electronic Columbia Suicide Severity Rating Scale (e-CSSRS) Dr. Kastelic and Ms. Lazzaretto, and Ms Bauzo-Rosario report no biomedical financial interests or potential conflicts of interest. NR 67 TC 49 Z9 50 U1 9 U2 52 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2013 VL 52 IS 3 BP 264 EP 278 DI 10.1016/j.jaac.2012.12.007 PG 15 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 099YA UT WOS:000315660700009 PM 23452683 ER PT J AU Roy, AK Fudge, JL Kelly, C Perry, JSA Daniele, T Carlisi, C Benson, B Castellanos, FX Milham, MP Pine, DS Ernst, M AF Roy, Amy K. Fudge, Julie L. Kelly, Clare Perry, Justin S. A. Daniele, Teresa Carlisi, Christina Benson, Brenda Castellanos, F. Xavier Milham, Michael P. Pine, Daniel S. Ernst, Monique TI Intrinsic Functional Connectivity of Amygdala-Based Networks in Adolescent Generalized Anxiety Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE generalized anxiety disorder (GAD); amygdala; intrinsic functional connectivity; functional magnetic resonance imaging (fMRI) ID PREFRONTAL CORTEX ACTIVATION; EMOTION REGULATION; FEAR RESPONSES; ANGRY FACES; CHILDREN; COMORBIDITY; CHILDHOOD; BRAIN; NEUROBIOLOGY; STIMULATION AB Objective: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the present study examines this issue in adolescents with GAD. Method: Resting state fMRI scans were obtained from 15 adolescents with GAD and 20 adolescents without anxiety who were group matched on age, sex, scanner, and intelligence. Functional connectivity of the centromedial, basolateral, and superficial amygdala subdivisions was compared between groups. We also assessed the relationship between amygdala network dysfunction and anxiety severity. Results: Adolescents with GAD exhibited disruptions in amygdala-based intrinsic functional connectivity networks that included regions in medial prefrontal cortex, insula, and cerebellum. Positive correlations between anxiety severity scores and amygdala functional connectivity with insula and superior temporal gyrus were also observed within the GAD group. There was some evidence of greater overlap (less differentiation of connectivity patterns) of the right basolateral and centromedial amygdala networks in the adolescents with, relative to those without, GAD. Conclusions: These findings suggest that adolescents with GAD manifest alterations in amygdala circuits involved in emotion processing, similar to findings in adults. In addition, disruptions were observed in amygdala-based networks involved in fear processing and the coding of interoceptive states. J. Am. Acad. Child Adolesc. Psychiatry; 2013; 52(3):290-299. C1 [Roy, Amy K.; Perry, Justin S. A.] Fordham Univ, Bronx, NY 10458 USA. [Fudge, Julie L.] Univ Rochester, Sch Med & Dent, Rochester, NY 14627 USA. [Kelly, Clare; Castellanos, F. Xavier] NYU, Langone Sch Med, Ctr Child Study, Phyllis Green & Randolph Cowen Inst Pediat Neuros, New York, NY 10003 USA. [Castellanos, F. Xavier; Milham, Michael P.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. [Milham, Michael P.] Child Mind Inst, New York, NY USA. [Daniele, Teresa; Carlisi, Christina; Benson, Brenda; Pine, Daniel S.; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, Rockville, MD USA. RP Roy, AK (reprint author), Fordham Univ, Dept Psychol, 441 East Fordham Rd, Bronx, NY 10458 USA. EM aroy3@fordham.edu RI Roy, Amy/J-7613-2013; Milham, Michael/K-9501-2014; Kelly, Clare/H-4629-2016; OI Kelly, Clare/0000-0001-8253-357X; Carlisi, Christina/0000-0002-0942-8586; Castellanos, Francisco/0000-0001-9192-9437 FU NIMH [K23 MH074821] FX The project described was supported by NIMH Career Development Award K23 MH074821 (A.K.R.). NR 57 TC 49 Z9 50 U1 4 U2 51 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2013 VL 52 IS 3 BP 290 EP 299 DI 10.1016/j.jaac.2012.12.010 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 099YA UT WOS:000315660700011 PM 23452685 ER PT J AU Dickinson, WP Glasgow, RE Fisher, L Dickinson, LM Christensen, SM Estabrooks, PA Miller, BF AF Dickinson, W. Perry Glasgow, Russell E. Fisher, Lawrence Dickinson, L. Miriam Christensen, Steven M. Estabrooks, Paul A. Miller, Benjamin F. TI Use of a Website to Accomplish Health Behavior Change: If You Build It, Will They Come? And Will It Work If They Do? SO JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE LA English DT Article DE Behavior Modification; Health Care Systems; Health Services; Lifestyle; Practice-based Research; Primary Health Care ID COMPUTER-ASSISTED INTERVENTION; BRIEF DIETARY ASSESSMENT; IMPROVING PRIMARY-CARE; SELF-MANAGEMENT; CHRONIC ILLNESS; PHYSICAL-ACTIVITY; COUNSELING INTERVENTIONS; AUTONOMY SUPPORT; OUTCOMES; PREVENTION AB Purpose: This article describes the development, implementation, and effectiveness of 2 interactive websites designed to support health behavior change around healthy eating, physical activity, smoking, and use of alcohol for primary care patients. Methods: Patients from 6 primary care practices were recruited and randomized to a basic website (including a health assessment with feedback of the results and educational materials about health behavior change) or an enhanced website that included the features of the basic site plus an action planning component. Patients were prompted to return for follow-up assessments at 3 and 6 months after enrollment. Results: Of 7706 participants, 169 (2.2%) targeted for recruitment actually used the website. Both web-based interventions seemed to assist patients with making positive changes in their behavior, especially activity level and healthful diet. There were no significant differences in the effectiveness of the basic and enhanced websites. Conclusions: Interactive behavior-change technology interventions can assist primary care patients and practices in health behavior change activities. Difficulties with patient recruitment and the lack of added effectiveness of the enhanced website suggest that such interventions work better if integrated into the interaction between primary care clinicians and patients rather than as a standalone intervention. (J Am Board Fam Med 2013; 26: 168-176.) C1 [Dickinson, W. Perry; Dickinson, L. Miriam; Miller, Benjamin F.] Univ Colorado Denver, Dept Family Med, Aurora, CO 80045 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fisher, Lawrence] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Christensen, Steven M.] InterVis Media, Eugene, OR USA. [Estabrooks, Paul A.] Virginia Tech, Dept Human Nutr Foods & Exercise, Blacksburg, VA USA. RP Dickinson, WP (reprint author), Univ Colorado Denver, Dept Family Med, Acad Off 1, Mail Stop F496,12631 East 17th Ave,Room 3223, Aurora, CO 80045 USA. EM perry.dickinson@ucdenver.edu OI Miller, Benjamin/0000-0003-1647-0122 FU Robert Wood Johnson Foundation FX The Robert Wood Johnson Foundation provided the funding for this project through its Prescription for Health initiative. NR 43 TC 7 Z9 8 U1 3 U2 28 PU AMER BOARD FAMILY MEDICINE PI LEXINGTON PA 2228 YOUNG DR, LEXINGTON, KY 40505 USA SN 1557-2625 J9 J AM BOARD FAM MED JI J. Am. Board Fam. Med. PD MAR-APR PY 2013 VL 26 IS 2 BP 168 EP 176 DI 10.3122/jabfm.2013.02.110344 PG 9 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 103US UT WOS:000315945600009 PM 23471930 ER PT J AU Sullivan, R Kowalczyk, JR Agarwal, B Ladenstein, R Fitzgerald, E Barr, R Steliarova-Foucher, E Magrath, I Howard, SC Kruger, M Valsecchi, MG Biondi, A Grundy, P Smith, MA Adamson, P Vassal, G Pritchard-Jones, K AF Sullivan, Richard Kowalczyk, Jerzy R. Agarwal, Bharat Ladenstein, Ruth Fitzgerald, Edel Barr, Ronald Steliarova-Foucher, Eva Magrath, Ian Howard, Scott C. Kruger, Mariana Valsecchi, Maria Grazia Biondi, Andrea Grundy, Paul Smith, Malcolm A. Adamson, Peter Vassal, Gilles Pritchard-Jones, Kathy TI New policies to address the global burden of childhood cancers SO LANCET ONCOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MIDDLE-INCOME COUNTRIES; PEDIATRIC ONCOLOGY; CLINICAL-TRIALS; ADULT SURVIVORS; HEALTH; CHILDREN; EUROPE; EPIDEMIOLOGY; OUTCOMES AB Childhood cancer is a major global health issue. Every year, almost 100 000 children die from cancer before the age of 15 years, more than 90% of them in resource-limited countries. Here, we review the key policy issues for the delivery of better care, research, and education of professionals and patients. We present a key list of time-limited proposals focusing on change to health systems and research and development. These include sector and system reforms to make care affordable to all, policies to promote growth of civil society around both cancer and Millennium Development Goals, major improvements to public health services (particularly the introduction of national cancer plans), improved career development, and increased remuneration of specialist health-care workers and government support for childhood cancer registries. Research and development proposals focus on sustainable funding, the establishment of more research networks, and clinical research specifically targeted at the needs of low-income and middle-income countries. Finally, we present proposals to address the need for clinical trial innovation, the complex dichotomy of regulations, and the threats to the availability of data for childhood cancers. C1 [Sullivan, Richard] Kings Hlth Partners Integrated Canc Ctr, Inst Canc Policy, London SE1 9RT, England. [Kowalczyk, Jerzy R.] Med Univ, Dept Paediat Haematol Oncol & Transplantol, Lublin, Poland. [Agarwal, Bharat] B J Wadia Hosp Children, Dept Paediat Haematol & Oncol, Bombay, Maharashtra, India. [Ladenstein, Ruth] St Anna Childrens Hosp, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Fitzgerald, Edel] European Org Res Treatment Canc, Brussels, Belgium. [Barr, Ronald] McMaster Univ, Dept Pathol, Hamilton, ON, Canada. [Barr, Ronald] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Steliarova-Foucher, Eva] Int Agcy Res Canc, F-69372 Lyon, France. [Magrath, Ian] Int Network Canc Treatment & Res, Brussels, Belgium. [Howard, Scott C.] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Kruger, Mariana] Univ Stellenbosch, Dept Paediat & Child Hlth, Fac Med & Hlth Sci, Cape Town, South Africa. [Valsecchi, Maria Grazia] Univ Milano Bicocca, Ctr Biostat Clin Epidemiol, Monza, Italy. [Biondi, Andrea] Univ Milano Bicocca, Dept Paediat, Monza, Italy. [Grundy, Paul] Alberta Hlth Serv, Edmonton, AB, Canada. [Smith, Malcolm A.] NIH, Rockville, MD USA. [Adamson, Peter] Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Vassal, Gilles] Inst Gustave Roussy, Villejuif, France. [Pritchard-Jones, Kathy] UCL, Inst Child Hlth, London, England. RP Sullivan, R (reprint author), Kings Hlth Partners Integrated Canc Ctr, Inst Canc Policy, Guys Hosp Campus, London SE1 9RT, England. EM richard.sullivan@kcl.ac.uk RI Howard, Scott/K-3401-2013; Pritchard-Jones, Kathy/F-4286-2014; OI Howard, Scott/0000-0003-2244-1686; Pritchard-Jones, Kathy/0000-0002-2384-9475; Sullivan, Richard/0000-0002-6435-1825 FU European Union's Seventh Framework Programme under European Network for Cancer Research in Children and Adolescents project [261474] FX This work has received funding from the European Union's Seventh Framework Programme (FP7/2007-13) under the European Network for Cancer Research in Children and Adolescents project (grant number 261474). NR 57 TC 29 Z9 30 U1 1 U2 16 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 MAR PY 2013 VL 14 IS 3 BP E125 EP E135 DI 10.1016/S1470-2045(13)70007-X PG 11 WC Oncology SC Oncology GA 103OV UT WOS:000315928800019 PM 23434339 ER PT J AU Andersen, SW Trentham-Dietz, A Figueroa, JD Titus, LJ Cai, QY Long, JR Hampton, JM Egan, KM Newcomb, PA AF Andersen, Shaneda Warren Trentham-Dietz, Amy Figueroa, Jonine D. Titus, Linda J. Cai, Qiuyin Long, Jirong Hampton, John M. Egan, Kathleen M. Newcomb, Polly A. TI Breast cancer susceptibility associated with rs1219648 (fibroblast growth factor receptor 2) and postmenopausal hormone therapy use in a population-based United States study SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Breast cancer; Genetics; Hormone therapy; Gene-environment interaction; Epidemiology ID GENOME-WIDE ASSOCIATION; AFRICAN-AMERICAN; FGFR2; RISK; VARIANTS; WOMEN; LOCI; GENE; DNA AB Objective: Genomewide association studies have consistently found variants in fibroblast growth factor receptor 2 (FGFR2) to be associated with breast cancer. Recent reports suggest that postmenopausal hormone therapy (HT) use may modify the association between single nucleotide polymorphisms (SNPs) in FGFR2 and breast cancer risk. We assessed the hypothesis that the association between rs1219648 (FGFR2) SNP and breast cancer risk is modified by postmenopausal HT use in a population-based case-control study. Methods: We evaluated rs1219648 SNP for an association with breast cancer risk using data obtained from 869 postmenopausal breast cancer cases diagnosed between 1995 and 2000 and from 808 postmenopausal community controls who participated in a study conducted in three US states. Detailed postmenopausal HT information was collected through a structured telephone interview, and DNA samples were collected by mail using an established mouthwash protocol. Odds ratios and 95% confidence intervals (CIs) were calculated using logistic regression models adjusted for age and state of residence. Results: We observed a significant association between rs1219648 and breast cancer risk (per-allele odds ratio, 1.22; 95% CI, 1.06-1.41; P = 0.007), which did not vary significantly by ever use of estrogen plus progestogen therapy (interaction P = 0.48). There was stronger evidence of an interaction between ever use of estrogen-only HT and increasing number of rs1219648 risk alleles to increase breast cancer risk (interaction P = 0.08). Conclusions: Our results are consistent with a risk association with FGFR2 but provide limited support for interaction with HT use. The study raises the possibility that the FGFR2 rs1219648 variant is more strongly associated with risk in estrogen-only hormone users, although this observation needs to be examined in larger studies. C1 [Andersen, Shaneda Warren; Trentham-Dietz, Amy; Hampton, John M.; Newcomb, Polly A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53726 USA. [Andersen, Shaneda Warren; Trentham-Dietz, Amy] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI 53726 USA. [Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Titus, Linda J.] Dartmouth Med Sch, Norris Cotton Canc Ctr, Lebanon, NH USA. [Cai, Qiuyin; Long, Jirong] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. [Egan, Kathleen M.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, Tampa, FL 33612 USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. RP Andersen, SW (reprint author), Univ Wisconsin, Carbone Canc Ctr, Room 307,610 Walnut St, Madison, WI 53726 USA. EM snandersen@wisc.edu FU National Institutes of Health Cancer Institute [CA47147, CA47305, CA69664, CA82004]; Avon Foundation; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services; National Institutes of Health [R01CA124558]; Vanderbilt-Ingram Cancer Center [P30 CA68485] FX This work was supported by grants from the National Institutes of Health Cancer Institute (grants CA47147, CA47305, CA69664, and CA82004) and the Avon Foundation, and by the Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services. Genotyping assays were supported by the National Institutes of Health (grant R01CA124558) and performed at the Vanderbilt University Survey and Biospecimen Share Resource, which was supported, in part, by the Vanderbilt-Ingram Cancer Center (grant P30 CA68485). NR 18 TC 4 Z9 4 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD MAR PY 2013 VL 20 IS 3 BP 354 EP 358 DI 10.1097/gme.0b013e318268ca46 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 099EN UT WOS:000315603200019 PM 23435034 ER PT J AU Holmstock, N Gonzalez, FJ Baes, M Annaert, P Augustijns, P AF Holmstock, Nico Gonzalez, Frank J. Baes, Myriam Annaert, Pieter Augustijns, Patrick TI PXR/CYP3A4-Humanized Mice for Studying Drug-Drug Interactions Involving Intestinal P-Glycoprotein SO MOLECULAR PHARMACEUTICS LA English DT Article DE in situ intestinal perfusion; humanized mouse; PXR; P-glycoprotein; rifampicin; darunavir ID PREGNANE-X-RECEPTOR; CYTOCHROME-P450 3A4; CACO-2 MONOLAYERS; RITONAVIR; PERFUSION; SULFORAPHANE; INHIBITION; ABSORPTION; EXPRESSION; RIFAMPICIN AB Rodent models are less suitable for predicting drug drug interactions at the level of the human intestinal mucosa, especially when nuclear receptors such as pregnane X receptor (PXR) are involved. Recently, a transgenic mouse model, expressing both human PXR and CYP3A4, was developed and shown to be a better predictor of CYP3A4 induction by xenobiotics in humans as compared to wild-type mice. In the present study, we tested the hypothesis that this mouse model can also predict PXR-mediated induction of intestinal P-gp in humans. By use of the in situ intestinal perfusion technique with mesenteric blood sampling, the effect of oral rifampicin treatment on intestinal permeability for the HIV protease inhibitor darunavir, a dual CYP3A4/P-gp substrate, was investigated. Rifampicin treatment lowered the intestinal permeability for darunavir by 50% compared to that in nontreated mice. The P-gp inhibitor GF120918 increased the permeability for darunavir by 400% in rifampicin-treated mice, whereas this was only 56% in mice that were not treated, thus indicating P-gp induction by rifampicin. The nonspecific P450 inhibitor aminobenzotriazole (100 mu M) did not affect the permeability for darunavir. Quantitative Western blot analysis of the intestinal tissue showed that rifampicin treatment induced intestinal P-gp levels 4-fold, while CYP3A4 levels remained unchanged. Oral co-administration of rifampicin with the phytochemical sulforaphane for 3 days increased the permeability for darunavir by 50% compared to that with rifampicin treatment alone. These data show that PXR/CYP3A4-humanized mice can be used to study the inducing effects of xenobiotics on intestinal P-gp. C1 [Holmstock, Nico; Annaert, Pieter; Augustijns, Patrick] Katholieke Univ Leuven, Lab Drug Delivery & Disposit, B-3000 Louvain, Belgium. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Baes, Myriam] Katholieke Univ Leuven, Lab Cell Metab, B-3000 Louvain, Belgium. RP Augustijns, P (reprint author), Katholieke Univ Leuven, Lab Drug Delivery & Disposit, Campus Gasthuisberg,O&N 2,Herestr 49 Box 921, B-3000 Louvain, Belgium. EM patrick.augustijns@pharm.kuleuven.be FU Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT); Fund for Scientific Research in Flanders (FWO); 'Onderzoeksfonds' of the KU Leuven in Belgium FX We would like to thank Lies Pauwels for performing the Western blot analysis. We would also like to thank the National Institutes of Health AIDS Research and Reference Reagent Program for providing darunavir and Johnson & Johnson for providing R426857. This research was funded by grants from (1) Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT), (2) Fund for Scientific Research in Flanders (FWO), and (3) 'Onderzoeksfonds' of the KU Leuven in Belgium. NR 26 TC 10 Z9 11 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD MAR PY 2013 VL 10 IS 3 BP 1056 EP 1062 DI 10.1021/mp300512r PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 101GP UT WOS:000315763500026 PM 23360470 ER PT J AU Prasad, AB Mullikin, JC Green, ED AF Prasad, Arjun B. Mullikin, James C. Green, Eric D. CA NISC Comparative Sequencing Progra TI A scalable and flexible approach for investigating the genomic landscapes of phylogenetic incongruence SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE Incongruence; Lineage sorting; Maximum likelihood; Homo-Pan-Gorilla; Platyrrhini ID MAMMALIAN EVOLUTION; LIKELIHOOD APPROACH; SPECIES TREES; GENE TREES; SEQUENCE; RECOMBINATION; DNA; CONGRUENCE; INFERENCE; INSIGHTS AB Analyses of DNA sequence datasets have repeatedly revealed inconsistencies in phylogenetic trees derived with different data. This is termed phylogenetic incongruence, and may arise from a methodological failure of the inference process or from biological processes, such as horizontal gene transfer, incomplete lineage sorting, and introgression. To better understand patterns of incongruence, we developed a method (PartFinder) that uses likelihood ratios applied to sliding windows for visualizing tree-support changes across genome-sequence alignments, allowing the comparative examination of complex phylogenetic scenarios among many species. As a pilot, we used PartFinder to investigate incongruence in the Homo-Pan-Gorilla group as well as Platyrrhini using high-quality bacterial artificial chromosome (BAC)-derived sequences as well as assembled whole-genome shotgun sequences. Our simulations verified the sensitivity of PartFinder, and our results were comparable to other studies of the Homo-Pan-Gorilla group. Analyses of the whole-genome alignments reveal significant associations between support for the accepted species relationship and specific characteristics of the genomic regions, such as GC-content, alignment score, exon content, and conservation. Finally, we analyzed sequence data generated for five platyrrhine species, and found incongruence that suggests a polytomy within Cebidae, in particular. Together, these studies demonstrate the utility of PartFinder for investigating the patterns of phylogenetic incongruence. Published by Elsevier Inc. C1 [Prasad, Arjun B.; Mullikin, James C.; Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; Green, Eric D.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Prasad, AB (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM aprasad@nhgri.nih.gov OI Prasad, Arjun/0000-0002-1343-8664 FU National Human Genome Research Institute, National Institutes of Health FX We thank Aida Andres, Megan Dennis, Joe Ryan, Praveen Cherukuri, Pedro Cruz, Nancy Hansen, and Jamie Teer for ideas and discussion during the development of this work. We thank members of the NISC Comparative Sequencing Program (particularly B. Blakesley, G. Bouffard, J. Idol, V. Maduro, J. McDowell, B. Maskeri, M. Park, J. Thomas, and P. Thomas) for providing leadership in the generation of the targeted comparative sequence data analyzed here. This work was supported by Intramural Research Programs of the National Human Genome Research Institute, National Institutes of Health. NR 67 TC 2 Z9 2 U1 0 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 EI 1095-9513 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD MAR PY 2013 VL 66 IS 3 BP 1067 EP 1074 DI 10.1016/j.ympev.2012.11.023 PG 8 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 098MM UT WOS:000315553400044 PM 23247042 ER PT J AU Dolgin, E Nabel, G AF Dolgin, Elie Nabel, Gary TI Straight talk with ... Gary Nabel SO NATURE MEDICINE LA English DT Editorial Material C1 [Nabel, Gary] US Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, Bethesda, MD USA. [Nabel, Gary] French Drug Giant Sanofi, Basic Res Operat, Cambridge, MA USA. [Nabel, Gary] Sanofi, Strateg Dev & Sci Advisory Council, Alnwick, England. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2013 VL 19 IS 3 BP 256 EP 256 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 105BN UT WOS:000316040700009 ER PT J AU Chatterjee, SS Joo, HS Duong, AC Dieringer, TD Tan, VY Song, Y Fischer, ER Cheung, GYC Li, M Otto, M AF Chatterjee, Som S. Joo, Hwang-Soo Duong, Anthony C. Dieringer, Thomas D. Tan, Vee Y. Song, Yan Fischer, Elizabeth R. Cheung, Gordon Y. C. Li, Min Otto, Michael TI Essential Staphylococcus aureus toxin export system SO NATURE MEDICINE LA English DT Article ID PHENOL-SOLUBLE MODULINS; VIRULENCE DETERMINANTS; BACTERIAL VIRULENCE; EPIDERMIDIS; PEPTIDES; INFECTION; INACTIVATION; PATHOGENESIS; EXPRESSION; BIOFILMS AB Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus(1) calls for alternative routes of drug development. Interfering with crucial virulence determinants is considered a promising new approach to control bacterial infection(2). Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis(3-5) and have a major impact on the ability of highly virulent S. aureus to cause disease(3,6). However, targeting PSMs for therapeutic intervention is hampered by their multitude and diversity. Here we report that an ATP-binding cassette transporter with previously unknown function is responsible for the export of all PSMs, thus representing a single target for complete obstruction of PSM production. The transporter had a strong effect on virulence phenotypes, such as neutrophil lysis, and the extent of its effect on the development of S. aureus infection was similar to that of the sum of all PSMs. Notably, the transporter was essential for bacterial growth. Furthermore, it contributed to producer immunity toward secreted PSMs and defense against PSM-mediated bacterial interference. Our study reveals a noncanonical, dedicated secretion mechanism for an important class of toxins and identifies this mechanism as a comprehensive potential target for the development of drugs to efficiently inhibit the growth and virulence of pathogenic staphylococci. C1 [Chatterjee, Som S.; Joo, Hwang-Soo; Duong, Anthony C.; Dieringer, Thomas D.; Tan, Vee Y.; Cheung, Gordon Y. C.; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Song, Yan; Li, Min] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Lab Med, Shanghai 200433, Peoples R China. [Fischer, Elizabeth R.] NIAID, Microscopy Unit, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI JOO, HWANG-SOO/0000-0003-4668-3225; Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); US National Institutes of Health (NIH) [ZIA AI000904-10]; National Natural Science Foundation of China [30900026, 81171623, 81261120387] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH) (grant ZIA AI000904-10) to M.O. and the National Natural Science Foundation of China (grants 30900026, 81171623 and 81261120387) to M.L. We thank J. Kok (University of Groningen), F. Lowy (Columbia University) and G. Dunny (University of Minnesota) for lactococcal strains and plasmids and A. Peschel for critically reading the manuscript. NR 29 TC 44 Z9 44 U1 2 U2 37 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 MAR PY 2013 VL 19 IS 3 BP 364 EP 367 DI 10.1038/nm.3047 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 105BN UT WOS:000316040700031 PM 23396209 ER PT J AU Park, SR Davis, M Doroshow, JH Kummar, S AF Park, Sook Ryun Davis, Myrtle Doroshow, James H. Kummar, Shivaani TI Safety and feasibility of targeted agent combinations in solid tumours SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID RENAL-CELL CARCINOMA; PHASE-II TRIAL; METASTATIC BREAST-CANCER; GROWTH-FACTOR RECEPTOR; BEVACIZUMAB PLUS ERLOTINIB; TYROSINE KINASE INHIBITOR; ADVANCED HEPATOCELLULAR-CARCINOMA; PANCREATIC NEUROENDOCRINE TUMORS; PREVIOUSLY TREATED PATIENTS; GYNECOLOGIC-ONCOLOGY-GROUP AB The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations. Park, S. R. et al. Nat. Rev. Clin. Oncol. 10,154-168; published online 29 January 2013; doi:10.1038/nrclinonc.2012.245 C1 [Park, Sook Ryun; Davis, Myrtle; Doroshow, James H.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kummar, S (reprint author), NCI, Div Canc Treatment & Diag, Ctr Canc Res, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov NR 151 TC 18 Z9 20 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD MAR PY 2013 VL 10 IS 3 BP 154 EP 168 DI 10.1038/nrclinonc.2012.245 PG 15 WC Oncology SC Oncology GA 104FE UT WOS:000315976400006 PM 23358316 ER PT J AU Brooke, CB Yewdell, JW AF Brooke, Christopher B. Yewdell, Jonathan W. TI Host versus flu: antibodies win a round? SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID INFLUENZA-VIRUS; MONOCLONAL-ANTIBODIES; HEMAGGLUTININ; SITES; HIV-1; H2N2 AB Structural and functional analyses of three neutralizing antibodies against influenza virus H2 HA may explain why this HA subtype has disappeared from circulation in the human population and point to a potential new avenue for antiflu therapeutics. C1 [Brooke, Christopher B.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Brooke, CB (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Intramural NIH HHS [ZIA AI001055-05] NR 16 TC 2 Z9 2 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2013 VL 20 IS 3 BP 245 EP 246 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 105BQ UT WOS:000316041000001 PM 23463305 ER PT J AU Cavalli, G Misteli, T AF Cavalli, Giacomo Misteli, Tom TI Functional implications of genome topology SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Review ID DOUBLE-STRAND BREAKS; NUCLEAR LAMINA INTERACTIONS; RECURRENT CHROMOSOMAL TRANSLOCATIONS; DNA-REPLICATION ORIGINS; LONG-RANGE INTERACTION; EMBRYONIC STEM-CELLS; GENE-EXPRESSION; DROSOPHILA GENOME; CHROMATIN INTERACTIONS; INTERCHROMOSOMAL ASSOCIATIONS AB Although genomes are defined by their sequence, the linear arrangement of nucleotides is only their most basic feature. A fundamental property of genomes is their topological organization in three-dimensional space in the intact cell nucleus. The application of imaging methods and genome-wide biochemical approaches, combined with functional data, is revealing the precise nature of genome topology and its regulatory functions in gene expression and genome maintenance. The emerging picture is one of extensive self-enforcing feedback between activity and spatial organization of the genome, suggestive of a self-organizing and self-perpetuating system that uses epigenetic dynamics to regulate genome function in response to regulatory cues and to propagate cell-fate memory. C1 [Cavalli, Giacomo] CNRS, UPR 1142, Inst Genet Humaine, Montpellier, France. [Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Cavalli, G (reprint author), CNRS, UPR 1142, Inst Genet Humaine, Montpellier, France. EM giacomo.cavalli@igh.cnrs.fr; mistelit@mail.nih.gov RI cavalli, giacomo/A-7958-2008 OI cavalli, giacomo/0000-0003-3709-3469 FU European Research Council [232947]; Centre National de la Recherche Scientifique; European Network of Excellence EpiGeneSys; Agence Nationale de la Recherche; Intramural Research Program of the US National Institutes of Health, the National Cancer Institute, the Center for Cancer Research FX G.C. was supported by the European Research Council (ERC-2008-AdG No 232947), the Centre National de la Recherche Scientifique, the European Network of Excellence EpiGeneSys and the Agence Nationale de la Recherche. T.M. was supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute, the Center for Cancer Research. NR 135 TC 151 Z9 154 U1 0 U2 61 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2013 VL 20 IS 3 BP 290 EP 299 DI 10.1038/nsmb.2474 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 105BQ UT WOS:000316041000010 PM 23463314 ER PT J AU Kouzine, F Gupta, A Baranello, L Wojtowicz, D Ben-Aissa, K Liu, JH Przytycka, TM Levens, D AF Kouzine, Fedor Gupta, Ashutosh Baranello, Laura Wojtowicz, Damian Ben-Aissa, Khadija Liu, Juhong Przytycka, Teresa M. Levens, David TI Transcription-dependent dynamic supercoiling is a short-range genomic force SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; TOPOLOGICAL DOMAIN SIZE; DNA TOPOISOMERASE-II; SHOCK GENE LOCUS; IN-VIVO; TORSIONAL TENSION; BETA-LAPACHONE; UPSTREAM DNA; HUMAN-CELLS; YEAST AB Transcription has the capacity to mechanically modify DNA topology, DNA structure and nucleosome arrangement. Resulting from ongoing transcription, these modifications in turn may provide instant feedback to the transcription machinery. To substantiate the connection between transcription and DNA dynamics, we charted an ENCODE map of transcription-dependent dynamic supercoiling in human Burkitt's lymphoma cells by using psoralen photobinding to probe DNA topology in vivo. Dynamic supercoils spread similar to 1.5 kilobases upstream of the start sites of active genes. Low- and high-output promoters handled this torsional stress differently, as shown by using inhibitors of transcription and topoisomerases and by chromatin immunoprecipation of RNA polymerase and topoisomerases I and II. Whereas lower outputs are managed adequately by topoisomerase I, high-output promoters additionally require topoisomerase II. The genome-wide coupling between transcription and DNA topology emphasizes the importance of dynamic supercoiling for gene regulation. C1 [Kouzine, Fedor; Gupta, Ashutosh; Baranello, Laura; Levens, David] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Gupta, Ashutosh] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Wojtowicz, Damian; Przytycka, Teresa M.] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. [Ben-Aissa, Khadija] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Liu, Juhong] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Levens, D (reprint author), NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. EM levens@helix.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural Research Program of the US National Institutes of Health, National Cancer Institute and Center for Cancer Research; National Library of Medicine and Food and Drug Administration FX Our research is supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute and Center for Cancer Research, National Library of Medicine and Food and Drug Administration. This study used the high-performance computational capabilities of the Helix Systems at the National Institutes of Health, Bethesda, Maryland (http://helix.nih.gov/). We thank R. Casellas and A. Yamane for Illumina sequencing, and D. Clark and E. Batchelor for critical comments. NR 60 TC 73 Z9 73 U1 3 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2013 VL 20 IS 3 BP 396 EP 403 DI 10.1038/nsmb.2517 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 105BQ UT WOS:000316041000023 PM 23416947 ER PT J AU Bleck, TP Nowinski, CJ Gershon, R Koroshetz, WJ AF Bleck, Thomas P. Nowinski, Cindy J. Gershon, Richard Koroshetz, Walter J. TI What is the NIH Toolbox, and what will it mean to neurology? SO NEUROLOGY LA English DT Editorial Material C1 [Bleck, Thomas P.] Rush Med Coll, Dept Neurol Sci, Chicago, IL 60612 USA. [Bleck, Thomas P.] Rush Med Coll, Dept Neurosurg, Chicago, IL 60612 USA. [Bleck, Thomas P.] Rush Med Coll, Dept Med, Chicago, IL 60612 USA. [Bleck, Thomas P.] Rush Med Coll, Dept Anesthesiol, Chicago, IL 60612 USA. [Nowinski, Cindy J.; Gershon, Richard] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. RP Bleck, TP (reprint author), Rush Med Coll, Dept Neurol Sci, Chicago, IL 60612 USA. EM tbleck@gmail.com OI Bleck, Thomas/0000-0002-8267-9787 NR 4 TC 2 Z9 2 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 IS 10 BP 874 EP 875 DI 10.1212/WNL.0b013e3182872ea0 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 101KI UT WOS:000315773500005 PM 23460616 ER PT J AU Haubenberger, D McCrossin, G Lungu, C Considine, E Toro, C Nahab, FB Auh, S Buchwald, P Grimes, GJ Starling, J Potti, G Scheider, L Kalowitz, D Bowen, D Carnie, A Hallett, M AF Haubenberger, Dietrich McCrossin, Gayle Lungu, Codrin Considine, Elaine Toro, Camilo Nahab, Fatta B. Auh, Sungyoung Buchwald, Peter Grimes, George J. Starling, Judith Potti, Gopal Scheider, Linda Kalowitz, Daniel Bowen, Daniel Carnie, Andrea Hallett, Mark TI Octanoic acid in alcohol-responsive essential tremor A randomized controlled study SO NEUROLOGY LA English DT Article ID MOVEMENT-DISORDERS; OPEN-LABEL; 1-OCTANOL AB Objective: To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). Methods: We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures. Results: OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F-1,F-16 = 5.49, p = 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F-1,F-16 = 6.1, p = 0.025). Conclusions: Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels. Classification of evidence: This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes. Neurology (R) 2013;80:933-940 C1 [Haubenberger, Dietrich; McCrossin, Gayle; Lungu, Codrin; Considine, Elaine; Scheider, Linda; Kalowitz, Daniel; Bowen, Daniel; Carnie, Andrea; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Auh, Sungyoung] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. [Haubenberger, Dietrich] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Haubenberger, Dietrich] Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria. [Toro, Camilo] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Nahab, Fatta B.] Univ Miami, Miller Sch Med, Dept Neurol & Neurosci, Miami, FL 33136 USA. [Buchwald, Peter] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Grimes, George J.; Starling, Judith; Potti, Gopal] NIH, Pharmaceut Dev Sect, Bethesda, MD 20892 USA. RP Haubenberger, D (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM haubenberger@meduniwien.ac.at OI Buchwald, Peter/0000-0003-2732-8180 FU National Institute of Neurological Disorders and Stroke Intramural Research Program; Austrian Science Fund FWF (Erwin Schroedinger Fellowship) [J2783-B09]; International Essential Tremor Foundation; National Institute of Neurological Disorders and Stroke/NIH; Neurotoxin Institute; Ariston Pharmaceuticals; NIH/National Institute of Neurological Disorders and Stroke; US Department of Defense (Army); NIH (from Brainsway); NIH Intramural Program; US Army via the Henry Jackson Foundation; Ariston Pharmaceutical Company via a Cooperative Research and Development Agreement (CRADA) with the NIH; Kinetics Foundation via a Clinical Trials Agreement with the NIH FX D. Haubenberger received research support through the National Institute of Neurological Disorders and Stroke Intramural Research Program and the Austrian Science Fund FWF (Erwin Schroedinger Fellowship, project number J2783-B09). Dr. Haubenberger serves as member of the Medical Advisory Board of the International Essential Tremor Foundation. Dr. Haubenberger received honoraria and conference support from Ipsen and UCB. G. McCrossin reports no disclosures. C. Lungu, E. Considine, and C. Toro report no disclosures. F. Nahab has received research support from the International Essential Tremor Foundation, National Institute of Neurological Disorders and Stroke/NIH, and is an inventor for patent applications of 1-octanol and octanoic acid filed by the National Institute of Neurological Disorders and Stroke/NIH and Ariston. S. Auh, P. Buchwald, G. Grimes, J. Starling, G. Potti, L. Scheider, D. Kalowitz, and A. Carnie report no disclosures. M. Hallett serves as Chair of the Medical Advisory Board for and receives funding for travel from the Neurotoxin Institute; serves as Chair of the Medical Advisory Board of the Benign Essential Blepharospasm Foundation and Chair of the Medical Advisory Board of the International Essential Tremor Foundation; may accrue revenue on US Patent #6,780,413 B2 (issued August 24, 2004): immunotoxin (MAB-Ricin) for the treatment of focal movement disorders; US Patent #7,407,478 (issued August 5, 2008): coil for magnetic stimulation and methods for using the same; receives research support from Ariston Pharmaceuticals, NIH/National Institute of Neurological Disorders and Stroke (Intramural Program), and the US Department of Defense (Army); has received license fee payments from the NIH (from Brainsway) for licensing the patent for the H-coil. Dr. Hallett's research at the NIH is largely supported by the NIH Intramural Program. Supplemental research funds are provided by the US Army via the Henry Jackson Foundation, Ariston Pharmaceutical Company via a Cooperative Research and Development Agreement (CRADA) with the NIH, and the Kinetics Foundation via a Clinical Trials Agreement with the NIH. Dr. Hallett is an inventor for patent applications of 1-octanol and octanoic acid filed by National Institute of Neurological Disorders and Stroke/NIH and Ariston. Go to Neurology.org for full disclosures. NR 18 TC 10 Z9 10 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 IS 10 BP 933 EP 940 DI 10.1212/WNL.0b013e3182840c4f PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 101KI UT WOS:000315773500016 PM 23408867 ER PT J AU Mari, Z Rosenthal, LS Darwin, KC Hallett, M Jinnah, HA AF Mari, Zoltan Rosenthal, Liana S. Darwin, Kristin C. Hallett, Mark Jinnah, H. A. TI Clinical Reasoning: A 57-year-old man with jaw spasms SO NEUROLOGY LA English DT Editorial Material ID HEMIMASTICATORY SPASM C1 [Mari, Zoltan; Rosenthal, Liana S.; Darwin, Kristin C.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Jinnah, H. A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. RP Mari, Z (reprint author), Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. EM zmari1@jhmi.edu OI Rosenthal, Liana/0000-0001-5140-3967 FU Intramural NIH HHS [Z99 NS999999] NR 9 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 IS 10 BP E104 EP E107 DI 10.1212/WNL.0b013e318285c14a PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 101KI UT WOS:000315773500002 PM 23460623 ER PT J AU Beaumont, JL Havlik, R Cook, KF Hays, RD Wallner-Allen, K Korper, SP Lai, JS Nord, C Zill, N Choi, S Yost, KJ Ustsinovich, V Brouwers, P Hoffman, HJ Gershon, R AF Beaumont, Jennifer L. Havlik, Richard Cook, Karon F. Hays, Ron D. Wallner-Allen, Kathleen Korper, Samuel P. Lai, Jin-Shei Nord, Christine Zill, Nicholas Choi, Seung Yost, Kathleen J. Ustsinovich, Vitali Brouwers, Pim Hoffman, Howard J. Gershon, Richard TI Norming plans for the NIH Toolbox SO NEUROLOGY LA English DT Article AB Objective: The NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox) is a comprehensive battery of brief assessment tools. The purpose of this article is to describe plans to establish normative reference values for the NIH Toolbox measures. Methods: A large sample will be obtained from the US population for the purpose of calculating normative values. The sample will be stratified by age (ages 3-85 years), sex, and language preference (English or Spanish) and have a total sample size of at least 4,205. The sample will include a minimum of 25-100 individuals in each targeted demographic and language subgroup. Results: Norming methods will include poststratification adjustment calculated using iterative proportional fitting, also known as raking, so that the weighted sample will have the same distribution on key demographic variables as the US population described in the 2010 Census. Conclusions: As with any set of norms, users should be mindful of the reference population andmake conclusions consistent with the limitations of normative sampling, since it is not a probability-based sample. However, the NIH Toolbox norming study has been designed to minimize bias and maximize representativeness and precision of estimates. The availability of a "toolbox" of normed measures will be an important foundation for addressing critical research questions in neurologic and behavioral health. Neurology (R) 2013; 80 (Suppl3):S87-S92 C1 [Beaumont, Jennifer L.; Cook, Karon F.; Lai, Jin-Shei; Choi, Seung; Ustsinovich, Vitali; Gershon, Richard] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Havlik, Richard; Wallner-Allen, Kathleen; Korper, Samuel P.; Nord, Christine; Zill, Nicholas] Westat Corp, Philadelphia, PA USA. [Hays, Ron D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Yost, Kathleen J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Brouwers, Pim; Hoffman, Howard J.] NIH, Bethesda, MD 20892 USA. RP Beaumont, JL (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. EM j-beaumont@northwestern.edu RI Hays, Ronald/D-5629-2013 FU Blueprint for Neuroscience Research, NIH [HHS-N-260-2006-00007-C]; NIH [5RC1NR01180402, 1U5AR057943-01, N01-AG-6-0007, HHSN260200600007, AG-260-06-01, HD05469]; North American Neuroendocrine Tumor Symposium; Center for Psychiatric Rehabilitation Boston University; InvivoData; Xenoport; BrightOutcome; Veteran's Affairs Research and Development; National Institute on Disability and Rehabilitation Research (NIDDR); Agency for Healthcare Research and Quality (AHRQ); NIDDR [H133B090024]; AHRQ [1R03HS020700-01]; NIA [AG020679-01, P30AG021684, P30-AG028748]; NIAMS [UAR057936A, AR052177]; NCMHD [2P20MD000182]; Agency for Healthcare Research and Quality [U18 HS016980]; Allergan; UBC; VA; SciMetrika; Pfizer, Inc.; National Council for Adoption; Brookings Institution; Marriage and Religion Research Institute; National Institute of Neurological Disorders and Stroke [U01 NS 056 975 02]; NHLBI [K23: K23HL085766] FX This study was funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, NIH, under Contract No. HHS-N-260-2006-00007-C.; J. Beaumont served as a consultant for NorthShore University HealthSystems, FACIT. org, and Georgia Gastroenterology Group PC; and has received funding for travel as an invited speaker at the North American Neuroendocrine Tumor Symposium. R. Havlik reports no disclosures. K. Cook has received financial support from Center for Psychiatric Rehabilitation Boston University, InvivoData, Xenoport, BrightOutcome, the NIH, Veteran's Affairs Research and Development, National Institute on Disability and Rehabilitation Research (NIDDR), and Agency for Healthcare Research and Quality (AHRQ). In addition to Toolbox, Dr. Cook receives other funding from NIH (5RC1NR01180402 and 1U5AR057943-01). She also is currently supported by grants from NIDDR (H133B090024) and AHRQ (1R03HS020700-01). R. Hays received research funding from the NIA (AG020679-01, P30AG021684, P30-AG028748), NIAMS (UAR057936A, AR052177), NCMHD (2P20MD000182), and the Agency for Healthcare Research and Quality (U18 HS016980). He also received consulting money from Allergan, UBC, the VA, and SciMetrika. K. Wallner-Allen and S. Korper report no disclosures. J.-S. Lai has received research support from the NIH, Agency for Healthcare Research and Quality, and Pfizer, Inc. C. Nord reports no disclosures. N. Zill received research support from the National Council for Adoption, the Brookings Institution, and the Marriage and Religion Research Institute. He served as a reviewer for an NIH SBIR Review Panel. He holds a TIAA-CREF Retirement Annuity Contract that invests in US Treasury Bonds and an International Stock Index Fund. He received consulting income and income from selling stock and exercising stock options from Westat, an employee-owned S Corporation. He holds an IRA and brokerage account with Vanguard that includes holdings in the Vanguard Health Care, Precious Metals and Mining, HighYield Corporate Bond, High-Yield Tax Exempt Bond, and Long-Term Corporate Bond mutual funds, as well as the Vanguard Consumer Discretionary, Consumer Staples, FTSE International Small Cap, and Corporate Long-Term Bond Exchange Traded Funds. He has holdings in a number of closed-ended mutual funds, including the Aberdeen Asia Pacific Income Fund, Templeton Global High Income Fund, Templeton Dragon Fund, Alliance-Bernstein Global High-Income Fund, Alliance-Bernstein Corporate Income Fund, Blackrock Income Opportunity Trust, Putnam Master Intermediate Income Trust, Nuveen Floating Rate Income Opportunity Fund, India Fund, Morgan Stanley India Investment Fund, Latin American Discovery Fund, Aberdeen Latin American Equity Fund, Singapore Fund, and Turkish Investment Fund. He has stock holdings in AT& T, Boardwalk Pipeline Partners, Banco de Columbia, Consolidated Edison, Exxon, Frontier Communications, Glaxo-Smith Kline, Honeywell, Huntington Ingalls Industries, IBM, Intel, 3M, MeadWestvaco, Newell Rubbermaid, Northrop Grumman, Occidental Petroleum, SCANA, SherwinWilliams, Siemens, Southern, Verizon, Johnson Controls, American Superconductor, Ocean Power Technology, and Maxwell Technology. Dr. Zill's wife, Karen, prepared discussion guides for the Independent Lens program on PBS. She holds a TIAA Retirement Annuity Contract that invests in US Treasury Bonds. S. Choi has received research support from Boehringer-Ingelheim, Novartis, and the NIH. K. Yost, V. Ustsinovich, P. Brouwers, and H. Hoffman report no disclosures. R. Gershon has received personal compensation for activities as a speaker and consultant with Sylvan Learning, Rockman, and the American Board of Podiatric Surgery.; He has several grants awarded by NIH: N01-AG-6-0007, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469, National Institute of Neurological Disorders and Stroke: U01 NS 056 975 02, NHLBI K23: K23HL085766, NIA: 1RC2AG036498-01, NIDRR: H133B090024, OppNet: N01-AG-6-0007. Go to Neurology. org for full disclosures. NR 10 TC 18 Z9 18 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S87 EP S92 DI 10.1212/WNL.0b013e3182872e70 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100015 PM 23479550 ER PT J AU Coldwell, SE Mennella, JA Duffy, VB Pelchat, ML Griffith, JW Smutzer, G Cowart, BJ Breslin, PAS Bartoshuk, LM Hastings, L Victorson, D Hoffman, HJ AF Coldwell, Susan E. Mennella, Julie A. Duffy, Valerie B. Pelchat, Marcia L. Griffith, James W. Smutzer, Gregory Cowart, Beverly J. Breslin, Paul A. S. Bartoshuk, Linda M. Hastings, Lloyd Victorson, David Hoffman, Howard J. TI Gustation assessment using the NIH Toolbox SO NEUROLOGY LA English DT Article ID BITTER TASTE; PERCEPTION; SENSITIVITY; PREFERENCES; GENETICS; CHILDREN; DAMAGE AB The NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox) is a set of brief measures for the assessment of cognitive function, emotional health, motor function, and sensory function for use in clinical trials and in epidemiologic and longitudinal studies. Gustatory perception is assessed as 1 of 6 areas of sensory function. A team of 11 scientists with expertise in taste perception selected 2 gustatory measures, 1 of which can be used in young pediatric populations. The measure selected for young pediatric populations assesses sucrose (sweet) taste preference and can also be used across the age span of 5 to 85 years. For adult populations, the selected measure is a regional test, which assesses variability in perceived intensity of quinine hydrochloride (bitter) when applied to the tongue tip as well as perceived with the whole mouth. The team also recommends the regional test for assessing other tastants, such as sodium chloride (salty). Validation studies have demonstrated that the measures modified for the NIH Toolbox correlate with more traditional assessments, and can identify known population differences in gustation. Neurology (R) 2013; 80 (Suppl 3):S20-S24 C1 [Coldwell, Susan E.] Univ Washington, Sch Dent, Seattle, WA 98195 USA. [Mennella, Julie A.; Pelchat, Marcia L.; Cowart, Beverly J.; Breslin, Paul A. S.] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Duffy, Valerie B.] Univ Connecticut, Coll Agr & Nat Resources, Storrs, CT USA. [Griffith, James W.; Victorson, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Smutzer, Gregory] Temple Univ, Philadelphia, PA 19122 USA. [Breslin, Paul A. S.] Rutgers State Univ, Sch Environm & Biol Sci, New Brunswick, NJ 08903 USA. [Bartoshuk, Linda M.] Univ Florida, Gainesville, FL USA. [Hastings, Lloyd] Osmic Enterprises Inc, Cincinnati, OH USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RP Coldwell, SE (reprint author), Univ Washington, Sch Dent, Seattle, WA 98195 USA. EM scoldwel@u.washington.edu RI Griffith, James/O-2551-2016 OI Griffith, James/0000-0002-4840-8692 FU Blueprint for Neuroscience Research, NIH [HHS-N-260-2006-00007-C]; University of Washington through the State of Washington; NIH [HHS-N-260-2006-00007-C, DE018768-S1, DE14254, DE016750, TW009071, TW007768, HD37119, HD072307, DC011287, DC008613, DC00283]; GlaxoSmithKline; Pennsylvania Tobacco Settlement Fund, Kikkoman Company; Ajinomoto Company; NIH USDA Hatch Project [CONS00827]; USDA SNAPEd; PHS/Centers for Disease Control [S8056]; Action for Healthy Kids; Bel Brands, USA; NIH Toolbox; Monell Chemical Senses Center, Army Research Office (ARO) [W911NF-11-1-0087]; Suntory, Ltd.; Coca-Cola Company; NorthShore University HealthSystem; Cleveland Clinic Foundation/Teva Neurosciences, Inc.; Ironwood Pharmaceuticals, Inc.; Forest Laboratories, Inc.; Department of Defense (DOD)-United States Army; FWO, Belgium; NIH Toolbox for Neurological and Behavioral Function [HHS-N-260-2006-00007-C]; phase II SBIR entitled "Cellulose-Based Strips for Human Taste Evaluation"; Temple University Undergraduate Research Fund; Rutgers; State University of New Jersey; Monell Chemical Senses Center; Bill and Melinda Gates Foundation; Suntory Business Expert Ltd.; Takasago International Corporation, USA; NIDCD [DC283, DC8613]; American Cancer Society (national and Illinois Division) FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, NIH, under contract no. HHS-N-260-2006-00007-C.; S. Coldwell receives financial support from the University of Washington through the State of Washington and through the Washington Dental Service Endowed Professorship. Additional financial support has been provided by the NIH through grants, contracts, and cooperative agreement numbers DE018768-S1, DE14254, DE016750, TW009071, TW007768, and HHS-N-260-2006-00007-C (NIH Toolbox). Additionally, she serves as a member of the 2011 US Pediatric Formulations Initiative (PFI) Taste, Smell, and Flavor Research in Infants and Children Working Group through NIH. Dr. Coldwell has received research support from GlaxoSmithKline. Dr. Coldwell's husband holds stock in Ascentium Corporation and LifeEdited. J. Mennella is funded, in addition to NIH Toolbox, by NIH grants HD37119, HD072307, and DC011287, and has received investigator-initiated research support from the Pennsylvania Tobacco Settlement Fund, Kikkoman Company, and the Ajinomoto Company. V. Duffy is funded, in addition to the NIH Toolbox, by NIH DC008613, DC00283, NIH USDA Hatch Project CONS00827 funds, USDA SNAPEd, PHS/Centers for Disease Control S8056, Action for Healthy Kids. She has received financial support from Bel Brands, USA to present, as a scientific expert, at the Food and Nutrition Conference of the American Dietetic Association, speaking on the satiating effects on taste and texture. M. Pelchat has received financial support from NIH Toolbox, the Monell Chemical Senses Center, Army Research Office (ARO) W911NF-11-1-0087, the Ajinomoto Company, Suntory, Ltd., and the Coca-Cola Company. J. Griffith has received financial support from NorthShore University HealthSystem, the Cleveland Clinic Foundation/Teva Neurosciences, Inc., Ironwood Pharmaceuticals, Inc., and Forest Laboratories, Inc., the NIH, the Department of Defense (DOD)-United States Army, and the FWO, Belgium. In addition to NIH Toolbox funding, he receives funding from the NIH for other research (grant U01 DK082342). He has also been a paid consultant to Dr. Kathryn Grant of DePaul University, and maintains a clinical psychology practice for which he bills for his services. G. Smutzer received funding from the NIH Toolbox for Neurological and Behavioral Function, contract no. HHS-N-260-2006-00007-C from 2009 to 2011. In addition, he received funds from a phase II SBIR entitled "Cellulose-Based Strips for Human Taste Evaluation" from October 1, 2007 to September 31, 2009 (2R44DC007291). He also received funds from an ARRA supplement for the Phase II SBIR mentioned above from September 1, 2009 to August 31, 2010. He also received funding from the Temple University Undergraduate Research Fund from 2010 to 2012. Dr. Smutzer submitted an invention disclosure to Temple University in June 2012 concerning the use of polycoated paper as a packaging material for edible taste strips, dried foods, and pharmaceuticals. B. Cowart has received financial support from the NIH P50 DC006760 and DC006760-05S2, the Army Research Office (ARO) W911NF-11-1-0087, and the Ajinomoto Company. She has also received institutional support from the Monell Chemical Senses Center, and served as a paid consultant to the NIH Toolbox. P. Breslin receives research support from Rutgers, The State University of New Jersey, and the Monell Chemical Senses Center. He receives support from NIH grants DC02995, DC06760, and DC011393. Dr. Breslin also receives support from the Bill and Melinda Gates Foundation Grand Challenges Explorations Fund. He also receives investigatorinitiated research support from Suntory Business Expert Ltd.; , and Takasago International Corporation, USA. He is an executive editor at the journal Chemical Senses for which he receives editorial support. L. Bartoshuk has received funding from NIDCD grants DC283 and DC8613. L. Hastings is president and majority shareholder in Osmic Enterprises, Inc., a company that develops and markets tests for the assessment of smell and taste function. Osmic Enterprises received funding from the NIH for other research (grants R44 DC6369 and R44 DC7291). D. Victorson holds stock options in Eli Lilly and Company, received an honoraria for serving on the Steering Committee of the Reeve Neuro-Recovery Network, was funded by NIH contracts HHSN265200423601C and HHS-N-260-2006-00007-C and grants R01HD054569-02NIDRR, 1U01NS056975-01, R01 CA104883, received support from the American Cancer Society (national and Illinois Division) for research in prostate cancer, received institutional support from NorthShore University HealthCare System for research in prostate cancer, received institutional support from the Medical University of South Carolina for sarcoidosis research, and received institutional support from the Northwestern Medical Faculty Foundation for urology research. H. Hoffman is an employee of the extramural program of the NIH. Go to Neurology.org for full disclosures. NR 23 TC 19 Z9 19 U1 1 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S20 EP S24 DI 10.1212/WNL.0b013e3182872e38 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100005 PM 23479539 ER PT J AU Dalton, P Doty, RL Murphy, C Frank, R Hoffman, HJ Maute, C Kallen, MA Slotkin, J AF Dalton, Pamela Doty, Richard L. Murphy, Claire Frank, Robert Hoffman, Howard J. Maute, Christopher Kallen, Michael A. Slotkin, Jerry TI Olfactory assessment using the NIH Toolbox SO NEUROLOGY LA English DT Article ID SMELL IDENTIFICATION TEST; DISEASE AB The human olfactory system provides us with information about our environment that is critical to our physical and psychological well-being. Individuals can vary widely in their ability to detect, recognize, and identify odors, but still be within the range of normal function. Although several standardized tests of odor identification are available, few specifically address the issues in testing very young children, most of whom are likely to be unfamiliar with many of the odor stimuli used in adult tests and have limited ability to read and identify labels to select among choices. Based on the format of the San Diego Odor Identification Test and the delivery system of the University of Pennsylvania Smell Identification Test, we developed 2 versions of an odor identification test using standardized odor stimuli in a scratch-and-sniff format in which participants match 5 (children) or 9 (adults) odors to pictures representing the odor source. Results from normative testing and validation showed that for most participants, the test could be completed in 5 minutes or less and that the poorer performance among the youngest children and the elderly was consistent with data from tests with larger numbers of items. Expanding on the pediatric version of the test with adult-specific and public health-relevant odors increased the ecological validity of the test and facilitated comparisons of intraindividual performance across developmental stages. Neurology (R) 2013; 80 (Suppl 3):S32-S36 C1 [Dalton, Pamela; Murphy, Claire] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Doty, Richard L.] Univ Penn, Ctr Smell & Taste, Perelman Sch Med, Philadelphia, PA 19104 USA. [Doty, Richard L.] Univ Penn, Dept Otorhinolaryngol Head & Neck, Perelman Sch Med, Philadelphia, PA 19104 USA. [Murphy, Claire] San Diego State Univ, San Diego, CA 92182 USA. [Frank, Robert] Ohio Univ, Athens, OH 45701 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Kallen, Michael A.; Slotkin, Jerry] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. RP Dalton, P (reprint author), Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. EM pdalton@pobox.upenn.edu RI Doty, Richard/G-1602-2013 FU Blueprint for Neuroscience Research, National Institutes of Health [HHS-N-260-2006-00007-C]; US Army Research Office [W911NF-11-1-0087]; Department of Defense (ARO); NIH [R01 DC 03275, P50 DC 006760, RO1 MH 59852, RO1 MH 63381, RO1 AG041795, U54 HD028138, NIH K01 MH090548-01]; Altria Inc.; International Flavors Fragrances; Reckitt Benckiser; Cadbury; SC Johnson Company; Department of Defense [USAMRAA W81XWH-09-1-0467]; Cambridge University Press; Informa; Johns Hopkins University Press; NIA [R01 AG04085-24]; NIDCD [DC02064-14] FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, National Institutes of Health, under contract no. HHS-N-260-2006-00007-C and with support from the US Army Research Office under grant no. W911NF-11-1-0087.; P. Dalton received grant funding from the Department of Defense (ARO) and the NIH (R01 DC 03275 and a subproject in P50 DC 006760) and received research support from Altria Inc., International Flavors & Fragrances, Reckitt Benckiser, Cadbury, and SC Johnson Company. She has been a consultant to Johnson & Johnson Co., Reckitt Benckiser, and an expert witness for legal proceedings to Premium Standard Farms (McGuire Woods, attorneys), and the City of Philadelphia. She has received honoraria from Columbia University, Mount Sinai Medical Center, and the International Fragrance Association. R. Doty receives grant funding from the NIH (RO1 MH 59852; RO1 MH 63381) and the Department of Defense (USAMRAA W81XWH-09-1-0467). He is a consultant to NIH grants RO1 AG041795 and U54 HD028138, and a mentor on NIH K01 MH090548-01. He is President and major shareholder of Sensonics, Inc., a manufacturer and distributor of tests of taste and smell. Over the last 2 years, he has been a consultant to Intelligent Beauty, Pfizer Inc., PBS Television, NIH, Western Medical Assessments, and a witness or consultant for legal proceedings. During this time, he received publishing royalties from Cambridge University Press, Informa, and Johns Hopkins University Press and honoraria from the American Academy of Oral Medicine, Australasian Association for ChemoSensory Science, Columbia University, Harvard University, Hospital ABC (Mexico City), Merck Pharmaceuticals, Monash University, and Mt. Sinai Medical Center. C. Murphy is funded by NIA grant R01 AG04085-24 and NIDCD grant DC02064-14. R. Frank, H. Hoffman, C. Maute, M. Kallen, and J. Slotkin report no disclosures. Go to Neurology.org for full disclosures. NR 15 TC 14 Z9 14 U1 2 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S32 EP S36 DI 10.1212/WNL.0b013e3182872eb4 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100007 PM 23479541 ER PT J AU Gershon, RC Wagster, MV Hendrie, HC Fox, NA Cook, KF Nowinski, CJ AF Gershon, Richard C. Wagster, Molly V. Hendrie, Hugh C. Fox, Nathan A. Cook, Karon F. Nowinski, Cindy J. TI NIH Toolbox for Assessment of Neurological and Behavioral Function SO NEUROLOGY LA English DT Editorial Material C1 [Gershon, Richard C.; Cook, Karon F.; Nowinski, Cindy J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Wagster, Molly V.] NIA, Bethesda, MD 20892 USA. [Hendrie, Hugh C.] Indiana Univ Sch Med, Ctr Aging Res, Indianapolis, IN USA. [Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. RP Gershon, RC (reprint author), Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. EM Gershon@northwestern.edu FU AHRQ HHS [1R03HS020700-01]; NHLBI NIH HHS [K23HL085766]; NIA NIH HHS [#R01AG009956, 1RC2AG036498-01, 5R01AG026 096-05, AG-260-06-01, N01-AG-6-0007, R01AG019181, R01AG029884, R01AG031222, UF20303/U01AG022376]; NIAMS NIH HHS [1U5AR057943-01]; NICHD NIH HHS [HD05469, P01HD064653, R37HD017899]; NIDDK NIH HHS [1U01DK082342-01]; NIMH NIH HHS [MH074454, P50MH078105, R01MH091363, R24MH080827, U01MH080759]; NINDS NIH HHS [U01 NS056 975 02]; NINR NIH HHS [5RC1NR011804-02]; PHS HHS [H133B090024, HHSN260200600007, HHSN260200600007C, HHSN265200423601C, HHSN267200700027C] NR 13 TC 43 Z9 43 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S2 EP S6 DI 10.1212/WNL.0b013e3182872e5f PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100002 PM 23479538 ER PT J AU Hodes, RJ Insel, TR Landis, SC AF Hodes, Richard J. Insel, Thomas R. Landis, Story C. CA NIH Blueprint Neurosci Res TI The NIH Toolbox Setting a standard for biomedical research INTRODUCTION SO NEUROLOGY LA English DT Editorial Material C1 [Hodes, Richard J.] NIA, Bethesda, MD 20892 USA. [Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. [Landis, Story C.] NINDS, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NIA, Bethesda, MD 20892 USA. EM wagsterm@nia.nih.gov NR 0 TC 10 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S1 EP S1 DI 10.1212/WNL.0b013e3182872e90 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100001 PM 23479536 ER PT J AU Rine, RM Schubert, MC Whitney, SL Roberts, D Redfern, MS Musolino, MC Roche, JL Steed, DP Corbin, B Lin, CC Marchetti, GF Beaumont, J Carey, JP Shepard, NP Jacobson, GP Wrisley, DM Hoffman, HJ Furman, G Slotkin, J AF Rine, RoseMarie M. Schubert, Michael C. Whitney, Susan L. Roberts, Dale Redfern, Mark S. Musolino, Mark C. Roche, Jennica L. Steed, Daniel P. Corbin, Bree Lin, Chia-Cheng Marchetti, Greg F. Beaumont, Jennifer Carey, John P. Shepard, Neil P. Jacobson, Gary P. Wrisley, Diane M. Hoffman, Howard J. Furman, Gabriel Slotkin, Jerry TI Vestibular function assessment using the NIH Toolbox SO NEUROLOGY LA English DT Article ID DYNAMIC VISUAL-ACUITY; DEVELOPMENTAL PERSPECTIVE; POSTURAL CONTROL; STABILITY; DEFICITS; BALANCE; POSTUROGRAPHY; HYPOFUNCTION; LOCOMOTION; CHILDREN AB Objective: Development of an easy to administer, low-cost test of vestibular function. Methods: Members of the NIH Toolbox Sensory Domain Vestibular, Vision, and Motor subdomain teams collaborated to identify 2 tests: 1) Dynamic Visual Acuity (DVA), and 2) the Balance Accelerometry Measure (BAM). Extensive work was completed to identify and develop appropriate software and hardware. More than 300 subjects between the ages of 3 and 85 years, with and without vestibular dysfunction, were recruited and tested. Currently accepted gold standard measures of static visual acuity, vestibular function, dynamic visual acuity, and balance were performed to determine validity. Repeat testing was performed to examine reliability. Results: The DVA and BAM tests are affordable and appropriate for use for individuals 3 through 85 years of age. The DVA had fair to good reliability (0.41-0.94) and sensitivity and specificity (50%-73%), depending on age and optotype chosen. The BAM test was moderately correlated with center of pressure (r = 0.42-0.48) and dynamic posturography (r = -0.48), depending on age and test condition. Both tests differentiated those with and without vestibular impairment and the young from the old. Each test was reliable. Conclusion: The newly created DVA test provides a valid measure of visual acuity with the head still and moving quickly. The novel BAM is a valid measure of balance. Both tests are sensitive to age-related changes and are able to screen for impairment of the vestibular system. Neurology (R) 2013; 80 (Suppl 3):S25-S31 C1 [Rine, RoseMarie M.; Corbin, Bree] Specialty Therapy Source LLC, Jacksonville, FL USA. [Schubert, Michael C.; Carey, John P.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Roberts, Dale] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Whitney, Susan L.; Lin, Chia-Cheng] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA USA. [Redfern, Mark S.; Roche, Jennica L.; Steed, Daniel P.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Furman, Gabriel] Univ Pittsburgh, Coll Arts & Sci, Pittsburgh, PA USA. [Musolino, Mark C.] Crossrd Consulting LLC, Johnstown, PA USA. [Marchetti, Greg F.] Duquesne Univ, Dept Phys Therapy, Pittsburgh, PA 15219 USA. [Beaumont, Jennifer; Slotkin, Jerry] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Shepard, Neil P.] Mayo Clin, Dept Otorhinolaryngol, Vestibular & Balance Lab, Rochester, MN USA. [Jacobson, Gary P.] Vanderbilt Univ, Med Ctr, Dept Hearing & Speech Sci, Div Audiol, Nashville, TN USA. [Wrisley, Diane M.] Lynchburg Coll, Dept Phys Therapy, Lynchburg, VA 24501 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Whitney, Susan L.] King Saud Univ, Rehabil Res Chair, Riyadh, Saudi Arabia. RP Rine, RM (reprint author), Specialty Therapy Source LLC, Jacksonville, FL USA. EM specialtytherapy@bellsouth.net FU Blueprint for Neuroscience Research, NIH [HHS-N-260-2006-00007-C]; NIH [5R44DC8022-3, K23 007926, R21EY019713, R01EY019347, R01EY001849 DOC H, R21NS059830, R01OH008986, P30 AG024827, R01 AG03111803, R01 DC005040, R01 DC002390, R01 DC009255, R01 DC006296]; Oxford Press; NSF [CNS-0931595, CNS-0931999, NSF-260116A, CNS-0964581]; Robert Bosch, LLC; Pittsburgh Foundation; Arthritis Foundation; Saunders Corporation; Otonomy; University of Nebraska; Mayo Clinic; University of Southampton; Emory University; American Academy of Otolaryngology; NeuroCom International Inc.; MicroMedical Corp.; Vanderbilt University; University of Cape Town South Africa; Plural publishing; Thomson Delmar Learning (Handbook of Balance Function Testing); Plural Publishing (Balance Function Assessment and Management); Foundation for Physical Therapy; New York Physical Therapy Association FX This study was funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, NIH, under contract no. HHS-N-260-2006-00007-C.; R.M. Rine has received travel reimbursement and honoraria from the British Audiological Society, the Royal Society of Medicine, the Hong Kong Physical Therapy Association, Emory University, Mayo Clinic, and the American Physical Therapy Association, served on the Scientific Review Committee of the Foundation for Physical Therapy Research, and was funded by NIH grant 5R44DC8022-3. M. Schubert was funded by NIH grant K23 007926, has worked as a consultant for a legal proceeding, and holds provisional patent C10585-P10585-02 (02240-283664). S. Whitney is a consultant for Visual Health Information, receives royalties from Oxford Press, and has received honoraria from the American Physical Therapy Association. D. Roberts is funded by NIH grants R21EY019713, R01EY019347, R01EY001849 DOC H, and R21NS059830. M. Redfern is funded by NIH grants R01OH008986, P30 AG024827, and R01 AG03111803, and by NSF grants CNS-0931595, CNS-0931999, and NSF-260116A. He holds US patent nos. 10/840,791 and 61/412,690 (which are not related to the current manuscript). M. Musolino reports no disclosures. J. Roche received funding from NSF grant CNS-0964581. D. Steed received partial funding for a project from Robert Bosch, LLC. B. Corbin and C.-C. Lin report no disclosures. G. Marchetti is a consultant for Eli Lilly Pharmaceuticals and received funding for a trip to Indianapolis, IN as part of consulting services. G. Marchetti has in the past received research support from the Pittsburgh Foundation, the Arthritis Foundation, and the Saunders Corporation. J. Beaumont served as a consultant for NorthShore University Health Systems, FACIT.org, and Georgia Gastroenterology Group PC, and has received funding for travel as an invited speaker at the North American Neuroendocrine Tumor Symposium. J. Carey has been funded by NIH grants R01 DC005040, R01 DC002390, R01 DC009255, and R01 DC006296. In addition, he is a paid consultant for Otonomy and has provided expert witness testimony for approximately 3 medicolegal cases. N. Shepard has received travel reimbursement, book royalty and honoraria from the University of Nebraska, Mayo Clinic, University of Southampton, Emory University, American Academy of Otolaryngology, NeuroCom International Inc., MicroMedical Corp., Vanderbilt University, University of Cape Town South Africa, and Plural publishing. G. Jacobson is a consultant for the company Interacoustics. He receives royalties from Thomson Delmar Learning (Handbook of Balance Function Testing) and Plural Publishing (Balance Function Assessment and Management). He receives compensation for his role as Editor-in-Chief of the Journal of the American Academy of Audiology (American Academy of Audiology). D. Wrisley was funded by the Foundation for Physical Therapy and the New York Physical Therapy Association and served as an educator for NeuroCom International. H. Hoffman,. G. Furman, and J. Slotkin report no disclosures. Go to Neurology. org for full disclosures. NR 28 TC 18 Z9 18 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S25 EP S31 DI 10.1212/WNL.0b013e3182872c6a PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100006 PM 23479540 ER PT J AU Salsman, JM Butt, Z Pilkonis, PA Cyranowski, JM Zill, N Hendrie, HC Kupst, MJ Kelly, MAR Bode, RK Choi, SW Lai, JS Griffith, JW Stoney, CM Brouwers, P Knox, SS Cella, D AF Salsman, John M. Butt, Zeeshan Pilkonis, Paul A. Cyranowski, Jill M. Zill, Nicholas Hendrie, Hugh C. Kupst, Mary Jo Kelly, Morgen A. R. Bode, Rita K. Choi, Seung W. Lai, Jin-Shei Griffith, James W. Stoney, Catherine M. Brouwers, Pim Knox, Sarah S. Cella, David TI Emotion assessment using the NIH Toolbox SO NEUROLOGY LA English DT Article ID POSITIVE EMOTIONS; PSYCHOLOGICAL STRESS; DEPRESSIVE SYMPTOMS; HEALTH; LIFE; WELL; LONELINESS; RECOVERY; PURPOSE; RISK AB One of the goals of the NIH Toolbox for Assessment of Neurological and Behavioral Function was to identify or develop brief measures of emotion for use in prospective epidemiologic and clinical research. Emotional health has significant links to physical health and exerts a powerful effect on perceptions of life quality. Based on an extensive literature reviewand expert input, the Emotion team identified 4 central subdomains: Negative Affect, Psychological Well-Being, Stress and Self-Efficacy, and Social Relationships. A subsequent psychometric review identified several existing self-report and proxy measures of these subdomains with measurement characteristics that met the NIH Toolbox criteria. In cases where adequate measures did not exist, robust item banks were developed to assess concepts of interest. A population-weighted sample was recruited by an online survey panel to provide initial item calibration andmeasure validation data. Participants aged 8 to 85 years completed self-report measures whereas parents/guardians responded for children aged 3 to 12 years. Data were analyzed using a combination of classic test theory and item response theory methods, yielding efficient measures of emotional health concepts. An overview of the development of the NIH Toolbox Emotion battery is presented along with preliminary results. Norming activities led to further refinement of the battery, thus enhancing the robustness of emotional health measurement for researchers using the NIH Toolbox. Neurology (R) 2013; 80 (Suppl3):S76-S86 C1 [Salsman, John M.; Butt, Zeeshan; Choi, Seung W.; Lai, Jin-Shei; Griffith, James W.; Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Bode, Rita K.] Northwestern Univ, Feinberg Sch Med, Dept Phys Med & Rehabil, Chicago, IL 60611 USA. [Salsman, John M.; Lai, Jin-Shei; Cella, David] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Butt, Zeeshan] Northwestern Univ, Comprehens Transplant Ctr, Chicago, IL 60611 USA. [Salsman, John M.; Butt, Zeeshan; Lai, Jin-Shei; Griffith, James W.; Cella, David] Northwestern Univ, Ctr Patient Centered Outcomes, Chicago, IL 60611 USA. [Pilkonis, Paul A.; Cyranowski, Jill M.; Kelly, Morgen A. R.] Univ Pittsburgh, Dept Psychiat, Med Ctr, Pittsburgh, PA USA. [Zill, Nicholas] Westat Corp, Rockville, MD USA. [Hendrie, Hugh C.] Indiana Univ Sch Med, Ctr Aging Res, Indianapolis, IN USA. [Kupst, Mary Jo] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Kelly, Morgen A. R.] Family Serv Western Pennsylvania, Pittsburgh, PA USA. [Kelly, Morgen A. R.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Stoney, Catherine M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Brouwers, Pim] NIH, Div AIDS Res, Bethesda, MD 20892 USA. [Knox, Sarah S.] W Virginia Univ, Sch Med, Dept Community Med, Morgantown, WV 26506 USA. RP Salsman, JM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. EM j-salsman@northwestern.edu RI Griffith, James/O-2551-2016 OI Griffith, James/0000-0002-4840-8692 FU Office of Behavioral and Social Sciences Research, NIH [HHS-N-260-2006-00007-C]; Blueprint for Neuroscience Research; NIH [HHSN265200423601C, U01 AR052177-05, KL2RR0254740, HD067440, DK091786, DK062467-10, DK06246708S1, AR052155, AT006453, MH056888, MH066302, MH090333, HL076852, AR52155, MH37896, MH085874, MH083647, AG012546, AR052186, MH086637, U01 DK082342]; GlaxoSmithKline; American Cancer SocietyIllinois Division [PSB-08-15]; National Cancer Institute [5K07CA158008-01A1]; Boehringer Ingelheim; Pfizer; Patient-Centered Outcomes Research Institute (PCORI); Daiichi Sankyo, Inc.; Frankel Foundation; Pittsburgh Foundation; National Council for Adoption; Brookings Institution; Marriage and Religion Research Institute; NorthShore University HealthSystem; Cleveland Clinic Foundation/Teva Neurosciences, Inc.; Ironwood Pharmaceuticals, Inc.; Forest Laboratories, Inc.; Department of Defense (DOD)-United States Army; FWO FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research and the Office of Behavioral and Social Sciences Research, NIH, under contract no. HHS-N-260-2006-00007-C.; J. Salsman served as an independent contractor for the RTOG (Study no. 0841) and has received research support from the NIH (Contract no. HHSN265200423601C), GlaxoSmithKline, the American Cancer SocietyIllinois Division (PSB-08-15), and the NIH (U01 AR052177-05). He currently receives research support from the National Cancer Institute (5K07CA158008-01A1). Z. Butt served as a consultant for Johnson & Johnson and the American Society of Transplant Surgeons. He received support from Boehringer Ingelheim, Pfizer, the Patient-Centered Outcomes Research Institute (PCORI), and NIH grant KL2RR0254740. He currently receives research support from Daiichi Sankyo, Inc., the Frankel Foundation, and NIH grants HD067440, DK091786, DK062467-10, and DK06246708S1. P. Pilkonis served as a consultant for Lundbeck Pharmaceuticals. He currently receives support from NIH grants AR052155, AT006453, MH056888, MH066302, and MH090333. J. Cyranowski has received research funding from the Pittsburgh Foundation and from NIH grants HL076852, AR52155, and MH37896; she currently receives research support from NIH grants MH085874, MH083647, AG012546, AR052186, and MH086637. N. Zill received research support from the National Council for Adoption, the Brookings Institution, and the Marriage and Religion Research Institute. He served as a reviewer for an NIH SBIR Review Panel. He holds a TIAA-CREF Retirement Annuity Contract that invests in US Treasury Bonds and an International Stock Index Fund. He received consulting income and income from selling stock and exercising stock options from Westat, an employee-owned S Corporation. He holds an IRA and brokerage account with Vanguard that includes holdings in the Vanguard Health Care, Precious Metals and Mining, High-Yield Corporate Bond, High-Yield Tax Exempt Bond, and Long-Term Corporate Bond mutual funds, as well as the Vanguard Consumer Discretionary, Consumer Staples, FTSE International Small Cap, and Corporate Long-Term Bond Exchange Traded Funds. He has holdings in a number of closed-ended mutual funds, including the Aberdeen Asia Pacific Income Fund, Templeton Global High Income Fund, Templeton Dragon Fund, Alliance-Bernstein Global High Income Fund, Alliance-Bernstein Corporate Income Fund, Blackrock Income Opportunity Trust, Putnam Master Intermediate Income Trust, Nuveen Floating Rate Income Opportunity Fund, India Fund, Morgan Stanley India Investment Fund, Latin American Discovery Fund, Aberdeen Latin American Equity Fund, Singapore Fund, and Turkish Investment Fund. He has stock holdings in AT& T, Boardwalk Pipeline Partners, Banco de Columbia, Consolidated Edison, Exxon, Frontier Communications, GlaxoSmithKline, Honeywell, Huntington Ingalls Industries, IBM, Intel, 3M, MeadWestvaco, Newell Rubbermaid, Northrop Grumman, Occidental Petroleum, SCANA, Sherwin-Williams, Siemens, Southern, Verizon, Johnson Controls, American Superconductor, Ocean Power Technology, and Maxwell Technology. Dr. Zill's wife, Karen, prepared discussion guides for the Independent Lens program on PBS. She holds a TIAA Retirement Annuity Contract that invests in US Treasury Bonds. H. Hendrie currently receives research funding from NIH/NIA grant R01AG009956, R24MH080827, 5R01AG026096-05, UF20303/U01AG022376, R01AG031222, R01AG019181, and R01AG029884. M. Kupst reports no disclosures. M. Kelly has been employed by the University of Pittsburgh School of Medicine and Family Services of Western Pennsylvania. Dr.; Kelly is the coprincipal investigator on a study sponsored by Ortho McNeil Janssen for which Family Services of Western Pennsylvania receives remuneration. Dr. Kelly does not receive direct remuneration for her role in that study. R. Bode reports no disclosures. S. Choi has received research support from Boehringer-Ingelheim, Novartis, and the NIH. J.-S. Lai has received research support from the NIH, Agency for Healthcare Research and Quality, and Pfizer, Inc. J. Griffith has received financial support from NorthShore University HealthSystem, the Cleveland Clinic Foundation/Teva Neurosciences, Inc., Ironwood Pharmaceuticals, Inc., and Forest Laboratories, Inc., the NIH, the Department of Defense (DOD)-United States Army, and the FWO, Belgium. In addition to NIH Toolbox funding, he receives funding from the NIH for other research (grant U01 DK082342). He has also been a paid consultant to Dr. Kathryn Grant of DePaul University, and maintains a clinical psychology practice for which he bills for his services. C. Stoney reports no disclosures. P. Brouwers and S. Knox report no disclosures. D. Cella serves on the editorial board of the Journal of Supportive Oncology, has received travel support from Pfizer, honoraria from Virginia Commonwealth University and Moffit Cancer Center for speaking engagements, and research support from Boehringer-Ingelheim, Novartis, and the NIH. He also receives royalties from Up to Date. Go to Neurology. org for full disclosures. NR 33 TC 10 Z9 10 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S76 EP S86 DI 10.1212/WNL.0b013e3182872e11 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100014 PM 23479549 ER PT J AU Varma, R McKean-Cowdin, R Vitale, S Slotkin, J Hays, RD AF Varma, Rohit McKean-Cowdin, Roberta Vitale, Susan Slotkin, Jerry Hays, Ron D. TI Vision assessment using the NIH Toolbox SO NEUROLOGY LA English DT Article ID QUALITY-OF-LIFE; VISUAL FUNCTION QUESTIONNAIRE; ELECTRONIC-EARLY TREATMENT; CHILDREN AGED 5; AMBLYOPIA TREATMENT; DIABETIC-RETINOPATHY; ACUITY PROTOCOLS; EYE; IMPAIRMENT; HEALTH AB Vision is a sensation that is created from complex processes and provides us with a representation of the world around us. There are many important aspects of vision, but visual acuity was judged to be the most appropriate vision assessment for the NIH Toolbox for Assessment of Neurological and Behavioral Function, both because of its central role in visual health and because acuity testing is common and relatively inexpensive to implement broadly. The impact of visual impairments on health-related quality of life also was viewed as important to assess, in order to gain a broad view of one's visual function. To test visual acuity, an easy-to-use software program was developed, based on the protocol used by the E-ETDRS. Children younger than 7 years were administered a version with only the letters H, O, T, and V. Reliability and validity of the Toolbox visual acuity test were very good. A 53-item vision-targeted, health-related quality of life survey was also developed. Neurology (R) 2013; 80 (Suppl 3):S37-S40 C1 [Varma, Rohit] Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA. [McKean-Cowdin, Roberta] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Slotkin, Jerry] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Varma, R (reprint author), Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA. EM rvarma@usc.edu RI Hays, Ronald/D-5629-2013 FU Blueprint for Neuroscience Research, NIH [HHS-N-260-2006-00007-C]; Allergan; Aquesys; Pfizer Ophthalmics; Replenish Inc.; NIH [NCI-PC-35016-20, R01-NR0122774-01, U10-EY-014472-01, U10-EY-11753]; NIA [AG020679-01, P30AG021684, P30-AG028748]; NIAMS [UAR057936A, AR052177]; NCMHD [2P20MD000182]; Agency for Healthcare Research and Quality [U18 HS016980]; UBC; VA; SciMetrika FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, NIH, under Contract No. HHS-N-260-2006-00007-C.; R. Varma serves as a consultant for Alcon Laboratories, Allergan, Aquesys, Bausch & Lomb Surgical, Genentech, Inc., Merck & Co., Pfizer Ophthalmics, and Replenish Inc. He receives grant support from Allergan, Aquesys, Pfizer Ophthalmics, and Replenish Inc. He has equity ownership with Aquesys and Replenish, Inc. R. McKean-Cowdin is funded by NIH grants NCI-PC-35016-20, R01-NR0122774-01, U10-EY-014472-01, and U10-EY-11753. S. Vitale and J. Slotkin report no disclosures. R. Hays received research funding from the NIA (AG020679-01, P30AG021684, P30-AG028748), NIAMS (UAR057936A, AR052177), NCMHD (2P20MD000182), and the Agency for Healthcare Research and Quality (U18 HS016980). He also received consulting money from Allergan, UBC, the VA, and SciMetrika. Go to Neurology.org for full disclosures. NR 24 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S37 EP S40 DI 10.1212/WNL.0b013e3182876e0a PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100008 PM 23479542 ER PT J AU Weintraub, S Dikmen, SS Heaton, RK Tulsky, DS Zelazo, PD Bauer, PJ Carlozzi, NE Slotkin, J Blitz, D Wallner-Allen, K Fox, NA Beaumont, JL Mungas, D Nowinski, CJ Richler, J Deocampo, JA Anderson, JE Manly, JJ Borosh, B Havlik, R Conway, K Edwards, E Freund, L King, JW Moy, C Witt, E Gershon, RC AF Weintraub, Sandra Dikmen, Sureyya S. Heaton, Robert K. Tulsky, David S. Zelazo, Philip D. Bauer, Patricia J. Carlozzi, Noelle E. Slotkin, Jerry Blitz, David Wallner-Allen, Kathleen Fox, Nathan A. Beaumont, Jennifer L. Mungas, Dan Nowinski, Cindy J. Richler, Jennifer Deocampo, Joanne A. Anderson, Jacob E. Manly, Jennifer J. Borosh, Beth Havlik, Richard Conway, Kevin Edwards, Emmeline Freund, Lisa King, Jonathan W. Moy, Claudia Witt, Ellen Gershon, Richard C. TI Cognition assessment using the NIH Toolbox SO NEUROLOGY LA English DT Article ID NEUROPSYCHOLOGICAL TEST-PERFORMANCE; CHILDRENS WORKING-MEMORY; EXECUTIVE FUNCTION; PROCESSING SPEED; BRAIN; SPAN; LIFE; INTELLIGENCE; CHILDHOOD; ATTENTION AB Cognition is 1 of 4 domains measured by the NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIH-TB), and complements modules testing motor function, sensation, and emotion. On the basis of expert panels, the cognition subdomains identified as most important for health, success in school and work, and independence in daily functioning were Executive Function, Episodic Memory, Language, Processing Speed, Working Memory, and Attention. Seven measures were designed to tap constructs within these subdomains. The instruments were validated in English, in a sample of 476 participants ranging in age from 3 to 85 years, with representation from both sexes, 3 racial/ethnic categories, and 3 levels of education. This report describes the development of the Cognition Battery and presents results on test-retest reliability, age effects on performance, and convergent and discriminant construct validity. The NIH-TB Cognition Battery is intended to serve as a brief, convenient set of measures to supplement other outcome measures in epidemiologic and longitudinal research and clinical trials. With a computerized format and national standardization, this battery will provide a "common currency" among researchers for comparisons across a wide range of studies and populations. Neurology (R) 2013; 80 (Suppl 3):S54-S64 C1 [Weintraub, Sandra; Borosh, Beth] Northwestern Feinberg Sch Med, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL USA. [Dikmen, Sureyya S.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Heaton, Robert K.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Tulsky, David S.; Carlozzi, Noelle E.] Univ Michigan, Dept Phys Med & Rehabil, Ann Arbor, MI 48109 USA. [Zelazo, Philip D.; Anderson, Jacob E.] Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. [Bauer, Patricia J.; Deocampo, Joanne A.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Slotkin, Jerry; Blitz, David; Beaumont, Jennifer L.; Nowinski, Cindy J.; Gershon, Richard C.] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Wallner-Allen, Kathleen; Havlik, Richard] Westat Corp, Rockville, MD USA. [Fox, Nathan A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Mungas, Dan] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [Richler, Jennifer] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. [Manly, Jennifer J.] Columbia Univ, Gertrude H Sergievsky Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Cognit Neurosci Div, New York, NY 10027 USA. [Conway, Kevin] NIDA, Rockville, MD USA. [Edwards, Emmeline] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Freund, Lisa] NICHHD, Bethesda, MD 20892 USA. [King, Jonathan W.] NIA, Bethesda, MD 20892 USA. [Moy, Claudia] NINDS, Bethesda, MD 20892 USA. [Witt, Ellen] NIAAA, Bethesda, MD USA. RP Weintraub, S (reprint author), Northwestern Feinberg Sch Med, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL USA. EM sweintraub@northwestern.edu OI Freund, Lisa/0000-0003-2095-4023 FU Blueprint for Neuroscience Research, NIH [HHS-N-260-2006-00007-C]; NIH [R01DC008552, P30AG013854, R01 NS058302, R01HD061400, P30MH062512, P50DA026306, P01DA012065, R01MH060720, R01MH073433, R01MH058076, R01MH078748, R01MH078737, U01MH083506]; NIDDK/NICHD [1699-6626312]; Baumann Foundation; Institute for Rehabilitation and Research; Frazier Rehabilitation Institute/Jewish Hospital; Craig Hospital; Casa Colina Centers for Rehabilitation; Canadian Institute for Health Research [201963]; NJ Department of Health and Senior Services; North American Neuroendocrine Tumor Symposium; National Institute on Aging; California Department of Public Health California Alzheimer's Disease Centers program; Department of Veteran's Affairs; Analysis Group; Novartis; Teva Pharmaceuticals; NIH. [R01MH083552, R01MH081861, H133B090024, H133N060022, H133G070138, B6237R, U01AR057929, R01HD054659, HD067359, R03NS065194, H133A070037-08A, HHSN265200423601C, HHSN260200600007C, HHSN267200700027C, R01AG028786, R01AG037212] FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, NIH, under contract no. HHS-N-260-2006-00007-C.; S. Weintraub is funded by NIH grants R01DC008552, P30AG013854, and the Ken and Ruth Davee Foundation, and conducts clinical neuropsychological evaluations (35% effort) for which her academic-based practice clinic bills. S. Dikmen receives research grant funding from NIH R01 NS058302 and R01HD061400, NIDRR H133A080035, NIDRR H133G090022, and NIDRR, H133A980023, and DoD W81XWH-0802-0159. R. Heaton is funded by NIH grants P30MH062512, P50DA026306, P01DA012065, R01MH060720, R01MH073433, R01MH058076, R01MH078748, R01MH078737, U01MH083506, R01MH083552, and R01MH081861. D. Tulsky is funded by NIH contracts H133B090024, H133N060022, H133G070138, B6237R, cooperative agreement U01AR057929, and grant R01HD054659. He has received consultant fees from the Institute for Rehabilitation and Research, Frazier Rehabilitation Institute/Jewish Hospital, Craig Hospital, and Casa Colina Centers for Rehabilitation. P. Zelazo serves on the editorial boards of Child Development, Development and Psychopathology, Frontiers in Human Neuroscience, Cognitive Development, Emotion, and Developmental Cognitive Neuroscience, and Monographs of the Society for Research in Child Development. He is a Senior Fellow of the Mind and Life Institute and President of the Jean Piaget Society. He receives research funding from the Canadian Institute for Health Research (grant 201963), NIDDK/NICHD (1699-6626312), and the Baumann Foundation. P. Bauer is funded by NIH grant HD067359. N. Carlozzi is funded by NIH grant R03NS065194 and by contracts H133B090024, B6237R, and H133G070138; she previously received funding from NIH grant H133A070037-08A and a grant from the NJ Department of Health and Senior Services. J. Slotkin, D. Blitz, and K. Wallner-Allen report no disclosures. N. Fox is funded by NIH grants R37HD017899, MH074454, U01MH080759, R01MH091363, P50MH078105, and P01HD064653. He serves on the scientific board of the National Scientific Council for the Developing Child. J. Beaumont served as a consultant for NorthShore University HealthSystem, FACIT. org, and Georgia Gastroenterology Group PC. She received funding for travel as an invited speaker at the North American Neuroendocrine Tumor Symposium. D. Mungas is funded by research grants from the National Institute on Aging and a grant from the California Department of Public Health California Alzheimer's Disease Centers program. C. Nowinski receives or has received research support from the NIH (contracts HHSN265200423601C, HHSN260200600007C, and HHSN267200700027C), the Department of Veteran's Affairs, the Analysis Group, Novartis, and Teva Pharmaceuticals. She has also received honoraria for writing and updating an article for Medlink. J. Richler is funded by NIH/NCRR grant UL1RR025761. J. Deocampo and J. Anderson report no disclosures. J. Manly is funded by NIH grants R01AG028786 and R01AG037212; she previously received funding from NIH grant R01AG016206 and a grant from the Alzheimer's Association (IIRG 05-14236). B. Borosh, R. Havlik, and K. Conway report no disclosures. E. Edwards is the Director of the Division of Extramural Research at NCCAM. Dr. Edwards declares that except for income received from her primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. L. Freund reports no disclosures. J.; King is the NIA Project Scientist for the NIH cooperative agreements U01AG014289, U01AG014276, U01AG14260, U01AG14282, and U01AG014263 (comprising the ACTIVE clinical trial). C. Moy and E. Witt report no disclosures. R. Gershon has received personal compensation for activities as a speaker and consultant with Sylvan Learning, Rockman, and the American Board of Podiatric Surgery. He has several grants awarded by NIH: N01-AG-6-0007, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469; NINDS: U01 NS 056 975 02; NHLBI K23: K23HL085766 NIA; 1RC2AG036498-01; NIDRR: H133B090024; OppNet: N01-AG-6-0007. Go to Neurology. org for full disclosures. NR 52 TC 64 Z9 65 U1 5 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S54 EP S64 DI 10.1212/WNL.0b013e3182872ded PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100012 PM 23479546 ER PT J AU Zecker, SG Hoffman, HJ Frisina, R Dubno, JR Dhar, S Wallhagen, M Kraus, N Griffith, JW Walton, JP Eddins, DA Newman, C Victorson, D Warrier, CM Wilson, RH AF Zecker, Steven G. Hoffman, Howard J. Frisina, Robert Dubno, Judy R. Dhar, Sumitrajit Wallhagen, Margaret Kraus, Nina Griffith, James W. Walton, Joseph P. Eddins, David A. Newman, Craig Victorson, David Warrier, Catherine M. Wilson, Richard H. TI Audition assessment using the NIH Toolbox SO NEUROLOGY LA English DT Article ID HEARING HANDICAP INVENTORY; RETEST RELIABILITY; NOISE; WORDS; ADULTS AB The NIH Toolbox project has assembled measurement tools to assess a wide range of human perception and ability across the lifespan. As part of this initiative, a small but comprehensive battery of auditory tests has been assembled. The main tool of this battery, pure-tone thresholds, measures the ability of people to hear at specific frequencies. Pure-tone thresholds have long been considered the "gold standard" of auditory testing, and are normally obtained in a clinical setting by highly trained audiologists. For the purposes of the Toolbox project, an automated procedure (NIH Toolbox Threshold Hearing Test) was developed that allows nonspecialists to administer the test reliably. Three supplemental auditory tests are also included in the Toolbox auditory test battery: assessment of middle-ear function (tympanometry), speech perception in noise (the NIH Toolbox Words-in-Noise Test), and self-assessment of hearing impairment (the NIH Toolbox Hearing Handicap Inventory Ages 18-64 and the NIH Toolbox Hearing Handicap Inventory Ages 641). Tympanometry can help differentiate conductive from sensorineural pathology. The NIH Toolbox Words-in-Noise Test measures a listener's ability to perceive words in noisy situations. This ability is not necessarily predicted by a person's pure-tone thresholds; some people with normal hearing have difficulty extracting meaning from speech sounds heard in a noisy context. The NIH Toolbox Hearing Handicap Inventory focuses on how a person's perceived hearing status affects daily life. The test was constructed to include emotional and social/situational subscales, with specific questions about how hearing impairment may affect one's emotional state or limit participation in specific activities. The 4 auditory tests included in the Toolbox auditory test battery cover a range of auditory abilities and provide a snapshot of a participant's auditory capacity. Neurology (R) 2013; 80 (Suppl 3):S45-S48 C1 [Zecker, Steven G.; Dhar, Sumitrajit; Kraus, Nina; Warrier, Catherine M.] Northwestern Univ, Evanston, IL 60208 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Frisina, Robert; Walton, Joseph P.; Eddins, David A.] Univ S Florida, Tampa, FL USA. [Dubno, Judy R.] Univ S Carolina, Charleston, SC USA. [Griffith, James W.; Victorson, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Wallhagen, Margaret] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Newman, Craig] Cleveland Clin, Cleveland, OH 44106 USA. [Wilson, Richard H.] VA Med Ctr, Mountain Home, TN USA. [Wilson, Richard H.] E Tennessee State Univ, Johnson City, TN 37614 USA. RP Zecker, SG (reprint author), Northwestern Univ, Evanston, IL 60208 USA. EM zecker@northwestern.edu RI Griffith, James/O-2551-2016 OI Griffith, James/0000-0002-4840-8692 FU Blueprint for Neuroscience Research, NIH [HHS-N-260-2006-00007-C]; National Institute on Aging; National Institute on Deafness and Other Communication Disorders (NIDCD); NIH Toolbox; NIH Toolbox project; NIH [R01 DC000184, P50 DC000422, RC3 DC010986, R21 DC011174, U01 DK082342, HHSN265200423601C, HHS-N-260-2006- 00007-C, R01HD054569-02NIDRR, 1U01NS056975-01, R01 CA104883]; NorthShore University HealthSystem; Cleveland Clinic Foundation/Teva Neurosciences, Inc.; Ironwood Pharmaceuticals, Inc.; Forest Laboratories, Inc.; Department of Defense (DOD)-United States Army; FWO, Belgium; National Science Foundation; American Cancer Society (national and Illinois Division); Northwestern Medical Faculty Foundation FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, NIH, under contract no. HHS-N-260-2006-00007-C.; S. Zecker and H. J. Hoffman report no disclosures. R. Frisina has received funding from the National Institute on Aging, the National Institute on Deafness and Other Communication Disorders (NIDCD), the NIH Toolbox, and the NIH Toolbox project. J. Dubno's research is funded by NIH grants R01 DC000184, P50 DC000422, RC3 DC010986, and R21 DC011174. S. Dhar reports no disclosures. M. Wallhagen serves on the board of HLAA without compensation. N. Kraus reports no disclosures. J. Griffith has received financial support from NorthShore University HealthSystem, the Cleveland Clinic Foundation/Teva Neurosciences, Inc., Ironwood Pharmaceuticals, Inc., and Forest Laboratories, Inc., the NIH, the Department of Defense (DOD)-United States Army, and the FWO, Belgium. In addition to NIH Toolbox funding, he receives funding from the NIH for other research (grant U01 DK082342). He has also been a paid consultant to Dr. Kathryn Grant of DePaul University, and maintains a clinical psychology practice for which he bills for his services. J. Walton receives funding from the National Institute on Aging, and the NIH Toolbox project. D. Eddins receives funding from the NIH, National Institute on Aging, National Institute on Deafness and Other Communication Disorders, the National Science Foundation, and the NIH Toolbox project. C. Newman reports no disclosures. D. Victorson holds stock options in Eli Lilly and Company, received an honoraria for serving on the Steering Committee of the Reeve Neuro-Recovery Network, was funded by NIH contracts HHSN265200423601C and HHS-N-260-2006- 00007-C and grants R01HD054569-02NIDRR, 1U01NS056975-01, R01 CA104883, received support from the American Cancer Society (national and Illinois Division) for research in prostate cancer, received institutional support from NorthShore University HealthCare System for research in prostate cancer, received institutional support from the Medical University of South Carolina for sarcoidosis research, and received institutional support from the Northwestern Medical Faculty Foundation for urology research. C. Warrier received NIH Toolbox funding for scientific support to the NIH Toolbox audition team from 2009 to 2011. R. Wilson is the developer of the Words-in-Noise Test (WIN), which is distributed on audio compact disc free of charge to US Government agencies and to researchers. Nongovernment audiologists can obtain the test materials through the East Tennessee State University Foundation for a suggested donation of $ 50. The money in the Foundation is used to support the Auditory Research Laboratories at East Tennessee State University and at the VA Medical Center, Mountain Home, Tennessee. Go to Neurology. org for full disclosures. NR 15 TC 5 Z9 5 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR PY 2013 VL 80 SU 3 BP S45 EP S48 DI 10.1212/WNL.0b013e3182872dd2 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 104LS UT WOS:000315995100010 PM 23479544 ER PT J AU Hardy, T Fourie, N Henderson, W Kitamura, N Longchamps, R Martino, A Reddy, S AF Hardy, Theresa Fourie, Nicolaas Henderson, Wendy Kitamura, Noriko Longchamps, Ryan Martino, Angela Reddy, Swarnalatha TI The Effect of Chronic Pain, Stress, and Body Fat on anti-Mullerian Hormone: A Pilot Study SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Fourie, Nicolaas; Henderson, Wendy; Kitamura, Noriko; Longchamps, Ryan; Martino, Angela; Reddy, Swarnalatha] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2013 VL 62 IS 2 BP E33 EP E33 PG 1 WC Nursing SC Nursing GA 103WX UT WOS:000315951300094 ER PT J AU Saneto, RP Cohen, BH Copeland, WC Naviaux, RK AF Saneto, Russell P. Cohen, Bruce H. Copeland, William C. Naviaux, Robert K. TI Alpers-Huttenlocher Syndrome SO PEDIATRIC NEUROLOGY LA English DT Review ID DNA-POLYMERASE-GAMMA; PROGRESSIVE NEURONAL DEGENERATION; POLG MUTATIONS; MITOCHONDRIAL DISEASE; W748S MUTATION; VALPROATE HEPATOTOXICITY; STATUS EPILEPTICUS; MTDNA DEPLETION; DISORDERS; CHILDHOOD AB Alpers-Huttenlocher syndrome is an uncommon mitochondrial disease most often associated with mutations in the mitochondrial DNA replicase, polymerase-gamma. Alterations in enzyme activity result in reduced levels or deletions in mitochondrial DNA. Phenotypic manifestations occur when the functional content of mitochondrial DNA reaches a critical nadir. The tempo of disease progression and onset varies among patients, even in identical genotypes. The classic clinical triad of seizures, liver degeneration, and progressive developmental regression helps define the disorder, but a wide range of clinical expression occurs. The majority of patients are healthy before disease onset, and seizures herald the disorder in most patients. Seizures can rapidly progress to medical intractability, with frequent episodes of epilepsia partialis continua or status epilepticus. Liver involvement may precede or occur after seizure onset. Regardless, eventual liver failure is common. Both the tempo of disease progression and range of organ involvement vary from patient to patient, and are only partly explained by pathogenic effects of genetic mutations. Diagnosis involves the constellation of organ involvement, not the sequence of signs. This disorder is relentlessly progressive and ultimately fatal. (C) 2013 Elsevier Inc. All rights reserved. C1 [Saneto, Russell P.] Univ Washington, Seattle Childrens Hosp, Div Pediat Neurol & Neurol, Seattle, WA 98195 USA. [Cohen, Bruce H.] Childrens Hosp Med Ctr Akron, Div Neurol, Neurodev Sci Ctr, Akron, OH USA. [Copeland, William C.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Naviaux, Robert K.] Univ Calif San Diego, Dept Pediat, Dept Med, San Diego, CA 92103 USA. [Naviaux, Robert K.] Univ Calif San Diego, Dept Pathol, Mitochondrial & Metab Dis Ctr, San Diego, CA 92103 USA. RP Saneto, RP (reprint author), Seattle Childrens Hosp, Div Pediat Neurol, 4800 Sand Point Way NE, Seattle, WA 98105 USA. EM russ.saneto@seattlechildrens.org FU National Institutes of Health through National Institute of Environmental Health [ES 065078]; National Institutes of Health [U54NS078059-01]; Mitochondrial Research Guild at Seattle Children's Hospital; University of California at San Diego; Wright Foundation; Lennox Foundation; Jane Botsford-Johnson Foundation; Hailey's Wish Foundation FX The authors thank the patients and their families who allowed us to participate in their medical care. This work was supported in part by the Intramural Research Program of the National Institutes of Health through National Institute of Environmental Health Sciences grant ES 065078 (to W.C.C.), National Institutes of Health grant U54NS078059-01, the Mitochondrial Research Guild at Seattle Children's Hospital (to R.P.S.), the Christini Fund at the University of California at San Diego, the Wright Foundation, the Lennox Foundation, the Jane Botsford-Johnson Foundation, and the Hailey's Wish Foundation (to R.K.N.). NR 77 TC 16 Z9 18 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD MAR PY 2013 VL 48 IS 3 BP 167 EP 178 DI 10.1016/j.pediatrneurol.2012.09.014 PG 12 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 099IZ UT WOS:000315616000003 PM 23419467 ER PT J AU Abdul-Karim, R Berkman, BE Wendler, D Rid, A Khan, J Badgett, T Hull, SC AF Abdul-Karim, Ruqayyah Berkman, Benjamin E. Wendler, David Rid, Annette Khan, Javed Badgett, Tom Hull, Sara Chandros TI Disclosure of Incidental Findings From Next-Generation Sequencing in Pediatric Genomic Research SO PEDIATRICS LA English DT Article DE pediatrics; ethics; incidental findings; whole genome sequencing; whole exome sequencing; return of results ID RESEARCH PARTICIPANTS; HUNTINGTON-DISEASE; GENETIC RESEARCH; ONSET CONDITIONS; YOUNG-PEOPLE; RETURN; RECOMMENDATIONS; COMMUNICATION; PERSPECTIVES; CHALLENGE AB Next-generation sequencing technologies will likely be used with increasing frequency in pediatric research. One consequence will be the increased identification of individual genomic research findings that are incidental to the aims of the research. Although researchers and ethicists have raised theoretical concerns about incidental findings in the context of genetic research, next-generation sequencing will make this once largely hypothetical concern an increasing reality. Most commentators have begun to accept the notion that there is some duty to disclose individual genetic research results to research subjects; however, the scope of that duty remains unclear. These issues are especially complicated in the pediatric setting, where subjects cannot currently but typically will eventually be able to make their own medical decisions at the age of adulthood. This article discusses the management of incidental findings in the context of pediatric genomic research. We provide an overview of the current literature and propose a framework to manage incidental findings in this unique context, based on what we believe is a limited responsibility to disclose. We hope this will be a useful source of guidance for investigators, institutional review boards, and bioethicists that anticipates the complicated ethical issues raised by advances in genomic technology. Pediatrics 2013;131:564-571 C1 [Abdul-Karim, Ruqayyah; Berkman, Benjamin E.; Wendler, David; Hull, Sara Chandros] NHGRI, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Berkman, Benjamin E.; Hull, Sara Chandros] NHGRI, Off Clin Director, Bethesda, MD 20892 USA. [Khan, Javed] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Kings Coll London, Dept Social Sci Hlth & Med, London WC2R 2LS, England. Univ Kentucky, Coll Med, Dept Pediat, Lexington, KY USA. RP Hull, SC (reprint author), NHGRI, Dept Bioeth, Ctr Clin, NIH, 10 Ctr Dr,Ste 1C118, Bethesda, MD 20892 USA. EM shull@mail.nih.gov FU Department of Bioethics at the Clinical Center of the National Institutes of Health; National Institutes of Health (NIH) FX The preparation of this manuscript was funded by the Department of Bioethics at the Clinical Center of the National Institutes of Health. The views expressed here are those of the authors and not necessarily a reflection of the policies of the National Institutes of Health or the US Department of Health and Human Services. Funded by the National Institutes of Health (NIH). NR 50 TC 35 Z9 35 U1 0 U2 12 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR PY 2013 VL 131 IS 3 BP 564 EP 571 DI 10.1542/peds.2012-0084 PG 8 WC Pediatrics SC Pediatrics GA 098ZI UT WOS:000315587400061 PM 23400601 ER PT J AU Moriyama, B Jarosinski, PF Figg, WD Henning, SA Danner, RL Penzak, SR Wayne, AS Walsh, TJ AF Moriyama, Brad Jarosinski, Paul F. Figg, William D. Henning, Stacey A. Danner, Robert L. Penzak, Scott R. Wayne, Alan S. Walsh, Thomas J. TI Pharmacokinetics of Intravenous Voriconazole in Obese Patients: Implications of CYP2C19 Homozygous Poor Metabolizer Genotype SO PHARMACOTHERAPY LA English DT Article DE voriconazole; obese; intravenous; CYP2C19; genotype; pharmacokinetics ID BODY-MASS INDEX; ADULT PATIENTS; PHARMACOGENOMICS; PREVALENCE; TRENDS AB There is a paucity of pharmacokinetic studies describing weight-based dosing of intravenous voriconazole in obese patients. In this case report, we describe the pharmacokinetics of intravenous voriconazole in an obese CYP2C19 homozygous poor metabolizer and review previously reported data regarding the use of intravenous voriconazole in obese patients. A 17-year-old obese Hispanic male patient (body mass index 35kg/m2) received intravenous voriconazole for the treatment of suspected aspergillosis. After 2.5days of voriconazole 4mg/kg intravenously every 12hours based on adjusted body weight, the voriconazole area under the serum concentrationtime curve over the course of a single (12-hr) dosing interval and trough concentration were 86,100ng center dot hr/ml and 6.2 mu g/ml, respectively. Sixdays later, the voriconazole dosage was decreased. A trough concentration measured just before the dosage reduction (after 8.5days of voriconazole 4mg/kg intravenously every 12hours based on adjusted body weight) remained elevated at 5.8 mu g/ml. Genotyping revealed a CYP2C19 homozygous poor metabolizer (CYP2C19*2/*2). Voriconazole was subsequently discontinued due to QTc prolongation. These data and those from two recent publications suggest that voriconazole does not distribute extensively into human adipose tissue and that obese patients should be dosed on an adjusted body weight basis. If an obese patient dosed on total body weight is also a CYP2C19 poor metabolizer, serum voriconazole concentrations will be further elevated, potentially leading to drug-induced toxicity. C1 [Moriyama, Brad; Jarosinski, Paul F.; Henning, Stacey A.; Penzak, Scott R.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Danner, Robert L.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Walsh, Thomas J.] Cornell Univ, Transplantat Oncol Infect Dis Program, Weill Cornell Med Ctr, New York, NY 10021 USA. RP Moriyama, B (reprint author), NIH, Ctr Clin, Dept Pharm, 10 Ctr Dr, Bethesda, MD 20892 USA. EM bmoriyama@cc.nih.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health, National Cancer Institute; Center for Cancer Research FX This work was supported in part by the intramural research program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research. NR 16 TC 5 Z9 6 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD MAR PY 2013 VL 33 IS 3 BP e19 EP e22 DI 10.1002/phar.1192 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 099TN UT WOS:000315645100001 PM 23400848 ER PT J AU Gaston-Johansson, F Fall-Dickson, JM Nanda, JP Sarenmalm, EK Browall, M Goldstein, N AF Gaston-Johansson, Fannie Fall-Dickson, Jane M. Nanda, Joy P. Sarenmalm, Elisabeth Kenne Browall, Maria Goldstein, Nancy TI Long-term effect of the self-management comprehensive coping strategy program on quality of life in patients with breast cancer treated with high-dose chemotherapy SO PSYCHO-ONCOLOGY LA English DT Article DE self-management; coping strategy; quality of life; high dose chemotherapy; breast cancer ID STEM-CELL TRANSPLANTATION; GUIDED IMAGERY; PAIN; INTERVENTION; EFFICACY; DISTRESS; THERAPY; WOMEN AB Background: This study aims to examine the effectiveness of a self-management multimodal comprehensive coping strategy program (CCSP) on quality of life (QOL) among breast cancer patients 1 year after treatment. Methods: Patients (n = 110) with stage II, III, or IV breast cancer scheduled to receive high dose chemotherapy and autologous hematopoietic stem cell transplantation were randomized to either CCSP treatment or control group. The CCSP intervention was taught 2 week before hospital admission with reinforcement at specified times during treatment and 3 months after discharge. The CCSP components included educational information, cognitive restructuring, coping skills enhancement, and relaxation with guided imagery. Instruments administered at baseline included the following: Quality of Life Index-Cancer Version (QOLI-CV), State-Trait Anxiety Inventory, Beck Depression Inventory, and Coping Strategies Questionnaire. At 1-year follow-up, patients (n = 73) completed and returned the follow-up QOLI-CV. Results: Patients were mainly >= 40 years of age, married, Caucasian, and diagnosed with advanced breast cancer. A model measuring effectiveness of CCSP on QOL (total and subscale) at 1-year follow-up showed that the CCSP group (n = 38) had significant improvement in overall QOL (p < 0.01), health and functioning (p < 0.05), and socioeconomic (p < 0.05) and psychological/spiritual well-being (p < 0.01) compared with the control group (n = 35). The CCSP patients frequently used the CCSP to manage psychological (51%) and sleep problems (60%). Conclusions: The CCSP improved QOL for patients at 1-year follow-up. Patients overwhelmingly reported that CCSP was beneficial. The CCSP as an effective coping intervention has potential as a self-management program for breast cancer survivors. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Gaston-Johansson, Fannie; Goldstein, Nancy] Johns Hopkins Univ, Sch Nursing, Dept Acute & Chron Care, Baltimore, MD USA. [Fall-Dickson, Jane M.] NINR, NIH, Symptom Management Branch, Bethesda, MD 20892 USA. [Nanda, Joy P.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Sarenmalm, Elisabeth Kenne] Skaraborg Hosp, Dept Res & Dev Ctr, Skovde, Sweden. [Browall, Maria] Univ Skovde, Sch Life Sci, Skovde, Sweden. RP Gaston-Johansson, F (reprint author), Johns Hopkins Univ, Dept Acute & Chron Care, Baltimore, MD 21218 USA. EM fgaston1@son.jhmi.edu RI Brovall, Maria/K-5489-2013 OI Brovall, Maria/0000-0003-0976-531X NR 41 TC 16 Z9 16 U1 3 U2 40 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD MAR PY 2013 VL 22 IS 3 BP 530 EP 539 DI 10.1002/pon.3031 PG 10 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 099VX UT WOS:000315652500007 PM 22290808 ER PT J AU Han, EY Lee, C Bolch, WE AF Han, Eun Young Lee, Choonsik Bolch, Wesley E. TI TEDE per cumulated activity for family members exposed to adult patients treated with I-131 SO RADIATION PROTECTION DOSIMETRY LA English DT Article ID SCHEMA; POINT; LINE AB In 1997, the United States Nuclear Regulatory Commission amended its criteria under which patients administered radioactive materials could be released from the hospital. The revised criteria ensures that the total effective dose equivalent (TEDE) to any individual exposed to the released patient will not likely exceed 5 mSv. Licensees are recommended to use one of the three options to release the patient in accordance with these regulatory requirements: administered activity, measured dose rate, or patient-specific dose calculation. The NRCs suggested calculation method is based on the assumption that the patient (source) and a family member (target) are each considered to be points in space. This point source/target assumption has been shown to be conservative in comparison to more realistic guidelines. In this present study, the effective doses to family members were calculated using a series of revised Oak Ridge National Laboratory stylised phantoms coupled with a Monte Carlo radiation transport code. A set of TEDE per cumulated activity values were calculated for three different distributions of I-131 (thyroid, abdomen and whole body), various separation distances and two exposure scenarios (face-to-face standing and side-by-side lying). The results indicate that an overestimation of TEDE per cumulated activity based on the point source/target method was 2-fold. The values for paediatric phantoms showed a strong age-dependency, which showed that dosimetry for children should be separately considered instead of using adult phantoms as a substitute. On the basis of the results of this study, a licensee may use less conservative patient-specific release criteria and provide the patient and the family members with more practical dose avoidance guidelines. C1 [Han, Eun Young] Univ Arkansas Med Sci, Dept Radiat Oncol, Little Rock, AR 72205 USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. RP Han, EY (reprint author), Univ Arkansas Med Sci, Dept Radiat Oncol, 4301 West Markham St 771, Little Rock, AR 72205 USA. EM eyhan@uams.edu RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 NR 15 TC 1 Z9 1 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD MAR PY 2013 VL 153 IS 4 BP 448 EP 456 DI 10.1093/rpd/ncs128 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 099TU UT WOS:000315645900007 PM 22821723 ER PT J AU Gold, JM Dickinson, D AF Gold, James M. Dickinson, Dwight TI "Generalized Cognitive Deficit" in Schizophrenia: Overused or Underappreciated? SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material C1 [Gold, James M.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Dickinson, Dwight] NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Gold, JM (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, POB 21247, Baltimore, MD 21201 USA. EM jgold@mprc.umaryland.edu FU Intramural NIH HHS; NIMH NIH HHS [MH080066, MH065034] NR 4 TC 13 Z9 13 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2013 VL 39 IS 2 BP 263 EP 265 DI 10.1093/schbul/sbs143 PG 3 WC Psychiatry SC Psychiatry GA 098NV UT WOS:000315556900008 PM 23211397 ER PT J AU Stefanis, NC Hatzimanolis, A Smyrnis, N Avramopoulos, D Evdokimidis, I van Os, J Stefanis, CN Straub, RE Weinberger, DR AF Stefanis, Nicholas C. Hatzimanolis, Alex Smyrnis, Nikolaos Avramopoulos, Dimitrios Evdokimidis, Ioannis van Os, Jim Stefanis, Costas N. Straub, Richard E. Weinberger, Daniel R. TI Schizophrenia Candidate Gene ERBB4: Covert Routes of Vulnerability to Psychosis Detected at the Population Level SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizotypy; working memory; psychotic symptoms; schizophrenia; stress; polymorphism ID HEALTHY CONTROLS; YOUNG MALES; ASSOCIATION; EXPRESSION; SYMPTOMS; SUSCEPTIBILITY; NEUREGULIN-1; VARIANTS; RISK; NRG1 AB Prior genetic and functional evidence established ERBB4 as a probable schizophrenia susceptibility gene that may confer risk via modulating brain information processing dependent on the integrity of frontotemporal brain circuitry. Utilizing retrospective data drawn from the cross-sectional population-based Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS) (n = 1127), we attempted to independently replicate and further extend previous findings by examining the effects of ERBB4 gene variants on 3 broad population based psychosis-related phenotypes: verbal working memory (VWM), trait schizotypy, and stress-induced subclinical psychotic experiences (PE). Three common ERBB4 single nucleotide polymorphisms that were previously associated with schizophrenia and impaired frontotemporal-related information processing (rs7598440, rs839523, and rs707284), their haplotypes, and corresponding diplotypes were tested. VWM performance was significantly associated with rs839523 and rs707284 markers even after correction for multiple testing, thus validating reported findings that have implicated ERBB4 gene variation on working memory. No associations were detected between these ERBB4 variants and trait schizotypy. However, we were able to detect a significant effect of rs7598440 marker on PE expressed under stressful environmental conditions. Combined haplotype analysis of the above 3 markers, identified a "yin-yang" pattern of association, confirmed at the diplotype level. While GGG haplotype homozygotes were associated with "protective" effects on VWM performance and PE, AAA "risk" haplotype carriers were associated with worse VWM performance and simultaneously exhibited significantly elevated PE. This dual, possibly pleiotropic, impact on frontotemporal circuitry and increased sensitivity to psychosocial stress may represent subtle manifestations of ERBB4-related vulnerability to psychosis, expressed at the population level. C1 [Stefanis, Nicholas C.; Evdokimidis, Ioannis; Stefanis, Costas N.] Univ Mental Hlth Res Inst, Athens, Greece. [Stefanis, Nicholas C.; Hatzimanolis, Alex; Smyrnis, Nikolaos] Univ Athens, Dept Psychiat, Athens 11528, Greece. [Stefanis, Nicholas C.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia. [Avramopoulos, Dimitrios] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [van Os, Jim] Maastricht Univ Med Ctr, EURON, South Limburg Mental Hlth Res & Teaching Network, Dept Psychiat & Neuropsychol, Maastricht, Netherlands. [Straub, Richard E.; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Stefanis, NC (reprint author), Univ Western Australia, Sch Psychiat & Clin Neurosci, Ctr Clin Res Neuropsychiat, John 23 Ave, Mt Claremont, WA 6010, Australia. EM nikos.stefanis@uwa.edu.au FU General Secretariat of Research and Technology of the Greek Ministry of Development [EKBAN 97]; National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA; European Community [HEALTH-F2-2009-241909] FX General Secretariat of Research and Technology of the Greek Ministry of Development (EKBAN 97 to C.N.S.). This research was also supported [in part] by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.; The authors have declared that there are no conflicts of interest in relation to the subject of this study. We wish to acknowledge the support from the European Community's Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). NR 40 TC 8 Z9 9 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2013 VL 39 IS 2 BP 349 EP 357 DI 10.1093/schbul/sbr169 PG 9 WC Psychiatry SC Psychiatry GA 098NV UT WOS:000315556900019 PM 22115776 ER PT J AU Luo, CL Zhang, JH Pan, JY AF Luo, Chunliu Zhang, Jihui Pan, Jiyang TI One-Year Course and Effects of Insomnia in Rural Chinese Adolescents SO SLEEP LA English DT Article DE Anxiety; depression; insomnia; longitudinal course; sleepiness ID SLEEP PROBLEMS; BEHAVIORAL-PROBLEMS; PSYCHIATRIC-DISORDERS; GENERAL-POPULATION; DAYTIME SLEEPINESS; NATURAL-HISTORY; SEVERITY INDEX; YOUNG-ADULTS; CHILDHOOD; PATTERNS AB Study Objectives: We aimed to explore the incidence and persistence of insomnia, the associated risk factors, and the potential bidirectional association of insomnia with depression, anxiety, and sleepiness in rural Chinese adolescents. Design: School-based prospective study. Setting: Five high schools in rural China. Participants: There were 2,787 adolescents studied. Interventions: N/A. Measures and Results: Insomnia was defined as having a score of equal to or higher than nine in the Insomnia Severity Index as validated in Chinese adolescents. Depression, anxiety, and sleepiness were determined by the Beck Depression Inventory (BDI), Zung Self-Rating Anxiety Scale (SAS), and Epworth Sleepiness Scale (ESS), respectively. The incidence and persistence rates of insomnia were 16.0% and 41.0%, respectively. Multivariate analyses in logistic regression models revealed that new incidence of insomnia was significantly associated with age, living in a rural area, habitual daytime napping, high life events, anxiety, and depression at baseline (range adjusted odds ratio = 1.12-1.61), whereas the persistence of insomnia was positively associated with age, female sex, high life events, and depression at baseline (range adjusted odds ratio = 1.26-1.55) but negatively associated with living in a rural area (odds ratio = 0.59). Insomnia at baseline could predict new onsets of both depression (odds ratio = 1.45) and anxiety (odds ratio = 1.98) but not sleepiness at follow-up after adjustment for age, sex, and baseline symptoms. The results in cross-lagged analyses further supported these observations in the bidirectional associations of insomnia with depression, anxiety, and sleepiness. Conclusions: Insomnia has considerable incidence and persistence rates in Chinese adolescents. We have identified several risk factors for the incidence and persistence of insomnia. There are bidirectional associations of insomnia with depression and anxiety but not sleepiness. C1 [Luo, Chunliu; Zhang, Jihui; Pan, Jiyang] Jinan Univ, Affiliated Hosp 1, Dept Psychiat, Guangzhou, Guangdong, Peoples R China. [Luo, Chunliu] Jinan Univ, Affiliated Hosp 1, Dept Nursing, Guangzhou, Guangdong, Peoples R China. [Zhang, Jihui] NIMH, Genet Epidemiol Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Zhang, Jihui] Chinese Univ Hong Kong, Dept Psychiat, Shatin, Hong Kong, Peoples R China. RP Pan, JY (reprint author), Jinan Univ, Affiliated Hosp 1, Dept Psychiat, Guangzhou, Guangdong, Peoples R China. EM jihui.zhang@nih.gov; jiypan@163.com FU Guangdong Provincial Medical Research Fund [A2010340] FX This study was funded by the Guangdong Provincial Medical Research Fund (A2010340). The authors would like to express their gratitude to the teachers and students for their kind participation and coordination in this study. NR 43 TC 10 Z9 15 U1 1 U2 11 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD MAR 1 PY 2013 VL 36 IS 3 BP 377 EP 384 DI 10.5665/sleep.2454 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 098VN UT WOS:000315577300014 PM 23450433 ER PT J AU Blair, RJR Lee, TMC AF Blair, R. J. R. Lee, Tatia M. C. TI The social cognitive neuroscience of aggression, violence, and psychopathy SO SOCIAL NEUROSCIENCE LA English DT Editorial Material DE Aggression; Violence; Psychopathy; Neurobiology; Amygdala ID VENTROMEDIAL PREFRONTAL CORTEX; DISRUPTIVE BEHAVIOR DISORDERS; CALLOUS-UNEMOTIONAL TRAITS; FEARFUL EXPRESSIONS; AMYGDALA; ATTENTION; MORALITY; CHILDREN; STIMULI; EMOTION C1 [Blair, R. J. R.] NIMH, Bethesda, MD 20892 USA. [Lee, Tatia M. C.] Univ Hong Kong, Lab Neuropsychol, Hong Kong, Hong Kong, Peoples R China. [Lee, Tatia M. C.] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R China. RP Blair, RJR (reprint author), NIMH, 15K North Dr, Bethesda, MD 20892 USA. EM JamesBlair@mail.nih.gov; tmclee@hku.hk NR 27 TC 7 Z9 7 U1 9 U2 83 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PD MAR 1 PY 2013 VL 8 IS 2 SI SI BP 108 EP 111 DI 10.1080/17470919.2012.757869 PG 4 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 101IT UT WOS:000315769300001 PM 23410514 ER PT J AU Anderson, CD Biffi, A Nalls, MA Devan, WJ Schwab, K Ayres, AM Valant, V Ross, OA Rost, NS Saxena, R Viswanathan, A Worrall, BB Brott, TG Goldstein, JN Brown, D Broderick, JP Norrving, B Greenberg, SM Silliman, SL Hansen, BM Tirschwell, DL Lindgren, A Slowik, A Schmidt, R Selim, M Roquer, J Montaner, J Singleton, AB Kidwell, CS Woo, D Furie, KL Meschia, JF Rosand, J AF Anderson, Christopher D. Biffi, Alessandro Nalls, Michael A. Devan, William J. Schwab, Kristin Ayres, Alison M. Valant, Valerie Ross, Owen A. Rost, Natalia S. Saxena, Richa Viswanathan, Anand Worrall, Bradford B. Brott, Thomas G. Goldstein, Joshua N. Brown, Devin Broderick, Joseph P. Norrving, Bo Greenberg, Steven M. Silliman, Scott L. Hansen, Bjoern M. Tirschwell, David L. Lindgren, Arne Slowik, Agnieszka Schmidt, Reinhold Selim, Magdy Roquer, Jaume Montaner, Joan Singleton, Andrew B. Kidwell, Chelsea S. Woo, Daniel Furie, Karen L. Meschia, James F. Rosand, Jonathan CA Int Stroke Genetics Consortium TI Common Variants Within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage SO STROKE LA English DT Article DE genes; mitochondria; OXPHOS; stroke ID COMPLEX I; ASSOCIATION; DISEASE; MICROBLEEDS; DYSFUNCTION; PATHWAY AB Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results-IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). Conclusions-This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. (Stroke. 2013;44:612-619.) C1 [Anderson, Christopher D.; Biffi, Alessandro; Devan, William J.; Valant, Valerie; Rost, Natalia S.; Saxena, Richa; Furie, Karen L.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Devan, William J.; Valant, Valerie; Rost, Natalia S.; Viswanathan, Anand; Greenberg, Steven M.; Furie, Karen L.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Devan, William J.; Schwab, Kristin; Ayres, Alison M.; Valant, Valerie; Rost, Natalia S.; Viswanathan, Anand; Goldstein, Joshua N.; Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Devan, William J.; Valant, Valerie; Rost, Natalia S.; Saxena, Richa; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Dept Neurogenet, Intramural Res Program, Bethesda, MD 20892 USA. [Ross, Owen A.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol & Publ Hlth Sci, Charlottesville, VA USA. [Brott, Thomas G.; Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Brown, Devin] Univ Michigan Hlth Syst, Stroke Program, Dept Neurol, Ann Arbor, MI USA. [Broderick, Joseph P.; Woo, Daniel] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA. [Norrving, Bo; Hansen, Bjoern M.; Lindgren, Arne] Lund Univ, Dept Clin Sci Lund, Lund, Sweden. [Norrving, Bo; Hansen, Bjoern M.; Lindgren, Arne] Skane Univ Hosp, Dept Neurol, Lund, Sweden. [Silliman, Scott L.] Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA. [Tirschwell, David L.] Univ Washington, Harborview Med Ctr, Stroke Ctr, Seattle, WA 98104 USA. [Slowik, Agnieszka] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland. [Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Selim, Magdy] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Roquer, Jaume] Univ Autonoma Barcelona, Neurovasc Res Unit, Dept Neurol, E-08193 Barcelona, Spain. [Roquer, Jaume] Univ Autonoma Barcelona, Program Inflammat & Cardiovasc Disorders, Inst Municipal Invest Med, Hosp del Mar, E-08193 Barcelona, Spain. [Montaner, Joan] Univ Autonoma Barcelona, Neurovasc Res Lab, E-08193 Barcelona, Spain. [Montaner, Joan] Univ Autonoma Barcelona, Neurovasc Unit, Inst Recerca, Hosp Vall dHebron, E-08193 Barcelona, Spain. [Kidwell, Chelsea S.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. RP Anderson, CD (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CZPN 5820, Boston, MA 02114 USA. EM cdanderson@partners.org RI Ross, Owen/D-7573-2013; Singleton, Andrew/C-3010-2009; Montaner, Joan/D-3063-2015; Goldstein, Joshua/H-8953-2016; IBIS, NEUROVASCULAR/O-1855-2015; OI Brown, Devin/0000-0002-9815-3421; Hansen, Bjorn/0000-0001-8661-9063; Norrving, Bo/0000-0002-8024-5096; Ayres, Alison/0000-0002-5492-1695; Anderson, Christopher/0000-0002-0053-2002 FU American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010 N]; National Institutes of Health (NIH)-National Institute for Neurological Disorders and Stroke (NINDS) [R01 NS059727, U01 NS069208, R01 NS42733, R01 NS39987, U54NS057405, NS36695, NS30678, K23NS042695, 5K23NS059774, R01NS059727, 5R01NS042147]; Keane Genetics Fund; Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; US NIH; National Heart, Lung, and Blood Institute STAMPEED genomics research program [R01 HL087676]; National Center for Research Resources [U54 RR020278]; American Brain Foundation; Intramural Research Program of NIH-National Institute on Aging (NIA) [Z01 AG000954-06, Z01 AG000015-50]; Marriott Disease Risk and Regenerative Medicine Initiative Award in Individualized Medicine; Marriott Mitochondrial Fund; American Heart Association, James and Esther King Biomedical Research Program; Florida Department of Health; Myron and Jane Hanley Award in Stroke Research; National Institute on Minority Health and Health Disparities (NIMHD) [U54NS057405]; Greater Cincinnati Foundation Grant (Cincinnati Control Cohort); Keane Stroke Genetics Research Fund; Edward and Maybeth Sonn Research Fund; University of Michigan General Clinical Research Center [M01 RR000042]; Instituto de Salud Carlos III, Spanish Research Networks Red HERACLES FEDER [RD06/009]; Polish Ministry of Education [NN402083934]; Lund University; Region Skane; King Gustaf V's and Queen Victoria's Foundation; Swedish Medical Research Council [K2010-61X-20378-04-3]; Austrian Science Fund [P20545-P05, P13180]; National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Minority Health and Health Disparities [NS U54NS057405] FX Massachusetts General Hospital/MIGen: These studies were funded by the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (0775010 N), the National Institutes of Health (NIH)-National Institute for Neurological Disorders and Stroke (NINDS; R01 NS059727, U01 NS069208), The Keane Genetics Fund, and the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke. The MIGen study was funded by the US NIH and National Heart, Lung, and Blood Institute STAMPEED genomics research program (R01 HL087676) and a grant from the National Center for Research Resources. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. C.D.A., A.B., and N.S.R. were supported in part by the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research, and C.D.A. was supported by the American Brain Foundation.; Ischemic Stroke Genetics Study/Siblings with Ischemic Stroke Study: These studies were funded by NIH-NINDS (R01 NS42733, R01 NS39987), the Intramural Research Program of NIH-National Institute on Aging (NIA; Z01 AG000954-06), and by the Marriott Disease Risk and Regenerative Medicine Initiative Award in Individualized Medicine and the Marriott Mitochondrial Fund. The inclusion of BLSA samples was supported in part by the Intramural Research Program of NIH-NIA (Z01 AG000015-50). O.A.R. was supported by the American Heart Association, James and Esther King Biomedical Research Program, the Florida Department of Health, and the Myron and Jane Hanley Award in Stroke Research.; International Stroke Genetics Consortium: The Differences in the Imaging of Primary Hemorrhage based on Ethnicity or Race (DECIPHER) project was supported by Award Number U54NS057405 from the NIH-NINDS and National Institute on Minority Health and Health Disparities (NIMHD) (U54NS057405). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health (DECIPHER). The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study was supported by NIH-NINDS (NS36695 and NS30678), and by the Greater Cincinnati Foundation Grant (Cincinnati Control Cohort). The Massachusetts General Hospital Intracerebral Hemorrhage Stroke Genome-Wide Association study was funded by NIH-NINDS (K23NS042695, 5K23NS059774, R01NS059727, and 5R01NS042147), the Keane Stroke Genetics Research Fund, the Edward and Maybeth Sonn Research Fund, by the University of Michigan General Clinical Research Center (M01 RR000042), and by a grant from the National Center for Research Resources. The Hospital del Mar ICH (HM-ICH) study was funded by the Instituto de Salud Carlos III, Spanish Research Networks Red HERACLES (RD06/009) FEDER. The Jagiellonian University Hemorrhagic Stroke Study (JUHSS) was supported by a grant funded by the Polish Ministry of Education (NN402083934). The Lund Stroke Register (LSR) was funded by Lund University, Region Skane, King Gustaf V's and Queen Victoria's Foundation, and the Swedish Medical Research Council (K2010-61X-20378-04-3). Biobank services and genotyping were done at Region Skane Competence Center (RSKC Malmo), Skane University Hospital, Malmo, Sweden. Controls from the Medical University of Graz ICH (MUG-ICH) study were from the Austrian Stroke Prevention Study, which is a population-based study funded by the Austrian Science Fund grant numbers P20545-P05 and P13180; the Medical University of Graz supports the databank of the Austrian Stroke Prevention Study.; This work used samples and clinical data from the National Institutes of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (NIH), Bethesda, MD (http://biowulf.nih.gov). The project described was supported in part by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Minority Health and Health Disparities (NS U54NS057405). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS or NIH. NR 30 TC 14 Z9 15 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2013 VL 44 IS 3 BP 612 EP + DI 10.1161/STROKEAHA.112.672089 PG 49 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 097AW UT WOS:000315447400013 PM 23362085 ER PT J AU He, M Bian, B Gesuwan, K Gulati, N Zhang, LS Nilubol, N Kebebew, E AF He, Mei Bian, Brent Gesuwan, Krisana Gulati, Neelam Zhang, Lisa Nilubol, Naris Kebebew, Electron TI Telomere Length Is Shorter in Affected Members of Families with Familial Nonmedullary Thyroid Cancer SO THYROID LA English DT Article ID ABERRANT HOMOLOGOUS RECOMBINATION; CARCINOMA; ANTICIPATION; INSTABILITY; PROTEINS; FEATURES; DISEASE AB Background: The theory that short telomere length and genetic defects in maintaining telomere length are associated with familial nonmedullary thyroid cancer (FNMTC) is controversial. Thus, the aim of this study was to determine whether telomere length and genes involved in maintaining telomere length are altered in FNMTC. Methods: Blood samples were collected from 44 members (13 affected and 31 unaffected) of six families with FNMTC and from 60 controls. Quantitative polymerase chain reaction (Q-PCR) and reverse transcription PCR were performed to analyze relative telomere length (RTL), gene copy number, and mRNA expression of telomerase reverse transcriptase (hTERT), telomere repeat binding factor 1 (TRF1), telomere repeat binding factor 2 (TRF2), repressor activator protein 1 (RAP1), TRF1 interacting nuclear factor 2 (TIN2), tripeptidyl peptidase 1 (TPP1), and protection of telomere 1 (POT1). Results: Affected members had shorter RTL, as compared with unaffected members (0.98 vs. 1.23, p < 0.01). There was no significant difference in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1 gene copy number or mRNA expression between affected and unaffected members. Conclusions: RTL is shorter in affected members with FNMTC but is not associated with altered copy number or expression in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. The small differences in RTL preclude the utility of RTL as a marker for FNMTC in at-risk individuals. C1 [He, Mei; Bian, Brent; Gesuwan, Krisana; Gulati, Neelam; Zhang, Lisa; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Branch, 9000 Rockville Pike,Bldg 10,Room 3-5840, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov FU Intramural Research Program; Center for Cancer Research; National Cancer Institute; National Institutes of Health FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, and National Institutes of Health. NR 26 TC 3 Z9 5 U1 0 U2 2 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 MAR PY 2013 VL 23 IS 3 BP 301 EP 307 DI 10.1089/thy.2012.0270 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 103XD UT WOS:000315951900009 PM 23009101 ER PT J AU Karani, R Ognibene, FP Fallar, R Gliatto, P AF Karani, Reena Ognibene, Frederick P. Fallar, Robert Gliatto, Peter TI Medical Students' Experiences With Authorship in Biomedical Research: A National Survey SO ACADEMIC MEDICINE LA English DT Article ID MISCONDUCT; HONORARY AB Purpose To explore authorship issues related to medical students' primary research projects, assess medical students' knowledge about authorship issues in biomedical research, and determine their interest in learning about authorship guidelines. Method In 2011, the authors developed and conducted an electronic survey of 243 U. S. medical students who attended an educational event at the National Institutes of Health as part of their funded, yearlong research fellowship programs. The authors then analyzed the results using descriptive statistics. Results Of 243 students, 152 (63%) responded. Most (120/151; 79%) had completed or were in the process of writing a manuscript based on their projects. Of these, most (95/119; 80%) wrote the entire manuscript independently or with guidance. Whereas almost two-thirds (99/152; 65%) indicated that expectations and criteria for authorship were clarified for them, 26% (40/152) indicated that they were not. Most students (108/118; 92%) were in the authorship position they expected and had no concerns about who the other authors were (91/119; 77%). Of those with concerns, 52% (11/21) did not raise the issue for fear of challenging their mentor. Two-thirds (95/145; 66%) never received formal training in authorship guidelines, and 41% (42/103) believed such training would be valuable. Conclusions Although a majority of students had conversations about authorship and were clear about the guidelines for ethical authorship, additional work is needed. The authors recommend that academic institutions develop a menu of options for teaching students about this important area in research ethics. C1 [Karani, Reena; Gliatto, Peter] Mt Sinai Sch Med, New York, NY 10029 USA. [Ognibene, Frederick P.] NIH, Off Clin Res Training & Med Educ, Bethesda, MD 20892 USA. [Ognibene, Frederick P.] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Fallar, Robert] Mt Sinai Hosp, Mt Sinai Med Ctr, Survey Ctr, New York, NY 10029 USA. RP Karani, R (reprint author), Mt Sinai Sch Med, 1 Gustave Levy Pl,Box 1257, New York, NY 10029 USA. EM reena.karani@mssm.edu OI Fallar, Robert/0000-0002-2968-7630 NR 13 TC 7 Z9 8 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD MAR PY 2013 VL 88 IS 3 BP 364 EP 368 DI 10.1097/ACM.0b013e31827fc6ae PG 5 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 098CJ UT WOS:000315522600023 PM 23348080 ER PT J AU Walsh, SL Heilig, M Nuzzo, PA Henderson, P Lofwall, MR AF Walsh, Sharon L. Heilig, Markus Nuzzo, Paul A. Henderson, Pam Lofwall, Michelle R. TI Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers SO ADDICTION BIOLOGY LA English DT Article DE Abuse liability; aprepitant; NK1 antagonist; opioid; oxycodone; substance P ID CHEMOTHERAPY-INDUCED NAUSEA; SUBSTANCE-P RECEPTORS; HUMAN-BRAIN; CYTOCHROME-P450 3A4; MICE LACKING; MORPHINE; PHARMACOKINETICS; DEPENDENCE; PHARMACOTHERAPY; METABOLISM AB Pre-clinical studies suggest that the neurokinin-1 (NK1) receptor may modulate the response to opioids, with NK1 inactivation leading to decreased opioid reinforcement, tolerance and withdrawal. Aprepitant is a selective NK1 antagonist currently marketed for clinical use as an anti-emetic. This 6-week in-patient study used a randomized, double-blind, double-dummy, within-subject, crossover design. Subjects (n=8; 6 male/2 female) were healthy, adult volunteers who provided subjective and objective evidence of current prescription opioid abuse (without physical dependence) and underwent careful medical and psychiatric screening. Fifteen experimental conditions, consisting of one aprepitant dose (0, 40 and 200mg, p.o. given as a 2-hour pre-treatment) in combination with one oxycodone dose [placebo, oral (20 and 40mg/70kg) and intranasal (15 and 30mg/70kg)], were examined. Sessions were conducted at least 48-hour apart and multi-dimensional measures were collected repeatedly throughout the 6-hour session duration. Oxycodone, by both routes of administration, produced significant dose-related effects on the predicted measures (e.g. subjective measures of abuse liability, respiratory depression and miosis). Pre-treatment with aprepitant (200mg) significantly enhanced ratings of oxycodone subjective effects related to euphoria and liking and doubled the street value estimates for the highest test doses of oxycodone by both routes. Some objective measures (respiratory function, observer-rated opioid agonist effects) were similarly enhanced by pre-treatment with the highest dose of aprepitant. All dose combinations were safely tolerated. These findings are discussed in the context of the potential utility of NK1 antagonists in the treatment of opioid use disorders. C1 [Walsh, Sharon L.; Nuzzo, Paul A.; Henderson, Pam; Lofwall, Michelle R.] Univ Kentucky, Ctr Drug & Alcohol Res, Lexington, KY USA. [Walsh, Sharon L.; Lofwall, Michelle R.] Univ Kentucky, Dept Behav Sci, Lexington, KY USA. [Walsh, Sharon L.; Lofwall, Michelle R.] Univ Kentucky, Dept Psychiat, Lexington, KY USA. [Heilig, Markus] NIAAA, Bethesda, MD USA. RP Walsh, SL (reprint author), Ctr Drug & Alcohol Res, 515 Oldham Court, Lexington, KY 40503 USA. EM sharon.walsh@uky.edu OI Heilig, Markus/0000-0003-2706-2482 FU National Institute on Drug Abuse [R01 DA027031]; Clinical and Translational Science Award [UL1RR033173]; University of Kentucky FX Support for this project was provided by the National Institute on Drug Abuse through grant funding (R01 DA027031; SLW) and through a Clinical and Translational Science Award to the University of Kentucky (UL1RR033173). Merck Sharp and Dohme Corporation graciously provided aprepitant tablets and matched placebo at no cost through their external grants program. The authors would like to thank the nursing staff at the Clinical Research-DOC, the research staff at the Center on Drug and Alcohol Research and Dr. Stephen Sitzlar at the Investigational Drug Services from the University of Kentucky for their expert services and support for this project. This study was registered at http://www.clinicaltrials.gov, October 20, 2009, with the identifier NCT00999544. NR 51 TC 10 Z9 10 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2013 VL 18 IS 2 BP 332 EP 343 DI 10.1111/j.1369-1600.2011.00419.x PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 097VB UT WOS:000315500500013 PM 22260216 ER PT J AU Syed, SS Balluz, RS Kabagambe, EK Meyer, WA Lukas, S Wilson, CM Kapogiannis, BG Nachman, SA Sleasman, JW AF Syed, Salma S. Balluz, Rula S. Kabagambe, Edmond K. Meyer, William A., III Lukas, Susan Wilson, Craig M. Kapogiannis, Bill G. Nachman, Sharon A. Sleasman, John W. TI Assessment of Biomarkers of Cardiovascular Risk Among HIV Type 1-Infected Adolescents: Role of Soluble Vascular Cell Adhesion Molecule As an Early Indicator of Endothelial Inflammation SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; AMERICAN-HEART-ASSOCIATION; C-REACTIVE PROTEIN; ANTIRETROVIRAL THERAPY; MICROBIAL TRANSLOCATION; SHORT-TERM; INFECTION; DISEASE; ACTIVATION; MARKERS AB Cardiovascular disease (CVD) biomarkers were examined in a cohort of HIV-infected and HIV-uninfected adolescents who participated in Adolescent Trials Network study 083 utilizing samples from the Reaching for Excellence in Adolescent Care cohort, a longitudinal study of youth infected through adult risk behavior. Nonfasting blood samples from 97 HIV-infected and 81 HIV-uninfected adolescents infected by adult risk behaviors were analyzed for total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglycerides, apolipoprotein A-I, high-sensitivity C-reactive protein (hsCRP), soluble vascular adhesion molecule-1 (sVCAM-1), myeloperoxidase, and neopterin at baseline and 18 months later. Results were analyzed using ANOVA, Wilcoxon signed-rank, and paired t tests. Among infected subjects 67 received antiretroviral therapy and 30 were treatment naive. The HIV-infected and HIV-uninfected subjects were similar in gender, ethnicity, and cardiovascular risk factors such as smoking and obesity. In all groups lipid parameters were within accepted guidelines for cardiovascular risk. Among HIV-infected youth on antiretroviral therapy (ART), HDL and apoprotein A-I were significantly lower when compared to uninfected youth. hsCRP was not elevated and thus not predictive for risk in any group. sVCAM-1 levels were significantly elevated in both HIV-infected groups: 1,435 ng/ml and 1,492 ng/ml in untreated and treated subjects, respectively, and 1,064 ng/ml in the uninfected group (p < 0.0001). Across all groups neopterin correlated with sVCAM at 18 months (Spearman correlation coefficient 0.58, p < 0.0001). Only 9% of ART-treated subjects fully suppressed virus. Lipid profiles and hsCRP, traditional markers of cardiovascular disease, are not abnormal among HIV-infected youth but elevated sVCAM may be an early marker of atherosclerosis. C1 [Syed, Salma S.; Nachman, Sharon A.] SUNY Stony Brook, Dept Pediat, Stony Brook, NY 11794 USA. [Balluz, Rula S.] Drexel Univ, St Christophers Hosp Children, Coll Med, Philadelphia, PA 19104 USA. [Kabagambe, Edmond K.; Wilson, Craig M.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Meyer, William A., III] Quest Diagnost, Baltimore, MD USA. [Lukas, Susan; Sleasman, John W.] Univ S Florida, Dept Pediat, St Petersburg, FL 33701 USA. [Kapogiannis, Bill G.] NICHHD, Bethesda, MD 20892 USA. RP Sleasman, JW (reprint author), Univ S Florida, Dept Pediat, 801 6th St South, St Petersburg, FL 33701 USA. EM jsleasma@health.usf.edu FU Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN); National Institutes of Child Health and Development [5 U01HD40533, 5 U01HD40474]; [5 U01 HD32842]; [R01 DA031017]; [R01 AI47723] FX This study was supported by the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN), which is supported by the National Institutes of Child Health and Development (5 U01HD40533 and 5 U01HD40474). REACH was supported by 5 U01 HD32842. The study was also supported by R01 DA031017 and R01 AI47723. The authors thank Drs. Bret Rudy and Kathleen Mulligan for their comments in preparing the manuscript. The contents of this publication are solely the responsibility of the authors and do not necessarily reflect the official views of the National Institutes of Health. NR 38 TC 5 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 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2013 VL 29 IS 3 BP 493 EP 500 DI 10.1089/aid.2012.0086 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 096VY UT WOS:000315434000013 PM 23062187 ER PT J AU McGinnis, KA Justice, AC Kraemer, KL Saitz, R Bryant, KJ Fiellin, DA AF McGinnis, Kathleen A. Justice, Amy C. Kraemer, Kevin L. Saitz, Richard Bryant, Kendall J. Fiellin, David A. TI Comparing Alcohol Screening Measures Among HIV-Infected and -Uninfected Men SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE AUDIT; HIV; Veterans; Alcohol-Related Disorders; Mass Screening ID IDENTIFICATION TEST AUDIT; USE DISORDERS; PRIMARY-CARE; CONSUMPTION QUESTIONS; DISEASE PROGRESSION; FOLLOW-UP; DRINKING; RELIABILITY; DRINKERS; RISK AB Background Brief measures of unhealthy alcohol use have not been well validated among people with HIV. We compared the Alcohol Use Disorders Identification Test (AUDIT) to reference standards for unhealthy alcohol use based on 30-day Timeline Follow Back (TLFB) and Composite International Diagnostic InterviewSubstance Abuse Module (CIDI-SAM), among 837 male HIV-infected and -uninfected patients in the Veterans Aging Cohort Study. Methods Three reference standards were (i) Risky drinkingbased on TLFB >14 drinks over 7 consecutive days or >4 drinks on 1day; (ii) Alcohol dependencebased on a CIDI-SAM diagnosis; and (iii) Unhealthy alcohol userisky drinking or a CIDI-SAM diagnosis of abuse or dependence. Various cutoffs for the AUDIT, AUDIT-C, and heavy episodic drinking were compared with the reference standards. Results Mean age of patients was 52years, 53% (444) were HIV-infected, and 53% (444) were African American. Among HIV-infected and -uninfected patients, the prevalence of risky drinking (14 vs. 12%, respectively), alcohol dependence (8 vs. 7%), and unhealthy alcohol use (22 vs. 20%) was similar. For risky drinking and alcohol dependence, multiple cutoffs of AUDIT, AUDIT-C, and heavy episodic drinking provided good sensitivity (80%) and specificity (90%). For unhealthy alcohol use, few cutoffs provided sensitivity 80%; however, many cutoffs provided good specificity. For all 3 alcohol screening measures, sensitivity improved when heavy episodic drinking was included with the cutoff. Sensitivity of measures for risky drinking and unhealthy alcohol use was lower in HIV-infected than in uninfected patients. Conclusions For identifying risky drinking, alcohol dependence, and unhealthy alcohol use, AUDIT-C performs as well as AUDIT and similarly in HIV-infected and -uninfected patients. Cutoffs should be based on the importance of specific operating characteristics for the intended research or clinical use. Incorporating heavy episodic drinking increased sensitivity for detecting alcohol dependence and unhealthy alcohol use. C1 [McGinnis, Kathleen A.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Med, Div Gen Internal Med, New Haven, CT USA. [Justice, Amy C.; Fiellin, David A.] West Haven VA Healthcare Syst, Vet Aging Cohort Study Coordinating Ctr, West Haven, CT USA. [Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT USA. [Kraemer, Kevin L.] Univ Pittsburgh, Dept Med, Ctr Res Hlth Care, Div Gen Internal Med, Pittsburgh, PA USA. [Saitz, Richard] Boston Med Ctr, Dept Med, Clin Addict Res & Educ CARE Unit, Gen Internal Med Sect, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. [Saitz, Richard] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bryant, Kendall J.] NIAAA, Bethesda, MD USA. RP McGinnis, KA (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr,151C-H, Pittsburgh, PA 15206 USA. EM kathleen.mcginnis3@va.gov OI Fiellin, David/0000-0002-4006-010X; /0000-0002-2535-1427 FU National Institute on Alcohol Abuse and Alcoholism [U10 AA 13566] FX The Veterans Aging Cohort Study is funded by the National Institute on Alcohol Abuse and Alcoholism (U10 AA 13566). NR 34 TC 15 Z9 15 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2013 VL 37 IS 3 BP 435 EP 442 DI 10.1111/j.1530-0277.2012.01937.x PG 8 WC Substance Abuse SC Substance Abuse GA 097VC UT WOS:000315500600009 PM 23050632 ER PT J AU Beavers, KM Beavers, DP Houston, DK Harris, TB Hue, TF Koster, A Newman, AB Simonsick, EM Studenski, SA Nicklas, BJ Kritchevsky, SB AF Beavers, Kristen M. Beavers, Daniel P. Houston, Denise K. Harris, Tamara B. Hue, Trisha F. Koster, Annemarie Newman, Anne B. Simonsick, Eleanor M. Studenski, Stephanie A. Nicklas, Barbara J. Kritchevsky, Stephen B. TI Associations between body composition and gait-speed decline: results from the Health, Aging, and Body Composition study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID PHYSICAL PERFORMANCE BATTERY; INCIDENT MOBILITY LIMITATION; LOWER-EXTREMITY FUNCTION; OLDER-ADULTS; MUSCLE STRENGTH; MASS INDEX; SUBSEQUENT DISABILITY; INFLAMMATORY MARKERS; ELDERLY-MEN; WOMEN AB Background: In older adults, every 0.1-m/s slower gait speed is associated with a 12% higher mortality. However, little research has identified risk factors for gait-speed decline. Objective: We assessed the association between several measures of body composition and age-related decline in gait speed. Design: Data were from 2306 older adults who were participating in the Health, Aging, and Body Composition cohort and were followed for 4 y (50% women; 38% black). Usual walking speed (m/s) over 20 m was measured in years 2 through 6, and the baseline and changes in several measures of body composition were included in mixed-effects models. Results: Gait speed declined by 0.06 +/- 0.00 m/s over the 4-y period. Baseline thigh intermuscular fat predicted the annual gait-speed decline (+/-SE) in both men and women (-0.01 +/- 0.00 and -0.02 +/- 0.00 m/s per 0.57 cm(2), respectively; P < 0.01). In men, but not in women, this relation was independent of total body adiposity. In longitudinal analyses, changes in thigh intermuscular fat and total thigh muscle were the only body-composition measures that predicted gait-speed decline in men and women combined. When modeled together, every 5.75-cm(2) increase in thigh intermuscular fat was associated with a 0.01 +/- 0.00-m/s decrease in gait speed, whereas every 16.92-cm(2) decrease in thigh muscle was associated with a 0.01 +/- 0.00-m/s decrease in gait speed. Conclusions: High and increasing thigh intermuscular fat are important predictors of gait-speed decline, implying that fat infiltration into muscle contributes to a loss of mobility with age. Conversely, a decreasing thigh muscle area is also predictive of a decline in gait speed. Am J Clin Nutr 2013;97:552-60. C1 [Beavers, Kristen M.; Houston, Denise K.; Nicklas, Barbara J.; Kritchevsky, Stephen B.] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Dept Internal Med, Winston Salem, NC 27157 USA. [Beavers, Daniel P.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Studenski, Stephanie A.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Hue, Trisha F.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Koster, Annemarie] Maastricht Univ, Sch Publ Hlth & Primary Care, Dept Social Med, Maastricht, Netherlands. RP Beavers, KM (reprint author), Wake Forest Sch Med, Sticht Ctr Aging, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM kbeavers@wakehealth.edu RI Newman, Anne/C-6408-2013; Koster, Annemarie/E-7438-2010; Beavers, Daniel/G-5338-2016; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; Wake Forest University Claude D Pepper Older Americans Independence Center [P30-AG21332]; NIH, National Institute on Aging; National Institute on Nursing Research [R01-NR012459]; [F32-AG039186] FX Supported by the National Institute on Aging (contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 and grant R01-AG028050), the National Institute on Nursing Research (grant R01-NR012459), the Wake Forest University Claude D Pepper Older Americans Independence Center (P30-AG21332), and an individual postdoctoral fellowship (F32-AG039186; to KMB) and supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 35 TC 39 Z9 40 U1 3 U2 24 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 MAR PY 2013 VL 97 IS 3 BP 552 EP 560 DI 10.3945/ajcn.112.047860 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 096UV UT WOS:000315431000014 PM 23364001 ER PT J AU Schliep, KC Schisterman, EF Mumford, SL Pollack, AZ Perkins, NJ Ye, AJ Zhang, CLJ Stanford, JB Porucznik, CA Hammoud, AO Wactawski-Wende, J AF Schliep, Karen C. Schisterman, Enrique F. Mumford, Sunni L. Pollack, Anna Z. Perkins, Neil J. Ye, Aijun Zhang, Cuilin J. Stanford, Joseph B. Porucznik, Christina A. Hammoud, Ahmad O. Wactawski-Wende, Jean TI Energy-containing beverages: reproductive hormones and ovarian function in the BioCycle Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SUGAR-SWEETENED BEVERAGES; FOOD FREQUENCY QUESTIONNAIRE; MARGINAL STRUCTURAL MODELS; SOFT DRINK CONSUMPTION; DIETARY FIBER INTAKE; MIDDLE-AGED WOMEN; PREMENOPAUSAL WOMEN; INSULIN-RESISTANCE; UNITED-STATES; WEIGHT-GAIN AB Background: Energy-containing beverages are widely consumed among premenopausal women, but their association with reproductive hormones is not well understood. Objective: The objective was to assess the association of energy-containing beverages, added sugars, and total fructose intake with reproductive hormones among ovulatory cycles and sporadic anovulation in healthy premenopausal women. Design: Women (n = 259) in the BioCycle Study were followed for up to 2 menstrual cycles; they provided fasting blood specimens during up to 8 visits/cycle and four 24-h dietary recalls/cycle. Results: Women who consumed >= 1 cup (1 cup = 237 mL) sweetened soda/d had 16.3% higher estradiol concentrations compared with women who consumed less sweetened soda (86.5 pg/mL compared with 74.4 pg/mL, P = 0.01) after adjustment for age, BMI, race, dietary factors, and physical activity. Similarly elevated estradiol concentrations were found for cup >= 1cup cola/d and noncola soda intake. Neither artificially sweetened soda nor fruit juice intake >= 1 >= 1 cup/d was significantly associated with reproductive hormones. Added sugar above the average US woman's intake (>= 73.2 g/d) or above the 66th percentile in total fructose intake (>= 41.5 g/d) was associated with significantly elevated estradiol but not consistently across all models. No associations were found between beverages, added sugars, or total fructose intake and anovulation after multi-variate adjustment. Conclusions: Even at moderate consumption amounts, sweetened soda is associated with elevated follicular estradiol concentrations among premenopausal women but does not appear to affect ovulatory function. Further research into the mechanism driving the association between energy-containing beverages and reproductive hormones, and its potential implications for women's health, is warranted. Am J Clin Nutr 2013;97:621-30. C1 [Schliep, Karen C.; Schisterman, Enrique F.; Mumford, Sunni L.; Pollack, Anna Z.; Perkins, Neil J.; Ye, Aijun; Zhang, Cuilin J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Schliep, Karen C.; Stanford, Joseph B.; Porucznik, Christina A.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. EM schistee@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 54 TC 6 Z9 6 U1 0 U2 7 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 MAR PY 2013 VL 97 IS 3 BP 621 EP 630 DI 10.3945/ajcn.111.024752 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 096UV UT WOS:000315431000021 PM 23364018 ER PT J AU Gage, JC Schiffman, M Hunt, WC Joste, N Ghosh, A Wentzensen, N Wheeler, CM AF Gage, Julia C. Schiffman, Mark Hunt, William C. Joste, Nancy Ghosh, Arpita Wentzensen, Nicolas Wheeler, Cosette M. CA New Mexico HPV Pap Registry Steer TI Cervical Histopathology Variability Among Laboratories A Population-Based Statewide Investigation SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Cervical intraepithelial neoplasia; Histopathology; Reproducibility ID INTRAEPITHELIAL NEOPLASIA; INTEROBSERVER VARIATION; EPITHELIAL ABNORMALITIES; BIOPSY SPECIMENS; DIAGNOSIS; PATHOLOGISTS; DYSPLASIA; CANCER AB To inform the proposed systematic adjudicative staining of cervical intraepithelial neoplasia grade 2 (CIN2) and equivocal diagnoses, we characterized diagnostic heterogeneity across 15 laboratories. Laboratory-specific distributions of 37,486 biopsy specimen diagnoses were compared after adjusting for preceding cytology. In a subset of preceding cytology specimens, HPV16 genotyping was considered an indicator of lesion severity. Distributions of normal and CIN1 diagnoses varied widely, with laboratories favoring either normal (5.5%-57.7%) or CIN1 diagnoses (23.3%-86.7%; P < .001 for normal:CIN1 variability). Excluding extreme values, 6.2% to 14.4% of diagnoses were CIN2 (P < .001). For CIN2 diagnoses, HPV16 positivity in the preceding cytology varied between 39.0% in the largest laboratory and 57.4% in others (P < .001), suggesting differential interpretation, not population differences, as a cause of variability. In conclusion, the frequency of diagnoses requiring special staining (p16(INK4a) a immunostaining) to adjudicate equivocal CIN2 will be sizable and vary between laboratories, especially if extended to a fraction of CIN1 lesions. C1 [Gage, Julia C.; Schiffman, Mark; Ghosh, Arpita; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Hunt, William C.; Joste, Nancy; Wheeler, Cosette M.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Wheeler, CM (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Pathol, House Prevent Epidemiol HOPE,1816 Sigma Chi Rd NE, Albuquerque, NM 87131 USA. EM cwheeler@salud.unm.edu FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, DHHS; University of New Mexico from Merck and Co, Whitehouse Station, NJ; GlaxoSmithKline, Philadelphia, PA; [R01CA134779] FX Supported by R01CA134779 (C.M.W.) and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, DHHS. HPV Linear Array reagents and equipment to automate HPV genotyping assays were provided by Roche Molecular Systems, Pleasanton, CA.; C.M.W. has received finding through the University of New Mexico from Merck and Co, Whitehouse Station, NJ, and GlaxoSmithKline, Philadelphia, PA, for HPV vaccine studies, as well as equipment and reagents from Roche Molecular Systems for HPV genotyping. The other authors report no conflicts of interest. NR 19 TC 7 Z9 8 U1 0 U2 2 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD MAR PY 2013 VL 139 IS 3 BP 330 EP 335 DI 10.1309/AJCPSD3ZXJXP7NNB PG 6 WC Pathology SC Pathology GA 099GC UT WOS:000315608500009 PM 23429369 ER PT J AU Keller, MF Nalls, MA Singleton, A AF Keller, M. F. Nalls, M. A. Singleton, A. TI Genome-wide associations for Parkinson's disease on the X chromosome SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 Temple Univ, Dept Anthropol, Philadelphia, PA 19122 USA. [Keller, M. F.; Nalls, M. A.; Singleton, A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2013 VL 25 IS 2 BP 262 EP 262 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 095TL UT WOS:000315357500049 ER PT J AU Van Horn, A Keller, MF Mao, JZ Kulathinal, RJ Rockwell, LC AF Van Horn, A. Keller, M. F. Mao, J. Z. Kulathinal, R. J. Rockwell, L. C. TI The Outer Limits: Genic and Intergenic Polymorphism Between Geographically Distinct Populations SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 [Van Horn, A.; Keller, M. F.; Rockwell, L. C.] Temple Univ, Dept Anthropol, Philadelphia, PA 19122 USA. [Keller, M. F.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mao, J. Z.; Kulathinal, R. J.] Temple Univ, Dept Biol, Philadelphia, PA 19122 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2013 VL 25 IS 2 BP 279 EP 279 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 095TL UT WOS:000315357500102 ER PT J AU Agochukwu, NB Solomon, BD Benson, LJ Muenke, M AF Agochukwu, Nneamaka B. Solomon, Benjamin D. Benson, Laurel J. Muenke, Maximilian TI Talocalcaneal coalition in Muenke syndrome: Report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Muenke syndrome; FGFR3 craniosynostosis; tarsal fusion craniosynostosis; tarsal coalition craniosynostosis; Talocalcaneal coalition; syndromic craniosynostosis tarsal coalition; FGFR craniosynostosis tarsal fusion; Muenke syndrome tarsal fusion; Muenke syndrome tarsal coalition; the feet Muenke syndrome ID GROWTH-FACTOR RECEPTOR-3; JACKSON-WEISS-SYNDROME; CROUZON-SYNDROME; PFEIFFER-SYNDROME; APERT SYNDROME; TARSAL COALITION; CORONAL CRANIOSYNOSTOSIS; RADIOGRAPHIC FINDINGS; ACANTHOSIS NIGRICANS; PRO250ARG MUTATION AB Muenke syndrome is an autosomal dominant craniosynostosis syndrome resulting from a defining point mutation in the Fibroblast Growth Factor Receptor3 (FGFR3) gene. Muenke syndrome is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay, and carpal and/or tarsal bone coalition. Tarsal coalition is a distinct feature of Muenke syndrome and has been reported since the initial description of the disorder in the 1990s. Although talocalcaneal coalition is the most common tarsal coalition in the general population, it has never previously been reported in a patient with Muenke syndrome. We present a 7-year-old female patient with Muenke syndrome and symptomatic talocalcaneal coalition. She presented at the age of 7 with limping, tenderness and pain in her right foot following a fall and strain of her right foot. She was treated with ibuprofen, shoe inserts, a CAM walker boot, and stretching exercises without much improvement in symptoms. A computed tomography (CT) scan revealed bilateral talocalcaneal coalitions involving the middle facet. She underwent resection of the talocalcaneal coalitions, remaining pain-free post-operatively with an improvement in her range of motion, gait, and mobility. This report expands the phenotype of tarsal coalition in Muenke syndrome to include talocalcaneal coalition. A literature review revealed a high incidence of tarsal coalition in all FGFR related craniosynostosis syndromes when compared to the general population, a difference that is statistically significant. The most common articulation involved in all syndromic craniosynostoses associated with FGFR mutations is the calcaneocuboid articulation. (c) 2013 Wiley Periodicals, Inc. C1 [Agochukwu, Nneamaka B.; Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Agochukwu, Nneamaka B.] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Benson, Laurel J.] Denver Childrens Hosp, Dept Orthopaed, Aurora, CO USA. RP Muenke, M (reprint author), NIH, MSC 3717 Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, United States of America) FX We would like to express our gratitude to the patient described in this article and the patient's family for their willingness to participate in our study and for their informed consent to participate in our study and to publish this report. We would also like to thank Dr. M. Michael Cohen Jr. for his critical review of this article. This research was supported by the Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, United States of America). NR 62 TC 4 Z9 4 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2013 VL 161A IS 3 BP 453 EP 460 DI 10.1002/ajmg.a.35233 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 095NQ UT WOS:000315341700007 PM 23378035 ER PT J AU Rapoport, JL AF Rapoport, Judith L. TI Prevention of Schizophrenia: An Impossible Dream? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID CHILDHOOD-ONSET SCHIZOPHRENIA; NONPSYCHOTIC SIBLINGS; RISK C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. EM rapoporj@mail.nih.gov FU Intramural NIH HHS [ZIA MH002581-22] NR 9 TC 1 Z9 2 U1 1 U2 8 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2013 VL 170 IS 3 BP 245 EP 247 DI 10.1176/appi.ajp.2012.12101287 PG 3 WC Psychiatry SC Psychiatry GA 097KU UT WOS:000315473800002 PM 23450283 ER PT J AU Baller, EB Wei, SM Kohn, PD Rubinow, DR Alarcon, G Schmidt, PJ Berman, KF AF Baller, Erica B. Wei, Shau-Ming Kohn, Philip D. Rubinow, David R. Alarcon, Gabriela Schmidt, Peter J. Berman, Karen F. TI Abnormalities of Dorsolateral Prefrontal Function in Women With Premenstrual Dysphoric Disorder: A Multimodal Neuroimaging Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID FEMALE RHESUS-MONKEYS; MENSTRUAL-CYCLE; GONADAL-STEROIDS; CORTEX; MOOD; HORMONES AB Objective: To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [O-15]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol. Method: PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [O-15]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol. Results: In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms. Conclusions: Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results. (Am J Psychiatry 2013; 170:305-314) C1 [Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch,NIH, Gene Cognit & Psychosis Program,Intramural Res Pr, Bethesda, MD 20892 USA. NIMH, Sect Behav Endocrinol, Intramural Res Programs, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch,NIH, Gene Cognit & Psychosis Program,Intramural Res Pr, Bethesda, MD 20892 USA. EM bermank@mail.nih.gov FU NIMH, NIH, Bethesda, Md. FX This research was supported by the Intramural Research Program, NIMH, NIH, Bethesda, Md. NR 34 TC 11 Z9 13 U1 2 U2 13 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2013 VL 170 IS 3 BP 305 EP 314 DI 10.1176/appi.ajp.2012.12030385 PG 10 WC Psychiatry SC Psychiatry GA 097KU UT WOS:000315473800011 PM 23361612 ER PT J AU White, SF Pope, K Sinclair, S Fowler, KA Brislin, SJ Williams, WC Pine, DS Blair, RJR AF White, Stuart F. Pope, Kayla Sinclair, Stephen Fowler, Katherine A. Brislin, Sarah J. Williams, W. Craig Pine, Daniel S. Blair, R. James R. TI Disrupted Expected Value and Prediction Error Signaling in Youths With Disruptive Behavior Disorders During a Passive Avoidance Task SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; CALLOUS-UNEMOTIONAL TRAITS; RESPONSE REVERSAL; PSYCHOPATHIC TENDENCIES; ANTISOCIAL-BEHAVIOR; ANTERIOR CINGULATE; CONDUCT DISORDER; DECISION-MAKING; REWARD; CHILDREN AB Objective: Youths with disruptive behavior disorders, including conduct disorder and oppositional defiant disorder, show major. impairments in reinforcement-based decision making. However, the neural basis of these difficulties remains poorly understood. This partly reflects previous failures to differentiate responses during decision making and feedback processing and to take advantage of computational model-based functional MRI (fMRI). Method: Participants were 38 community youths ages 10-18 (20 had disruptive behavior disorders, and 18 were healthy comparison youths). Model-based fMRI was used to assess the computational processes involved in decision making and feedback processing in the ventromedial prefrorital cortex, insula, and caudate. Results: Youths with disruptive behavior disorders showed reduced use of expected value information within the ventromedial prefrontal cortex when choosing to respond and within the anterior insula when choosing not to respond. In addition, they showed reduced responsiveness to positive prediction errors and increased responsiveness to negative prediction errors within the caudate during feedback. Conclusions: This study is the first to determine impairments in the use of expected value within the ventromedial prefrontal cortex and insula during choice and in prediction error-signaling within the caudate during feedback in youths with disruptive behavior disorders. (Am J Psychiatry 2013; 170:315-323) C1 [White, Stuart F.] NIMH, Bethesda, MD 20892 USA. Boys Town Natl Res Hosp, Omaha, NE 68131 USA. RP White, SF (reprint author), NIMH, Bethesda, MD 20892 USA. EM whitesf@mail.nih.gov FU NIMH/NIH [1-ZIA-MH002860-08] FX Supported by the Intramural Research Program of NIMH/NIH under grant 1-ZIA-MH002860-08. NR 35 TC 39 Z9 39 U1 3 U2 22 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2013 VL 170 IS 3 BP 315 EP 323 DI 10.1176/appi.ajp.2012.12060840 PG 9 WC Psychiatry SC Psychiatry GA 097KU UT WOS:000315473800012 PM 23450288 ER PT J AU Hall, EC Segev, DL Engels, EA AF Hall, E. C. Segev, D. L. Engels, E. A. TI Racial/Ethnic Differences in Cancer Risk After Kidney Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Cancer risk attributable to transplantation; cumulative incidence of cancer; ethinic; racial disparities in cancer risk ID RENAL-CELL CARCINOMA; HISPANIC WHITE WOMEN; BREAST-CANCER; LUNG-CANCER; AFRICAN-AMERICANS; PROSTATE-CANCER; DISPARITIES; RECIPIENTS; EPIDEMIOLOGY; PROGNOSIS AB Transplant recipients have elevated cancer risk, but it is unknown if cancer risk differs across race and ethnicity as in the general population. US kidney recipients (N = 87,895) in the Transplant Cancer Match Study between 1992 and 2008 were evaluated for racial/ethnic differences in risk for six common cancers after transplantation. Compared to white recipients, black recipients had lower incidence of non-Hodgkin lymphoma (NHL) (adjusted incidence rate ratio [aIRR] 0.60, p<0.001) and higher incidence of kidney (aIRR 2.09, p<0.001) and prostate cancer (aIRR 2.14, p<0.001); Hispanic recipients had lower incidence of NHL (aIRR 0.64, p = 0.001), lung (aIRR 0.41, p < 0.001), breast (aIRR 0.53, p = 0.003) and prostate cancer (aIRR 0.72, p = 0.05). Colorectal cancer incidence was similar across groups. Standardized incidence ratios (SIRs) measured the effect of transplantation on cancer risk and were similar for most cancers (p0.1). However, black and Hispanic recipients had larger increases in kidney cancer risk with transplantation (SIRs: 8.96 in blacks, 5.95 in Hispanics vs. 4.44 in whites), and only blacks had elevated prostate cancer risk following transplantation (SIR: 1.21). Racial/ethnic differences in cancer risk after transplantation mirror general population patterns, except for kidney and prostate cancers where differences reflect the effects of end-stage renal disease or transplantation. C1 [Hall, E. C.; Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Hall, E. C.; Segev, D. L.] Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA. RP Hall, EC (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM ehall@jhsph.edu FU National Cancer Institute; Clinical and Laboratory Research Training for Surgical Oncologists [T32CA126607]; Arbor Research Collaborative for Health in Ann Arbor, MI [HHSH234200537009C]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Georgia [5U58DP000817-05]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Illinois [5658DP000805-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Michigan [5U58DP000812-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New Jersey [5U58/DP000808-05]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New York [15-0351]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; SEER Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261201000034C]; SEER Program of the National Cancer Institute: Connecticut [HHSN261201000024C]; SEER Program of the National Cancer Institute: Hawaii [HHSN261201000037C, N01-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute: Iowa [N01-PC-35143]; SEER Program of the National Cancer Institute: New Jersey [HHSN261201000027C N01-PC-54405]; SEER Program of the National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; SEER Program of the National Cancer Institute: Utah [HHSN261201000026C]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of New Jersey; state of New York (Cancer Surveillance Improvement Initiative) [14-2491]; state of Texas; state of Washington; Fred Hutchinson Cancer Research Center in Seattle, WA; state of Georgia; state of Hawaii; state of Michigan; state of New York; state of North Carolina; state of Utah; state of Seattle-Puget Sound area of Washington FX The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries or their contractors. This research was supported in part by the Intramural Research Program of the National Cancer Institute and by training grant number T32CA126607, Clinical and Laboratory Research Training for Surgical Oncologists.; During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP000817-05), Illinois (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP000808-05), New York (15-0351), North Carolina (U58DP000832) and Texas (5U58DP000824-04). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137 and N01-PC-35139), Iowa (N01-PC-35143), New Jersey (HHSN261201000027C N01-PC-54405), Seattle-Puget Sound (N01-PC-35142) and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 14-2491), Texas and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, WA.; The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (including Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California (Christina Clarke), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii (Marc Goodman), Iowa (Charles Lynch), Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey (Karen Pawlish, Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Melanie Williams) and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Ruth Parsons). NR 41 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2013 VL 13 IS 3 BP 714 EP 720 DI 10.1111/ajt.12066 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 097CW UT WOS:000315452600023 PM 23331953 ER PT J AU Gao, SY Sandstrom, DJ Smith, HE High, B Marsh, JW Nash, HA AF Gao, Shuying Sandstrom, David J. Smith, Harold E. High, Brigit Marsh, Jon W. Nash, Howard A. TI Drosophila Ryanodine Receptors Mediate General Anesthesia by Halothane SO ANESTHESIOLOGY LA English DT Article ID LONG QT SYNDROME; INTRACELLULAR CALCIUM; MELANOGASTER GENOME; GENETIC-ANALYSIS; RELEASE CHANNEL; EXCITABILITY; CA2+; DYSREGULATION; SENSITIVITY; ACTIVATION AB Background: Although in vitro studies have identified numerous possible targets, the molecules that mediate the in vivo effects of volatile anesthetics remain largely unknown. The mammalian ryanodine receptor (Ryr) is a known halothane target, and the authors hypothesized that it has a central role in anesthesia. Methods: Gene function of the Drosophila Ryr (dRyr) was manipulated in the whole body or in specific tissues using a collection of mutants and transgenes, and responses to halothane were measured with a reactive climbing assay. Cellular responses to halothane were studied using Ca2+ imaging and patch clamp electrophysiology. Results: Halothane potency strongly correlates with dRyr gene copy number, and missense mutations in regions known to be functionally important in the mammalian Ryrs gene cause dominant hypersensitivity. Tissue-specific manipulation of dRyr shows that expression in neurons and glia, but not muscle, mediates halothane sensitivity. In cultured cells, halothane-induced Ca2+ efflux is strictly dRyr-dependent, suggesting a close interaction between halothane and dRyr. Ca2+ imaging and electrophysiology of Drosophila central neurons reveal halothane-induced Ca2+ flux that is altered in dRyr mutants and correlates with strong hyperpolarization. Conclusions: In Drosophila, neurally expressed dRyr mediates a substantial proportion of the anesthetic effects of halothane in vivo, is potently activated by halothane in vitro, and activates an inhibitory conductance. The authors' results provide support for Ryr as an important mediator of immobilization by volatile anesthetics. C1 [Gao, Shuying; Sandstrom, David J.; Smith, Harold E.; High, Brigit; Marsh, Jon W.; Nash, Howard A.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sandstrom, DJ (reprint author), Univ Maryland Coll Pk, Biol Sci Program, Univ Shady Grove Campus,9630 Gudelsky Dr,Bldg 2,R, Rockville, MD 20850 USA. EM sandstrd@umd.edu FU National Institute of Mental Health, Division of Intramural Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland FX Received from the Laboratory of Molecular Biology, National Institute of Mental Health, National Institutes of Health. Submitted for publication March 20, 2012. Accepted for publication November 1, 2012. Supported by the National Institute of Mental Health, Division of Intramural Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Drs. Gao and Sandstrom contributed equally to this work. NR 42 TC 5 Z9 5 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2013 VL 118 IS 3 BP 587 EP 601 DI 10.1097/ALN.0b013e31827e52c6 PG 15 WC Anesthesiology SC Anesthesiology GA 093LH UT WOS:000315192900016 PM 23254148 ER PT J AU Odden, MC Tager, IB Gansevoort, RT Bakker, SJL Fried, LF Newman, AB Katz, R Satterfield, S Harris, TB Sarnak, MJ Siscovick, D Shlipak, MG AF Odden, Michelle C. Tager, Ira B. Gansevoort, Ron T. Bakker, Stephan J. L. Fried, Linda F. Newman, Anne B. Katz, Ronit Satterfield, Suzanne Harris, Tamara B. Sarnak, Mark J. Siscovick, David Shlipak, Michael G. TI Hypertension and low HDL cholesterol were associated with reduced kidney function across the age spectrum: a collaborative study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Chronic kidney insufficiency; Aged; Hypertension; Cholesterol; Obesity; Smoking ID SERUM CYSTATIN-C; URINARY ALBUMIN EXCRETION; CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; RENAL DYSFUNCTION; BLOOD-PRESSURE; POPULATION; RISK; ATHEROSCLEROSIS; PREDICTORS AB Purpose: To determine if the associations among established risk factors and reduced kidney function vary by age. Methods: We pooled cross-sectional data from 14,788 nondiabetics aged 40 to 100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort. Results: Hypertension and low high-density lipoprotein (HDL) cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 23 (95% confidence interval [CI], 0.1, 4.4), 5.1 (95% Cl, 4.1, 6.1), and 6.9 (95% CI, 3.0, 10.4) mL/min/1.73 m(2) lower eGFR in participants 40 to 59, 60 to 79, and at least 80 years, respectively (P for interaction < .001). The association of low HDL cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (95% CI, 3.5, 6.3), 7.1 (95% CI, 6.0, 83), 8.9 (95% CI, 5.4,11.9) mL/min/1.73 m(2) (P for interaction < .001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest. Conclusions: Hypertension, obesity, smoking, and low HDL cholesterol are modestly associated with reduced kidney function in nondiabetics. The associations of hypertension and HDL cholesterol with reduced kidney function seem to be stronger in older adults. (C) 2013 Elsevier Inc. All rights reserved. C1 [Odden, Michelle C.] Oregon State Univ, Sch Biol & Populat Hlth Sci, Corvallis, OR 97331 USA. [Tager, Ira B.] Univ Calif Berkeley, Dept Epidemiol, Berkeley, CA 94720 USA. [Gansevoort, Ron T.; Bakker, Stephan J. L.] Univ Groningen, Univ Med Ctr Groningen, Div Nephrol, Dept Internal Med, Groningen, Netherlands. [Fried, Linda F.] Vet Affairs Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Katz, Ronit] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Med, Hlth Sci Ctr, Memphis, TN 38104 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Dept Med, Boston, MA USA. [Siscovick, David] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA USA. RP Odden, MC (reprint author), Oregon State Univ, 321 Milam Hall, Corvallis, OR 97331 USA. EM Michelle.Odden@oregonstate.edu RI Newman, Anne/C-6408-2013; Bakker, Stephan/J-4023-2015 OI Newman, Anne/0000-0002-0106-1150; Bakker, Stephan/0000-0003-3356-6791 FU National Heart, Lung, and Blood Institute (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, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133]; NHLBI [HL080295, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95169]; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, R01AG027002]; National Institute of Nursing Research [R01-NR012459]; NIH, NIA; Dutch Kidney Foundation, Bussum, The Netherlands [E013]; National Institute of Diabetes and Digestive, and Kidney Diseases [T32DK07791, DK52866]; American Heart Association Western States Affiliate Clinical Research Program; National Institute on Aging [K01AG039387]; [R01-HL-63963-01A1] FX The Cardiovascular Health Study was supported by National Heart, Lung, and Blood Institute (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 and NHLBI grant HL080295, with additional contribution from National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging (NIA). See also http://www.chs-nhlbi.org/pi.htm. Health ABC was supported through the NIA contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA grant R01-AG028050, and National Institute of Nursing Research grant R01-NR012459. In addition, this research was supported in part by the Intramural Research Program of the NIH, NIA. MESA was supported by grant R01-HL-63963-01A1 and by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the NHLBI. PREVEND is supported by grant E013 of the Dutch Kidney Foundation, Bussum, The Netherlands, and grants T32DK07791 and DK52866 from the National Institute of Diabetes and Digestive, and Kidney Diseases.; This project was also supported by grant R01AG027002 from the NIA. Dr. Odden is supported by a the American Heart Association Western States Affiliate Clinical Research Program and the National Institute on Aging (K01AG039387). NR 34 TC 8 Z9 8 U1 1 U2 10 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 MAR PY 2013 VL 23 IS 3 BP 106 EP 111 DI 10.1016/j.annepidem.2012.12.004 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 095XI UT WOS:000315367900002 PM 23313266 ER PT J AU George, A Johnson, M Blinkhorn, A Ajwani, S Bhole, S Yeo, AE Ellis, S AF George, A. Johnson, M. Blinkhorn, A. Ajwani, S. Bhole, S. Yeo, A. E. Ellis, S. TI The oral health status, practices and knowledge of pregnant women in south-western Sydney SO AUSTRALIAN DENTAL JOURNAL LA English DT Article DE Oral health; pregnancy; antenatal care; dental service; Australia ID RANDOMIZED-CONTROLLED-TRIAL; PERIODONTAL-DISEASE; DENTAL SERVICES; CARE; PERCEPTIONS; PREVENTION; CHILDHOOD; MIDWIVES; CARIES AB Background Current evidence highlights the importance of oral health during pregnancy. However, little is known about the oral health of pregnant women in Australia. The aim of this study was to report the oral health status, knowledge and practices of pregnant women in south-western Sydney. Methods A cross-sectional survey of 241 pregnant women attending a large hospital in south-western Sydney. Results More than half (59.3%) reported dental problems during pregnancy, less than a third (30.5%) saw a dentist in the last six months, only 10% had received any information about perinatal oral health and many (>50%) were unaware of the potential impact of poor maternal oral health on pregnancy and infant outcomes. Analysis revealed a significant difference (<0.05) in the uptake of dental services among pregnant women who had higher household incomes, private health insurance, received information about perinatal oral health and knowledge about maternal oral health. Conclusions The participants reported significant barriers to obtaining dental care including limited access to affordable dental services and lack of awareness about the importance of maternal oral health. The findings suggest the need for preventive strategies involving dentists and antenatal providers to improve maternal oral health in Australia. C1 [George, A.; Johnson, M.] Univ Western Sydney, Ctr Appl Nursing Res, Ingham Inst Appl Med Res, South Western Sydney Local Hlth Dist, Liverpool Bc, NSW 1871, Australia. [Johnson, M.] Univ Western Sydney, Sch Nursing & Midwifery, Ingham Inst Appl Med Res, South Western Sydney Local Hlth Dist, Liverpool Bc, NSW 1871, Australia. [Blinkhorn, A.] Univ Sydney, NSW Chair Populat Oral Hlth, Fac Dent, Sydney, NSW 2006, Australia. [Ajwani, S.; Bhole, S.] Univ Sydney, South Western Sydney Local Hlth Dist Oral Hlth Se, Sydney, NSW 2006, Australia. [Ajwani, S.; Bhole, S.] Univ Sydney, Sydney Dent Hosp, Sydney, NSW 2006, Australia. [Ajwani, S.; Bhole, S.] Univ Sydney, Fac Dent, Sydney, NSW 2006, Australia. [Yeo, A. E.] NIH, Bethesda, MD USA. [Ellis, S.] S Western Sydney Local Hlth Dist, Camden Hosp, Sydney, NSW, Australia. [Ellis, S.] S Western Sydney Local Hlth Dist, Campbelltown Hosp, Sydney, NSW, Australia. RP George, A (reprint author), Univ Western Sydney, Ctr Appl Nursing Res, Ingham Inst Appl Med Res, South Western Sydney Local Hlth Dist, Locked Bag 7103, Liverpool Bc, NSW 1871, Australia. EM ajesh.george@sswahs.nsw.gov.au OI Johnson, Maree/0000-0001-6653-3780 FU NSW Centre for Oral Health Strategy; Australian Dental Association (NSW Branch) FX Funding for this study is gratefully acknowledged from the NSW Centre for Oral Health Strategy and the Australian Dental Association (NSW Branch). NR 42 TC 7 Z9 9 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0045-0421 J9 AUST DENT J JI Aust. Dent. J. PD MAR PY 2013 VL 58 IS 1 BP 26 EP 33 DI 10.1111/adj.12024 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 097QQ UT WOS:000315489000005 PM 23441789 ER PT J AU Alavanja, MCR Ross, MK Bonner, MR AF Alavanja, Michael C. R. Ross, Matthew K. Bonner, Matthew R. TI Increased Cancer Burden Among Pesticide Applicators and Others Due to Pesticide Exposure SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review DE pesticides; cancer burden; carcinogen; risk; environmental cancer; public health ID NON-HODGKIN-LYMPHOMA; PLASMA ORGANOCHLORINE LEVELS; AGRICULTURAL RISK-FACTORS; SOFT-TISSUE SARCOMA; ENDOCRINE DISRUPTING CHEMICALS; ATOMIC-BOMB SURVIVORS; OXIDATIVE DNA-DAMAGE; REPAIR PATHWAY GENES; BREAST-CANCER; PROSTATE-CANCER AB A growing number of well-designed epidemiological and molecular studies provide substantial evidence that the pesticides used in agricultural, commercial, and home and garden applications are associated with excess cancer risk. This risk is associated both with those applying the pesticide and, under some conditions, those who are simply bystanders to the application. In this article, the epidemiological, molecular biology, and toxicological evidence emerging from recent literature assessing the link between specific pesticides and several cancers including prostate cancer, non-Hodgkin lymphoma, leukemia, multiple myeloma, and breast cancer are integrated. Although the review is not exhaustive in its scope or depth, the literature does strongly suggest that the public health problem is real. If we are to avoid the introduction of harmful chemicals into the environment in the future, the integrated efforts of molecular biology, pesticide toxicology, and epidemiology are needed to help identify the human carcinogens and thereby improve our understanding of human carcinogenicity and reduce cancer risk. CA Cancer J Clin 2013;63:120-142. (C) 2013 American Cancer Society.* C1 [Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, North Bethesda, MD 20892 USA. [Ross, Matthew K.] Mississippi State Univ, Coll Vet Med, Ctr Environm Hlth Sci, Dept Basic 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, 1620 Execut Blvd, North Bethesda, MD 20892 USA. EM alavanjm@mail.nih.gov NR 187 TC 51 Z9 54 U1 5 U2 58 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAR-APR PY 2013 VL 63 IS 2 BP 120 EP 142 DI 10.3322/caac.21170 PG 23 WC Oncology SC Oncology GA 099TZ UT WOS:000315646500006 PM 23322675 ER PT J AU Welsh, JL Wagner, BA van't Erve, TJ Zehr, PS Berg, DJ Halfdanarson, TR Yee, NS Bodeker, KL Du, J Roberts, LJ Drisko, J Levine, M Buettner, GR Cullen, JJ AF Welsh, J. L. Wagner, B. A. van't Erve, T. J. Zehr, P. S. Berg, D. J. Halfdanarson, T. R. Yee, N. S. Bodeker, K. L. Du, J. Roberts, L. J., II Drisko, J. Levine, M. Buettner, G. R. Cullen, J. J. TI Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Pancreatic neoplasm; Ascorbic acid; Clinical trial; Phase 1; Gemcitabine; Drug toxicity ID VITAMIN-C PHARMACOKINETICS; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; ACID; EPR; BIOMARKERS; PRODUCTS; LIPIDS; VIVO AB Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma. Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of a parts per thousand yen350 mg/dL (a parts per thousand yen20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored. Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 +/- A 0.02 vs. 0.78 +/- A 0.09 mg/dL, i.e., 83 vs. 44 mu M, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 +/- A 2 months. Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted. C1 [Welsh, J. L.; Cullen, J. J.] Univ Iowa, Dept Surg, Carver Coll Med, Iowa City, IA 52242 USA. [Wagner, B. A.; van't Erve, T. J.; Bodeker, K. L.; Du, J.; Buettner, G. R.; Cullen, J. J.] Univ Iowa, Dept Radiat Oncol, Carver Coll Med, Iowa City, IA 52242 USA. [Zehr, P. S.; Berg, D. J.; Halfdanarson, T. R.; Buettner, G. R.; Cullen, J. J.] Univ Iowa, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. [Berg, D. J.; Halfdanarson, T. R.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Yee, N. S.] Penn State Hershey Canc Inst, Hershey, PA USA. [Roberts, L. J., II] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Drisko, J.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Levine, M.] NIDDKD, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Cullen, J. J.] Vet Affairs Med Ctr, Iowa City, IA 52242 USA. RP Cullen, JJ (reprint author), Univ Iowa, Dept Surg, Carver Coll Med, 1528 JCP UIHC, Iowa City, IA 52242 USA. EM joseph-cullen@uiowa.edu OI Bodeker, Kellie/0000-0002-8930-2819; van 't Erve, Thomas/0000-0002-3260-6627; Buettner, Garry/0000-0002-5594-1903 FU Iowa Superfund Research Program Training Core [P42 ES013661]; National Institutes of Health [GM42056, GM073929, P42ES013661, P30 CA086862, CA137230, CA148062]; Medical Research Service of the Department of Veterans Affairs; Holden Comprehensive Cancer Center; Susan L. Bader Foundation of Hope; Intramural Research Program NIDDK, NIH FX The authors thank the John (Jack) Widness lab and the Sysmex Corporation, Kobe, Japan, for the use of XE-2100 and XT-2000 automated hematology analyzers. The authors also thank the Holden Comprehensive Cancer Center for its support for the clinical trial. TJvE gratefully acknowledges support from the Iowa Superfund Research Program (P42 ES013661) Training Core. The content is solely the responsibility of the authors and does not represent views of the National Institutes of Health. The University of Iowa ESR Facility provided invaluable support. This work was supported by the National Institutes of Health [grant numbers GM42056, GM073929, P42ES013661, P30 CA086862, CA137230, and CA148062], the Medical Research Service of the Department of Veterans Affairs, the Holden Comprehensive Cancer Center, and the Susan L. Bader Foundation of Hope. Dr. Mark Levine is supported by the Intramural Research Program NIDDK, NIH. NR 26 TC 46 Z9 48 U1 2 U2 17 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 MAR PY 2013 VL 71 IS 3 BP 765 EP 775 DI 10.1007/s00280-013-2070-8 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 096OH UT WOS:000315413500023 PM 23381814 ER PT J AU Banerjee, T Aggarwal, M Brosh, RM AF Banerjee, Taraswi Aggarwal, Monika Brosh, Robert M., Jr. TI A new development in DNA repair modulation Discovery of a BLM helicase inhibitor SO CELL CYCLE LA English DT Editorial Material ID RECQ HELICASES; GENE C1 [Banerjee, Taraswi; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Aggarwal, Monika] Georgetown Univ, Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov NR 8 TC 3 Z9 3 U1 1 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 1 PY 2013 VL 12 IS 5 BP 713 EP 714 DI 10.4161/cc.23953 PG 2 WC Cell Biology SC Cell Biology GA 098CG UT WOS:000315522200004 PM 23422862 ER PT J AU Wantha, S Alard, JE Megens, RTA van der Does, AM Doring, Y Drechsler, M Pham, CTN Wang, MW Wang, JM Gallo, RL von Hundelshausen, P Lindbom, L Hackeng, T Weber, C Soehnlein, O AF Wantha, Sarawuth Alard, Jean-Eric Megens, Remco T. A. van der Does, Anne M. Doering, Yvonne Drechsler, Maik Pham, Christine T. N. Wang, Ming-Wei Wang, Ji-Min Gallo, Richard L. von Hundelshausen, Philipp Lindbom, Lennart Hackeng, Tilman Weber, Christian Soehnlein, Oliver TI Neutrophil-Derived Cathelicidin Promotes Adhesion of Classical Monocytes SO CIRCULATION RESEARCH LA English DT Article DE cathelicidin; chemokine; inflammation; monocyte; neutrophil; recruitment ID GREEN FLUORESCENT PROTEIN; PEPTIDE LL-37; BLOOD MONOCYTES; DENDRITIC CELLS; CATHEPSIN-G; MICE; RECEPTOR; ATHEROSCLEROSIS; SUBSETS; IDENTIFICATION AB Rationale: The leukocyte response in acute inflammation is characterized by an initial recruitment of neutrophils preceding a second wave of monocytes. Neutrophil-derived granule proteins were suggested to hold an important role in this cellular switch. The exact mechanisms by which neutrophils mediate these processes are only partially understood. Objective: To investigate the role of neutrophils and their granule contents in the adhesion of monocyte subpopulations in acute inflammation. Methods and Results: Here, we show that neutrophil-derived cathelicidins (human: LL37, mouse: CRAMP) induce adhesion of classical monocytes but not of nonclassical monocytes in the mouse cremaster muscle and in in vitro flow chamber assays. CRAMP is released from emigrated neutrophils and then transported across the endothelium, where it is presented to rolling leukocytes. Endothelial-bound cathelicidin activates formyl-peptide receptor 2 on classical monocytes, resulting in monocytic beta(1)- and beta(2)-integrin conformational change toward an extended, active conformation that allows for adhesion to their respective ligands, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. Conclusions: These data elucidate a novel mechanism of neutrophil-mediated monocyte recruitment, which could be targeted in conditions where recruitment of classical monocytes plays an unfavorable role. (Circ Res. 2013;112:792-801.) C1 [Wantha, Sarawuth; Alard, Jean-Eric; Megens, Remco T. A.; Doering, Yvonne; Drechsler, Maik; von Hundelshausen, Philipp; Weber, Christian; Soehnlein, Oliver] LMU, IPEK, Munich, Germany. [Wantha, Sarawuth] Rhein Westfal TH Aachen, IMCAR, Aachen, Germany. [van der Does, Anne M.; Lindbom, Lennart] Karolinska Inst, Dept Physiol, S-10401 Stockholm, Sweden. [Pham, Christine T. N.] Washington Univ, Dept Med, St Louis, MO USA. [Wang, Ming-Wei] Natl Ctr Drug Screening, Shanghai, Peoples R China. [Wang, Ji-Min] NCI, Mol Immunoregulat Lab, Frederick, MD 21701 USA. [Gallo, Richard L.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Hackeng, Tilman; Weber, Christian] Univ Maastricht, CARIM, Maastricht, Netherlands. [Weber, Christian; Soehnlein, Oliver] Munich Heart Alliance, Munich, Germany. [Soehnlein, Oliver] Univ Amsterdam, Acad Med Ctr Amsterdam, Dept Pathol, Amsterdam, Netherlands. RP Soehnlein, O (reprint author), Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent IPEK, Pettenkoferstr 9, D-80336 Munich, Germany. EM oliver.soehnlein@gmail.com RI Drechsler, Maik/C-3829-2008; Doring, Yvonne/E-1796-2013; von Hundelshausen, Philipp/F-7435-2014; OI Weber, Christian/0000-0003-4610-8714; von Hundelshausen, Philipp/0000-0001-7474-9370; van der Does, Anne/0000-0002-1613-106X; Lindbom, Lennart/0000-0001-9243-257X; Gallo, Richard/0000-0002-1401-7861 FU German Research Foundation [SO876/3-1, SO876/4-1, HU1618/1-2, SFB914 TPB08]; German-Israeli Foundation; Else Kroner Fresenius Stiftung; Nederlandse Organisatie voor Wetenschappelijk Onderzoek (VIDI) [91712303]; European Research Council [249929]; Alexander von Humboldt Foundation FX This study was supported by the German Research Foundation (SO876/3-1, SO876/4-1, HU1618/1-2, SFB914 TPB08), the German-Israeli Foundation, the Else Kroner Fresenius Stiftung, the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (VIDI project 91712303), and the European Research Council (Advanced Grant 249929). J.E. Alard is recipient of a postdoctoral scholarship from the Alexander von Humboldt Foundation. NR 52 TC 56 Z9 57 U1 2 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 1 PY 2013 VL 112 IS 5 BP 792 EP 801 DI 10.1161/CIRCRESAHA.112.300666 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 098YV UT WOS:000315585900010 PM 23283724 ER PT J AU Obiakor, H Avril, M MacDonald, NJ Srinivasan, P Reiter, K Anderson, C Holmes, KL Fried, M Duffy, PE Smith, JD Narum, DL Miller, LH AF Obiakor, Harold Avril, Marion MacDonald, Nicholas J. Srinivasan, Prakash Reiter, Karine Anderson, Charles Holmes, Kevin L. Fried, Michal Duffy, Patrick E. Smith, Joseph D. Narum, David L. Miller, Louis H. TI Identification of VAR2CSA Domain-Specific Inhibitory Antibodies of the Plasmodium falciparum Erythrocyte Membrane Protein 1 Using a Novel Flow Cytometry Assay SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CHONDROITIN-SULFATE-A; PREGNANCY-ASSOCIATED MALARIA; CROSS-REACTIVE ANTIBODIES; CSA-BINDING PARASITES; INFECTED ERYTHROCYTES; PLACENTAL MALARIA; VAR GENES; ADHESION; VARIANT; SURFACE AB VAR2CSA, a member of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family, is a leading candidate for use in vaccines to protect first-time mothers from placental malaria (PM). VAR2CSA, which is comprised of a series of six Duffy binding-like (DBL) domains, binds chondroitin sulfate A (CSA) on placental syncytiotrophoblast. Several recombinant DBL domains have been shown to bind CSA. In order to identify and develop recombinant proteins suitable for clinical development, DBL2X and DBL3X, as well as their respective third subdomain (S3) from the FCR3 parasite clone, were expressed in Escherichia coli, refolded, and purified. All but DBL3X-S3 recombinant proteins bound to CSA expressed on Chinese hamster ovary (CHO)-K1 cells but not to CHO-pgsA745 cells, which are CSA negative as determined by flow cytometry. All but DBL3X-S3 bound to CSA on chondroitin sulfate proteoglycan (CSPG) as determined by surface plasmon resonance (SPR) analysis. Purified IgG from rats and rabbits immunized with these four recombinant proteins bound homologous and some heterologous parasite-infected erythrocytes (IE). Using a novel flow cytometry inhibition-of-binding assay (flow-IBA), antibodies against DBL3X-S3 inhibited 35% and 45% of IE binding to CSA on CHO-K1 cells compared to results for soluble CSA (sCSA) and purified multigravida (MG) IgG, respectively, from areas in Tanzania to which malaria is endemic. Antibodies generated against the other domains provided little or no inhibition of IE binding to CSA on CHO-K1 cells as determined by the flow cytometry inhibition-of-binding assay. These results demonstrate for the first time the ability to identify antibodies to VAR2CSA DBL domains and subdomains capable of inhibiting VAR2CSA parasite-IE binding to CSA by flow cytometry. The flow cytometry inhibition-of-binding assay was robust and provided an accurate, reproducible, and reliable means to identify blocking of IE binding to CSA and promises to be significant in the development of a vaccine to protect pregnant women. C1 [Obiakor, Harold; MacDonald, Nicholas J.; Reiter, Karine; Anderson, Charles; Fried, Michal; Duffy, Patrick E.; Narum, David L.] NIAID NIH, Lab Malaria Immunol & Vaccinol, Rockville, MD 20892 USA. [Srinivasan, Prakash; Miller, Louis H.] NIAID NIH, Lab Malaria Vector Res, Rockville, MD USA. [Holmes, Kevin L.] NIH, Flow Cytometry Sect, Res Technol Branch, Bethesda, MD 20892 USA. [Smith, Joseph D.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. RP Narum, DL (reprint author), NIAID NIH, Lab Malaria Immunol & Vaccinol, Rockville, MD 20892 USA. EM dnarum@niaid.nih.gov; lmiller@niaid.nih.gov FU NIH Intramural Research Program FX This study was supported by the NIH Intramural Research Program. NR 44 TC 8 Z9 8 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAR PY 2013 VL 20 IS 3 BP 433 EP 442 DI 10.1128/CVI.00638-12 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 096NL UT WOS:000315411100014 PM 23345587 ER PT J AU Moore, K Townsend, J Spieler, J Coffey, PS Blithe, D Arndorfer, E Dawes, E AF Moore, Kirsten Townsend, John Spieler, Jeff Coffey, Patricia S. Blithe, Diana Arndorfer, Elizabeth Dawes, Elizabeth TI A greenprint for sustainable contraceptive research and development SO CONTRACEPTION LA English DT Editorial Material C1 [Moore, Kirsten; Arndorfer, Elizabeth; Dawes, Elizabeth] Reprod Hlth Technol Project, Washington, DC 20036 USA. [Townsend, John] Populat Council, Washington, DC 20008 USA. [Spieler, Jeff] United States Agcy Int Dev, Washington, DC 20523 USA. [Coffey, Patricia S.] PATH, Seattle, WA 98121 USA. [Blithe, Diana] US NIH, Bethesda, MD 20892 USA. RP Dawes, E (reprint author), Reprod Hlth Technol Project, Washington, DC 20036 USA. EM edawes@rhtp.org NR 5 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 J9 CONTRACEPTION JI Contraception PD MAR PY 2013 VL 87 IS 3 BP 347 EP 351 DI 10.1016/j.contraception.2012.07.020 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 096SS UT WOS:000315425200015 PM 22974594 ER PT J AU Nasonkin, IO Merbs, SL Lazo, K Oliver, VF Brooks, M Patel, K Enke, RA Nellissery, J Jamrich, M Le, YZ Bharti, K Fariss, RN Rachel, RA Zack, DJ Rodriguez-Boulan, EJ Swaroop, A AF Nasonkin, Igor O. Merbs, Shannath L. Lazo, Kevin Oliver, Verity F. Brooks, Matthew Patel, Krushangi Enke, Raymond A. Nellissery, Jacob Jamrich, Milan Le, Yun Z. Bharti, Kapil Fariss, Robert N. Rachel, Rivka A. Zack, Donald J. Rodriguez-Boulan, Enrique J. Swaroop, Anand TI Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis SO DEVELOPMENT LA English DT Article DE Retina development; DNA methylation; Cell-cell interaction; Morphogenesis; Epigenetics; Mouse ID EMBRYONIC STEM-CELLS; CONE OPSIN EXPRESSION; MAMMALIAN RETINA; VISUAL FUNCTION; VERTEBRATE EYE; MOUSE RETINA; GENE-EXPRESSION; CRE RECOMBINASE; OPTIC VESICLE; NEURAL RETINA AB Dysfunction or death of photoreceptors is the primary cause of vision loss in retinal and macular degenerative diseases. As photoreceptors have an intimate relationship with the retinal pigment epithelium (RPE) for exchange of macromolecules, removal of shed membrane discs and retinoid recycling, an improved understanding of the development of the photoreceptor-RPE complex will allow better design of gene-and cell-based therapies. To explore the epigenetic contribution to retinal development we generated conditional knockout alleles of DNA methyltransferase 1 (Dnmt1) in mice. Conditional Dnmt1 knockdown in early eye development mediated by Rx-Cre did not produce lamination or cell fate defects, except in cones; however, the photoreceptors completely lacked outer segments despite near normal expression of phototransduction and cilia genes. We also identified disruption of RPE morphology and polarization as early as E15.5. Defects in outer segment biogenesis were evident with Dnmt1 exon excision only in RPE, but not when excision was directed exclusively to photoreceptors. We detected a reduction in DNA methylation of LINE1 elements (a measure of global DNA methylation) in developing mutant RPE as compared with neural retina, and of Tuba3a, which exhibited dramatically increased expression in mutant retina. These results demonstrate a unique function of DNMT1-mediated DNA methylation in controlling RPE apicobasal polarity and neural retina differentiation. We also establish a model to study the epigenetic mechanisms and signaling pathways that guide the modulation of photoreceptor outer segment morphogenesis by RPE during retinal development and disease. C1 [Nasonkin, Igor O.; Lazo, Kevin; Brooks, Matthew; Patel, Krushangi; Nellissery, Jacob; Rachel, Rivka A.; Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. [Merbs, Shannath L.; Oliver, Verity F.; Enke, Raymond A.] Johns Hopkins Univ, Wilmer Eye Inst, Div Oculoplast Surg, Baltimore, MD 21287 USA. [Jamrich, Milan] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Le, Yun Z.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK 73104 USA. [Bharti, Kapil] NEI, Unit Ocular Stem Cells & Translat Res, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Biol Imaging Core, Bethesda, MD 20892 USA. [Zack, Donald J.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD 21287 USA. [Zack, Donald J.] Johns Hopkins Univ, Dept Mol Biol & Genet, Baltimore, MD 21287 USA. [Zack, Donald J.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21287 USA. [Zack, Donald J.] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD 21287 USA. [Zack, Donald J.] Univ Paris 06, Inst Vis, Paris, France. [Rodriguez-Boulan, Enrique J.] Weill Cornell Med Coll, Dyson Vis Res Inst, New York, NY 10065 USA. RP Swaroop, A (reprint author), NEI, N NRL, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov RI Oliver, Verity/K-7336-2012; OI Oliver, Verity/0000-0003-4786-8272; Zack, Don/0000-0002-7966-1973; Swaroop, Anand/0000-0002-1975-1141 FU Intramural Research Program of the National Eye Institute, National Institutes of Health [EY08538, EY020900, EY009769, P20RR024215, P30EY001765]; Foundation Fighting Blindness and Research to Prevent Blindness FX This research was supported by Intramural Research Program of the National Eye Institute, National Institutes of Health [grants EY08538, EY020900, EY009769, P20RR024215 and P30EY001765]; and by The Foundation Fighting Blindness and Research to Prevent Blindness. Deposited in PMC for release after 12 months. NR 91 TC 22 Z9 23 U1 1 U2 21 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 MAR PY 2013 VL 140 IS 6 BP 1330 EP 1341 DI 10.1242/dev.086603 PG 12 WC Developmental Biology SC Developmental Biology GA 097AH UT WOS:000315445800019 PM 23406904 ER PT J AU Kursawe, R Caprio, S Giannini, C Narayan, D Lin, AP D'Adamo, E Shaw, M Pierpont, B Cushman, SW Shulman, GI AF Kursawe, Romy Caprio, Sonia Giannini, Cosimo Narayan, Deepak Lin, Aiping D'Adamo, Ebe Shaw, Melissa Pierpont, Bridget Cushman, Samuel W. Shulman, Gerald I. TI Decreased Transcription of ChREBP-alpha/beta Isoforms in Abdominal Subcutaneous Adipose Tissue of Obese Adolescents With Prediabetes or Early Type 2 Diabetes Associations With Insulin Resistance and Hyperglycemia SO DIABETES LA English DT Article ID FATTY LIVER-DISEASE; ENZYME GENE-EXPRESSION; HEPATIC STEATOSIS; ADIPOCYTE DIFFERENTIATION; GLUCOSE-TOLERANCE; PROTEIN; MICE; ADIPONUTRIN; MELLITUS; QUANTIFICATION AB Insulin resistance associated with altered fat partitioning in liver and adipose tissues is a prediabetic condition in obese adolescents. We investigated interactions between glucose tolerance, insulin sensitivity, and the expression of lipogenic genes in abdominal subcutaneous adipose and liver tissue in 53 obese adolescents. Based on their 2-h glucose tests they were stratified in the following groups: group 1, 2-h glucose level <120 mg/dL; group 2, 2-h glucose level between 120 and 140 mg/dL; and group 3, 2-h glucose level >140 mg/dL. Liver and adipose tissue insulin sensitivity were greater in group 1 than in group 2 and group 3, and muscle insulin sensitivity progressively decreased from group 1 to group 3. The expression of the carbohydrate-responsive element-binding protein (ChREBP) was decreased in adipose tissue but increased in the liver (eight subjects) in adolescents with impaired glucose tolerance or type 2 diabetes. The expression of adipose ChREBP alpha and ChREBP beta was inversely related to 2-h glucose level and positively correlated to insulin sensitivity. Improvement of glucose tolerance in four subjects was associated with an increase of ChREBP/GLUT4 expression in the adipose tissue. In conclusion, early in the development of prediabetes/type 2 diabetes in youth, ChREBP beta expression in adipose tissue predicts insulin resistance and, therefore, might play a role in the regulation of glucose tolerance. Diabetes 62:837-844, 2013 C1 [Kursawe, Romy; Caprio, Sonia; Giannini, Cosimo; D'Adamo, Ebe; Shaw, Melissa; Pierpont, Bridget] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Narayan, Deepak] Yale Univ, Sch Med, Dept Plast Surg, New Haven, CT USA. [Lin, Aiping] Yale Univ, Sch Med, WM Keck Fdn Biostat Resource, New Haven, CT USA. [Cushman, Samuel W.] NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. RP Caprio, S (reprint author), Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. EM sonia.caprio@yale.edu FU National Institutes of Health (NIH) [R01-HD40787, R01-HD28016, K24-HD01464]; National Center for Research Resources (NCRR), a component of the NIH [UL1 RR0249139]; American Diabetes Association [DK-49230, DK-085638]; Diabetes and Endocrinology Research Center [P30 DK045735]; European Society for Paediatric Endocrinology Long-Term Research Fellowship; Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases; [R01-EB006494] FX This study was supported by grants from the National Institutes of Health (NIH) (R01-HD40787, R01-HD28016, and K24-HD01464) to S.C. and by the Clinical and Translational Science Award Grant UL1 RR0249139 from the National Center for Research Resources (NCRR), a component of the NIH, and R01-EB006494 (Bioimage Suite), and by Distinguished Clinical Scientist Awards from the American Diabetes Association, DK-49230 (S.C.) and DK-085638 (G.I.S.), the Diabetes and Endocrinology Research Center Grant P30 DK045735, and the European Society for Paediatric Endocrinology Long-Term Research Fellowship (to C.G.). S.W.C. was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. This publication was and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 42 TC 25 Z9 25 U1 1 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2013 VL 62 IS 3 BP 837 EP 844 DI 10.2337/db12-0889 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 098NQ UT WOS:000315556400027 PM 23209190 ER PT J AU Hunter, CS Dixit, S Cohen, T Ediger, B Wilcox, C Ferreira, M Westphal, H Stein, R May, CL AF Hunter, Chad S. Dixit, Shilpy Cohen, Tsadok Ediger, Benjamin Wilcox, Crystal Ferreira, Mark Westphal, Heiner Stein, Roland May, Catherine Lee TI Islet alpha-, beta-, and delta-cell Development Is Controlled by the Ldb1 Coregulator, Acting Primarily With the Islet-1 Transcription Factor SO DIABETES LA English DT Article ID INSULIN GENE-TRANSCRIPTION; LIM-HOMEODOMAIN PROTEINS; ENDOCRINE PANCREAS; MOUSE PANCREAS; MOTOR-NEURON; PDX-1; EXPRESSION; DIFFERENTIATION; PAX6; IDENTIFICATION AB Ldb1 and Ldb2 are coregulators that mediate Lin11-Isl1-Mec3 (LIM)homeodomain (HD) and LIM-only transcription factor-driven gene regulation. Although both Ldb1 and Ldb2 mRNA was produced in the developing and adult pancreas, immunohistochemical analysis illustrated a broad Ldb1 protein expression pattern during early pancreatogenesis, which subsequently became enriched in islet and ductal cells perinatally. The islet-enriched pattern of Ldb1 was similar to pan-endocrine cellexpressed Islet-1 (Isl1), which was demonstrated in this study to be the primary LIM-HD transcription factor in developing and adult islet cells. Endocrine cellspecific removal of Ldb1 during mouse development resulted in a severe reduction of hormone(+) cell numbers (i.e., alpha, beta, and delta) and overt postnatal hyperglycemia, reminiscent of the phenotype described for the Isl1 conditional mutant. In contrast, neither endocrine cell development nor function was affected in the pancreas of Ldb2(-/-) mice. Gene expression and chromatin immunoprecipitation (ChIP) analyses demonstrated that many important Isl1-activated genes were coregulated by Ldb1, including MafA, Arx, insulin, and Glp1r. However, some genes (i.e., Hb9 and Glut2) only appeared to be impacted by Ldb1 during development. These findings establish Ldb1 as a critical transcriptional coregulator during islet alpha-, beta-, and delta-cell development through Isl1-dependent and potentially Isl1-independent control. Diabetes 62:875-886, 2013 C1 [Hunter, Chad S.; Dixit, Shilpy; Stein, Roland] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37203 USA. [Cohen, Tsadok; Westphal, Heiner] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mammalian Mol Genet, Program Genom Dev, NIH, Bethesda, MD USA. [Ediger, Benjamin; Wilcox, Crystal; Ferreira, Mark; May, Catherine Lee] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Ediger, Benjamin; Wilcox, Crystal; Ferreira, Mark; May, Catherine Lee] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Stein, R (reprint author), Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37203 USA. EM roland.stein@vanderbilt.edu; catheril@mail.med.upenn.edu FU National Institutes of Health (NIH) [DK-078606, DK-090570-02, F32-DK-083160, T32-GM-07229]; Juvenile Diabetes Research Foundation [2-2007-730]; Vanderbilt University Diabetes Research and Training Center [P60-DK-20593]; NIH [CA-68485, DK-20593, DK-58404, HD-15052, DK-59637, EY-08126] FX This work was supported by the National Institutes of Health (NIH) (grants DK-078606 to R.S. and C.L.M., DK-090570-02 to R.S., F32-DK-083160 to C.S.H., and T32-GM-07229 to B.E.) and the Juvenile Diabetes Research Foundation (Grant 2-2007-730 to C.L.M.). Partial support was also provided by the Vanderbilt University Diabetes Research and Training Center (Public Health Service Grant P60-DK-20593). Confocal microscopy was performed in the NIH-supported Vanderbilt University Medical Center Cell Imaging Shared Resource (NIH grants CA-68485, DK-20593, DK-58404, HD-15052, DK-59637, and EY-08126). NR 60 TC 15 Z9 16 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 MAR PY 2013 VL 62 IS 3 BP 875 EP 886 DI 10.2337/db12-0952 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 098NQ UT WOS:000315556400031 PM 23193182 ER PT J AU Gardner, SE Hillis, SL Heilmann, K Segre, JA Grice, EA AF Gardner, Sue E. Hillis, Stephen L. Heilmann, Kris Segre, Julia A. Grice, Elizabeth A. TI The Neuropathic Diabetic Foot Ulcer Microbiome Is Associated With Clinical Factors SO DIABETES LA English DT Article ID CHRONIC WOUND-INFECTION; SKIN MICROBIOME; RISK-FACTORS; DIVERSITY; AMPUTATION; BACTERIA; VALIDITY; DISEASE AB Nonhealing diabetic foot ulcers (DFUs) are a common and costly complication of diabetes. Microbial burden, or "bioburden," is believed to underlie delayed healing, although little is known of those clinical factors that may influence microbial load, diversity, and/or pathogenicity. We profiled the microbiomes of neuropathic nonischemic DFUs without clinical evidence of infection in 52 individuals using high-throughput sequencing of the bacterial 16S ribosomal RNA gene. Comparatively, wound cultures, the standard diagnostic in the clinic, vastly underrepresent microbial load, microbial diversity, and the presence of potential pathogens. DFU microbiomes were heterogeneous, even in our tightly restricted study population, but partitioned into three clusters distinguished primarily by dominant bacteria and diversity. Ulcer depth was associated with ulcer cluster, positively correlated with abundance of anaerobic bacteria, and negatively correlated with abundance of Staphylococcus. Ulcer duration was positively correlated with bacterial diversity, species richness, and relative abundance of Proteobacteria, but was negatively correlated with relative abundance of Staphylococcus. Finally, poor glycemic control was associated with ulcer cluster, with poorest median glycemic control concentrating to Staphylococcus-rich and Streptococcus-rich ulcer clusters. Analyses of microbial community membership and structure may provide the most useful metrics in prospective studies to delineate problematic bioburden from benign colonization that can then be used to chive clinical treatment. Diabetes 62:923-930,2013 C1 [Gardner, Sue E.] Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. [Hillis, Stephen L.; Heilmann, Kris] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Segre, Julia A.] NHGRI, NIH, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Grice, Elizabeth A.] Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Gardner, SE (reprint author), Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. EM sue-gardner@uiowa.edu; egrice@upenn.edu OI Grice, Elizabeth/0000-0003-3939-2200; Hillis, Stephen/0000-0002-4886-8584 FU National Institutes of Health (NIH),; National Institute of Nursing Research [NINR R01 NR009448]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS R00 AR060873]; NTH Intramural Research Program; National Center for Research Resources; National Center for Advancing Translational Sciences [UL1-RR-024979] FX This project was funded by National Institutes of Health (NIH), National Institute of Nursing Research (S.E.G., NINR R01 NR009448), National Institute of Arthritis and Musculoskeletal and Skin Diseases (E.A.G., NIAMS R00 AR060873), and the NTH Intramural Research Program (J.A.S). It was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, through grant UL1-RR-024979 (S.E.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NTH. NR 37 TC 51 Z9 51 U1 2 U2 38 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2013 VL 62 IS 3 BP 923 EP 930 DI 10.2337/db12-0771/-/DC1 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 098NQ UT WOS:000315556400036 PM 23139351 ER PT J AU Zhang, YM Boerwinkel, DF He, S Weusten, BLAM Xue, LY Fleischer, DE Lu, N Dawsey, SM Zuo, SM Qin, XM Dou, LZ Bergman, JJGHM Wang, GQ AF Zhang, Y. M. Boerwinkel, D. F. He, S. Weusten, B. L. A. M. Xue, L. Y. Fleischer, D. E. Lu, N. Dawsey, S. M. Zuo, S. M. Qin, X. M. Dou, L. Z. Bergman, J. J. G. H. M. Wang, G. Q. TI Prospective feasibility study on the use of multiband mucosectomy for endoscopic resection of early squamous neoplasia in the esophagus SO ENDOSCOPY LA English DT Article ID CELL CARCINOMA; MUCOSAL RESECTION; RADIOFREQUENCY ABLATION; BARRETTS-ESOPHAGUS; LOCAL RECURRENCE; LYMPH-NODE; CANCER; RISK; METASTASIS; CHINA AB Background and study aims: Endoscopic resection for esophageal squamous high-grade intraepithelial neoplasia (HGIN) or intramucosal cancer (esophageal squamous cell carcinoma [ESCC]) with the endoscopic resection cap technique is technically difficult, and requires submucosal lifting and multiple snares for piecemeal resections. Multiband mucosectomy (MBM) is an easy-to-use endoscopic resection technique and may be the modality of choice in China, where ESCC is extremely prevalent. The aim of the current study was to prospectively evaluate MBM for piecemeal endoscopic resection of squamous neoplasia of the esophagus. Methods: Patients with HGIN/ESCC and no signs of submucosal invasion or metastatic disease were included in the study. Lesions were delineated using electrocoagulation and resected using the MBM technique. Endpoints were procedure time, endoscopic radicality, complications, histology of the endoscopic resection specimens, and absence of HGIN/ESCC at the endoscopic resection scar during follow-up. Results: A total of 41 patients (26 male; mean age 61 years) underwent MBM; all lesions were visible with white light endoscopy (median length 5 cm, interquartile range [IQR] 4-6 cm; median circumferential extent 42%, IQR 25-50%). Median procedure time was 12 minutes (IQR 8-24 minutes). Median number of resections was 5 (IQR 3-6). Endoscopic complete resection was achieved in all lesions. There was one perforation, which was treated by application of clips. No other complications were observed. The worst histology was ESCC (n=19), HGIN (n=17), middle grade intraepithelial neoplasia (n=4), and normal squamous epithelium (n=1). Endoscopic follow-up at 3 months showed HGIN at the endoscopic resection scar in two patients, which was effectively treated endoscopically, and showed normal squamous epithelium in all patients at final follow-up (median 15 months, IQR 12-24 months). Conclusion: This first prospective study on MBM for piecemeal endoscopic resection of early esophageal squamous neoplasia showed that MBM was effective for the complete removal of lesions with short procedure time, few complications, effective histological assessment of resected specimens, and durable treatment effect. C1 [Zhang, Y. M.; He, S.; Qin, X. M.; Dou, L. Z.; Wang, G. Q.] Chinese Acad Med Sci, Peking Union Med Coll, Canc Inst & Hosp, Dept Endoscopy, Beijing 100021, Peoples R China. [Boerwinkel, D. F.; Weusten, B. L. A. M.; Bergman, J. J. G. H. M.] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands. [Weusten, B. L. A. M.] St Antonius Hosp, Dept Gastroenterol & Hepatol, Nieuwegein, Netherlands. [Dawsey, S. M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fleischer, D. E.] Mayo Clin, Dept Gastroenterol & Hepatol, Scottsdale, AZ USA. [Xue, L. Y.; Lu, N.; Zuo, S. M.] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Pathol, Beijing 100021, Peoples R China. RP Wang, GQ (reprint author), Chinese Acad Med Sci, Peking Union Med Coll, Canc Inst & Hosp, Dept Endoscopy, 17 Panjiayuan, Beijing 100021, Peoples R China. EM j.j.bergman@amc.uva.nl; wangguiq@126.com NR 24 TC 5 Z9 7 U1 0 U2 3 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0013-726X J9 ENDOSCOPY JI Endoscopy PD MAR PY 2013 VL 45 IS 3 BP 167 EP 173 DI 10.1055/s-0032-1326011 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 098RI UT WOS:000315566000003 PM 23258547 ER PT J AU Dagna, L Pritchett, JC Lusso, P AF Dagna, Lorenzo Pritchett, Joshua C. Lusso, Paolo TI lmmunomodulation and immunosuppression by human herpesvirus 6A and 6B SO FUTURE VIROLOGY LA English DT Review DE antigen-presenting cells; a CD46; chemokines; cytokines; HHV-6A; HHV-6B; immunomodulation; immunosuppression; receptors; T cells ID MULTIPLE-SCLEROSIS PATIENTS; MEMBRANE COFACTOR PROTEIN; CD4(+) T-CELLS; TRANSCRIPTIONAL DOWN-REGULATION; HUMAN-HERPESVIRUS-6 VARIANT-A; BETA-CHEMOKINE RECEPTOR; MYELIN BASIC-PROTEIN; CELLULAR RECEPTOR; HHV-6 INFECTION; DENDRITIC CELLS AB Like other members of the Herpesviridae family, human herpesvirus (HHV)-6A and HHV-6B have developed a wide variety of strategies to modulate or suppress host immune responses and, thereby, facilitate their own spread and persistence in vivo. Long considered two variants of the same virus, HHV-6A and HHV-6B have recently been reclassified as distinct viral species, although the established nomenclature has been maintained. In this review, we summarize the distinctive profiles of interaction of these two viruses with the human immune system. Both HHV-6A and HHV-6B display a tropism for CD4(+) T lymphocytes, but they can also infect, in a productive or nonproductive fashion, other cells of the immune system. However, there are important differences regarding the ability of each virus to infect cytotoxic effector cells, as HHV-6A has been shown to productively infect several of these cells, whereas HHV-6B infects them inefficiently at best. In addition to direct cytopathic effects, both HHV-6A and HHV-6B can interfere with immunologic functions to varying degrees via cytokine modulation, including blockade of IL-12 production by professional antigen-presenting cells, modulation of cell-surface molecules essential for 1-cell activation, and expression of viral chemokines and chemokine receptors. Some of these effects are related to signaling through and downregulation of the viral receptor, CD46, a key molecule linking innate and adaptive immune responses. Increasing attention has recently been focused on the importance of viral interactions with dendritic cells, which may serve both as targets of virus-mediated immunosuppression and as vehicles for viral transfer to CD4(+) T cells. Our deepening knowledge of the mechanisms developed by HHV-6A and HHV-6B to evade immunologic control may lead to new strategies for the prevention and treatment of the diseases associated with these viruses. Moreover, elucidation of these viral mechanisms may uncover new avenues to therapeutically manipulate or modulate the immune system in immunologically mediated human diseases. C1 [Dagna, Lorenzo] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Dept Med & Clin Immunol, I-20132 Milan, Italy. [Pritchett, Joshua C.] HHV 6 Fdn, Santa Barbara, CA 93108 USA. [Lusso, Paolo] NIAID, Viral Pathogenesis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Lusso, P (reprint author), NIAID, Viral Pathogenesis Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Dagna, Lorenzo/0000-0002-7428-315X FU Intramural Research Program of the NIAID; NIH FX This work was supported in part by the Intramural Research Program of the NIAID, NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 117 TC 8 Z9 9 U1 0 U2 14 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0794 J9 FUTURE VIROL JI Future Virol. PD MAR PY 2013 VL 8 IS 3 BP 273 EP 287 DI 10.2217/FVL.13.7 PG 15 WC Virology SC Virology GA 100LR UT WOS:000315703200011 PM 24163703 ER PT J AU Nagy, GA Botond, G Borhegyi, Z Plummer, NW Freund, TF Hajos, N AF Nagy, Gergo A. Botond, Gergo Borhegyi, Zsolt Plummer, Nicholas W. Freund, Tamas F. Hajos, Norbert TI DAG-sensitive and Ca2+ permeable TRPC6 channels are expressed in dentate granule cells and interneurons in the hippocampal formation SO HIPPOCAMPUS LA English DT Article DE hippocampus; dendrite; GABAergic cell; feed-forward inhibition; feed-back inhibition ID METABOTROPIC GLUTAMATE RECEPTORS; RAT HIPPOCAMPUS; PYRAMIDAL CELLS; STRATUM-ORIENS; CA1 AREA; POSTSYNAPTIC TARGETS; EXCITATORY SYNAPSES; GABAERGIC NEURONS; ACTIVATION; DIACYLGLYCEROL AB Members of the transient receptor potential (TRP) cation channel family play important roles in several neuronal functions. To understand the precise role of these channels in information processing, their presence on neuronal elements must be revealed. In this study, we investigated the localization of TRPC6 channels in the adult hippocampal formation. Immunostainings with a specific antibody, which was validated in Trpc6 knockout mice, showed that in the dentate gyrus, TRPC6 channels are strongly expressed in granule cells. Immunogold staining revealing the subcellular localization of TRPC6 channels clarified that these proteins were predominantly present on the membrane surface of the dendritic shafts of dentate granule cells, and also in their axons, often associated with intracellular membrane cisternae. In addition, TRPC6 channels could be observed in the dendrites of some interneurons. Double immunofluorescent staining showed that TRPC6 channels were present in the dendrites of hilar interneurons and hippocampal interneurons with horizontal dendrites in the stratum oriens expressing mGlu1a receptors, whereas parvalbumin immunoreactivity was revealed in TRPC6-expressing dendrites with radial appearance in the stratum radiatum. Electron microscopy showed that the immunogold particles depicting TRPC6 channels were located on the surface membranes of the interneuron dendrites. Our results suggest that TRPC6 channels are in a key position to alter the information entry into the trisynaptic loop of the hippocampal formation from the entorhinal cortex, and to control the function of both feed-forward and feed-back inhibitory circuits in this brain region. (c) 2012 Wiley Periodicals, Inc. C1 [Nagy, Gergo A.; Botond, Gergo; Borhegyi, Zsolt; Freund, Tamas F.; Hajos, Norbert] Hungarian Acad Sci, Inst Expt Med, H-1450 Budapest, Hungary. [Plummer, Nicholas W.] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hajos, N (reprint author), Hungarian Acad Sci, Inst Expt Med, POB 67, H-1450 Budapest, Hungary. EM hajos@koki.hu OI Plummer, Nicholas/0000-0003-2971-814X; Borhegyi, Zsolt/0000-0001-5556-8742 FU Wellcome Trust International Senior Research Fellowship; National Office for Research and Technology [OMFB-01678/2009]; The Intramural Research Program of the NIH [Z01-ES-101684] FX Grant sponsor: Wellcome Trust International Senior Research Fellowship; Grant sponsor: National Office for Research and Technology; Grant number: OMFB-01678/2009; Grant sponsor: The Intramural Research Program of the NIH; Grant number: Z01-ES-101684. NR 55 TC 6 Z9 6 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 J9 HIPPOCAMPUS JI Hippocampus PD MAR PY 2013 VL 23 IS 3 BP 221 EP 232 DI 10.1002/hipo.22081 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 098BV UT WOS:000315520200006 PM 23193081 ER PT J AU Horton, JA Chung, EJ Hudak, KE Sowers, A Thetford, A White, AO Mitchell, JB Citrin, DE AF Horton, Jason A. Chung, Eun Joo Hudak, Kathryn E. Sowers, Anastasia Thetford, Angela White, Ayla O. Mitchell, James B. Citrin, Deborah E. TI Inhibition of radiation-induced skin fibrosis with imatinib SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article DE Radiation; dermal; fibrosis; imatinib; Platelet-derived growth factor-receptor ID GROWTH-FACTOR-BETA; INDUCED LUNG INJURY; SYSTEMIC-SCLEROSIS; IONIZING-RADIATION; STIMULATORY AUTOANTIBODIES; MOLECULAR-MECHANISMS; B GENE; MESYLATE; MOUSE; RADIOSENSITIVITY AB Purpose : Dermal fibrosis is a disabling late toxicity of radiotherapy. Several lines of evidence suggest that overactive signaling via the Platelet-derived growth factor receptor-beta (PDGFR-beta) and V-abl Abelson murine leukemia viral oncogene homolog 1 (cAbl) may be etiologic factors in the development of radiation-induced fibrosis. We tested the hypothesis that imatinib, a clinically available inhibitor of PDGFR-beta, Mast/stem cell growth factor receptor (c-kit) and cAbl, would reduce the severity of dermal fibrosis in a murine model. Materials and methods : The right hind legs of female C3H/HeN mice were exposed to 35 Gy of X-rays. Cohorts of mice were maintained on chow formulated with imatinib 0.5 mg/g or control chow for the duration of the experiment. Bilateral hind limb extension was measured serially to assess fibrotic contracture. Immunohistochemistry and biochemical assays were used to evaluate the levels of collagen and cytokines implicated in radiation-induced fibrosis. Results : Imatinib treatment significantly reduced hind limb contracture and dermal thickness after irradiation. Immunohistochemical studies demonstrated a substantial reduction in PDGFR-beta phosphorylation. We also observed reduced Transforming Growth factor-beta (TGF-beta) and collagen expression in irradiated skin of imatinib-treated mice, suggesting that imatinib may suppress the fibrotic process by interrupting cross-talk between these pathways. Conclusions : Taken together, these results support that imatinib may be a useful agent in the prevention and treatment of radiation-induced dermal fibrosis. C1 [Horton, Jason A.; Chung, Eun Joo; Hudak, Kathryn E.; White, Ayla O.; Citrin, Deborah E.] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Sowers, Anastasia; Thetford, Angela; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NCI, Sect Translat Radiat Oncol, Radiat Oncol Branch, Ctr Canc Res, 10 CRC Hatfield Clin Res Ctr,B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Bethesda, MD, USA FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA. NR 42 TC 6 Z9 7 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0955-3002 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD MAR PY 2013 VL 89 IS 3 BP 162 EP 170 DI 10.3109/09553002.2013.741281 PG 9 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 099PN UT WOS:000315633800004 PM 23083077 ER PT J AU Scahill, L Hallett, V Aman, MG McDougle, CJ Arnold, LE McCracken, JT Tierney, E Deng, YH Dziura, J Vitiello, B AF Scahill, Lawrence Hallett, Victoria Aman, Michael G. McDougle, Christopher J. Arnold, L. Eugene McCracken, James T. Tierney, Elaine Deng, Yanhong Dziura, James Vitiello, Benedetto CA Res Units Pediatric TI Brief Report: Social Disability in Autism Spectrum Disorder: Results from Research Units on Pediatric Psychopharmacology (RUPP) Autism Network Trials SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Social disability; Autism; Research Units on Pediatric Psychopharmacology (RUPP) Autism Network; Social withdrawal; Risperidone; Aberrant Behavior Checklist ID PERVASIVE DEVELOPMENTAL DISORDERS; ABERRANT BEHAVIOR CHECKLIST; YOUNG-PEOPLE; CHILDREN; RISPERIDONE; SYMPTOMS; IRRITABILITY; ARIPIPRAZOLE; INDIVIDUALS; ADOLESCENTS AB There is growing interest in measuring social disability as a core element of autism spectrum disorders in medication trials. We conducted a secondary analysis on the Aberrant Behavior Checklist Social Withdrawal subscale using data from two federally-funded, multi-site, randomized trials with risperidone. Study 1 included 52 subjects assigned to placebo and 49 subjects to risperidone under double-blind conditions. Study 2 included 49 subjects assigned to risperidone only and 75 subjects assigned to risperidone plus parent training. After 8 weeks of treatment, all active treatments were superior to placebo (effect sizes ranging from 0.42 to 0.65). The findings suggest that the Social Withdrawal subscale may be a useful measure of social disability in acute treatment trials. C1 [Scahill, Lawrence; Hallett, Victoria] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. [Scahill, Lawrence; Hallett, Victoria] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Aman, Michael G.; Arnold, L. Eugene] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [McDougle, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lurie Ctr Autism, Boston, MA USA. [McDougle, Christopher J.] Indiana Univ, Indinapolis, IN USA. [McCracken, James T.] Univ Calif Los Angeles, Div Child Psychiat, Los Angeles, CA USA. [Tierney, Elaine] Johns Hopkins Univ, Baltimore, MD USA. [Tierney, Elaine] Kennedy Krieger Inst, Baltimore, MD USA. [Deng, Yanhong] Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Dziura, James] Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Scahill, L (reprint author), Emory Univ, Dept Pediat, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. EM lawrence.scahill@emory.edu OI Scahill, Lawrence/0000-0001-5073-1707 FU NCATS NIH HHS [UL1 TR001108]; NCRR NIH HHS [UL1 RR025761, UL1 RR024139, UL1 RR025755]; NIDA NIH HHS [N01MH80011]; NIMH NIH HHS [U10 MH066768, U10MH66766, N01MH70009, K24 MH001805, U10 MH066764, U01 MH070009, U10MH66768, N01MH80011, N01MH70010, U10 MH066766, U01 MH070010, U10MH66764, N01MH70001] NR 28 TC 13 Z9 13 U1 1 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD MAR PY 2013 VL 43 IS 3 BP 739 EP 746 DI 10.1007/s10803-012-1689-3 PG 8 WC Psychology, Developmental SC Psychology GA 095LU UT WOS:000315336800020 PM 23104617 ER PT J AU Cartwright, TA Campos, CR Cannon, RE Miller, DS AF Cartwright, Tara A. Campos, Christopher R. Cannon, Ronald E. Miller, David S. TI Mrp1 is essential for sphingolipid signaling to p-glycoprotein in mouse blood-brain and blood-spinal cord barriers SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE blood-brain barrier; confocal microscopy; endothelium; pharmacology; physiology ID RESISTANCE-ASSOCIATED PROTEINS; DRUG-DELIVERY; SPHINGOSINE-1-PHOSPHATE; CELLS; TRAFFICKING; EXPRESSION; TRANSPORT; EXPORT; MICE AB At the blood-brain and blood-spinal cord barriers, P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to central nervous system (CNS) pharmacotherapy. Recently, we showed that signaling through tumor necrosis factor-alpha (TNF-alpha), sphingolipids, and sphingosine-1-phosphate receptor 1 (S1PR1) rapidly and reversibly reduced basal P-glycoprotein transport activity in the rat blood-brain barrier. The present study extends those findings to the mouse blood-brain and blood-spinal cord barriers and, importantly, identifies multidrug resistance-associated protein 1 (Mrp1, Abcc1) as the transporter that mediates S1P efflux from brain and spinal cord endothelial cells. In brain and spinal cord capillaries isolated from wild-type mice, TNF-alpha, sphingosine, S1P, the S1PR agonist fingolimod (FTY720), and its active, phosphorylated metabolite, FTY720P, reduced P-glycoprotein transport activity; these effects were abolished by a specific S1PR1 antagonist. In brain and spinal cord capillaries isolated from Mrp1-null mice, neither TNF-alpha nor sphingosine nor FTY720 reduced P-glycoprotein transport activity. However, S1P and FTY720P had the same S1PR1-dependent effects on transport activity as in capillaries from wild-type mice. Thus, deletion of Mrp1 alone terminated endogenous signaling to S1PR1. These results identify Mrp1 as the transporter essential for S1P efflux from the endothelial cells and thus for inside-out S1P signaling to P-glycoprotein at the blood-brain and blood-spinal cord barriers. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 381-388; doi:10.1038/jcbfm.2012.174; published online 21 November 2012 C1 [Cartwright, Tara A.; Campos, Christopher R.; Cannon, Ronald E.; Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 30 TC 19 Z9 19 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAR PY 2013 VL 33 IS 3 BP 381 EP 388 DI 10.1038/jcbfm.2012.174 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 099AG UT WOS:000315590200010 PM 23168528 ER PT J AU Freidlin, B Korn, EL AF Freidlin, Boris Korn, Edward L. TI Adaptive Randomization Versus Interim Monitoring SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Freidlin, Boris; Korn, Edward L.] NCI, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Bethesda, MD 20892 USA. NR 6 TC 4 Z9 4 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2013 VL 31 IS 7 BP 969 EP 970 DI 10.1200/JCO.2012.45.0254 PG 2 WC Oncology SC Oncology GA 097AU UT WOS:000315447200029 PM 23341515 ER PT J AU Vatsalya, V Schmidt, VY Ramchandani, VA AF Vatsalya, Vatsalya Schmidt, Veronica Y. Ramchandani, Vijay A. TI Subjective and Motor Responses to Acute Intravenous (IV) Alcohol: Comparison of Clamp and Oral-Mimic Infusion Paradigms SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Eastern Regional Meeting of the American-Federation-for-Medical-Research (AFMR) CY APR 16-17, 2013 CL Washington, DC SP Amer Federat Med Res (AFMR) C1 [Vatsalya, Vatsalya; Schmidt, Veronica Y.; Ramchandani, Vijay A.] NIAAA, LCTS, Sect Human Psychopharmacol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2013 VL 61 IS 3 BP 663 EP 663 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 097GU UT WOS:000315462800035 ER PT J AU Xie, XF Colberg-Poley, A Das, J Li, JL Zhang, AP Tang, P Jerebtsova, M Gutkind, JS Ray, P AF Xie, Xuefang Colberg-Poley, Anamaris Das, Jharna Li, Jinliang Zhang, Aiping Tang, Pingato Jerebtsova, Marina Gutkind, J. Silvio Ray, Patricio TI The Basic Domain of HIV-Tat is Essential for Targeting Tat to Lipid Rafts (LR) and its Regulation of FGF-2 Signaling in Human Podocytes SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Eastern Regional Meeting of the American-Federation-for-Medical-Research (AFMR) CY APR 16-17, 2013 CL Washington, DC SP Amer Federat Med Res (AFMR) C1 [Xie, Xuefang; Das, Jharna; Li, Jinliang; Tang, Pingato; Jerebtsova, Marina; Ray, Patricio] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA. [Colberg-Poley, Anamaris; Zhang, Aiping] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [Colberg-Poley, Anamaris; Zhang, Aiping; Jerebtsova, Marina; Ray, Patricio] George Washington Univ, Washington, DC USA. [Gutkind, J. Silvio] Natl Inst Dent & Craneofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2013 VL 61 IS 3 BP 671 EP 671 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 097GU UT WOS:000315462800059 ER PT J AU Michalczyk, I Sikorski, AF Kotula, L Junghans, RP Dubielecka, PM AF Michalczyk, Izabela Sikorski, Aleksander F. Kotula, Leszek Junghans, Richard P. Dubielecka, Patrycja M. TI The emerging role of protein kinase C theta in cytoskeletal signaling SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE cytoskeleton; immunological synapse; membrane translocation; spectrin aggregate ID T-CELL-ACTIVATION; KAPPA-B ACTIVATION; PKC-THETA; IMMUNOLOGICAL SYNAPSE; SKELETAL-MUSCLE; INSULIN-RESISTANCE; ACTIN CYTOSKELETON; MOLECULAR-CLONING; IN-VITRO; DEPENDENT PHOSPHORYLATION AB Cytoskeletal rearrangements often occur as the result of transduction of signals from the extracellular environment. Efficient awakening of this powerful machinery requires multiple activation and deactivation steps, which usually involve phosphorylation or dephosphorylation of different signaling units by kinases and phosphatases, respectively. In this review, we discuss the signaling characteristics of one of the nPKC isoforms, PKC theta, focusing on PKC theta-mediated signal transduction to cytoskeletal elements, which results in cellular rearrangements critical for cell type-specific responses to stimuli. PKC theta is the major PKC isoform present in hematopoietic and skeletal muscle cells. PKC theta plays roles in T cell signaling through the IS, survival responses in adult T cells, and T cell FasL-mediated apoptosis, all of which involve cytoskeletal rearrangements and relocation of this enzyme. PKC theta has been linked to the regulation of cell migration, lymphoid cell motility, and insulin signaling and resistance in skeletal muscle cells. Additional roles were suggested for PKC theta in mitosis and cell-cycle regulation. Comprehensive understanding of cytoskeletal regulation and the cellular "modus operandi" of PKC theta holds promise for improving current therapeutic applications aimed at autoimmune diseases. J. Leukoc. Biol. 93: 319-327; 2013. C1 [Michalczyk, Izabela; Sikorski, Aleksander F.] Univ Wroclaw, Fac Biotechnol, Lab Cytobiochem, PL-50138 Wroclaw, Poland. [Kotula, Leszek] New York State Inst Basic Res Dev Disabil, Staten Isl, NY 10314 USA. [Junghans, Richard P.] Boston Univ, Sch Med, Roger Williams Med Ctr, Providence, RI 02908 USA. [Dubielecka, Patrycja M.] Boston Univ, Sch Med, Roger Williams Med Ctr, Signal Transduct Lab, Providence, RI 02908 USA. RP Dubielecka, PM (reprint author), Boston Univ, Sch Med, NIH Ctr Biomed Res Excellence, Signal Transduct Lab,Roger Williams Med Ctr, Providence, RI 02908 USA. EM dubielec@bu.edu FU U.S. Department of Defense [W81XWH-09-1-0039]; U.S. National Institutes of Health [5P20RR018757-10, 8P20GM103414-10] FX The authors acknowledge the following grants: U.S. Department of Defense W81XWH-09-1-0039 and U.S. National Institutes of Health 5P20RR018757-10 and 8P20GM103414-10. We also thank Dr. Nicola Kouttab and Nayab Nadeem for helpful discussions. NR 106 TC 4 Z9 4 U1 0 U2 9 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2013 VL 93 IS 3 BP 319 EP 327 DI 10.1189/jlb.0812371 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 098WL UT WOS:000315579700001 PM 23192428 ER PT J AU Dickensheets, H Sheikh, F Park, O Gao, B Donnelly, RP AF Dickensheets, Harold Sheikh, Faruk Park, Ogyi Gao, Bin Donnelly, Raymond P. TI Interferon-lambda (IFN-lambda) induces signal transduction and gene expression in human hepatocytes, but not in lymphocytes or monocytes SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE IFN-alpha; tyrosine-phosphorylated; hepatitis C virus; ISG; STAT ID C VIRUS-REPLICATION; CHRONIC HEPATITIS-C; JAK-STAT PATHWAY; TARGETED DISRUPTION; RECEPTOR; ALPHA; CELLS; IDENTIFICATION; TRANSCRIPTION; ACTIVATION AB This study compared the ability of IFN-alpha and IFN-lambda to induce signal transduction and gene expression in primary human hepatocytes, PBLs, and monocytes. IFN-alpha drug products are widely used to treat chronic HCV infection; however, IFN-alpha therapy often induces hematologic toxicities as a result of the broad expression of IFNARs on many cell types, including most leukocytes. rIFN-lambda 1 is currently being tested as a potential alternative to IFN-alpha for treating chronic HCV. Although IFN-lambda has been shown to be active on hepatoma cell lines, such as HepG2 and Huh-7, its ability to induce responses in primary human hepatocytes or leukocytes has not been examined. We found that IFN-lambda induces activation of Jak/STAT signaling in mouse and human hepatocytes, and the ability of IFN-lambda to induce STAT activation correlates with induction of numerous ISGs. Although the magnitude of ISG expression induced by IFN-alpha in hepatocytes was generally lower than that induced by IFN-lambda, the repertoire of regulated genes was quite similar. Our findings demonstrate that although IFN-alpha and IFN-lambda signal through distinct receptors, they induce expression of a common set of ISGs in hepatocytes. However, unlike IFN-alpha, IFN-lambda did not induce STAT activation or ISG expression by purified lymphocytes or monocytes. This important functional difference may provide a clinical advantage for IFN-lambda as a treatment for chronic HCV infection, as it is less likely to induce the leukopenias that are often associated with IFN-alpha therapy. J. Leukoc. Biol. 93: 377-385; 2013. C1 [Dickensheets, Harold; Sheikh, Faruk; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, CDER, Bethesda, MD 20892 USA. [Park, Ogyi; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. RP Donnelly, RP (reprint author), US FDA, Div Therapeut Prot, CDER, Bldg 29A,Room 3B15,HFD-122,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raymond.donnelly@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Drug Evaluation and Research; U.S. National Institutes of Health FX This study was supported by intramural research funds from the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, and the U.S. National Institutes of Health. NR 42 TC 34 Z9 34 U1 0 U2 10 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2013 VL 93 IS 3 BP 377 EP 385 DI 10.1189/jlb.0812395 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 098WL UT WOS:000315579700007 PM 23258595 ER PT J AU Baron, J Blex, C Rohrbeck, A Rachakonda, SK Birnbaumer, L Ahnert-Hilger, G Brunk, I AF Baron, Jens Blex, Christian Rohrbeck, Astrid Rachakonda, Sivarama Krishna Birnbaumer, Lutz Ahnert-Hilger, Gudrun Brunk, Irene TI The alpha-subunit of the trimeric GTPase Go2 regulates axonal growth SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE axonal growth; Girdin; Go2 alpha; heterotrimeric G-proteins; Rap1; Rap1GAP ID NUCLEOTIDE EXCHANGE FACTOR; G-PROTEIN HETEROTRIMERS; SYNAPTIC VESICLES; NEURITE OUTGROWTH; BEHAVIORAL SENSITIZATION; SIGNAL-TRANSDUCTION; ACTIVATING PROTEIN; ADENYLATE-CYCLASE; MOLECULAR-CLONING; CELL-MIGRATION AB The Go splice variants Go1 and Go2 are subunits of the most abundant G-proteins in brain, Go1 and Go2. Only a few interacting partners binding to Go1 have been described so far and splice variant-specific differences are not known. Using a yeast two-hybrid screen with constitutively active Go2 as bait, we identified Rap1GTPase activating protein (Rap1GAP) and Girdin as interacting partners of Go2, which was confirmed by co-immunoprecipitation. Comparison of subcellular fractions from brains of wild type and Go2/ mice revealed no differences in the overall expression level of Girdin or Rap1GAP. However, we found higher amounts of active Rap1-GTP in brains of Go2 deficient mutants, indicating that Go2 may increase Rap1GAP activity, thereby effecting the Rap1 activation/deactivation cycle. Rap1 has been shown to be involved in neurite outgrowth and given a Rap1GAP-Go2 interaction, we found that the loss of Go2 affected axonal outgrowth. Axons of cultured cortical and hippocampal neurons prepared from embryonic Go2/ mice grew longer and developed more branches than those from wild-type mice. Taken together, we provide evidence that Go2 regulates axonal outgrowth and branching. C1 [Baron, Jens; Blex, Christian; Rachakonda, Sivarama Krishna; Ahnert-Hilger, Gudrun; Brunk, Irene] Charite Univ Med Berlin, Inst Integrat Neuroanat, Ctr Anat, Berlin, Germany. [Rohrbeck, Astrid] Hannover Med Sch MHH, Inst Toxicol, Hannover, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Brunk, I (reprint author), Inst Integrat Neuroanat, Philippstr 12, D-10115 Berlin, Germany. EM gudrun.ahnert@charite.de; irene.brunk@charite.de FU Deutsche Forschungsgemeinschaft [DFG Ah67/3-3]; Intramural Research Program of the NIH [Z01-ES-101643] FX The authors are indebted to Birgit Metze, Marion Mobes, and Antje Drager for skillfull technical assistance, to Sam Booker for linguistic corrections and to the Deutsche Forschungsgemeinschaft for financial support (DFG Ah67/3-3). Part of this research was supported by the Intramural Research Program of the NIH (Project Z01-ES-101643 to LB). None of the authors has to declare any conflict of interest. NR 50 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2013 VL 124 IS 6 BP 782 EP 794 DI 10.1111/jnc.12123 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 100OI UT WOS:000315710100005 PM 23373526 ER PT J AU Harberts, E Datta, D Chen, S Wohler, JE Oh, U Jacobson, S AF Harberts, Erin Datta, Dibyadeep Chen, Selby Wohler, Jillian E. Oh, Unsong Jacobson, Steven TI Translocator Protein 18 kDa (TSPO) Expression in Multiple Sclerosis Patients SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE TSPO; PBR28; Multiple sclerosis; Neuroinflammation ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; MITOCHONDRIAL; BINDING; BRAIN; CELLS; STEROIDOGENESIS; ACTIVATION; APOPTOSIS AB Translocator protein (18 kDa) (TSPO) is a marker of inflammation in the brain. Positron emission tomography (PET) scans with ligands for this receptor show increased expression of TSPO in many neuropathologic conditions. However, expression of TSPO in the periphery and its possible correlation to central nervous system (CNS) inflammation has been largely unstudied. In this paper PBR28, a recently synthesized ligand for TSPO that is shown to have 80-fold higher specific binding than its predecessor PK11195, is used to quantify peripheral TSPO. Data presented in this study show that monocytes account for the majority of TSPO measured in peripheral blood mononuclear cells (PBMC), and that TSPO expression is stable over time in healthy individuals. Previous studies show that areas of increased PBR28 binding in the brains of multiple sclerosis (MS) patients correlate with active demylinating lesions found during magnetic resonance imaging (MRI). To measure peripheral TSPO expression in an inflammatory disease of the CNS, PBR28 is used in an in vitro radioligand binding assay to measure the amount of TSPO in the PBMC of MS and healthy donor cohorts. Surprisingly, MS patients are found to have a significantly lower amount of peripheral TSPO than healthy donors. We suggest that TSPO protein expression is a potential peripheral biomarker of MS, more research is needed to determine if peripheral TSPO expression may also be altered in other neuroinflammatory conditions. C1 [Harberts, Erin; Datta, Dibyadeep; Chen, Selby; Wohler, Jillian E.; Oh, Unsong; Jacobson, Steven] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5C103,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002817-18, Z01 NS002817-19, Z01 NS003040-01]; NCATS NIH HHS [KL2 TR000057] NR 30 TC 10 Z9 10 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2013 VL 8 IS 1 BP 51 EP 57 DI 10.1007/s11481-012-9397-5 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 096YV UT WOS:000315441900008 PM 22956240 ER PT J AU Mocchetti, I Campbell, LA Harry, GJ Avdoshina, V AF Mocchetti, Italo Campbell, Lee A. Harry, G. Jean Avdoshina, Valeriya TI When Human Immunodeficiency Virus Meets Chemokines and Microglia: Neuroprotection or Neurodegeneration? SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Review DE HIV; CCL5; CXCL12; Dopamine; Glutamate; Cytokines ID CENTRAL-NERVOUS-SYSTEM; NEURONAL CELL-DEATH; MULTINUCLEATED GIANT-CELLS; DEFICIENCY-SYNDROME AIDS; HIV-ASSOCIATED DEMENTIA; RECEPTOR-GAMMA CHAIN; METHYL-D-ASPARTATE; ADULT-RAT BRAIN; NEUROTROPHIC FACTOR; PROTEIN GP120 AB Chemokines are chemotactic cytokines that were originally discovered as promoters of leukocyte proliferation and mobility. In recent years, however, evidence has demonstrated constitutive expression of chemokines and chemokine receptors in a variety of cells in the central and peripheral nervous system and has proposed a role for chemokines in neurodegenerative diseases characterized by inflammation and microglia proliferation. In addition, chemokine receptors, and in particular CXCR4 and CCR5, mediate human immunodeficiency virus type 1 (HIV) infection of immunocompetent cells as well as microglia. Subsequently, HIV, through a variety of mechanisms, promotes synapto-dendritic alterations and neuronal loss that ultimately lead to motor and cognitive impairments. These events are accompanied by microglia activation. Nevertheless, a microglia-mediated mechanism of neuronal degeneration alone cannot fully explain some of the pathological features of HIV infected brain such as synaptic simplification. In this article, we present evidence that some of the microglia responses to HIV are beneficial and neuroprotective. These include the ability of microglia to release anti-inflammatory cytokines, to remove dying cells and to promote axonal sprouting. C1 [Mocchetti, Italo; Campbell, Lee A.; Avdoshina, Valeriya] Georgetown Univ, Dept Neurosci, Med Ctr, Washington, DC 20057 USA. [Harry, G. Jean] NIEHS, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. RP Mocchetti, I (reprint author), Georgetown Univ, Dept Neurosci, Med Ctr, Res Bldg,Room EP04 Box 571464, Washington, DC 20057 USA. EM moccheti@georgetown.edu FU National Institute of Drug Abuse [1R01DA026174, 1F31DA032282]; National Institute of Neurological Disorders and Stroke [1R21NS074916]; National Institute of Environmental Health Sciences FX This work was supported by grants from the National Institute of Drug Abuse 1R01DA026174 and 1F31DA032282, and National Institute of Neurological Disorders and Stroke 1R21NS074916 and the Intramural Research Program of the National Institute of Environmental Health Sciences. The authors have no conflict of interest to declare. The views expressed in this article are those of the authors and they do not represent the views or policies of the National Toxicology Program or National Institute of Environmental Health Sciences. NR 169 TC 5 Z9 7 U1 1 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2013 VL 8 IS 1 BP 118 EP 131 DI 10.1007/s11481-012-9353-4 PG 14 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 096YV UT WOS:000315441900014 PM 22527632 ER PT J AU Suri, RS Larive, B Sherer, S Eggers, P Gassman, J James, SH Lindsay, RM Lockridge, RS Ornt, DB Rocco, MV Ting, GO Kliger, AS AF Suri, Rita S. Larive, Brett Sherer, Susan Eggers, Paul Gassman, Jennifer James, Sam H. Lindsay, Robert M. Lockridge, Robert S. Ornt, Daniel B. Rocco, Michael V. Ting, George O. Kliger, Alan S. CA Frequent Hemodialysis Network TI Risk of Vascular Access Complications with Frequent Hemodialysis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID QUALITY-OF-LIFE; CONVENTIONAL HEMODIALYSIS; HOME HEMODIALYSIS; 3 TIMES; TRIAL; BUTTONHOLE; FISTULAS AB Frequent hemodialysis requires using the vascular access more often than with conventional hemodialysis, but whether this increases the risk for access-related complications is unknown. In two separate trials, we randomly assigned 245 patients to receive in-center daily hemodialysis (6 days per week) or conventional hemodialysis (3 days per week) and 87 patients to receive home nocturnal hemodialysis (6 nights per week) or conventional hemodialysis, for 12 months. The primary vascular access outcome was time to first access event (repair, loss, or access-related hospitalization). Secondary outcomes were time to all repairs and time to all losses. In the Daily Trial, 77 (31%) of 245 patients had a primary outcome event: 33 repairs and 15 losses in the daily group and 17 repairs, 11 losses, and 1 hospitalization in the conventional group. Overall, the risk for a first access event was 76% higher with daily hemodialysis than with conventional hemodialysis (hazard ratio [H RI, 1.76; 95% confidence interval [CI], 1.11-2.79; P=0.017); among the 198 patients with an arteriovenous (AV) access at randomization, the risk was 90% higher with daily hemodialysis (HR, 1.90; 95% CI, 1.11-3.25; P=0.02). Daily hemodialysis patients had significantly more total AV access repairs than conventional hemodialysis patients (P=0.011), with 55% of all repairs involving thrombectomy or surgical revision. Losses of AV access did not differ between groups (P=0.58). We observed similar trends in the Nocturnal Trial, although the results were not statistically significant. In conclusion, frequent hemodialysis increases the risk of vascular access complications. The nature of the AV access repairs suggests that this risk likely results from increased hemodialysis frequency rather than heightened surveillance. J Am Soc Nephrol 24: 498-505, 2013. doi: 10.1681/ASN.2012060595 C1 [Suri, Rita S.; Lindsay, Robert M.] Univ Western Ontario, Div Nephrol, London, ON N6A 4G5, Canada. [Larive, Brett; Sherer, Susan] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Eggers, Paul] NIDDK, Bethesda, MD USA. [James, Sam H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lockridge, Robert S.] Univ Virginia, Div Nephrol, Richmond, VA USA. [Ornt, Daniel B.] Rochester Inst Technol, Coll Hlth Sci & Technol, Rochester, NY 14623 USA. [Rocco, Michael V.] Wake Forest Sch Med, Nephrol Sect, Winston Salem, NC USA. [Ting, George O.] El Camino Hosp, El Camino Dialysis Serv, Mountain View, CA USA. [Kliger, Alan S.] Hosp St Raphael, New Haven, CT 06511 USA. [Kliger, Alan S.] Yale Univ, Sch Med, New Haven, CT USA. RP Suri, RS (reprint author), Univ Western Ontario, Kidney Clin Res Unit, Victoria Hosp, Room A2-346,800 Commissioners Rd East, London, ON N6A 4G5, Canada. EM rita.suri@lhsc.on.ca RI Suri, Rita/G-3348-2011 OI Suri, Rita/0000-0002-0519-3927 FU National Institute of Diabetes and Digestive and Kidney Diseases; Centers for Medicare & Medicaid Services; National Institutes of Health (NTH) Research Foundation; Fresenius Medical Care; Canadian Institutes of Health Randomized Trials Mentorship Award; Fresenius Medical Care Canada; Baxter Inc. FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the Centers for Medicare & Medicaid Services, and the National Institutes of Health (NTH) Research Foundation. The investigators and sponsors are grateful for the support of contributors to the NIH Foundation: Amgen, Baxter, and Dialysis Clinics, and support from Fresenius Medical Care. R.S. was funded by a Canadian Institutes of Health Randomized Trials Mentorship Award.; R.S.S. and R.M.L. have unrestricted research grants from Fresenius Medical Care Canada and Baxter Inc. M.R. is a consultant for Amgen and DaVita. R.S.L. sits on the Machine Medical Advisory Board for Fresenius Medical Care North America (Sorbent Machine). NR 24 TC 50 Z9 51 U1 1 U2 8 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2013 VL 24 IS 3 BP 498 EP 505 DI 10.1681/ASN.2012060595 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 097KI UT WOS:000315472600019 PM 23393319 ER PT J AU Kuznetsov, SA Mankani, MH Robey, PG AF Kuznetsov, Sergei A. Mankani, Mahesh H. Robey, Pamela Gehron TI In vivo formation of bone and haematopoietic territories by transplanted human bone marrow stromal cells generated in medium with and without osteogenic supplements SO JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE LA English DT Article DE human bone marrow stromal cells; in vitro cultivation; dexamethasone; ascorbic acid phosphate; in vivo transplantation; bone formation; haematopoietic territories ID MESENCHYMAL STEM-CELLS; ASCORBIC-ACID; MATRIX PROTEINS; DEXAMETHASONE; VITRO; FIBROBLAST; COLLAGEN; CULTURE; DIFFERENTIATION; PHENOTYPE AB Autologous transplantation of human bone marrow stromal cells (BMSCs) has been successfully used for bone reconstruction. However, in order to advance this approach into the mainstream of bone tissue engineering, the conditions for BMSC cultivation and transplantation must be optimized. In a recent report, cultivation with dexamethasone (Dex) significantly increased bone formation by human BMSCs in vivo. Based on this important conclusion, we analysed the data accumulated by our laboratory, where human BMSCs have been routinely generated using media both with and without a combination of two osteogenic supplements: Dex at 108m and ascorbic acid phosphate (AscP) at 104m. Our data demonstrate that for 22/24 donors, BMSC strains propagated with and without Dex/AscP formed similar amounts of bone in vivo. Thus, human BMSCs do not appear to need to be induced to osteogenic differentiation ex vivo prior to transplantation. Similarly, for 12/14 donors, BMSC strains cultured with and without Dex/AscP formed haematopoietic territories to a comparable extent. While Dex/AscP did not increase bone formation, they significantly stimulated BMSC in vitro proliferation without affecting the number of BMSC colonies formed by the colony-forming unitsfibroblasts. We conclude that for the substantial majority of donors, Dex/AscP have no effect on the ability of BMSCs to form bone and myelosupportive stroma in vivo. However, due to increased BMSC proliferation, the total osteogenic population obtained from a single marrow sample is larger after cultivation with Dex/AscP than without them. Secondary to increased BMSC proliferation, Dex/AscP may stimulate bone formation if BMSCs and/or the transplantation system are less than optimal. Published 2011. This article is a U.S. Government work and is in the public domain in the USA C1 [Kuznetsov, Sergei A.; Mankani, Mahesh H.; Robey, Pamela Gehron] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kuznetsov, SA (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bldg 30,Room 228,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM skuznets@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Division of Intramural Research of the National Institute of Dental and Craniofacial Research; Division of Intramural Research of the Intramural Research Program, NIH, DHHS FX The authors are indebted to Zimmer (Warsaw, IN, USA) for its gift of HA/TCP and to Ms Li Li (NIDCR, NIH, USA) for excellent technical assistance. This study was supported by the Division of Intramural Research of the National Institute of Dental and Craniofacial Research, of the Intramural Research Program, NIH, DHHS. NR 64 TC 7 Z9 8 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-6254 J9 J TISSUE ENG REGEN M JI J. Tissue Eng. Regen. Med. PD MAR PY 2013 VL 7 IS 3 BP 226 EP 235 DI 10.1002/term.515 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Engineering, Biomedical SC Cell Biology; Biotechnology & Applied Microbiology; Engineering GA 099US UT WOS:000315648700006 PM 22052864 ER PT J AU Abente, EJ Sosnovtsev, SV Sandoval-Jaime, C Parra, GI Bok, K Green, KY AF Abente, Eugenio J. Sosnovtsev, Stanislav V. Sandoval-Jaime, Carlos Parra, Gabriel I. Bok, Karin Green, Kim Y. TI The Feline Calicivirus Leader of the Capsid Protein Is Associated with Cytopathic Effect SO JOURNAL OF VIROLOGY LA English DT Article ID MONOCYTE-DERIVED MACROPHAGES; VIRUS MESSENGER-RNA; NONSTRUCTURAL POLYPROTEIN; SEQUENCES DOWNSTREAM; SIGNALING PROTEINS; PRECURSOR PROTEIN; CULTURED-CELLS; SUBGENOMIC RNA; INFECTED-CELLS; NORWALK VIRUS AB Open reading frame 2 (ORF2) of the feline calicivirus (FCV) genome encodes a capsid precursor that is posttranslationally processed to release the mature capsid protein (VP1) and a small protein of 124 amino acids, designated the leader of the capsid (LC). To investigate the role of the LC protein in the virus life cycle, mutations and deletions were introduced into the LC coding region of an infectious FCV cDNA clone. Three cysteine residues that are conserved among all vesivirus LC sequences were found to be critical for the recovery of FCV with a characteristic cytopathic effect in feline kidney cells. A cell-rounding phenotype associated with the transient expression of wild-type and mutagenized forms of the LC correlated with the cytopathic and growth properties of the corresponding engineered viruses. The host cellular protein annexin A2 was identified as a binding partner of the LC protein, consistent with a role for the LC in mediating host cell interactions that alter the integrity of the cell and enable virus spread. C1 [Abente, Eugenio J.; Sosnovtsev, Stanislav V.; Sandoval-Jaime, Carlos; Parra, Gabriel I.; Bok, Karin; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Abente, Eugenio J.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. RP Green, KY (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM kgreen@niaid.nih.gov OI Abente, Eugenio/0000-0002-3390-2786; Parra, Gabriel/0000-0002-1102-4740 FU Intramural Research Program of the NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 54 TC 7 Z9 8 U1 0 U2 1 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 MAR PY 2013 VL 87 IS 6 BP 3003 EP 3017 DI 10.1128/JVI.02480-12 PG 15 WC Virology SC Virology GA 095QD UT WOS:000315348500003 PM 23269802 ER PT J AU Brooke, CB Ince, WL Wrammert, J Ahmed, R Wilson, PC Bennink, JR Yewdell, JW AF Brooke, Christopher B. Ince, William L. Wrammert, Jens Ahmed, Rafi Wilson, Patrick C. Bennink, Jack R. Yewdell, Jonathan W. TI Most Influenza A Virions Fail To Express at Least One Essential Viral Protein SO JOURNAL OF VIROLOGY LA English DT Article ID RIBONUCLEOPROTEIN COMPLEXES; INTERFERON-PRODUCTION; INFECTED-CELLS; VIRUS; RNA; POLYMERASE; PARTICLES; TRANSPORT; SEGMENTS; SEQUENCE AB Segmentation of the influenza A virus (IAV) genome enables rapid gene reassortment at the cost of complicating the task of assembling the full viral genome. By simultaneously probing for the expression of multiple viral proteins in MDCK cells infected at a low multiplicity with IAV, we observe that the majority of infected cells lack detectable expression of one or more essential viral proteins. Consistent with this observation, up to 90% of IAV-infected cells fail to release infectious progeny, indicating that many IAV virions scored as noninfectious by traditional infectivity assays are capable of single-round infection. This fraction was not significantly affected by target or producer cell type but varied widely between different IAV strains. These data indicate that IAV exists primarily as a swarm of complementation-dependent semi-infectious virions, and thus traditional, propagation-dependent assays of infectivity may drastically misrepresent the true infectious potential of a virus population. C1 [Brooke, Christopher B.; Ince, William L.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Wrammert, Jens; Ahmed, Rafi] Emory Univ, Emory Vaccine Ctr, Atlanta, GA USA. [Wrammert, Jens; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Div Infect Dis,Dept Med, Atlanta, GA 30322 USA. [Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Comm Immunol,Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Division of Intramural Research, NIAID FX This work was generously supported by the Division of Intramural Research, NIAID. NR 32 TC 32 Z9 32 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 MAR PY 2013 VL 87 IS 6 BP 3155 EP 3162 DI 10.1128/JVI.02284-12 PG 8 WC Virology SC Virology GA 095QD UT WOS:000315348500016 PM 23283949 ER PT J AU Escaffre, O Borisevich, V Carmical, JR Prusak, D Prescott, J Feldmann, H Rockx, B AF Escaffre, Olivier Borisevich, Viktoriya Carmical, J. Russ Prusak, Deborah Prescott, Joseph Feldmann, Heinz Rockx, Barry TI Henipavirus Pathogenesis in Human Respiratory Epithelial Cells SO JOURNAL OF VIROLOGY LA English DT Article ID NIPAH-VIRUS-INFECTION; DISTRESS-SYNDROME; HENDRA VIRUS; GENE-EXPRESSION; NOSOCOMIAL TRANSMISSIBILITY; INTERFERON INDUCTION; CLINICAL-FEATURES; ABATTOIR WORKERS; LUNG INJURY; V-PROTEIN AB Hendra virus (HeV) and Nipah virus (NiV) are deadly zoonotic viruses for which no vaccines or therapeutics are licensed for human use. Henipavirus infection causes severe respiratory illness and encephalitis. Although the exact route of transmission in human is unknown, epidemiological studies and in vivo studies suggest that the respiratory tract is important for virus replication. However, the target cells in the respiratory tract are unknown, as are the mechanisms by which henipaviruses can cause disease. In this study, we characterized henipavirus pathogenesis using primary cells derived from the human respiratory tract. The growth kinetics of NiV-Malaysia, NiV-Bangladesh, and HeV were determined in bronchial/tracheal epithelial cells (NHBE) and small airway epithelial cells (SAEC). In addition, host responses to infection were assessed by gene expression analysis and immunoassays. Viruses replicated efficiently in both cell types and induced large syncytia. The host response to henipavirus infection in NHBE and SAEC highlighted a difference in the inflammatory response between HeV and NiV strains as well as intrinsic differences in the ability to mount an inflammatory response between NHBE and SAEC. These responses were highest during HeV infection in SAEC, as characterized by the levels of key cytokines (interleukin 6 [IL-6], IL-8, IL-1 alpha, monocyte chemoattractant protein 1 [MCP-1], and colony-stimulating factors) responsible for immune cell recruitment. Finally, we identified virus strain-dependent variability in type I interferon antagonism in NHBE and SAEC: NiV-Malaysia counteracted this pathway more efficiently than NiV-Bangladesh and HeV. These results provide crucial new information in the understanding of henipavirus pathogenesis in the human respiratory tract at an early stage of infection. C1 [Escaffre, Olivier; Borisevich, Viktoriya; Rockx, Barry] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Rockx, Barry] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Carmical, J. Russ; Prusak, Deborah] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Prescott, Joseph; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Rockx, B (reprint author), Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. EM barockx@UTMB.EDU FU University of Texas Medical Branch startup funds; Intramural Research Program, NIAID, NIH; Philippe Foundation FX The study was funded by University of Texas Medical Branch startup funds and by the Intramural Research Program, NIAID, NIH. We also thank the Philippe Foundation for financial support to O.E. NR 72 TC 19 Z9 19 U1 1 U2 21 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 MAR PY 2013 VL 87 IS 6 BP 3284 EP 3294 DI 10.1128/JVI.02576-12 PG 11 WC Virology SC Virology GA 095QD UT WOS:000315348500029 PM 23302882 ER PT J AU Vaccari, M Halwani, R Patterson, LJ Boasso, A Beal, J Tryniszewska, E Hryniewicz, A Venzon, D Haddad, EK El-Far, M Rosati, M Pavlakis, GN Felber, BK Al-Muhsen, S Robert-Guroff, M Sekaly, RP Franchini, G AF Vaccari, Monica Halwani, Rabih Patterson, L. Jean Boasso, Adriano Beal, Jennifer Tryniszewska, Elzbieta Hryniewicz, Anna Venzon, David Haddad, Elias K. El-Far, Mohamed Rosati, Margherita Pavlakis, George N. Felber, Barbara K. Al-Muhsen, Saleh Robert-Guroff, Marjorie Sekaly, Rafick-Pierre Franchini, Genoveffa TI Antibodies to gp120 and PD-1 Expression on Virus-Specific CD8(+) T Cells in Protection from Simian AIDS SO JOURNAL OF VIROLOGY LA English DT Article ID PRIME-BOOST IMMUNIZATION; RECOMBINANT ADENOVIRAL VACCINE; PREVENT HIV-1 INFECTION; RHESUS MACAQUES; IMMUNE-RESPONSES; DENDRITIC CELLS; SIVMAC251 INFECTION; SHIV89.6P CHALLENGE; SHIV CHALLENGE; B7 FAMILY AB We compared the relative efficacies against simian immunodeficiency virus (SIV) challenge of three vaccine regimens that elicited similar frequencies of SIV-specific CD4(+) and CD8(+) T-cell responses but differed in the level of antibody responses to the gp120 envelope protein. All macaques were primed with DNA plasmids expressing SIV gag, pol, env, and Retanef genes and were boosted with recombinant modified vaccinia Ankara virus (MVA) expressing the same genes, either once (1 x MVA) or twice (2 x MVA), or were boosted once with MVA followed by a single boost with replication-competent adenovirus (Ad) type 5 host range mutant (Ad5 h) expressing SIV gag and nef genes but not Retanef or env (1 x MVA/Ad5). While two of the vaccine regimens (1 x MVA and 1 x MVA/Ad5) protected from high levels of SIV replication only during the acute phase of infection, the 2 x MVA regimen, with the highest anti-SIV gp120 titers, protected during the acute phase and transiently during the chronic phase of infection. Mamu-A*01 macaques of this third group exhibited persistent Gag CD8(+)CM9(+) effector memory T cells with low expression of surface Programmed death-1 (PD-1) receptor and high levels of expression of genes associated with major histocompatibility complex class I (MHC-I) and MHC-II antigen. The fact that control of SIV replication was associated with both high titers of antibodies to the SIV envelope protein and durable effector SIV-specific CD8(+) T cells suggests the hypothesis that the presence of antibodies at the time of challenge may increase innate immune recruiting activity by enhancing antigen uptake and may result in improvement of the quality and potency of secondary SIV-specific CD8(+) T-cell responses. C1 [Vaccari, Monica; Tryniszewska, Elzbieta; Hryniewicz, Anna; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. [Halwani, Rabih; El-Far, Mohamed; Al-Muhsen, Saleh] King Saud Univ, Coll Med, Prince Naif Ctr Immunol Res, Riyadh 11461, Saudi Arabia. [Halwani, Rabih; El-Far, Mohamed; Al-Muhsen, Saleh] King Saud Univ, Coll Med, Dept Pediat, Riyadh 11461, Saudi Arabia. [Patterson, L. Jean; Beal, Jennifer; Robert-Guroff, Marjorie] NCI, Immune Biol Retroviral Infect Sect, Bethesda, MD 20892 USA. [Boasso, Adriano] Univ London Imperial Coll Sci Technol & Med, Immunol Sect, Chelsea & Westminster Hosp, London, England. [Tryniszewska, Elzbieta] Med Univ Bialystok, Dept Microbiol Diagnost, Bialystok, Poland. [Haddad, Elias K.; Sekaly, Rafick-Pierre] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Rosati, Margherita; Pavlakis, George N.] Frederick Natl Lab Canc Res, Ctr Canc Res, Human Retrovirus Sect, Frederick, MD USA. [Felber, Barbara K.] Frederick Natl Lab Canc Res, Ctr Canc Res, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Frederick, MD USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov OI Boasso, Adriano/0000-0001-9673-6319 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. NR 66 TC 4 Z9 4 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 MAR PY 2013 VL 87 IS 6 BP 3526 EP 3537 DI 10.1128/JVI.02686-12 PG 12 WC Virology SC Virology GA 095QD UT WOS:000315348500049 PM 23325679 ER PT J AU Vaccari, M Keele, BF Bosinger, SE Doster, MN Ma, ZM Pollara, J Hryniewicz, A Ferrari, G Guan, YJ Forthal, DN Venzon, D Fenizia, C Morgan, T Montefiori, D Lifson, JD Miller, CJ Silvestri, G Rosati, M Felber, BK Pavlakis, GN Tartaglia, J Franchini, G AF Vaccari, Monica Keele, Brandon F. Bosinger, Steven E. Doster, Melvin N. Ma, Zhong-Min Pollara, Justin Hryniewicz, Anna Ferrari, Guido Guan, Yongjun Forthal, Donald N. Venzon, David Fenizia, Claudio Morgan, Tia Montefiori, David Lifson, Jeffrey D. Miller, Chris J. Silvestri, Guido Rosati, Margherita Felber, Barbara K. Pavlakis, George N. Tartaglia, James Franchini, Genoveffa TI Protection Afforded by an HIV Vaccine Candidate in Macaques Depends on the Dose of SIVmac251 at Challenge Exposure SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; AFRICAN-GREEN MONKEYS; CD8(+) T-CELLS; RHESUS MACAQUES; IMMUNE-RESPONSES; SIVAGM INFECTION; DNA VACCINATION; ALVAC; AIDS; REPLICATION AB We used the simian immunodeficiency virus mac251 (SIVmac251) macaque model to study the effect of the dose of mucosal exposure on vaccine efficacy. We immunized macaques with a DNA prime followed by SIV gp120 protein immunization with ALVAC-SIV and gp120 in alum, and we challenged them with SIVmac251 at either a single high dose or at two repeated low-dose exposures to a 10-fold-lower dose. Infection was neither prevented nor modified following a single high-dose challenge of the immunized macaques. However, two exposures to a 10-fold-lower dose resulted in protection from SIVmac251 acquisition in 3 out of 12 macaques. The remaining animals that were infected had a modulated pathogenesis, significant downregulation of interferon responsive genes, and upregulation of genes involved in B- and T-cell responses. Thus, the choice of the experimental model greatly influences the vaccine efficacy of vaccines for human immunodeficiency virus (HIV). C1 [Vaccari, Monica; Doster, Melvin N.; Hryniewicz, Anna; Fenizia, Claudio; Morgan, Tia; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccine Sect, Bethesda, MD 20892 USA. [Keele, Brandon F.; Lifson, Jeffrey D.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Bosinger, Steven E.; Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Ma, Zhong-Min; Miller, Chris J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Pollara, Justin; Ferrari, Guido; Montefiori, David] Duke Univ, Dept Surg, Durham, NC USA. [Guan, Yongjun] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Guan, Yongjun] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Forthal, Donald N.] Univ Calif Irvine, Irvine, CA USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Rosati, Margherita; Pavlakis, George N.] Frederick Natl Lab Canc Res, Human Retrovirus Sect, Frederick, MD USA. [Felber, Barbara K.] Frederick Natl Lab Canc Res, Human Retrovirus Pathogenesis Sect, Frederick, MD USA. [Tartaglia, James] Sanofi Pasteur Inc, Swiftwater, PA USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccine Sect, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov RI Ferrari, Guido/A-6088-2015 FU National Cancer Institute, National Institutes of Health; [HHSN261200800001E] FX This work was supported with federal funds from the National Cancer Institute, National Institutes of Health, and in part with contract no. HHSN261200800001E. NR 48 TC 28 Z9 28 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 MAR PY 2013 VL 87 IS 6 BP 3538 EP 3548 DI 10.1128/JVI.02863-12 PG 11 WC Virology SC Virology GA 095QD UT WOS:000315348500050 PM 23325681 ER PT J AU Checkley, MA Luttge, BG Mercredi, PY Kyere, SK Donlan, J Murakami, T Summers, MF Cocklin, S Freed, EO AF Checkley, Mary Ann Luttge, Benjamin G. Mercredi, Peter Y. Kyere, Sampson K. Donlan, Justin Murakami, Tsutomu Summers, Michael F. Cocklin, Simon Freed, Eric O. TI Reevaluation of the Requirement for TIP47 in Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Incorporation SO JOURNAL OF VIROLOGY LA English DT Article ID TRANS-GOLGI NETWORK; GP41 CYTOPLASMIC TAIL; 6-PHOSPHATE RECEPTOR TRAFFICKING; MATRIX PROTEIN; ENV INCORPORATION; INTERACTING PROTEIN; NONDIVIDING CELLS; LIPID DROPLETS; RAB9 GTPASE; VIRIONS AB Incorporation of the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins into assembling particles is crucial for virion infectivity. Genetic and biochemical data indicate that the matrix (MA) domain of Gag and the cytoplasmic tail of the transmembrane glycoprotein gp41 play an important role in coordinating Env incorporation; however, the molecular mechanism and possible role of host factors in this process remain to be defined. Recent studies suggested that Env incorporation is mediated by interactions between matrix and tail-interacting protein of 47 kDa (TIP47; also known as perilipin-3 and mannose-6-phosphate receptor-binding protein 1), a member of the perilipin, adipophilin, TIP47 (PAT) family of proteins implicated in protein sorting and lipid droplet biogenesis. We have confirmed by nuclear magnetic resonance spectroscopy titration experiments and surface plasmon resonance that MA binds TIP47. We also reevaluated the role of TIP47 in HIV-1 Env incorporation in HeLa cells and in the Jurkat T-cell line. In HeLa cells, TIP47 overexpression or RNA interference (RNAi)-mediated depletion had no significant effect on HIV-1 Env incorporation, virus release, or particle infectivity. Similarly, depletion of TIP47 in Jurkat cells did not impair HIV-1 Env incorporation, virus release, infectivity, or replication. Our results thus do not support a role for TIP47 in HIV-1 Env incorporation or virion infectivity. C1 [Checkley, Mary Ann; Luttge, Benjamin G.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res,Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Mercredi, Peter Y.; Kyere, Sampson K.; Donlan, Justin; Summers, Michael F.] Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Dept Chem & Biochem, Baltimore, MD 21228 USA. [Murakami, Tsutomu] Natl Inst Infect Dis, AIDS Res Ctr, Shinjuku Ku, Tokyo 1628640, Japan. [Cocklin, Simon] Drexel Univ, Dept Biochem & Mol Biol, Coll Med, Philadelphia, PA 19104 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res,Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. EM efreed@nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; Intramural AIDS Targeted Antiviral Program; NIH/NIAID [1R03AI078790-01A1, AI30917] FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, by the Intramural AIDS Targeted Antiviral Program, and by NIH/NIAID grants 1R03AI078790-01A1 (S.C.) and AI30917 (M.F.S.). NR 52 TC 14 Z9 14 U1 0 U2 12 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 MAR PY 2013 VL 87 IS 6 BP 3561 EP 3570 DI 10.1128/JVI.03299-12 PG 10 WC Virology SC Virology GA 095QD UT WOS:000315348500052 PM 23325685 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, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2013 VL 42 IS 3 BP 83 EP 83 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 096UK UT WOS:000315429900016 PM 23423295 ER PT J AU Narver, HL AF Narver, Heather Lyons TI Care and monitoring of a mouse model of melanoma SO LAB ANIMAL LA English DT Article ID MICE; CANCER AB Melanoma is a devastating form of skin cancer in humans that is rising in incidence. Animal models of melanoma continue to be instrumental for understanding the disease and for developing and testing therapies. A novel Line of melanoma-bearing mice developed at the National Institute of Neurological Disorders and Stroke is monitored and cared for by the Animal Health Care Section. Although these mice develop heavy tumor burdens, they show few signs of pain or distress and seem to have high levels of physiologic fitness. The author discusses the monitoring and care of these mice, advocating early flagging and frequent monitoring of melanoma-bearing mice. In the care of melanoma-bearing mice, an emphasis should be placed on evaluating the whole animal and considering new endpoints rather than relying on historically accepted guidelines for maximum tumor size and weight, which may be inappropriate for some mice. C1 NINDS, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Narver, HL (reprint author), NINDS, US Natl Inst Hlth, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM narverh@ninds.nih.gov FU National Institutes of Health; NINDS FX I thank Dr. Katherine Roche and her lab at NINDS (including Kyu Yeong Choi, Kai Chang and John Badger II), in addition to Dr. James Pickel of the Transgenic Core Facility at the National Institute of Mental Health. Supportive pathology information was provided by Dr. Matthew Starost and Dr. Mark Bryant of the. Division of Veterinary Resources at the US National Institutes of Health. Dr. Judith Davis and Dr. James O'Malley both provided helpful comments that improved the manuscript. I thank the WINDS Animal Health Care Section Staff for their monitoring and care of the melanoma-bearing mice. This research was supported in part by the Intramural Research Program of the National Institutes of Health, NINDS. The views expressed in this article are solely those of the author and do not reflect the views of the National Institutes of Health or the US Government. NR 17 TC 1 Z9 1 U1 1 U2 8 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 MAR PY 2013 VL 42 IS 3 BP 92 EP 98 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA 096UK UT WOS:000315429900019 PM 23423298 ER PT J AU Hayes, ER AF Hayes, Erika R. TI Benefiting human health through animal research SO LAB ANIMAL LA English DT Editorial Material C1 NIEHS, Alpha Omega Bioserv Inc, Res Triangle Pk, NC 27709 USA. RP Hayes, ER (reprint author), NIEHS, Alpha Omega Bioserv Inc, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2013 VL 42 IS 3 BP 105 EP 105 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 096UK UT WOS:000315429900022 ER PT J AU Glaser, R Dimitrakakis, C AF Glaser, Rebecca Dimitrakakis, Constantine TI Testosterone therapy in women: Myths and misconceptions SO MATURITAS LA English DT Review DE Testosterone; Implants; Women; Therapy; Safety; Misconceptions ID LOW SERUM TESTOSTERONE; POSTMENOPAUSAL WOMEN; ANDROGEN RECEPTOR; DOUBLE-BLIND; HEART-FAILURE; MEN; BREAST; AGGRESSION; PROPIONATE; MORTALITY AB Although testosterone therapy is being increasingly prescribed for men, there remain many questions and concerns about testosterone (T) and in particular, T therapy in women. A literature search was performed to elucidate the origin of, and scientific basis behind many of the concerns and assumptions about T and T therapy in women. This paper refutes 10 common myths and misconceptions, and provides evidence to support what is physiologically plausible and scientifically evident: T is the most abundant biologically active female hormone, T is essential for physical and mental health in women, T is not masculinizing, T does not cause hoarseness, T increases scalp hair growth, T is cardiac protective, parenteral T does not adversely affect the liver or increase clotting factors, T is mood stabilizing and does not increase aggression, T is breast protective, and the safety of T therapy in women is under research and being established. Abandoning myths, misconceptions and unfounded concerns about T and T therapy in women will enable physicians to provide evidenced based recommendations and appropriate therapy. (c) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Glaser, Rebecca] Millennium Wellness Ctr, Dayton, OH 45458 USA. [Glaser, Rebecca] Wright State Univ, Boonshoft Sch Med, Dept Surg, Dayton, OH 45435 USA. [Dimitrakakis, Constantine] Univ Athens, Sch Med, Dept Ob Gyn 1, Athens 11528, Greece. [Dimitrakakis, Constantine] NICHD, NIH, Bethesda, MD 20892 USA. RP Glaser, R (reprint author), 228 E Spring Valley Rd, Dayton, OH 45458 USA. EM rglaser@woh.rr.com; dimitrac@ymail.com NR 43 TC 2 Z9 3 U1 1 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-5122 EI 1873-4111 J9 MATURITAS JI Maturitas PD MAR PY 2013 VL 74 IS 3 BP 230 EP 234 DI 10.1016/j.maturitas.2013.01.003 PG 5 WC Geriatrics & Gerontology; Obstetrics & Gynecology SC Geriatrics & Gerontology; Obstetrics & Gynecology GA 098JF UT WOS:000315544800007 PM 23380529 ER PT J AU Simon, A Drenth, JPH Matern, D Goetzman, ES Hager, EJ Gibson, KM AF Simon, Anna Drenth, Joost P. H. Matern, Dietrich Goetzman, Eric S. Hager, Elizabeth J. Gibson, K. Michael TI Long chain fatty acid (Lcfa) abnormalities in hyper Igd syndrome (Hids) and familial Mediterranean fever (Fmf): New insight into heritable periodic fevers SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Periodic fever syndrome; Essential fatty acids; Mevalonate kinase deficiency; Hyper IgD syndrome; Familial Mediterranean fever ID MEVALONATE KINASE-DEFICIENCY; HYPERIMMUNOGLOBULINEMIA-D; KAPPA-B; EXPRESSION; COLCHICINE; PALMITATE; SPECTRUM; RELEASE; PATHWAY; ALPHA AB Objective: To examine essential fatty acids (EFAs) in hyper-IgD syndrome (HIDS) and Familial Mediterranean Fever (FMF). Methods: EFAs were determined in sera derived from an archival, cross-sectional group of HIDS/FMF patients, stratified for presence and absence of fever. Control populations included healthy afebrile adults, and individuals with non-periodic fever (septic shock). EFAs were quantified using isotope dilution gas chromatography-mass spectrometry and data analyzed employing a Kruskal-Wallis non-parametric ANOVA with Dunn's post-hoc test. Results: Sera samples derived from HIDS patients showed significantly decreased C20, C26, phytanic and pristanic acids during febrile crises that normalized in the afebrile state, and a significantly increased afebrile C22_4 omega 6 level that normalized with fever. Samples derived from FMF patients revealed increased omega-oxidized LCFAs as compared to controls, and the trend was for these same species to be increased in comparison to febrile, but not afebrile, HIDS patients. Individuals with non-periodic fever demonstrated global decreases in C10-C24 fatty acids, both saturated and unsaturated, accompanied by an elevated triene/tetraene ratio. Conclusions: Our results suggest that different mechanisms are active in hereditary periodic fever syndromes that appear unrelated to fever, including depletion of very long chain fatty acids (VLCFAs) in febrile HIDS patients and increased omega-oxidized LCFAs in patients with FMF. These findings underscore new roles for EFAs in the potential production of inflammatory species in patients with hereditary periodic fever. (C) 2013 Elsevier Inc. All rights reserved. C1 [Simon, Anna] Radboud Univ Nijmegen, Med Ctr, Dept Gen Internal Med, Nijmegen, Netherlands. [Drenth, Joost P. H.] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, Nijmegen, Netherlands. [Matern, Dietrich] Mayo Clin, Coll Med, Biochem Genet Lab, Rochester, MN USA. [Goetzman, Eric S.] Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA USA. [Hager, Elizabeth J.] NCI, Biol Testing Branch, Frederick, MD 21701 USA. [Gibson, K. Michael] Washington State Univ, Clin Pharmacol Sect, Spokane, WA 99210 USA. RP Gibson, KM (reprint author), Washington State Univ, Coll Pharm, Div Clin Pharmacol, POB 1495, Spokane, WA 99210 USA. EM mike.gibson@wsu.edu RI Simon, Anna/D-3757-2009; Drenth, J.P.H./H-8025-2014 OI Simon, Anna/0000-0002-6141-7921; FU NIH HD [57864]; Sterol and Isoprenoid Diseases (STAIR) consortium; NICHD [1U54HD061939]; NIH Office of Rare Diseases Research (ORDR) FX This work was supported in part by NIH HD 57864 (KMG) and the Sterol and Isoprenoid Diseases (STAIR) consortium. STAIR is a part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by a grant (1U54HD061939) from NICHD and the NIH Office of Rare Diseases Research (ORDR). The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government NR 23 TC 1 Z9 1 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2013 VL 108 IS 3 BP 166 EP 171 DI 10.1016/j.ymgme.2013.01.004 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 099IV UT WOS:000315615600004 PM 23375471 ER PT J AU Loisel, DA Billstrand, C Murray, K Patterson, K Chaiworapongsa, T Romero, R Ober, C AF Loisel, Dagan A. Billstrand, Christine Murray, Kathleen Patterson, Kristen Chaiworapongsa, Tinnakorn Romero, Roberto Ober, Carole TI The maternal HLA-G 1597C null mutation is associated with increased risk of pre-eclampsia and reduced HLA-G expression during pregnancy in African-American women SO MOLECULAR HUMAN REPRODUCTION LA English DT Article DE genetic predisposition; DNA variants; soluble HLA-G; toxemia of pregnancy; mutation ID INTRAUTERINE GROWTH-RETARDATION; G PROMOTER REGION; G MESSENGER-RNA; G GENE; UNITED-STATES; G GENOTYPE; POPULATION STRATIFICATION; GESTATIONAL HYPERTENSION; 3-UNTRANSLATED REGION; EMPIRICAL-DATA AB The non-classical major histocompatibility complex molecule, human leukocyte antigen (HLA)-G, is thought to contribute to maternal immune tolerance and successful placentation during pregnancy. Genetic polymorphisms in HLA-G are known to influence expression levels as well as the relative expression of individual protein isoforms. As diminished or aberrant HLA-G expression patterns may contribute to the development of certain pregnancy complications, we sought to investigate the association between functional HLA-G polymorphisms and the risk of pre-eclampsia (PE) in African-American women. The association between maternal and fetal genotype at six HLA-G polymorphisms and risk of PE was assessed in 372 pregnancies (314 normotensive; 58 pre-eclamptic). We observed an elevated risk of PE (P 0.00027) in pregnancies where the mother carried the 1597C allele, a null allele that abolishes expression of full-length HLA-G isoforms. Furthermore, the frequency of the maternal 1597C allele was highest in the subset of pre-eclamptic pregnancies that were delivered preterm, suggesting an association between the null allele and the severity of PE. We then replicated the association between higher maternal 1597C allele frequency and increased severity of PE (P 0.038) in an independent sample of 533 African-American women. Finally, to investigate the mechanistic basis of this association, we measured circulating soluble HLA-G (sHLA-G) concentrations in maternal serum collected during pregnancy in 51 healthy, normotensive African-American control women and found significantly lower levels in women carrying the 1597C allele (P 0.012). These results demonstrate that maternal HLA-G genotype is significantly associated with risk of PE in African-American women and is predictive of circulating sHLA-G levels during pregnancy. C1 [Loisel, Dagan A.; Billstrand, Christine; Murray, Kathleen; Patterson, Kristen; Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ober, Carole] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto] NICHD, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,DHHS, Bethesda, MD USA. RP Ober, C (reprint author), Univ Chicago, Dept Human Genet, 920 E 58th St, Chicago, IL 60637 USA. EM c-ober@genetics.uchicago.edu FU Chicago Lying-In Women's Board and the Department of OB/GYN; National Institutes of Health [P01HD049480, UL1RR024999]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; NIH [F32HL095268, T32 HL007605] FX The authors thank Drs Joan Hunt, Margaret Petroff, Daniel Geraghty, J. Lee Nelson, D. Michael Nelson, Dale Abrahamson and David Albertini for helpful discussions on study design and interpretation of results; Dr Marshall Lindheimer for his clinical expertise; Shaneisha Allen for CLIPP recruitment and study coordination; the University of Chicago Institute of Medicine CTSA for core services, and the Chicago Lying-In Women's Board and the Department of OB/GYN for supporting the CLIPP biobank.; This work was supported by the National Institutes of Health (P01HD049480 to C.O., UL1RR024999 to the Institute for Translation Medicine at the University of Chicago) and the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. D.A.L. was supported by NIH grants F32HL095268 and T32 HL007605. NR 61 TC 11 Z9 12 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1360-9947 EI 1460-2407 J9 MOL HUM REPROD JI Mol. Hum. Reprod. PD MAR PY 2013 VL 19 IS 3 BP 144 EP 152 DI 10.1093/molehr/gas041 PG 9 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 099PJ UT WOS:000315633400004 PM 23002110 ER PT J AU Steel, JC Di Pasquale, G Ramlogan, CA Patel, V Chiorini, JA Morris, JC AF Steel, Jason C. Di Pasquale, Giovanni Ramlogan, Charmaine A. Patel, Vyomesh Chiorini, John A. Morris, John C. TI Oral Vaccination With Adeno-associated Virus Vectors Expressing the Neu Oncogene Inhibits the Growth of Murine Breast Cancer SO MOLECULAR THERAPY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; AAV GENE-TRANSFER; DENDRITIC CELLS; IMMUNE-RESPONSES; DNA VACCINATION; SEROTYPE 6; TRANSDUCTION; INDUCTION; DELIVERY; RECEPTOR AB Recombinant adeno-associated viruses (AAV) have been used for therapeutic gene transfer. These vectors offer a number of advantages including resistance to the effects of pH, a broad cellular tropism, efficient gene transfer, persistence of gene expression, and little toxicity. AAV vectors; however, at high doses can induce humoral and cellular immune responses. While potentially problematic for replacement gene therapy, this effect may be advantageous for antitumor vaccination. We examined the activity of an oral and intramuscular antitumor vaccination using AAV serotypes 5 and 6 expressing a truncated neu oncogene in a neu-positive murine TUBO breast cancer. model. Mice receiving a single oral administration of AAV5-neu or AAV6-neu demonstrated improved survival. Oral vaccination significantly improved survivals compared with intramuscular vaccination. Mice vaccinated with AAV6-neu survived longer than those treated with AAV5-neu. Vaccination with AAV5-neu or AAV6-neu induced both humoral and cellular immune responses against the NEU antigen. These responses were more robust in the mice undergoing oral vaccination compared with mice receiving the intramuscular vaccination. Protection from tumor was long lasting with 80% of the animals treated with oral AAV6-neu surviving a re-challenge with TUBO cells at 120 and 320 days post-vaccination. Further evaluation of AAV-based vectors as tumor vaccines is warranted. C1 [Steel, Jason C.; Ramlogan, Charmaine A.; Morris, John C.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steel, Jason C.; Ramlogan, Charmaine A.; Morris, John C.] Univ Cincinnati, Dept Med, Div Hematol Oncol, Cincinnati, OH 45267 USA. [Di Pasquale, Giovanni; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, AAV Biol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Patel, Vyomesh] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Morris, JC (reprint author), Univ Cincinnati, Dept Med, Div Hematol Oncol, Med Sci Bldg,ML 0562,231 Albert Sabin Way, Cincinnati, OH 45267 USA. EM morri2j7@uc.edu RI Steel, Jason/D-1805-2013 OI Steel, Jason/0000-0003-3608-7542 FU National Institutes of Health, National Cancer Institute, National Institute of Dental and Craniofacial Research; Division of Hematology-Oncology, University of Cincinnati FX We thank Alfredo Molinolo for technical help in isolating the stomach-associated lymph nodes. This work is supported in part by National Institutes of Health, National Cancer Institute, National Institute of Dental and Craniofacial Research intramural grants to J.A.C., and the Division of Hematology-Oncology, University of Cincinnati. The authors declared no conflict of interest. NR 35 TC 6 Z9 6 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2013 VL 21 IS 3 BP 680 EP 687 DI 10.1038/mt.2012.260 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 099GQ UT WOS:000315609900024 PM 23295951 ER PT J AU Pugh, TJ Morozova, O Attiyeh, EF Asgharzadeh, S Wei, JS Auclair, D Carter, SL Cibulskis, K Hanna, M Kiezun, A Kim, J Lawrence, MS Lichenstein, L McKenna, A Pedamallu, CS Ramos, AH Shefler, E Sivachenko, A Sougnez, C Stewart, C Ally, A Birol, I Chiu, R Corbett, RD Hirst, M Jackman, SD Kamoh, B Khodabakshi, AH Krzywinski, M Lo, A Moore, RA Mungall, KL Qian, J Tam, A Thiessen, N Zhao, YJ Cole, KA Diamond, M Diskin, SJ Mosse, YP Wood, AC Ji, LY Sposto, R Badgett, T London, WB Moyer, Y Gastier-Foster, JM Smith, MA Auvil, JMG Gerhard, DS Hogarty, MD Jones, SJM Lander, ES Gabriel, SB Getz, G Seeger, RC Khan, J Marra, MA Meyerson, M Maris, JM AF Pugh, Trevor J. Morozova, Olena Attiyeh, Edward F. Asgharzadeh, Shahab Wei, Jun S. Auclair, Daniel Carter, Scott L. Cibulskis, Kristian Hanna, Megan Kiezun, Adam Kim, Jaegil Lawrence, Michael S. Lichenstein, Lee McKenna, Aaron Pedamallu, Chandra Sekhar Ramos, Alex H. Shefler, Erica Sivachenko, Andrey Sougnez, Carrie Stewart, Chip Ally, Adrian Birol, Inanc Chiu, Readman Corbett, Richard D. Hirst, Martin Jackman, Shaun D. Kamoh, Baljit Khodabakshi, Alireza Hadj Krzywinski, Martin Lo, Allan Moore, Richard A. Mungall, Karen L. Qian, Jenny Tam, Angela Thiessen, Nina Zhao, Yongjun Cole, Kristina A. Diamond, Maura Diskin, Sharon J. Mosse, Yael P. Wood, Andrew C. Ji, Lingyun Sposto, Richard Badgett, Thomas London, Wendy B. Moyer, Yvonne Gastier-Foster, Julie M. Smith, Malcolm A. Auvil, Jaime M. Guidry Gerhard, Daniela S. Hogarty, Michael D. Jones, Steven J. M. Lander, Eric S. Gabriel, Stacey B. Getz, Gad Seeger, Robert C. Khan, Javed Marra, Marco A. Meyerson, Matthew Maris, John M. TI The genetic landscape of high-risk neuroblastoma SO NATURE GENETICS LA English DT Article ID ACTIVATING MUTATIONS; SOMATIC MUTATIONS; NOONAN-SYNDROME; CHILDHOOD-CANCER; SOLID TUMORS; ALK KINASE; AMPLIFICATION; LEUKEMIA; DISEASE; PTPN11 AB Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers. C1 [Pugh, Trevor J.; Auclair, Daniel; Carter, Scott L.; Cibulskis, Kristian; Hanna, Megan; Kiezun, Adam; Kim, Jaegil; Lawrence, Michael S.; Lichenstein, Lee; McKenna, Aaron; Pedamallu, Chandra Sekhar; Ramos, Alex H.; Shefler, Erica; Sivachenko, Andrey; Sougnez, Carrie; Stewart, Chip; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Meyerson, Matthew] Broad Inst MIT & Harvard, Cambridge, MA USA. [Pugh, Trevor J.; Ramos, Alex H.; London, Wendy B.; Meyerson, Matthew] Harvard Univ, Sch Med, Boston, MA USA. [Pugh, Trevor J.; Hanna, Megan; Pedamallu, Chandra Sekhar; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Morozova, Olena; Ally, Adrian; Birol, Inanc; Chiu, Readman; Corbett, Richard D.; Hirst, Martin; Jackman, Shaun D.; Kamoh, Baljit; Khodabakshi, Alireza Hadj; Krzywinski, Martin; Lo, Allan; Moore, Richard A.; Mungall, Karen L.; Qian, Jenny; Tam, Angela; Thiessen, Nina; Zhao, Yongjun; Jones, Steven J. M.; Marra, Marco A.] Univ British Columbia, British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1M9, Canada. [Morozova, Olena; Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Attiyeh, Edward F.; Cole, Kristina A.; Diamond, Maura; Diskin, Sharon J.; Mosse, Yael P.; Wood, Andrew C.; Hogarty, Michael D.; Maris, John M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Attiyeh, Edward F.; Cole, Kristina A.; Diamond, Maura; Diskin, Sharon J.; Mosse, Yael P.; Wood, Andrew C.; Hogarty, Michael D.; Maris, John M.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Attiyeh, Edward F.; Cole, Kristina A.; Diamond, Maura; Diskin, Sharon J.; Mosse, Yael P.; Wood, Andrew C.; Hogarty, Michael D.; Maris, John M.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Asgharzadeh, Shahab; Ji, Lingyun; Sposto, Richard; Seeger, Robert C.] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Asgharzadeh, Shahab; Ji, Lingyun; Sposto, Richard; Seeger, Robert C.] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [Asgharzadeh, Shahab; Ji, Lingyun; Sposto, Richard; Seeger, Robert C.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Wei, Jun S.; Badgett, Thomas; Khan, Javed] NIH, Pediat Oncol Branch, Oncogen Sect, Ctr Canc Res, Gaithersburg, MD USA. [London, Wendy B.] Childrens Hosp Boston, Dana Farber Canc Inst, Boston, MA USA. [London, Wendy B.] Childrens Oncol Grp, Boston, MA USA. [Moyer, Yvonne; Gastier-Foster, Julie M.] Nationwide Childrens Hosp, Biopathol Ctr, Columbus, OH USA. [Moyer, Yvonne; Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Auvil, Jaime M. Guidry; Gerhard, Daniela S.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. RP Marra, MA (reprint author), Univ British Columbia, British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1M9, Canada. EM mmarra@bcgsc.ca; matthew_meyerson@dfci.harvard.edu; maris@chop.edu RI Tang, Macy/B-9798-2014; Khan, Javed/P-9157-2014; Cole, Kristina/M-3922-2015; Hirst, Martin/B-7684-2016; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011 OI Khan, Javed/0000-0002-5858-0488; Birol, Inanc/0000-0003-0950-7839 FU US National Institutes of Health [CA98543, CA98413, RC1MD004418, CA124709, CA060104]; National Human Genome Research Institute grant [U54HG003067]; National Cancer Institute, US National Institutes of Health [HHSN261200800001E]; Canadian Institutes of Health Research Fellowship; Roman M. Babicki Fellowship in Medical Research at the University of British Columbia; Canada Research Chair in Genome Science; Giulio D'Angio Endowed Chair; Alex's Lemonade Stand Foundation; Arms Wide Open Foundation; Cookies for Kids Foundation FX We thank the Children's Oncology Group for the collection and annotation of samples for this study, and all TARGET co-investigators for scientific support of this project. Funding was provided by US National Institutes of Health grants CA98543 and CA98413 to the Children's Oncology Group, RC1MD004418 to the TARGET consortium, CA124709 (J.M.M.) and CA060104 (R.C.S.) and National Human Genome Research Institute grant U54HG003067 (E.S.L., D.A., S.B.G., G.G. and M.M.), as well as a contract from the National Cancer Institute, US National Institutes of Health (HHSN261200800001E). Additional support included a Canadian Institutes of Health Research Fellowship (T.J.P.), a Roman M. Babicki Fellowship in Medical Research at the University of British Columbia (O.M.), the Canada Research Chair in Genome Science (M.A.M.), the Giulio D'Angio Endowed Chair (J.M.M.), the Alex's Lemonade Stand Foundation (J.M.M.), the Arms Wide Open Foundation (J.M.M.) and the Cookies for Kids Foundation (J.M.M.). We thank E. Nickerson, S. Charmer, K. Novik, C. Suragh and R. Roscoe for project management support. We also thank the staff of the Genome Sciences Centre Biospecimen Core, Library Construction, Sequencing and Bioinformatics teams, and the staff of the Broad Institute Biological Samples, Genome Sequencing and Genetic Analysis Platforms for their expertise in genomic processing of samples, and generating the sequencing data used in this analysis. NR 70 TC 228 Z9 230 U1 8 U2 67 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2013 VL 45 IS 3 BP 279 EP 284 DI 10.1038/ng.2529 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 099ZP UT WOS:000315664800011 PM 23334666 ER PT J AU Kirby, A Gnirke, A Jaffe, DB Baresova, V Pochet, N Blumenstiel, B Ye, C Aird, D Stevens, C Robinson, JT Cabili, MN Gat-Viks, I Kelliher, E Daza, R DeFelice, M Hulkova, H Sovova, J Vylet'al, P Antignac, C Guttman, M Handsaker, RE Perrin, D Steelman, S Sigurdsson, S Scheinman, SJ Sougnez, C Cibulskis, K Parkin, M Green, T Rossin, E Zody, MC Xavier, RJ Pollak, MR Alper, SL Lindblad-Toh, K Gabriel, S Hart, PS Regev, A Nusbaum, C Kmoch, S Bleyer, AJ Lander, ES Daly, MJ AF Kirby, Andrew Gnirke, Andreas Jaffe, David B. Baresova, Veronika Pochet, Nathalie Blumenstiel, Brendan Ye, Chun Aird, Daniel Stevens, Christine Robinson, James T. Cabili, Moran N. Gat-Viks, Irit Kelliher, Edward Daza, Riza DeFelice, Matthew Hulkova, Helena Sovova, Jana Vylet'al, Petr Antignac, Corinne Guttman, Mitchell Handsaker, Robert E. Perrin, Danielle Steelman, Scott Sigurdsson, Snaevar Scheinman, Steven J. Sougnez, Carrie Cibulskis, Kristian Parkin, Melissa Green, Todd Rossin, Elizabeth Zody, Michael C. Xavier, Ramnik J. Pollak, Martin R. Alper, Seth L. Lindblad-Toh, Kerstin Gabriel, Stacey Hart, P. Suzanne Regev, Aviv Nusbaum, Chad Kmoch, Stanislav Bleyer, Anthony J. Lander, Eric S. Daly, Mark J. TI Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing SO NATURE GENETICS LA English DT Article ID GENETIC DIAGNOSIS; CHROMOSOME 1Q21; REFINEMENT; LINKAGE; LOCUS; MCKD1; MAP AB Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (similar to 1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing. C1 [Kirby, Andrew; Gnirke, Andreas; Jaffe, David B.; Pochet, Nathalie; Blumenstiel, Brendan; Ye, Chun; Aird, Daniel; Stevens, Christine; Robinson, James T.; Cabili, Moran N.; Gat-Viks, Irit; Daza, Riza; DeFelice, Matthew; Guttman, Mitchell; Handsaker, Robert E.; Perrin, Danielle; Steelman, Scott; Sigurdsson, Snaevar; Sougnez, Carrie; Cibulskis, Kristian; Parkin, Melissa; Green, Todd; Rossin, Elizabeth; Zody, Michael C.; Xavier, Ramnik J.; Lindblad-Toh, Kerstin; Gabriel, Stacey; Regev, Aviv; Nusbaum, Chad; Lander, Eric S.; Daly, Mark J.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Kirby, Andrew; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Baresova, Veronika; Hulkova, Helena; Sovova, Jana; Vylet'al, Petr; Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Prague, Czech Republic. [Pochet, Nathalie] Univ Ghent VIB, Dept Plant Syst Biol, Dept Plant Biotechnol & Bioinformat, B-9052 Ghent, Belgium. [Cabili, Moran N.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Gat-Viks, Irit] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel. [Antignac, Corinne] INSERM, U983, Paris, France. [Antignac, Corinne] Univ Paris 05, Inst Imagine, Paris, France. [Antignac, Corinne] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Dept Genet, Paris, France. [Handsaker, Robert E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Scheinman, Steven J.] Commonwealth Med Coll, Scranton, PA USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Ctr Study Inflammatory Bowe, Boston, MA USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Pollak, Martin R.; Alper, Seth L.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Pollak, Martin R.; Alper, Seth L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lindblad-Toh, Kerstin] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab Uppsala, Uppsala, Sweden. [Hart, P. Suzanne] NHGRI, Off Clin Director, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Bleyer, Anthony J.] Wake Forest Sch Med, Sect Nephrol, Winston Salem, NC 27106 USA. RP Bleyer, AJ (reprint author), Wake Forest Sch Med, Sect Nephrol, Winston Salem, NC 27106 USA. EM ableyer@wfubmc.edu; lander@broadinstitute.org; mjdaly@atgu.mgh.harvard.edu RI Vyletal, Petr/F-4771-2017 OI Vyletal, Petr/0000-0002-9357-1237 FU Carlos Slim Health Institute; Intramural Research Program of the US NIH, National Human Genome Research Institute (NHGRI); Charles University [PRVOUK-P24/LF1/3, UNCE 204011]; Ministry of Education [LH12015, NT13116-4/2012]; US NIH grant [DK34854]; Human Frontier Science Program, Alon; Israeli Centers of Research Excellence (I-CORE); Edmond J. Safra Center for Bioinformatics at Tel Aviv University; Ministry of Health of the Czech Republic FX We thank T.L. Hatte for reagent use. We thank D. Altshuler, T. Carter and J. Schlondorff for useful discussions and M. Cortes, M. Ilzarbe and M. Betancourt for helpful project management. We also thank F. Letendre, M. Coole, R.P. Frere, C. Bonnet, L. Mulrain, N. Norbui and H. Arachchi for Sanger sequencing. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint United States-Mexico project funded by the Carlos Slim Health Institute. This research was supported in part by the Intramural Research Program of the US NIH, National Human Genome Research Institute (NHGRI). S.K., H.H., J.S. and V.B. were funded by Charles University programs PRVOUK-P24/LF1/3 and UNCE 204011, and their work was supported by grants LH12015 and NT13116-4/2012 from the Ministry of Education and the Ministry of Health of the Czech Republic. S.L.A. was supported by US NIH grant DK34854 (The Harvard Digestive Diseases Center). N.P. is a Broad Fellow of the Broad Institute and a postdoctoral research fellow of the Fund for Scientific Research-Flanders (FWO Vlaanderen, Belgium). I.G.-V. was supported by the Human Frontier Science Program, Alon, the Israeli Centers of Research Excellence (I-CORE) and the Edmond J. Safra Center for Bioinformatics at Tel Aviv University. NR 19 TC 50 Z9 53 U1 1 U2 25 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 MAR PY 2013 VL 45 IS 3 BP 299 EP 303 DI 10.1038/ng.2543 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 099ZP UT WOS:000315664800015 PM 23396133 ER PT J AU Verhoeven, VJM Hysi, PG Wojciechowski, R Fan, Q Guggenheim, JA Hohn, R MacGregor, S Hewitt, AW Nag, A Cheng, CY Yonova-Doing, E Zhou, X Ikram, MK Buitendijk, GHS McMahon, G Kemp, JP St Pourcain, B Simpson, CL Makela, KM Lehtimaki, T Kahonen, M Paterson, AD Hosseini, SM Wong, HS Xu, L Jonas, JB Parssinen, O Wedenoja, J Yip, SP Ho, DWH Pang, CP Chen, LJ Burdon, KP Craig, JE Klein, BEK Klein, R Haller, T Metspalu, A Khor, CC Tai, ES Aung, T Vithana, E Tay, WT Barathi, VA Chen, P Li, RY Liao, JM Zheng, YF Ong, RT Doring, A Evans, DM Timpson, NJ Verkerk, AJMH Meitinger, T Raitakari, O Hawthorne, F Spector, TD Karssen, LC Pirastu, M Murgia, F Ang, W Mishra, A Montgomery, GW Pennell, CE Cumberland, PM Cotlarciuc, I Mitchell, P Wang, JJ Schache, M Janmahasathian, S Igo, RP Lass, JH Chew, E Iyengar, SK Gorgels, TGMF Rudan, I Hayward, C Wright, AF Polasek, O Vatavuk, Z Wilson, JF Fleck, B Zeller, T Mirshahi, A Muller, C Uitterlinden, AG Rivadeneira, F Vingerling, JR Hofman, A Oostra, B Amin, N Bergen, AAB Teo, YY Rahi, JS Vitart, V Williams, C Baird, PN Wong, TY Oexle, K Pfeiffer, N Mackey, DA Young, TL van Duijn, CM Saw, SM Bailey-Wilson, JE Stambolian, D Klaver, CC Hammond, CJ AF Verhoeven, Virginie J. M. Hysi, Pirro G. Wojciechowski, Robert Fan, Qiao Guggenheim, Jeremy A. Hoehn, Rene MacGregor, Stuart Hewitt, Alex W. Nag, Abhishek Cheng, Ching-Yu Yonova-Doing, Ekaterina Zhou, Xin Ikram, M. Kamran Buitendijk, Gabrielle H. S. McMahon, George Kemp, John P. St Pourcain, Beate Simpson, Claire L. Makela, Karl-Matti Lehtimaki, Terho Kahonen, Mika Paterson, Andrew D. Hosseini, S. Mohsen Wong, Hoi Suen Xu, Liang Jonas, Jost B. Parssinen, Olavi Wedenoja, Juho Yip, Shea Ping Ho, Daniel W. H. Pang, Chi Pui Chen, Li Jia Burdon, Kathryn P. Craig, Jamie E. Klein, Barbara E. K. Klein, Ronald Haller, Toomas Metspalu, Andres Khor, Chiea-Chuen Tai, E-Shyong Aung, Tin Vithana, Eranga Tay, Wan-Ting Barathi, Veluchamy A. Chen, Peng Li, Ruoying Liao, Jiemin Zheng, Yingfeng Ong, Rick T. Doering, Angela Evans, David M. Timpson, Nicholas J. Verkerk, Annemieke J. M. H. Meitinger, Thomas Raitakari, Olli Hawthorne, Felicia Spector, Tim D. Karssen, Lennart C. Pirastu, Mario Murgia, Federico Ang, Wei Mishra, Aniket Montgomery, Grant W. Pennell, Craig E. Cumberland, Phillippa M. Cotlarciuc, Ioana Mitchell, Paul Wang, Jie Jin Schache, Maria Janmahasathian, Sarayut Igo, Robert P., Jr. Lass, Jonathan H. Chew, Emily Iyengar, Sudha K. Gorgels, Theo G. M. F. Rudan, Igor Hayward, Caroline Wright, Alan F. Polasek, Ozren Vatavuk, Zoran Wilson, James F. Fleck, Brian Zeller, Tanja Mirshahi, Alireza Mueller, Christian Uitterlinden, Andre G. Rivadeneira, Fernando Vingerling, Johannes R. Hofman, Albert Oostra, Ben A. Amin, Najaf Bergen, Arthur A. B. Teo, Yik-Ying Rahi, Jugnoo S. Vitart, Veronique Williams, Cathy Baird, Paul N. Wong, Tien-Yin Oexle, Konrad Pfeiffer, Norbert Mackey, David A. Young, Terri L. van Duijn, Cornelia M. Saw, Seang-Mei Bailey-Wilson, Joan E. Stambolian, Dwight Klaver, Caroline C. Hammond, Christopher J. CA CREAM Diabet Control Complications Trial WTCCC2 Fuchs' Genetics Multi-Ctr Study Gr TI Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia SO NATURE GENETICS LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; ADAPTED MOUSE RETINA; EYE GROWTH; POTASSIUM CHANNEL; SERINE-PROTEASE; ASSOCIATION; ACID; EXPRESSION; VARIANTS; GENE AB Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia. C1 [Verhoeven, Virginie J. M.; Buitendijk, Gabrielle H. S.; Vingerling, Johannes R.; Klaver, Caroline C.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Verhoeven, Virginie J. M.; Buitendijk, Gabrielle H. S.; Karssen, Lennart C.; Uitterlinden, Andre G.; Rivadeneira, Fernando; Vingerling, Johannes R.; Hofman, Albert; Amin, Najaf; van Duijn, Cornelia M.; Klaver, Caroline C.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hysi, Pirro G.; Nag, Abhishek; Yonova-Doing, Ekaterina; Spector, Tim D.; Hammond, Christopher J.] Kings Coll London, Sch Med, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Wojciechowski, Robert; Simpson, Claire L.; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, US Natl Inst Hlth, Baltimore, MD USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Khor, Chiea-Chuen; Tai, E-Shyong; Chen, Peng; Li, Ruoying; Ong, Rick T.; Teo, Yik-Ying; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Guggenheim, Jeremy A.; Ho, Daniel W. H.] Hong Kong Polytech Univ, Sch Optometry, Ctr Myopia Res, Hong Kong, Hong Kong, Peoples R China. [Hoehn, Rene; Mirshahi, Alireza; Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, Mainz, Germany. [MacGregor, Stuart; Mishra, Aniket] Queensland Inst Med Res, Dept Stat Genet, Brisbane, Qld 4006, Australia. [Hewitt, Alex W.; Wang, Jie Jin; Schache, Maria; Baird, Paul N.; Mackey, David A.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, CERA, Melbourne, Vic, Australia. [Hewitt, Alex W.; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Cheng, Ching-Yu; Ikram, M. Kamran; Khor, Chiea-Chuen; Aung, Tin; Barathi, Veluchamy A.; Liao, Jiemin; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Singapore, Natl Univ Hlth Syst, Dept Ophthalmol, Singapore 117548, Singapore. [Cheng, Ching-Yu; Ikram, M. Kamran; Aung, Tin; Vithana, Eranga; Tay, Wan-Ting; Barathi, Veluchamy A.; Zheng, Yingfeng; Wong, Tien-Yin; Saw, Seang-Mei] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [McMahon, George; Kemp, John P.; Evans, David M.; Timpson, Nicholas J.] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Sch Social & Community Med, Bristol, Avon, England. [St Pourcain, Beate; Williams, Cathy] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Makela, Karl-Matti; Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FIN-33101 Tampere, Finland. [Makela, Karl-Matti; Lehtimaki, Terho; Kahonen, Mika] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Kahonen, Mika] Univ Tampere, Tampere Univ Hosp, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Paterson, Andrew D.; Hosseini, S. Mohsen; Wong, Hoi Suen] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Paterson, Andrew D.; Hosseini, S. Mohsen; Wong, Hoi Suen] Univ Toronto, Toronto, ON, Canada. [Xu, Liang] Capital Med Univ, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing, Peoples R China. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Parssinen, Olavi] Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland. [Parssinen, Olavi] Univ Jyvaskyla, Gerontol Res Ctr, Jyvaskyla, Finland. [Parssinen, Olavi] Cent Hosp Cent Finland, Dept Ophthalmol, Jyvaskyla, Finland. [Wedenoja, Juho] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Yip, Shea Ping] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [Ho, Daniel W. H.; Pang, Chi Pui] Chinese Univ Hong Kong, Hong Kong Eye Hosp, Dept Ophthalmol & Visual Sci, Kowloon, Hong Kong, Peoples R China. [Chen, Li Jia] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Ophthalmol & Visual Sci, Shatin, Hong Kong, Peoples R China. [Burdon, Kathryn P.; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Haller, Toomas; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Khor, Chiea-Chuen] Natl Univ Singapore, Dept Pediat, Singapore 117548, Singapore. [Khor, Chiea-Chuen] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Tai, E-Shyong; Barathi, Veluchamy A.; Saw, Seang-Mei] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Doering, Angela] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, Neuherberg, Germany. [Doering, Angela; Uitterlinden, Andre G.] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Verkerk, Annemieke J. M. H.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Meitinger, Thomas; Oexle, Konrad] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Hawthorne, Felicia; Young, Terri L.] Duke Eye Ctr Human Genet, Dept Pediat Ophthalmol, Durham, NC USA. [Pirastu, Mario; Murgia, Federico; Bergen, Arthur A. B.] CNR, Inst Populat Genet, Sassari, Italy. [Ang, Wei; Pennell, Craig E.] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia. [Montgomery, Grant W.; Rahi, Jugnoo S.] Queensland Inst Med Res, Dept Mol Epidemiol, Brisbane, Qld 4006, Australia. [Cumberland, Phillippa M.] UCL, Inst Child Hlth, MRC, Ctr Epidemiol Child Hlth, London, England. [Cumberland, Phillippa M.; Rahi, Jugnoo S.] UCL, Ulverscroft Vis Res Grp, London, England. [Cotlarciuc, Ioana] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Brain Sci, ICCRU, London, England. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Janmahasathian, Sarayut; Igo, Robert P., Jr.; Lass, Jonathan H.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Lass, Jonathan H.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA. [Lass, Jonathan H.; Iyengar, Sudha K.] Univ Hosp Eye Inst, Cleveland, OH USA. [Chew, Emily] NEI, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Gorgels, Theo G. M. F.; Bergen, Arthur A. B.] NIN, Dept Clin & Mol Ophthalmogenet, Amsterdam, Netherlands. [Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Hayward, Caroline; Wright, Alan F.; Vitart, Veronique] Univ Edinburgh, Human Genet Unit, MRC, Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Polasek, Ozren] Univ Split, Fac Med, Split, Croatia. [Vatavuk, Zoran] Sisters Mercy Univ Hosp, Dept Ophthalmol, Zagreb, Croatia. [Fleck, Brian] Princess Alexandra Eye Pavil, Edinburgh, Midlothian, Scotland. [Zeller, Tanja; Mueller, Christian] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Uitterlinden, Andre G.; Rivadeneira, Fernando; Hofman, Albert] Netherlands Genom Initiat, Netherlands Consortium Hlth Ageing, The Hague, Netherlands. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Bergen, Arthur A. B.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Bergen, Arthur A. B.] Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Rahi, Jugnoo S.] Moorfields Eye Hosp, Inst Ophthalmol, London, England. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. RP Klaver, CC (reprint author), Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. EM c.c.w.klaver@erasmusmc.nl RI Paterson, Andrew/A-4088-2011; Rudan, Igor/I-1467-2012; Mackey, David/H-5340-2014; Hayward, Caroline/M-8818-2016; Ho, Daniel Wai Hung/O-1194-2016; Fox, Laura /C-6249-2016; Biino, Ginevra/B-5334-2013; Delcourt, Cecile/I-2627-2013; Chen, Peng/E-5546-2015; Jankowski, Janusz/H-2706-2012; Blackwell, Jenefer/H-3015-2015; DeAngelis, e/J-7863-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Yip, Shea Ping/A-1185-2016; Klaver, Caroline/A-2013-2016; Hewitt, Alex/D-1936-2013; Deloukas, Panos/B-2922-2013; Northstone, Kate/A-8165-2011; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Evans, David/H-6325-2013; Bergen, Arthur/J-3637-2013; Cheng, Ching-Yu/K-7017-2013; Hosseini, Mohsen/K-7133-2013; Burdon, Kathryn/A-5026-2009; Macgregor, Stuart/C-6442-2009; Chen, Li Jia/I-5078-2014; Pang, Chi/I-5388-2014 OI Klein, Ronald/0000-0002-4428-6237; Timpson, Nicholas/0000-0002-7141-9189; Khor, Chiea Chuen/0000-0002-1128-4729; Hammond, Christopher/0000-0002-3227-2620; Kemp, John/0000-0002-9105-2249; Ikram, Mohammad Kamran/0000-0003-0173-9571; Evans, David/0000-0003-0663-4621; Wedenoja, Juho/0000-0002-6155-0378; Tai, E Shyong/0000-0003-2929-8966; Karssen, Lennart C./0000-0002-1959-342X; Wojciechowski, Robert/0000-0002-9593-4652; Baird, Paul/0000-0002-1305-3502; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Hohn, Rene /0000-0003-2870-1469; Paterson, Andrew/0000-0002-9169-118X; Rudan, Igor/0000-0001-6993-6884; Mackey, David/0000-0001-7914-4709; Hayward, Caroline/0000-0002-9405-9550; Ho, Daniel Wai Hung/0000-0003-3884-296X; St Pourcain, Beate/0000-0002-4680-3517; Guggenheim, Jeremy/0000-0001-5164-340X; Bailey-Wilson, Joan/0000-0002-9153-2920; Biino, Ginevra/0000-0002-9936-946X; Delcourt, Cecile/0000-0002-2099-0481; Chen, Peng/0000-0002-1422-4641; Jankowski, Janusz/0000-0003-2130-9181; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; Yip, Shea Ping/0000-0002-2170-8185; Hewitt, Alex/0000-0002-5123-5999; Deloukas, Panos/0000-0001-9251-070X; Northstone, Kate/0000-0002-0602-1983; Wang, Jie Jin/0000-0001-9491-4898; Cheng, Ching-Yu/0000-0003-0655-885X; Hosseini, Mohsen/0000-0003-3626-9928; Burdon, Kathryn/0000-0001-8217-1249; Macgregor, Stuart/0000-0001-6731-8142; Chen, Li Jia/0000-0003-3500-5840; FU Chief Scientist Office [CZB/4/438, CZB/4/710]; Department of Health [CDF-2009-02-35, SRF/01/010]; Intramural NIH HHS; Medical Research Council [4882, G9815508, MC_U127584475]; NCATS NIH HHS [UL1 TR000041]; NEI NIH HHS [K08 EY022943, 1K08EY022943‐01, 1R01EY018246, EY016379, N01EY22112, N01EY92109, P30 EY014800, P30EY11373, R01 EY018246, R01 EY020483, R01 EY023196, R01EY01824601, R01EY020483, R01EY03083, R01EY16482, R21EY015145]; NHLBI NIH HHS [N01HC25195, N02HL64278]; NIDDK NIH HHS [N01 DK062204, N01 DK062204-A, N01‐DK‐6‐2204, R01 DK077510, R01 DK‐077510]; Wellcome Trust [076113, 076467, 083478, 08547508Z, 085475B08Z, 090532, 092731, WT083431MA] NR 39 TC 118 Z9 124 U1 7 U2 84 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2013 VL 45 IS 3 BP 314 EP 318 DI 10.1038/ng.2554 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 099ZP UT WOS:000315664800018 PM 23396134 ER PT J AU DeFelipe, J Lopez-Cruz, PL Benavides-Piccione, R Bielza, C Larranaga, P Anderson, S Burkhalter, A Cauli, B Fairen, A Feldmeyer, D Fishell, G Fitzpatrick, D Freund, TF Gonzalez-Burgos, G Hestrin, S Hill, S Hof, PR Huang, J Jones, EG Kawaguchi, Y Kisvarday, Z Kubota, Y Lewis, DA Marin, O Markram, H McBain, CJ Meyer, HS Monyer, H Nelson, SB Rockland, K Rossier, J Rubenstein, JLR Rudy, B Scanziani, M Shepherd, GM Sherwood, CC Staiger, JF Tamas, G Thomson, A Wang, Y Yuste, R Ascoli, GA AF DeFelipe, Javier Lopez-Cruz, Pedro L. Benavides-Piccione, Ruth Bielza, Concha Larranaga, Pedro Anderson, Stewart Burkhalter, Andreas Cauli, Bruno Fairen, Alfonso Feldmeyer, Dirk Fishell, Gord Fitzpatrick, David Freund, Tamas F. Gonzalez-Burgos, Guillermo Hestrin, Shaul Hill, Sean Hof, Patrick R. Huang, Josh Jones, Edward G. Kawaguchi, Yasuo Kisvarday, Zoltan Kubota, Yoshiyuki Lewis, David A. Marin, Oscar Markram, Henry McBain, Chris J. Meyer, Hanno S. Monyer, Hannah Nelson, Sacha B. Rockland, Kathleen Rossier, Jean Rubenstein, John L. R. Rudy, Bernardo Scanziani, Massimo Shepherd, Gordon M. Sherwood, Chet C. Staiger, Jochen F. Tamas, Gabor Thomson, Alex Wang, Yun Yuste, Rafael Ascoli, Giorgio A. TI New insights into the classification and nomenclature of cortical GABAergic interneurons SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID RAT SOMATOSENSORY CORTEX; CAJAL-RETZIUS CELLS; NEOCORTICAL INTERNEURONS; NEURONAL MORPHOLOGIES; COLUMNS; MOUSE; INHIBITION; DIVERSITY; ORIGINS; MAMMALS AB A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxononnical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus. C1 [DeFelipe, Javier; Benavides-Piccione, Ruth] Univ Politecn Madrid, CTB, Lab Cajal Circuitos Cort, Madrid 28223, Spain. [DeFelipe, Javier; Benavides-Piccione, Ruth] CSIC, Inst Cajal, E-28002 Madrid, Spain. [Lopez-Cruz, Pedro L.; Bielza, Concha; Larranaga, Pedro] Univ Politecn Madrid, Dept Inteligencia Artificial, E-28660 Madrid, Spain. [Ascoli, Giorgio A.] George Mason Univ, Krasnow Inst Adv Study MS2A1, Mol Neurosci Dept, Ctr Neural Informat Struct & Plast, Fairfax, VA 22030 USA. [Anderson, Stewart] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Burkhalter, Andreas] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Cauli, Bruno] Univ Paris 06, Reseau Cort & Couplage Neurovasc, Lab Neurobiol Proc Adaptatifs, UMR 7102,CNRS, F-75005 Paris, France. [Fairen, Alfonso; Marin, Oscar] CSIC, Inst Neurociencias, Alicante 03550, Spain. [Fairen, Alfonso; Marin, Oscar] Univ Miguel Hernandez, Alicante 03550, Spain. [Feldmeyer, Dirk] Forschungszentrum Julich, Inst Neurosci & Med, INM 2, Funct Neuronal Microcircuits Grp, D-52425 Julich, Germany. [Feldmeyer, Dirk] Univ Aachen, Rhein Westfal TH Aachen, Dept Psychiat & Psychotherapy, D-52074 Aachen, Germany. [Fishell, Gord] NYU, Langone Med Ctr, Dept Neurosci & Physiol, Inst Neurosci, New York, NY 10016 USA. [Fitzpatrick, David] Max Planck Florida Inst Neurosci, Jupiter, FL 33468 USA. [Freund, Tamas F.] Hungarian Acad Sci, Inst Expt Med, H-1083 Budapest, Hungary. [Gonzalez-Burgos, Guillermo; Lewis, David A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. [Hestrin, Shaul] Stanford Univ, Sch Med, Dept Comparat Med, Stanford, CA 94305 USA. [Hill, Sean; Markram, Henry] Ecole Polytech Fed Lausanne, Brain Mind Inst, CH-1015 Lausanne, Switzerland. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Huang, Josh] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Kawaguchi, Yasuo; Kubota, Yoshiyuki] Natl Inst Physiol Sci, Div Cerebral Circuitry, Okazaki, Aichi 4448787, Japan. [Kisvarday, Zoltan] Univ Debrecen, Dept Anat Histol & Embryol, Debrecen, Hungary. [McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Meyer, Hanno S.] Tech Univ Munich, Dept Neurosurg, D-81675 Munich, Germany. [Monyer, Hannah] Univ Heidelberg Hosp, Dept Clin Neurobiol, D-69120 Heidelberg, Germany. [Monyer, Hannah] German Canc Res Ctr DKFZ Heidelberg, D-69120 Heidelberg, Germany. [Nelson, Sacha B.] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. [Nelson, Sacha B.] Brandeis Univ, Ctr Behav Genom, Waltham, MA 02454 USA. [Rockland, Kathleen] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Rossier, Jean] Hop St Anne, INSERM, CPN, U894, F-75014 Paris, France. [Rubenstein, John L. R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rudy, Bernardo] NYU, New York, NY 10016 USA. [Scanziani, Massimo] Univ Calif San Diego, Howard Hughes Med Inst, Neurobiol Sect, Div Biol, La Jolla, CA 92093 USA. [Shepherd, Gordon M.] Yale Univ, Sch Med, Dept Neurosci, New Haven, CT 06520 USA. [Sherwood, Chet C.] George Washington Univ, Ctr Adv Study Hominid Paleobiol, Dept Anthropol, Washington, DC 20052 USA. [Sherwood, Chet C.] George Washington Univ, GW Inst Neurosci, Washington, DC 20052 USA. [Staiger, Jochen F.] Univ Gottingen, Zentrum Anat, Abt Neuroanat, D-37075 Gottingen, Germany. [Tamas, Gabor] Univ Szeged, Dept Physiol Anat & Neurosci, H-6726 Szeged, Hungary. [Thomson, Alex] UCL, Sch Pharm, Dept Pharmacol, London WC1N 1AX, England. [Wang, Yun] Wenzhou Med Coll, Sch Optometry & Ophthalmol, Wenzhou 325027, Zhejiang, Peoples R China. [Wang, Yun] Tufts Med Sch, Steward St Elizabeths Med Ctr, Boston, MA 02135 USA. [Yuste, Rafael] Columbia Univ, Howard Hughes Med Inst, New York, NY 10027 USA. RP DeFelipe, J (reprint author), Univ Politecn Madrid, CTB, Lab Cajal Circuitos Cort, Campus Montegancedo S-N, Madrid 28223, Spain. EM defelipe@cajal.csic.es; pedro.larranaga@fl.upm.es; ascoli@gmu.edu RI Feldmeyer, Dirk/H-5940-2013; Lewis, David/G-4053-2014; benavides-piccione, ruth/D-7889-2014; Marin, Oscar/F-3856-2012; Bielza, Concha/F-9277-2013; Larranaga, Pedro/F-9293-2013; OI Rudy, Bernardo/0000-0001-5748-6900; Kubota, Yoshiyuki/0000-0002-0950-7460; Feldmeyer, Dirk/0000-0002-1716-8972; Lewis, David/0000-0002-3225-6778; benavides-piccione, ruth/0000-0003-3288-9820; Marin, Oscar/0000-0001-6264-7027; Bielza, Concha/0000-0001-7109-2668; Larranaga, Pedro/0000-0003-0652-9872; Nelson, Sacha/0000-0002-0108-8599; Huang, Z. Josh/0000-0003-0592-028X FU Spanish Ministry of Economy and Competitiveness [TIN2010-20900-C04-04, SAF2009-09394]; Cajal Blue Brain Project, Spanish partner of the Blue Brain Project initiative from EPFL; National Institutes of Health [R01-39600] FX We thank the experts who took part in testing neuron classification using the web-based interactive system (in addition to the authors of the article), in alphabetical order: L. Alonso-Nanclares, C. David, H. Geoffroy, M. man, V. Garcia-Marin, A. Merchan-Perez, L. McGarry, A. Munoz, C. Palazzetti, N. Povysheva, D. Rotaru, R. Scott, R. Tremblay and A. Zaitsev. This work was supported by funding from the Spanish Ministry of Economy and Competitiveness (grants TIN2010-20900-C04-04 (to P.L.), SAF2009-09394 (to J.DF.) and the Cajal Blue Brain Project, Spanish partner of the Blue Brain Project initiative from EPFL (to J.DF. and P.L.)) and the National Institutes of Health under Grant R01-39600 (to G.A.A.). NR 42 TC 213 Z9 214 U1 6 U2 93 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD MAR PY 2013 VL 14 IS 3 BP 202 EP 216 DI 10.1038/nrn3444 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 100MF UT WOS:000315704600014 PM 23385869 ER PT J AU Petralia, RS Wang, YX Indig, FE Bushlin, I Wu, FB Mattson, MP Yao, PJ AF Petralia, Ronald S. Wang, Ya-Xian Indig, Fred E. Bushlin, Ittai Wu, Fangbai Mattson, Mark P. Yao, Pamela J. TI Reduction of AP180 and CALM Produces Defects in Synaptic Vesicle Size and Density SO NEUROMOLECULAR MEDICINE LA English DT Article DE AP180; CALM; Hippocampal synapse; Synaptic vesicle ID CLATHRIN ASSEMBLY PROTEIN; MYELOID-LEUKEMIA CALM; HIPPOCAMPAL-NEURONS; MEDIATED ENDOCYTOSIS; COATED VESICLES; BINDING; DOMAIN; RAT; LOCALIZATION; TRAFFICKING AB Clathrin assembly proteins AP180 and CALM regulate the assembly of clathrin-coated vesicles (CCVs), which mediate diverse intracellular trafficking processes, including synaptic vesicle (SV) recycling at the synapse. Although studies using several invertebrate model systems have indicated a role for AP180 in SV recycling, less is known about AP180's or CALM's function in the synapse of mammalian neurons. In this study, we examined synapses of rat hippocampal neurons in which the level of AP180 or CALM had been reduced by RNA interference (RNAi). Using light microscopy, we visualized synaptic puncta in these AP180- or CALM-reduced neurons by co-expressing Synaptophysin::EGFP (Syp::EGFP). We found that neurons with reduced AP180 or reduced CALM had smaller Syp::EGFP-illuminated puncta. Using electron microscopy, we further examined the ultrastructure of the AP180- or CALM-reduced presynaptic terminals. We found that SVs became variably enlarged in both the AP180-reduced and CALM-reduced presynaptic terminals. Lower AP180 and CALM also reduced the density of SVs and the size of SV clusters. Our findings demonstrate that in the presynaptic terminals of hippocampal neurons, AP180 and CALM have a similar role in regulating synaptic vesicles. This overlapping activity may be necessary for high-precision and high-efficacy SV formation during endocytosis. C1 [Petralia, Ronald S.; Wang, Ya-Xian] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Indig, Fred E.] NIA, Confocal Imaging Facil, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Bushlin, Ittai; Wu, Fangbai; Mattson, Mark P.; Yao, Pamela J.] NIA, Neurosci Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov FU NIA/NIH; NIDCD/NIH FX We thank the anonymous reviewers for helpful suggestions. We also thank Dr. Jane Sullivan for Synapto-physin::EGFP and Dr. Hollis T. Cline for the EGFP::mHRP construct. This work was supported by the Intramural Research Programs of the NIA/NIH and NIDCD/NIH. NR 41 TC 13 Z9 13 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2013 VL 15 IS 1 BP 49 EP 60 DI 10.1007/s12017-012-8194-x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 099OL UT WOS:000315631000003 PM 22851330 ER PT J AU Thanos, PK Subrize, M Delis, F Cooney, RN Culnan, D Sun, MJ Wang, GJ Volkow, ND Hajnal, A AF Thanos, Panayotis K. Subrize, Mike Delis, Foteini Cooney, Robert N. Culnan, Derek Sun, Mingjie Wang, Gene-Jack Volkow, Nora D. Hajnal, Andras TI Gastric Bypass Increases Ethanol and Water Consumption in Diet-Induced Obese Rats (vol 22, pg 1884, 2012) SO OBESITY SURGERY LA English DT Correction C1 [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, Intramural Program, NIH, Bethesda, MD USA. [Thanos, Panayotis K.; Subrize, Mike; Delis, Foteini; Wang, Gene-Jack] Brookhaven Natl Lab, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Sun, Mingjie; Hajnal, Andras] Penn State Univ, Dept Neural & Behav Sci, University Pk, PA 16802 USA. [Culnan, Derek] Penn State Univ, Dept Surg, University Pk, PA 16802 USA. [Cooney, Robert N.; Sun, Mingjie; Hajnal, Andras] Penn State Univ, Dept Surg, Coll Med, Hershey, PA USA. RP Thanos, PK (reprint author), NIAAA, Lab Neuroimaging, Intramural Program, NIH, Bethesda, MD USA. EM thanos@bnl.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 J9 OBES SURG JI Obes. Surg. PD MAR PY 2013 VL 23 IS 3 BP 424 EP 424 DI 10.1007/s11695-012-0842-6 PG 1 WC Surgery SC Surgery GA 096VZ UT WOS:000315434100024 ER PT J AU Spong, CY Berghella, V Wenstrom, KD Mercer, BM Saade, GR AF Spong, Catherine Y. Berghella, Vincenzo Wenstrom, Katharine D. Mercer, Brian M. Saade, George R. TI Preventing the First Cesarean Delivery Summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop EDITORIAL COMMENTS SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Obstet & Gynecol, Div Maternal Fetal Med, Philadelphia, PA 19107 USA. Brown Univ, Women & Infants Hosp, Brown Alpert Sch Med, Dept Obstet & Gynecol,Div Maternal Fetal Med, Providence, RI USA. Case Western Reserve Univ, Dept Obstet & Gynecol, MetroHlth Med Ctr, Cleveland, OH 44106 USA. Univ Texas Med Branch, Dept Obstet & Gynecol, Div Maternal Fetal Med, Galveston, TX 77555 USA. Soc Maternal Fetal Med, Publicat & Execut Comm, Washington, DC USA. RP Spong, CY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD MAR PY 2013 VL 68 IS 3 BP 177 EP 180 DI 10.1097/01.ogx.0000428154.72524.9b PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 098DO UT WOS:000315526600004 ER PT J AU Glasier, A Cameron, ST Blithe, D Scherrer, B Mathe, H Levy, D Gainer, E Ulmann, A AF Glasier, Anna Cameron, Sharon T. Blithe, Diana Scherrer, Bruno Mathe, Henri Levy, Delphine Gainer, Erin Ulmann, Andre TI Can We Identify Women at Risk of Pregnancy Despite Using Emergency Contraception? Data From Randomized Trials of Ulipristal Acetate and Levonorgestrel EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Glasier, Anna; Cameron, Sharon T.] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Blithe, Diana] NICHHD, Bethesda, MD 20892 USA. [Scherrer, Bruno; Mathe, Henri; Levy, Delphine; Gainer, Erin; Ulmann, Andre] cHRA Phrama, Paris, France. RP Glasier, A (reprint author), Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. NR 0 TC 0 Z9 0 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD MAR PY 2013 VL 68 IS 3 BP 208 EP 210 DI 10.1097/OGX.0b013e318285bc06 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 098DO UT WOS:000315526600019 ER PT J AU Monfredi, O Maltsev, VA Lakatta, EG AF Monfredi, Oliver Maltsev, Victor A. Lakatta, Edward G. TI Modern Concepts Concerning the Origin of the Heartbeat SO PHYSIOLOGY LA English DT Review ID CARDIAC-PACEMAKER CELLS; RABBIT SINOATRIAL NODE; HYPERPOLARIZING-ACTIVATED CURRENT; BETA-ADRENERGIC STIMULATION; RECTIFIER POTASSIUM CURRENT; INTRACELLULAR CA2+ RELEASE; PROTEIN-KINASE-A; RYANODINE RECEPTOR; MICE LACKING; I-F AB Physiological processes governing the heart beat have been under investigation for several hundred years. Major advances have been made in the recent past. A review of the present paradigm is presented here, including a look back at important steps that led us to where we are today, alongside a glimpse into the exciting future of pacemaker research. C1 [Monfredi, Oliver] Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England. [Maltsev, Victor A.] NIA, Cellular Biophys Sect, Cardiovasc Sci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Programme, NIH, Baltimore, MD 21224 USA. RP Monfredi, O (reprint author), Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England. EM LakattaE@grc.nia.nih.gov OI Monfredi, Oliver/0000-0003-1292-2902 NR 85 TC 25 Z9 26 U1 2 U2 30 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1548-9213 EI 1548-9221 J9 PHYSIOLOGY JI Physiology PD MAR PY 2013 VL 28 IS 2 BP 74 EP 92 DI 10.1152/physiol.00054.2012 PG 19 WC Physiology SC Physiology GA 100DL UT WOS:000315675900004 PM 23455768 ER PT J AU Harris, ML Pavan, WJ AF Harris, Melissa L. Pavan, William J. TI Postnatal lineage mapping of follicular melanocytes with the Tyr::CreERT2 transgene SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanocyte; hair follicle; melanocyte stem cell; lineage mapping; Cre recombinase ID STEM-CELLS; RECOMBINASE ACTIVITY; MELANOMA; MAINTENANCE; ROLES; MICE; REGENERATION; ACTIVATION; EXPRESSION; MITF AB One of the main advantages of using inducible and conditional transgenes to study pigment cell biology is that they allow for genetic manipulation within melanocytes after roles in general neural crest or melanoblast development have been fulfilled. Specifically, we focus here on the ability of the Tyr::CreERT2 transgenic line to alter genes within follicular melanocytes postnatally. Using the Gt(ROSA)26Sortm1sor reporter allele, we present in detail the expression and activity of Tyr::CreERT2 when induced during hair morphogenesis and adult hair cycling. We find that despite similarities in expression pattern to endogenous TYR, Tyr::CreERT2 is effective at targeting both undifferentiated and differentiated melanocytes within the hair follicle. We also find that Tyr::CreERT2 provides the highest levels of recombination when induced during the early phases of hair growth. In conclusion, the descriptions provided here will guide future analyses of gene function within the melanocyte system of the hair follicle when using this Tyr::CreERT2 transgene. C1 [Harris, Melissa L.; Pavan, William J.] Natl Human Genome Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Harris, ML (reprint author), Natl Human Genome Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM harrisml2@mail.nih.gov FU National Human Genome Research Institute FX We thank Glenn Merlino and Marcus Bosenberg for providing the Tyr::CreERT2 mice. The National Human Genome Research Institute's Intramural Research Program supported this work. NR 24 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2013 VL 26 IS 2 DI 10.1111/pcmr.12048 PG 7 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 097IN UT WOS:000315467300017 PM 23176440 ER PT J AU Hyter, S Coleman, DJ Ganguli-Indra, G Merrill, GF Ma, S Yanagisawa, M Indra, AK AF Hyter, Stephen Coleman, Daniel J. Ganguli-Indra, Gitali Merrill, Gary F. Ma, Steven Yanagisawa, Masashi Indra, Arup K. TI Endothelin-1 is a transcriptional target of p53 in epidermal keratinocytes and regulates ultraviolet-induced melanocyte homeostasis SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE endothelin-1; p53; paracrine; ultraviolet B; BQ788 ID B-RECEPTOR; SIGNALING MECHANISMS; BINDING-SITES; GROWTH-FACTOR; RXR-ALPHA; SKIN; MICE; PROLIFERATION; EXPRESSION; PIGMENTATION AB Keratinocytes contribute to melanocyte activity by influencing their microenvironment, in part, through secretion of paracrine factors. Here, we discovered that p53 directly regulates Edn1 expression in epidermal keratinocytes and controls UV-induced melanocyte homeostasis. Selective ablation of endothelin-1 (EDN1) in murine epidermis (EDN1ep/) does not alter melanocyte homeostasis in newborn skin but decreases dermal melanocytes in adult skin. Results showed that keratinocytic EDN1 in a non-cell autonomous manner controls melanocyte proliferation, migration, DNA damage, and apoptosis after ultraviolet B (UVB) irradiation. Expression of other keratinocyte-derived paracrine factors did not compensate for the loss of EDN1. Topical treatment with EDN1 receptor (EDNRB) antagonist BQ788 abrogated UV-induced melanocyte activation and recapitulated the phenotype seen in EDN1ep/ mice. Altogether, the present studies establish an essential role of EDN1 in epidermal keratinocytes to mediate UV-induced melanocyte homeostasis in vivo. C1 [Hyter, Stephen; Coleman, Daniel J.; Ganguli-Indra, Gitali; Indra, Arup K.] Oregon State Univ, Dept Pharmaceut Sci, Corvallis, OR 97331 USA. [Hyter, Stephen; Coleman, Daniel J.; Ganguli-Indra, Gitali; Indra, Arup K.] Oregon State Univ, Mol & Cellular Biol Program, Corvallis, OR 97331 USA. [Merrill, Gary F.; Indra, Arup K.] Oregon State Univ, Environm Hlth Sci Ctr, Corvallis, OR 97331 USA. [Merrill, Gary F.] Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA. [Indra, Arup K.] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97201 USA. [Ma, Steven] NIAID, Immunol Core Lab, Bethesda, MD 20892 USA. [Yanagisawa, Masashi] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA. RP Indra, AK (reprint author), Oregon State Univ, Dept Pharmaceut Sci, Corvallis, OR 97331 USA. EM arup.indra@oregonstate.edu FU NIEHS at National Institutes of Health [ES016629-01A1]; OHSU Medical Research Foundation; NIEHS Center [ES00210]; National Institute of Environmental Health Sciences (NIEHS) [T32 ES007060]; National Cancer Institute of the National Institutes of Health [T32CA106195]; National Cancer Institute FX We would like to thank Sharmeen Chagani for assistance in the histological analyses. We also thank Drs. Mark Zabriskie and Gary DeLander of the OSU College of Pharmacy for continuous support and encouragement. These studies were supported by grant ES016629-01A1 (AI) from NIEHS at National Institutes of Health, an OHSU Medical Research Foundation grant to AI, and by a NIEHS Center grant (ES00210) to the Oregon State University Environmental Health Sciences Center. The project described was also supported by Award Number T32 ES007060 from the National Institute of Environmental Health Sciences (NIEHS) and by the National Cancer Institute of the National Institutes of Health under award number T32CA106195 'Training in the Molecular Basis of Skin/Mucosa Pathobiology' to OHSU from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIEHS or the National Institutes of Health (NIH). NR 43 TC 10 Z9 10 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2013 VL 26 IS 2 DI 10.1111/pcmr.12063 PG 13 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 097IN UT WOS:000315467300014 PM 23279852 ER PT J AU Kolle, SN Basketter, DA Casati, S Stokes, WS Strickland, J van Ravenzwaay, B Vohr, HW Landsiedel, R AF Kolle, Susanne N. Basketter, David A. Casati, Silvia Stokes, William S. Strickland, Judy van Ravenzwaay, Bennard Vohr, Hans-Werner Landsiedel, Robert TI Performance standards and alternative assays: Practical insights from skin sensitization SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Performance standards; Validation; Local lymph node assay; Lymph node cell counts; Skin sensitization; Alternatives ID LYMPH-NODE ASSAY; CELL COUNT MEASUREMENTS; CONTACT-DERMATITIS; ICCVAM EVALUATION; EC3 VALUES; EXPERIENCE; POTENCY AB To encourage the development and validation of alternative toxicity test methods, the effort required for validation of test methods proposed for regulatory purposes should be minimized. Performance standards (PS) facilitate efficient validation by requiring limited testing. Based on the validated method, PS define accuracy and reliability values that must be met by the new similar test method. The OECD adopted internationally harmonized PS for evaluating new endpoint versions of the local lymph node assay (LLNA). However, in the process of evaluating a lymph node cell count alternative (LNCC), simultaneous conduct of the regulatory LLNA showed that this standard test may not always perform in perfect accord with its own PS. The LNCC results were similar to the concurrent LLNA. Discrepancies between PS, LLNA and LNCC were largely associated with "borderline" substances and the variability of both endpoints. Two key lessons were learned: firstly, the understandable focus on substances close to the hazard classification borderline are more likely to emphasise issues of biological variability, which should be taken into account during the evaluation of results; secondly, variability in the results for the standard assay should be considered when selecting reference chemicals for PS. (C) 2013 Elsevier Inc. All rights reserved. C1 [Kolle, Susanne N.; van Ravenzwaay, Bennard; Landsiedel, Robert] BASF SE, Expt Toxicol & Ecol, D-67056 Ludwigshafen, Germany. [Basketter, David A.] DABMEB Consultancy Ltd, Sharnbrook, Beds, England. [Casati, Silvia] EURL ECVAM, JRC, Ispra, Italy. [Stokes, William S.] Natl Toxicol Program Interagcy Ctr Evaluat Altern, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Strickland, Judy] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Vohr, Hans-Werner] Bayer HealthCare, Bayer Pharma, Wuppertal, Germany. RP Kolle, SN (reprint author), BASF SE, Expt Toxicol & Ecol, Z570, D-67056 Ludwigshafen, Germany. EM susanne.kolle@basf.com FU BASF SE; NIEHS [N01-ES 35504] FX LLNA and LNCC are conducted at BASF SE for commercial purposes. DAB, SNK, BvR, and RL were paid by BASF SE for the preparation of this manuscript. The participation of JS was supported by NIEHS contract N01-ES 35504. DAB, SC, WSS and JS were variously involved in the original production of the LLNA PS. NR 35 TC 7 Z9 7 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD MAR PY 2013 VL 65 IS 2 BP 278 EP 285 DI 10.1016/j.yrtph.2012.12.006 PG 8 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 096UG UT WOS:000315429200012 PM 23279805 ER PT J AU Muniyappa, R Sowers, JR AF Muniyappa, Ranganath Sowers, James R. TI Role of insulin resistance in endothelial dysfunction SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE Nitric oxide; Insulin resistance; Endothelial dysfunction; Metabolic syndrome ID NITRIC-OXIDE SYNTHASE; DEPENDENT DIABETES-MELLITUS; POLYCYSTIC-OVARY-SYNDROME; CORONARY-ARTERY-DISEASE; ORAL VITAMIN-C; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; ESSENTIAL-HYPERTENSION; OXIDATIVE STRESS; BLOOD-PRESSURE AB Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin. C1 [Muniyappa, Ranganath] NIDDK, Clin Endocrine Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Sowers, James R.] Univ Missouri, Sch Med, Dept Internal Med, Columbia, MO 65212 USA. [Sowers, James R.] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO 65212 USA. [Sowers, James R.] Harry S Truman Mem Vet Hosp, Columbia, MO 65201 USA. RP Sowers, JR (reprint author), Univ Missouri, Sch Med, Dept Internal Med, 1 Hosp Dr, Columbia, MO 65212 USA. EM sowersj@health.missouri.edu FU Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); NIH [R01 HL73101-08, R01 HL107910-03]; Veterans Affairs Merit System [0018] FX This work was supported by the Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). The research of J.R.S. is supported by NIH (R01 HL73101-08 and R01 HL107910-03) and Veterans Affairs Merit System 0018. NR 78 TC 70 Z9 75 U1 3 U2 25 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD MAR PY 2013 VL 14 IS 1 BP 5 EP 12 DI 10.1007/s11154-012-9229-1 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 098SC UT WOS:000315568000002 PM 23306778 ER PT J AU Patterson, AP Tabak, LA Fauci, AS Collins, FS Howard, S AF Patterson, Amy P. Tabak, Lawrence A. Fauci, Anthony S. Collins, Francis S. Howard, Sally TI A Framework for Decisions About Research with HPAI H5N1 Viruses SO SCIENCE LA English DT Editorial Material ID AVIAN FLU TRANSMISSION; FERRETS; PAUSE C1 [Patterson, Amy P.; Tabak, Lawrence A.; Fauci, Anthony S.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. [Howard, Sally] US Dept HHS, Washington, DC 20201 USA. RP Patterson, AP (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM pattersa@od.nih.gov FU Intramural NIH HHS [Z99 OD999999, Z99 AI999999] NR 12 TC 14 Z9 14 U1 1 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 1 PY 2013 VL 339 IS 6123 BP 1036 EP 1037 DI 10.1126/science.1236194 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 097CQ UT WOS:000315452000025 PM 23429700 ER PT J AU Carotenuto, M Pedone, E Diana, D de Antonellis, P Dzeroski, S Marino, N Navas, L Di Dato, V Scoppettuolo, MN Cimmino, F Correale, S Pirone, L Monti, SM Bruder, E Zenko, B Slavkov, I Pastorino, F Ponzoni, M Schulte, JH Schramm, A Eggert, A Westermann, F Arrigoni, G Accordi, B Basso, G Saviano, M Fattorusso, R Zollo, M AF Carotenuto, Marianeve Pedone, Emilia Diana, Donatella de Antonellis, Pasqualino Dzeroski, Saso Marino, Natascia Navas, Luigi Di Dato, Valeria Scoppettuolo, Maria Nunzia Cimmino, Flora Correale, Stefania Pirone, Luciano Monti, Simona Maria Bruder, Elisabeth Zenko, Bernard Slavkov, Ivica Pastorino, Fabio Ponzoni, Mirco Schulte, Johannes H. Schramm, Alexander Eggert, Angelika Westermann, Frank Arrigoni, Gianluigi Accordi, Benedetta Basso, Giuseppe Saviano, Michele Fattorusso, Roberto Zollo, Massimo TI Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction SO SCIENTIFIC REPORTS LA English DT Article ID TYROSINE-PHOSPHATASE-ALPHA; SQUAMOUS-CELL CARCINOMA; H-PRUNE; N-MYC; CANCER METASTASIS; BREAST-CARCINOMA; NM23-H1; GENE; EXPRESSION; PROTEIN AB Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment. C1 [Carotenuto, Marianeve; de Antonellis, Pasqualino; Marino, Natascia; Di Dato, Valeria; Scoppettuolo, Maria Nunzia; Cimmino, Flora; Zollo, Massimo] Ctr Ingn Genet & Biotecnol Avanzate CEINGE, Naples, Italy. [Carotenuto, Marianeve; de Antonellis, Pasqualino; Di Dato, Valeria; Scoppettuolo, Maria Nunzia; Cimmino, Flora; Zollo, Massimo] Univ Naples Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy. [Pedone, Emilia; Diana, Donatella; Correale, Stefania; Monti, Simona Maria; Fattorusso, Roberto] CNR, Ist Biostrutture & Bioimmagini, I-80125 Naples, Italy. [Fattorusso, Roberto] Univ Naples 2, Dipartimento Sci Ambientali, Caserta, Italy. [Navas, Luigi] Univ Naples Federico II, Sez Clin Chirurg, Dipartimento Sci Clin Vet, Naples, Italy. [Bruder, Elisabeth] Univ Basel, Dept Pathol, Basel, Switzerland. [Dzeroski, Saso; Zenko, Bernard; Slavkov, Ivica] Jozef Stefan Inst, Dept Knowledge Technol, Ljubljana 1000, Slovenia. [Pastorino, Fabio; Ponzoni, Mirco] Osped Pediat, Ist Giannina Gaslini, I-16148 Genoa, Italy. [Schulte, Johannes H.; Schramm, Alexander; Eggert, Angelika] Univ Childrens Hosp Essen, Dept Paediat Oncol & Haematol, D-45122 Essen, Germany. [Westermann, Frank] German Canc Res Ctr, Dept Tumour Genet, Heidelberg, Germany. [Arrigoni, Gianluigi] Univ Milan, Osped San Raffaele, Dept Pathol, I-20127 Milan, Italy. [Basso, Giuseppe] Univ Padua, Dept Paediat, Haematooncol Lab, Padua, Italy. [Pirone, Luciano; Saviano, Michele] CNR, Ist Cristallog, I-70126 Bari, Italy. [Marino, Natascia] NCI, Womens Canc Sect, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Zollo, M (reprint author), Ctr Ingn Genet & Biotecnol Avanzate CEINGE, Naples, Italy. EM massimo.zollo@unina.it RI Schulte, Johannes/G-3981-2010; Pirone, Luciano/G-7256-2015; Pedone, Emilia Maria/K-2229-2015; Di Dato, Valeria/L-2484-2015; Zollo, Massimo/K-5857-2016; Ponzoni, Mirco/J-7713-2016; Cimmino, Flora/K-6205-2016; OI Fattorusso, Roberto/0000-0002-3539-5343; Pirone, Luciano/0000-0002-7014-4689; Pedone, Emilia Maria/0000-0003-0203-8611; Di Dato, Valeria/0000-0001-9720-6619; Zollo, Massimo/0000-0002-0970-7243; Ponzoni, Mirco/0000-0002-6164-4286; Cimmino, Flora/0000-0003-1538-9285; Saviano, Michele/0000-0001-5086-2459; Schramm, Alexander/0000-0001-7670-7529; NAVAS, Luigi/0000-0002-1851-5016; BASSO, GIUSEPPE/0000-0002-2634-9302 FU PRIN [E5AZ5F]; AIRC; FP6-EET pipeline [LSH-CT-2006-037260]; FP7- Tumic [HEALTH-F2-2008-201662]; Fondazione italiana per la lotta al Neuroblastoma; Dottorato in Biologia Computazionale e Bioinformatica, Federico II of Naples FX For critical discussions, help in devoloping previous data, and for helpful suggestions, the authors would like to thank (in alphabetical order): Alessandra Andre, AnnaMaria Bello, Richard Cambdam, Anna D'Angelo, Luigi Del Vecchio & FACS Service Facility CEINGE, Alessia Galasso, Cristin Roma, Frank Speleman, Angelo Taglialatela, Luigi Terracciano, GianPaolo Tonini, and Jo Vandesopele. Financial support: PRIN (E5AZ5F) 2008 (MZ), AIRC (MZ), FP6-EET pipeline LSH-CT-2006-037260 (MZ), FP7- Tumic HEALTH-F2-2008-201662 (MZ), Fondazione italiana per la lotta al Neuroblastoma (MZ); MC is supported by Dottorato in Biologia Computazionale e Bioinformatica, Federico II of Naples. NR 45 TC 9 Z9 9 U1 0 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 1 PY 2013 VL 3 AR 1351 DI 10.1038/srep01351 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098RC UT WOS:000315565400001 PM 23448979 ER PT J AU Saito, K Moore, R Negishi, M AF Saito, Kosuke Moore, Rick Negishi, Masahiko TI Nuclear Receptor CAR Specifically Activates the Two-Pore K Channel Kcnk1 Gene in Male Mouse Livers, Which Attenuates Phenobarbital-Induced Hepatic Hyperplasia SO TOXICOLOGICAL SCIENCES LA English DT Article DE phenobarbital; CAR; KCNK1; hepatic hyperplasia ID CONSTITUTIVE ANDROSTANE RECEPTOR; GROWTH-HORMONE; CELL-PROLIFERATION; MESSENGER-RNA; CYP2B GENE; RAT-LIVER; EXPRESSION; MICE; INDUCTION; PROMOTION AB KCNK1, a member of the family of two-pore K ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (2441/2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1(/) male mice compared with those of Kcnk1(/) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1(/) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice. C1 [Saito, Kosuke; Moore, Rick; Negishi, Masahiko] Natl Inst Environm Hlth Sci, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), Natl Inst Environm Hlth Sci, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural Research Program of National Institute of Environmental Health Sciences at National Institutes of Health [Z01ES1005-01] FX Intramural Research Program of National Institute of Environmental Health Sciences at National Institutes of Health (Z01ES1005-01). NR 42 TC 4 Z9 5 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2013 VL 132 IS 1 BP 151 EP 161 DI 10.1093/toxsci/kfs338 PG 11 WC Toxicology SC Toxicology GA 096WB UT WOS:000315434300015 PM 23291559 ER PT J AU Boertien, WE Meijer, E Li, J Bost, JE Struck, J Flessner, MF Gansevoort, RT Torres, VE AF Boertien, Wendy E. Meijer, Esther Li, Jie Bost, James E. Struck, Joachim Flessner, Michael F. Gansevoort, Ron T. Torres, Vicente E. CA Consortium Radiologic Imaging Stud TI Relationship of Copeptin, a Surrogate Marker for Arginine Vasopressin, With Change in Total Kidney Volume and GFR Decline in Autosomal Dominant Polycystic Kidney Disease: Results From the CRISP Cohort SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Autosomal dominant polycystic kidney disease; polycystic kidney disease; total kidney volume; kidney function; glomerular filtration rate; copeptin; arginine vasopressin; disease progression ID V2 RECEPTOR ANTAGONIST; RENAL-FUNCTION DECLINE; PROGRESSION; CONSORTIUM; TOLVAPTAN; PLASMA; MODEL; PCK AB Background: Experimental studies indicate that arginine vasopressin (AVP) may have deleterious effects in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, the significance of AVP in human ADPKD is unclear. Study Design: Longitudinal observational study with 8.5 (IQR, 7.7-9.0) years' follow-up (CRISP [Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease]). Setting & Participants: 241 patients with ADPKD with creatinine clearance >70 mL/min. Predictor: Plasma copeptin concentration, a surrogate marker for AVP. Outcomes: Change in measured glomerular filtration rate (mGFR, assessed by iothalamate clearance) and total kidney volume (measured by magnetic resonance imaging). Measurements: Baseline copeptin level, plasma and urinary osmolality, and measurements of total kidney volume and mGFR during follow-up. Results: In these patients (median age, 34 [IQR, 25-40] years; 38% men; median mGFR, 94 [IQR, 79-145] mL/min/1.73 m(2); median total kidney volume, 859 [IQR, 577-1,299] mL), median copeptin level was 2.9 (IQR, 1.8-5.1) pmol/L. Copeptin was not associated with plasma osmolality (P = 0.3), the physiologic stimulus for AVP release, but was associated significantly with change in total kidney volume during follow-up (P < 0.001). This association remained significant after adjusting for sex, age, cardiovascular risk factors, and diuretic use (P = 0.03). Copeptin level was associated borderline significantly with change in mGFR after adjusting for these variables (P = 0.09). Limitations: No standardization of hydration status at time of copeptin measurement. Conclusions: These data show that in ADPKD, copeptin level, as a marker for AVP, is not correlated with plasma osmolality. Most importantly, high copeptin levels are associated independently with disease progression in early ADPKD. This is in line with experimental studies that indicate a disease-promoting role for AVP. Am J Kidney Dis. 61(3):420-429. (C) 2013 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Boertien, Wendy E.; Meijer, Esther; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Nephrol, Groningen, Netherlands. [Li, Jie; Bost, James E.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Struck, Joachim] ThermoFisher Sci, BRAHMS Biomarkers, Hennigsdorf, Germany. [Flessner, Michael F.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Torres, Vicente E.] Mayo Coll Med, Div Nephrol & Hypertens, Rochester, MN USA. RP Gansevoort, RT (reprint author), Univ Med Ctr Groningen, Dept Nephrol, POB 30-001, NL-9700 RB Groningen, Netherlands. EM r.t.gansevoort@umcg.nl FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [DK056943, DK056956, DK056957, DK056961]; National Center for Research Resources (NCRR) GCRCs at Emory [RR000039]; National Center for Research Resources (NCRR) GCRCs at Mayo [RR00585]; National Center for Research Resources (NCRR) GCRCs at Kansas [RR23940]; National Center for Research Resources (NCRR) GCRCs at UAB [RR000052]; NCRR CTSAs at Emory [RR025008]; NCRR CTSAs at Mayo [RR024150]; NCRR CTSAs at Kansas [RR033179]; NCRR CTSAs at UAB [RR025777]; NCRR CTSAs at Pittsburgh [RR024153]; Otsuka Pharmaceutical Development & Commercialization Inc, Rockville, MD FX Support: The CRISP Study is supported by cooperative agreements from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (DK056943, DK056956, DK056957, and DK056961) and by the National Center for Research Resources (NCRR) GCRCs at each institution (RR000039 Emory, RR00585 Mayo, RR23940 Kansas, and RR000052 UAB) and the NCRR CTSAs at each institution (RR025008 Emory, RR024150 Mayo, RR033179 Kansas, RR025777 UAB, and RR024153 Pittsburgh).; Financial Disclosure: Dr Struck is an employee of ThermoFisher Scientific, B. R. A. H. M. S. Biomarkers, which manufactures and holds patent rights on the copeptin assay. Drs Gansevoort and Torres are members of the Steering Committee of the TEMPO 3/4 Study, a randomized placebo-controlled clinical trial, that investigates the renoprotective effect of an AVPR2 antagonist in ADPKD. The TEMPO Study is sponsored by Otsuka Pharmaceutical Development & Commercialization Inc, Rockville, MD. NR 32 TC 32 Z9 34 U1 0 U2 9 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 MAR PY 2013 VL 61 IS 3 BP 420 EP 429 DI 10.1053/j.ajkd.2012.08.038 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 090GF UT WOS:000314966600012 PM 23089511 ER PT J AU Holton, P Ryten, M Nalls, M Trabzuni, D Weale, ME Hernandez, D Crehan, H Gibbs, JR Mayeux, R Haines, JL Farrer, LA Pericak-Vance, MA Schellenberg, GD Ramirez-Restrepo, M Engel, A Myers, AJ Corneveaux, JJ Huentelman, MJ Dillman, A Cookson, MR Reiman, EM Singleton, A Hardy, J Guerreiro, R AF Holton, Patrick Ryten, Mina Nalls, Michael Trabzuni, Daniah Weale, Michael E. Hernandez, Dena Crehan, Helen Gibbs, J. Raphael Mayeux, Richard Haines, Jonathan L. Farrer, Lindsay A. Pericak-Vance, Margaret A. Schellenberg, Gerard D. Ramirez-Restrepo, Manuel Engel, Anzhelika Myers, Amanda J. Corneveaux, Jason J. Huentelman, Matthew J. Dillman, Allissa Cookson, Mark R. Reiman, Eric M. Singleton, Andrew Hardy, John Guerreiro, Rita CA Alzheimer's Dis Genetics Consortiu TI Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci SO ANNALS OF HUMAN GENETICS LA English DT Article DE Alzheimer's disease; genetic risk; GWAS ID GENOME-WIDE ASSOCIATION; AMYLOID PRECURSOR PROTEIN; ATP-BINDING CASSETTE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; C3B/C4B RECEPTOR CR-1; ABC TRANSPORTERS; COMMON VARIANTS; HUMAN BRAIN; IN-VITRO; DISEASE AB Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease. C1 [Holton, Patrick; Ryten, Mina; Trabzuni, Daniah; Hernandez, Dena; Crehan, Helen; Gibbs, J. Raphael; Hardy, John; Guerreiro, Rita] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Nalls, Michael; Hernandez, Dena; Gibbs, J. Raphael; Dillman, Allissa; Cookson, Mark R.; Singleton, Andrew] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, Guys Hosp, London WC2R 2LS, England. [Mayeux, Richard] Columbia Univ, Gertrude H Sergievsky Ctr, Dept Neurol, New York, NY 10027 USA. [Mayeux, Richard] Columbia Univ, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA. [Haines, Jonathan L.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Haines, Jonathan L.] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Pericak-Vance, Margaret A.] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA. [Pericak-Vance, Margaret A.] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA. [Schellenberg, Gerard D.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Ramirez-Restrepo, Manuel; Engel, Anzhelika; Myers, Amanda J.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Ramirez-Restrepo, Manuel; Engel, Anzhelika; Myers, Amanda J.] Johnnie B Byrd Sr Alzheimers Ctr & Res Inst, Tampa, FL USA. [Corneveaux, Jason J.; Huentelman, Matthew J.; Reiman, Eric M.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. [Corneveaux, Jason J.; Huentelman, Matthew J.; Reiman, Eric M.] Arizona Alzheimers Consortium, Phoenix, AZ USA. [Dillman, Allissa] Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. [Reiman, Eric M.] Univ Arizona, Banner Alzheimers Inst, Phoenix, AZ USA. [Reiman, Eric M.] Univ Arizona, Dept Psychiat, Phoenix, AZ USA. [Reiman, Eric M.] Univ Arizona, Dept Psychiat, Tucson, AZ USA. [Hardy, John] UCL Inst Neurol, Reta Lila Weston Labs, London, England. RP Hardy, J (reprint author), UCL Inst Neurol, Dept Mol Neurosci, London, England. EM j.hardy@ion.ucl.ac.uk; j.hardy@ion.ucl.ac.uk RI Haines, Jonathan/C-3374-2012; Hardy, John/C-2451-2009; Kowall, Neil/G-6364-2012; Saykin, Andrew/A-1318-2007; Singleton, Andrew/C-3010-2009; Weale, Michael/F-2587-2010; Tsuang, Debby/L-7234-2016; Trabzuni, Daniah/C-4034-2012; OI Kowall, Neil/0000-0002-6624-0213; Saykin, Andrew/0000-0002-1376-8532; Weale, Michael/0000-0003-4593-1186; Tsuang, Debby/0000-0002-4716-1894; Farrer, Lindsay/0000-0001-5533-4225; Reisberg, Barry/0000-0002-9104-7423; Trabzuni, Daniah/0000-0003-4826-9570; Ferris, Steven/0000-0001-8641-6223 FU National Institute of Health, National Institute on Aging [Z01-AG000950-10]; National Institute on Aging [R01 AG034504, R01 AG031581, P30 AG19610, Z01 AG000950-06, P30AG10161, R01AG15819]; National Institute of Neurological Disorders and Stroke The Banner Alzheimer's Foundation [R01 NS059873]; Johnnie B. Byrd Sr. Alzheimer's Disease Institute; Medical Research Council; state of Arizona; National Alzheimer's Coordinating Center (NACC) [U01 AG016976]; MRC through the MRC Sudden Death Brain Bank; MRC Training Fellowship; King Faisal Hospital; National Institutes of Health, National Institute on Aging (NIH-NIA) [P01 AG019724, P30 AG028383, AG05144, P50 AG008671, P30 AG010124, P50 AG005133, AG030653, P50 AG005142, P30 AG012300, R01 AG027944, AG010491, AG027944, AG021547, AG019757, P50 AG005136, P50 AG005681, P01 AG03991, UO1 HG004610, UO1 AG06781, P30 AG10133, P50 AG005146, R01 AG020688, P50 AG005134, P50 AG016574]; NINDS [NS39764]; NIMH [MH60451]; Glaxo Smith Kline; Alzheimer's Association [IIRG-0889720, IIRG-05-14147]; US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program; Wellcome Trust; Howard Hughes Medical Institute; Canadian Institute of Health Research; Northern California Institute for Research and Education; Abbott; AstraZeneca AB; Bayer Schering Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Development; Elan Corporation; Genentech; GE Healthcare; GlaxoSmithKline; Innogenetics; Johnson and Johnson; Eli Lilly and Co.; Medpace, Inc.; Merck and Co., Inc.; Novartis AG; Pfizer Inc; F. Hoffman-La Roche; Schering-Plough; Synarc, Inc.; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Dana Foundation; National Institute of Biomedical Imaging and Bioengineering; NIA [U01 AG024904]; National Institutes of Health, National Institute on Aging (NIH-NIA). [U01 AG016976, U01 AG032984, RC2 AG036528, U24 AG021886, U24 AG026395, U24 AG026390, P30 AG019610, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193, P50 AG008702, R37 AG015473, P30 AG028377, AG05128]; National Institutes of Health, National Institute of Aging (NIH-NIA) [AG025688, RC2 AG036535, K01 AG030514, P50 AG005138, P01 AG002219]; National Institutes of Health (NIH), National Institute of Aging (NIH-NIA) [R01 AG031581, R01 NS059873, R01 AG026916, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146, P50 AG016582, UL1RR02777, P30 AG010129, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577, P50 AG016570, P50 AG005131, P50 AG023501]; National Institutes of Health (NIH), National Institute of Aging (NIH-NIA). [P30 AG08051, MO1RR00096, UL1 RR029893, P30 AG013854, P30 AG008017] FX The authors have no conflicts of interest regarding this study. This work was supported in part by the Intramural Research Program of the National Institute of Health, National Institute on Aging (Z01-AG000950-10), and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). Genotyping of the TGEN2 cohort was supported by Kronos Science; The National Institute on Aging [R01 AG034504, R01 AG031581, P30 AG19610, Z01 AG000950-06, P30AG10161, R01AG15819]; The National Institute of Neurological Disorders and Stroke [R01 NS059873] The Banner Alzheimer's Foundation; The Johnnie B. Byrd Sr. Alzheimer's Disease Institute; The Medical Research Council; and the state of Arizona. Many data and biomaterials were collected from several National Institute on Aging (NIA) and National Alzheimer's Coordinating Center (NACC, grant #U01 AG016976) funded sites. This work was also partially supported by the MRC through the MRC Sudden Death Brain Bank. MR was supported by an MRC Training Fellowship and DT was supported by King Faisal Hospital.; We thank the brain donors and their families for their selfless donation to the fight against this disease. Amanda J. Myers, PhD (University of Miami, Department of Psychiatry) and John A. Hardy, PhD (Reta Lila Weston Institute, University College London) collected and prepared the series. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD andWalter Kukull, PhD are thanked for helping to co-ordinate this collection. The directors, pathologist and technicians involved include: University of Michigan (NIH grant P50-AG08671): Dr. Roger Albin, Lisa Bain, Eszter Gombosi, The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek): Inge Huitinga, MD, Marleen Rademaker, Michiel Kooreman. We thank Colin Smith and Robert Walker at the Sudden Death Brain Bank for their help.; The National Institutes of Health, National Institute on Aging (NIH-NIA) supported the ADGC through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-0889720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P. S. G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.; ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514.; ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. NR 68 TC 22 Z9 22 U1 0 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD MAR PY 2013 VL 77 BP 85 EP 105 DI 10.1111/ahg.12000 PN 2 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA 093MW UT WOS:000315197000001 PM 23360175 ER PT J AU Kley, RA van der Ven, PFM Olive, M Hohfeld, J Goldfarb, LG Furst, DO Vorgerd, M AF Kley, Rudolf A. van der Ven, Peter F. M. Olive, Montse Hoehfeld, Joerg Goldfarb, Lev G. Fuerst, Dieter O. Vorgerd, Matthias TI Impairment of protein degradation in myofibrillar myopathy caused by FLNC/filamin C mutations SO AUTOPHAGY LA English DT Editorial Material DE filaminopathy; myofibrillar myopathy; autophagy; chaperone-associated selective autophagy; ubiquitin proteasome system; heat shock proteins; immunolocalization studies AB Myofibrillar myopathy caused by FLNC/filamin C mutations is characterized by disintegration of myofibrils and a massive formation of protein aggregates within skeletal muscle fibers. We performed immunofluorescence studies in skeletal muscle sections from filaminopathy patients to detect disturbances of protein quality control mechanisms. Our analyses revealed altered expression of chaperone proteins and components of proteasomal and autophagic degradation pathways in abnormal muscle fibers that harbor protein deposits but not in neighboring muscle fibers without pathological protein aggregation. These findings suggest a dysfunction of protein stabilizing and degrading mechanisms that leads to a pathological accumulation of protein aggregates in abnormal fibers. Accordingly, a pharmacological modulation of chaperone activity may be a promising therapeutic strategy to prevent protein aggregation and to reduce disease progression. Newly established filaminopathy cell culture models provide a suitable basis for testing such pharmacological approaches. C1 [Kley, Rudolf A.; Vorgerd, Matthias] Ruhr Univ Bochum, Dept Neurol, Neuromuscular Ctr Ruhrgebiet, Univ Hosp Bergmannsheil, Bochum, Germany. [van der Ven, Peter F. M.; Hoehfeld, Joerg; Fuerst, Dieter O.] Univ Bonn, Inst Cell Biol, Bonn, Germany. [Olive, Montse] Hosp Univ Bellvitge, Inst Neuropathol, Dept Pathol, Neuromuscular Unit,Dept Neurol,IDIBELL, Barcelona, Spain. [Olive, Montse] Hosp Llobregat, CIBERNED, Barcelona, Spain. [Goldfarb, Lev G.] NIH, Bethesda, MD 20892 USA. RP Kley, RA (reprint author), Ruhr Univ Bochum, Dept Neurol, Neuromuscular Ctr Ruhrgebiet, Univ Hosp Bergmannsheil, Univ Str 150, Bochum, Germany. EM rudolf.kley@rub.de OI Olive, Montse/0000-0001-5727-0165 NR 0 TC 10 Z9 10 U1 0 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD MAR PY 2013 VL 9 IS 3 BP 422 EP 423 DI 10.4161/auto.22921 PG 2 WC Cell Biology SC Cell Biology GA 094XY UT WOS:000315300000018 PM 23238331 ER PT J AU Fradejas, N Carlson, BA Rijntjes, E Becker, NP Tobe, R Schweizer, U AF Fradejas, Noelia Carlson, Bradley A. Rijntjes, Eddy Becker, Niels-Peter Tobe, Ryuta Schweizer, Ulrich TI Mammalian Trit1 is a tRNA([Ser]Sec)-isopentenyl transferase required for full selenoprotein expression SO BIOCHEMICAL JOURNAL LA English DT Article DE dimethylallyl:tRNA([Ser]Sec) transferase; N-6-isopentenyladenosine (i(6)A); isopentenyl tRNA transferase (IPT); isopentenylation; selenium; tRNA modification ID SELENOCYSTEINE TRANSFER-RNAS; TUMOR-SUPPRESSOR GENE; ESCHERICHIA-COLI; ANTICODON; LACKING; CANCER; N6-(DELTA2-ISOPENTENYL)ADENOSINE; DIMETHYLALLYLTRANSFERASE; BIOSYNTHESIS; SNAPSHOTS AB Selenoproteins are proteins carrying the rare amino acid Sec (selenocysteine). Full expression of selenoproteins requires modification of tRNA([Ser]Sec), including N-6-isopentenylation of base A(37). We show that Trit1 is a dimethylallyl:tRNA([Ser]Sec) transferase. Knockdown of Trit1 reduces expression of selenoproteins. Incubation of in vitro transcribed tRNA([Ser]Sec) with recombinant Trit1 transfers [C-14]dimethylallyl pyrophosphate to tRNA([Ser]Sec). 37A>G tRNA([Ser]Sec) is resistant to isopentenylation by Trit1. C1 [Fradejas, Noelia; Rijntjes, Eddy; Becker, Niels-Peter; Schweizer, Ulrich] Charite, Inst Expt Endokrinol, D-13353 Berlin, Germany. [Carlson, Bradley A.; Tobe, Ryuta] NCI, Mol Biol Selenium Sect, BRL, NIH, Bethesda, MD 20892 USA. [Schweizer, Ulrich] Univ Bonn, Inst Biochem & Mol Biol, D-53115 Bonn, Germany. RP Schweizer, U (reprint author), Charite, Inst Expt Endokrinol, D-13353 Berlin, Germany. EM ulrich.schweizer@uni-bonn.de RI Schweizer, Ulrich/E-8105-2013; OI Schweizer, Ulrich/0000-0003-1380-4780 FU Junta de Comunidades de Castilla-La Mancha (Spain); Deutsche Forschungsgemeinschaft [Schw914/2-1]; Charite-Universitatsmedizin Berlin FX N.F. was supported by Junta de Comunidades de Castilla-La Mancha (Spain). U.S. was supported by Deutsche Forschungsgemeinschaft [grant number Schw914/2-1] and Charite-Universitatsmedizin Berlin. NR 31 TC 7 Z9 7 U1 0 U2 8 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAR 1 PY 2013 VL 450 BP 427 EP 432 DI 10.1042/BJ20121713 PN 2 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 094HJ UT WOS:000315253300018 PM 23289710 ER PT J AU Carmona-Rivera, C Simeonov, DR Cardillo, ND Gahl, WA Cadilla, CL AF Carmona-Rivera, Carmelo Simeonov, Dimitre R. Cardillo, Nicholas D. Gahl, William A. Cadilla, Carmen L. TI A divalent interaction between HPS1 and HPS4 is required for the formation of the biogenesis of lysosome-related organelle complex-3 (BLOC-3) SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE HPS; Hermansky-Pudlak syndrome; Oculocutaneous albinism; Bleeding; BLOC-3; Lysosome-related organelle ID HERMANSKY-PUDLAK-SYNDROME; DYSTROPHIN RESTORATION; GENE; PROTEINS; MUTATIONS; FORM; AUTOINHIBITION; TRAFFICKING; CHIPS AB Hermansky-Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism, a bleeding tendency, and sporadic pulmonary fibrosis, granulomatous colitis or infections. Nine HPS-causing genes have been identified in humans. HPS-1 is the most severe subtype with a prevalence of similar to 1/1800 in northwest Puerto Rico due to a founder mutation in the HPS1 gene. Mutations in HPS genes affect the biogenesis of lysosome-related organelles such as melanosomes in melanocytes and platelet dense granules. Two of these genes (HPS1 and HPS4) encode the HPS1 and HPS4 proteins, which assemble to form a complex known as Biogenesis of Lysosome-related Organelle Complex 3 (BLOC-3). We report the identification of the interacting regions in HPS1 and HPS4 required for the formation of this complex. Two regions in HPS1, spanning amino acids 1-249 and 506-700 are required for binding to HPS4; the middle portion of HPS1 (residues 250-505) is not required for this interaction. Further interaction studies showed that the N-termini of HPS1 and HPS4 interact with each other and that a discrete region of HPS4 (residues 340-528) interacts with both the N- and C-termini of the HPS1 protein. Several missense mutations found in HPS-1 patients did not affect interaction with HPS4, but some mutations involving regions interacting with HPS4 caused instability of HPS1. These observations extend our understanding of BLOC-3 assembly and represent an important first step in the identification of domains responsible for the biogenesis of lysosome-related organelles. (C) 2012 Elsevier B.V. All rights reserved. C1 [Carmona-Rivera, Carmelo; Cadilla, Carmen L.] Univ Puerto Rico, Sch Med, Dept Biochem, San Juan, PR 00936 USA. [Carmona-Rivera, Carmelo; Simeonov, Dimitre R.; Cardillo, Nicholas D.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Cadilla, CL (reprint author), Univ Puerto Rico, Sch Med, Dept Biochem, POB 365067, San Juan, PR 00936 USA. EM carmen.cadilla@upr.edu FU NIH-IRTA Program; National Center for Research Resources [2G12RR003051]; National Institute on Minority Health and Health Disparities [8G12MD007600]; UPR School of Medicine Associate; [MBRS RISE R25GM068138] FX We thank Drs. J. S. Bonifacino, R. Mattera, G. A. Mardones, P. V. Burgos and R.A. Spritz for kind gifts of reagents and/or critical reading of the manuscript. This work was partially supported by the NIH-IRTA Program and grant MBRS RISE R25GM068138. Infrastructure support was provided in part by grants from the National Center for Research Resources (2G12RR003051) and the National Institute on Minority Health and Health Disparities (8G12MD007600). Funds to support this project were also provided by the UPR School of Medicine Associate Deanship of Biomedical Sciences. NR 29 TC 8 Z9 8 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD MAR PY 2013 VL 1833 IS 3 BP 468 EP 478 DI 10.1016/j.bbamcr.2012.10.019 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 095AY UT WOS:000315308100004 PM 23103514 ER PT J AU Di Florio, A Sancho, V Moreno, P Delle Fave, G Jensen, RT AF Di Florio, Alessia Sancho, Veronica Moreno, Paola Delle Fave, Gianfranco Jensen, Robert T. TI Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Neuroendocrine tumors; Transactivation; Gastrointestinal hormones; Cell growth; Pancreatic endocrine tumors ID GASTRIN-RELEASING-PEPTIDE; LUNG-CANCER CELLS; PANCREATIC ENDOCRINE TUMORS; PROTEIN-COUPLED RECEPTORS; TYROSINE PHOSPHORYLATION; SIGNALING PATHWAYS; CARCINOID-TUMORS; DNA-SYNTHESIS; EXPRESSION; KINASE AB Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGF alpha and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGF alpha and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs. Published by Elsevier B.V. C1 [Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Delle Fave, Gianfranco] Univ Roma La Sapienza, S Andrea Hosp, Sch Med 2, Digest & Liver Dis Unit, I-00189 Rome, Italy. RP Jensen, RT (reprint author), 10 Ctr Dr,Bldg 10,Room 9C103, Bethesda, MD 20814 USA. EM robertj@bdg10.niddk.nih.gov FU NIDDK, NIH FX This work is partially supported by the Intramural Research Program of the NIDDK, NIH. NR 57 TC 12 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD MAR PY 2013 VL 1833 IS 3 BP 573 EP 582 DI 10.1016/j.bbamcr.2012.11.021 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 095AY UT WOS:000315308100015 PM 23220008 ER PT J AU Shah, S Wolitz, R Emanuel, E AF Shah, Seema Wolitz, Rebecca Emanuel, Ezekiel TI REFOCUSING THE RESPONSIVENESS REQUIREMENT SO BIOETHICS LA English DT Article DE international research ethics; global health; priority setting; responsiveness ID DEVELOPING-COUNTRIES; PRIORITIES; HEALTH; KENYA AB Many guidelines for international research require that studies be responsive to host community health needs or health priorities. Although responsiveness possesses great intuitive and rhetorical appeal, existing conceptions are confusing and difficult to apply. Not only are there few examples of what research the responsiveness requirement permits and what it rejects, but its application can lead to contradictory results. Because of the practical difficulties in applying responsiveness and the danger that misapplying responsiveness could harm the interests of developing countries, we argue that responsiveness should be refocused in three ways: in terms of (1) who enforces it, (2) under what standard, and (3) in what cases. We conclude that responsiveness should be applied by host country officials at the policy level with the exercise of judgment when externally funded research threatens to displace scarce local resources. C1 [Shah, Seema; Wolitz, Rebecca; Emanuel, Ezekiel] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Shah, Seema] NIH, Div AIDS, Bethesda, MD 20892 USA. RP Shah, S (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU National Institutes of Health through the Warren G. Magnussen Clinical Center FX We thank Annette Rid, Nicola Barsdorf, Joe Millum, Chiara Lepora, Joel Breman, Harold Pollack, Ruth Macklin, Christine Grady, and various members of the Department of Bioethics for their helpful feedback, criticism, and suggestions. This research was supported by the Intramural Research Program of the National Institutes of Health through the Warren G. Magnussen Clinical Center. The opinions expressed are the view of the authors and do not represent any position or policy of the US National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. NR 49 TC 9 Z9 9 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 J9 BIOETHICS JI Bioethics PD MAR PY 2013 VL 27 IS 3 BP 151 EP 159 DI 10.1111/j.1467-8519.2011.01903.x PG 9 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 091KS UT WOS:000315048800006 PM 21797911 ER PT J AU Chigurupati, S Mughal, MR Okun, E Das, S Kumar, A McCaffery, M Seal, S Mattson, MP AF Chigurupati, Srinivasulu Mughal, Mohamed R. Okun, Eitan Das, Soumen Kumar, Amit McCaffery, Michael Seal, Sudipta Mattson, Mark P. TI Effects of cerium oxide nanoparticles on the growth of keratinocytes, fibroblasts and vascular endothelial cells in cutaneous wound healing SO BIOMATERIALS LA English DT Article DE Cerium oxide nanoparticles; Vascular endothelial cells; Keratinocytes; Fibroblasts; Wound healing; Oxidative stress ID TUBBY MICE; NANOCERIA; ANTIOXIDANT; ANGIOGENESIS; DEGENERATION; MODULATION; PROTECTION; PROTEINS; REPAIR AB Rapid and effective wound healing requires a coordinated cellular response involving fibroblasts, keratinocytes and vascular endothelial cells (VECs). Impaired wound healing can result in multiple adverse health outcomes and, although antibiotics can forestall infection, treatments that accelerate wound healing are lacking. We now report that topical application of water soluble cerium oxide nanoparticles (Nanoceria) accelerates the healing of full-thickness dermal wounds in mice by a mechanism that involves enhancement of the proliferation and migration of fibroblasts, keratinocytes and VECs. The Nanoceria penetrated into the wound tissue and reduced oxidative damage to cellular membranes and proteins, suggesting a therapeutic potential for topical treatment of wounds with antioxidant nanoparticles. Published by Elsevier Ltd. C1 [Chigurupati, Srinivasulu; Mughal, Mohamed R.; Okun, Eitan; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Chigurupati, Srinivasulu] Univ Cent Florida, Burnett Sch Biomed Sci, Dept Mol Biol & Microbiol, Orlando, FL 32816 USA. [Chigurupati, Srinivasulu; Das, Soumen; Kumar, Amit; Seal, Sudipta] Univ Cent Florida, Nanosci Technol Ctr NSTC, Adv Mat Proc & Anal Ctr, Orlando, FL 32816 USA. [McCaffery, Michael] Johns Hopkins Univ, Engn Oncol Ctr, Dept Biol, Integrated Imaging Ctr, Baltimore, MD 21218 USA. [McCaffery, Michael] Johns Hopkins Univ, Inst NanoBiotechnol, Baltimore, MD 21218 USA. [Okun, Eitan] Bar Ilan Univ, Leslie & Susan Gonda Multidisciplinary Brain Res, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM Sudipta.Seal@ucf.edu; mattsonm@grc.nia.nih.gov RI Kumar, Amit/E-9483-2011 FU National Institute on Aging Intramural Research Program of the NIH; National Science Foundation (NIRT: CBET) FX This research was supported by the National Institute on Aging Intramural Research Program of the NIH. SS acknowledges the grant from National Science Foundation (NIRT: CBET) for funding the nanotechnology research. NR 32 TC 57 Z9 58 U1 12 U2 65 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD MAR PY 2013 VL 34 IS 9 BP 2194 EP 2201 DI 10.1016/j.biomaterials.2012.11.061 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 093GH UT WOS:000315179200005 PM 23266256 ER PT J AU Hall, C Troutman, SM Price, DK Figg, WD Kang, MH AF Hall, Connor Troutman, Sarah M. Price, Douglas K. Figg, William D. Kang, Min H. TI Bcl-2 Family of Proteins as Therapeutic Targets in Genitourinary Neoplasms SO CLINICAL GENITOURINARY CANCER LA English DT Review DE Apoptosis; Bcl-2 inhibitors ID RENAL-CELL CARCINOMA; PROSTATE-CANCER CELLS; DOCETAXEL PLUS PREDNISONE; RANDOMIZED PHASE-III; HUMAN BREAST-CANCER; BLADDER-CANCER; OBLIMERSEN SODIUM; IMMUNOHISTOCHEMICAL ANALYSIS; IN-VITRO; ANTISENSE OLIGONUCLEOTIDE AB Introduction: Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms. Materials and Methods: PubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology. Results: To date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(-)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors. Conclusion: Antiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation. Clinical Genitourinary Cancer, Vol. 11, No. 1, 10-9 Published by Elsevier Inc. C1 [Hall, Connor; Kang, Min H.] TTUHSC, Sch Med, Ctr Canc, Lubbock, TX 79416 USA. [Hall, Connor; Kang, Min H.] TTUHSC, Sch Med, Lubbock, TX 79416 USA. [Troutman, Sarah M.; Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Branch, Bethesda, MD 20892 USA. [Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. RP Kang, MH (reprint author), TTUHSC, Sch Med, 3601 4th St STOP 9445, Lubbock, TX 79416 USA. EM min.kang@ttuhsc.edu RI Figg Sr, William/M-2411-2016 NR 109 TC 7 Z9 7 U1 1 U2 16 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 MAR PY 2013 VL 11 IS 1 BP 10 EP 19 DI 10.1016/j.clgc.2012.09.002 PG 10 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 094PL UT WOS:000315276200003 PM 23083798 ER PT J AU Zhao, Y Li, CM Sun, X Mu, WW McGoogan, JM He, Y Cheng, YW Tang, ZR Li, HQ Ni, MJ Ma, Y Chen, RY Liu, ZF Zhang, FJ AF Zhao, Yan Li, Chunming Sun, Xin Mu, Weiwei McGoogan, Jennifer M. He, Yun Cheng, Yuewu Tang, Zhirong Li, Huiqin Ni, Mingjian Ma, Ye Chen, Ray Y. Liu, Zhongfu Zhang, Fujie TI Mortality and Treatment Outcomes of China's National Pediatric Antiretroviral Therapy Program SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; mortality; pediatric; antiretroviral therapy; China ID HIV-INFECTED CHILDREN; HIV-1-INFECTED CHILDREN; CLINICAL-OUTCOMES; OBSERVATIONAL COHORT; CD4; ART; ADOLESCENTS; RESPONSES; CAMBODIA; DATABASE AB Background. The aim of this study was to describe 3-year mortality rates, associated risk factors, and long-term clinical outcomes of children enrolled in China's national free pediatric antiretroviral therapy (ART) program. Methods. Records were abstracted from the national human immunodeficiency virus (HIV)/AIDS case reporting and national pediatric ART databases for all HIV-positive children <= 15 years old who initiated ART prior to December 2010. Mortality risk factors over 3 years of follow-up were examined using Cox proportional hazards regression models. Life tables were used to determine survival rate over time. Longitudinal plots of CD4(+) T-cell percentage (CD4%), hemoglobin level, weight-for-age z (WAZ) score, and height-for-age z (HAZ) score were created using generalized estimating equation models. Results. Among the 1818 children included in our cohort, 93 deaths were recorded in 4022 child-years (CY) of observed time for an overall mortality rate of 2.31 per 100 CY (95% confidence interval [CI], 1.75-2.78). The strongest factor associated with mortality was baseline WAZ score <-2 (adjusted hazard ratio [HR] = 9.1; 95% CI, 2.5-33.2), followed by World Health Organization stage III or IV disease (adjusted HR = 2.4; 95% CI, 1.1-5.2), and hemoglobin <90 g/L (adjusted HR = 2.2; 95% CI, 1.2-3.9). CD4%, hemoglobin level, WAZ score, and HAZ score increased over time. Conclusions. Our finding that 94% of children engaged in this program are still alive and of improved health after 3 years of treatment demonstrates that China's national pediatric ART program is effective. This program needs to be expanded to better meet treatment demands, and efforts to identify HIV-positive children earlier must be prioritized. C1 [Zhao, Yan; Li, Chunming; Sun, Xin; Mu, Weiwei; McGoogan, Jennifer M.; Ma, Ye; Liu, Zhongfu; Zhang, Fujie] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing 100050, Peoples R China. [Chen, Ray Y.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Zhang, Fujie] Capital Med Univ, Beijing Ditan Hosp, Beijing, Peoples R China. RP Zhang, FJ (reprint author), Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, 27 Nanwei Rd, Beijing 100050, Peoples R China. OI Chen, Ray/0000-0001-6344-1442 FU Chinese government; Important National Science and Technology Specific Projects [2008ZX10001-007]; Fogarty International Center; National Institute on Drug Abuse of the US National Institutes of Health [5U2RTW006918-07] FX This work was supported by the Chinese government; the Important National Science and Technology Specific Projects (2008ZX10001-007); and the Fogarty International Center and the National Institute on Drug Abuse of the US National Institutes of Health (5U2RTW006918-07 to Y. Z.). NR 39 TC 12 Z9 14 U1 1 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 1 PY 2013 VL 56 IS 5 BP 735 EP 744 DI 10.1093/cid/cis941 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 091OR UT WOS:000315060200022 PM 23175558 ER PT J AU Marti, JD Bassi, GL Rigol, M Saucedo, L Ranzani, OT Esperatti, M Luque, N Ferrer, M Vilaro, J Kolobow, T Torres, A AF Daniel Marti, Joan Li Bassi, Gianluigi Rigol, Montserrat Saucedo, Lina Tavares Ranzani, Otavio Esperatti, Mariano Luque, Nestor Ferrer, Miguel Vilaro, Jordi Kolobow, Theodor Torres, Antoni TI Effects of Manual Rib Cage Compressions on Expiratory Flow and Mucus Clearance During Mechanical Ventilation SO CRITICAL CARE MEDICINE LA English DT Article DE expiratory flow; mechanical ventilation; mucus; physiotherapy ID CHEST PHYSIOTHERAPY; POSTURAL DRAINAGE; MUCOUS VELOCITY; TRANSPORT; AIRWAYS; INFANTS; COUGH; MODEL AB Objectives: We investigated the effects of two different types of manual rib cage compression on expiratory flow and mucus clearance during prolonged mechanical ventilation in pigs. Design: Prospective randomized animal study. Setting: Animal research facility, University of Barcelona, Spain. Subjects: Nine healthy pigs. Measurement and Main Results: Pigs were tracheally intubated, sedated, paralyzed, and mechanically ventilated. The animals were prone on a surgical bed in the anti-Trendelenburg position. The experiments were carried out at approximately 60 and 80 hrs from the beginning of mechanical ventilation. Two types of manual rib cage compressions were tested: Hard and brief rib cage compressions synchronized with early expiratory phase (hard manual rib cage compression) and soft and gradual rib cage compressions applied during the late expiratory phase (soft manual rib cage compression). The interventions were randomly applied for 15 min with a 15-min interval between treatments. Respiratory flow and mucus movement were assessed during the interventions. Respiratory mechanics and hemodynamics were assessed prior to and after the interventions. Peak expiratory flow increased to 60.1 +/- 7.1 L/min in comparison to 51.2 +/- 4.6L/min without treatment (p < 0.0015) and 48.7 +/- 4.3 L/min with soft manual rib cage compression (p = 0.0002). Similarly, mean expiratory flow increased to 28.4 +/- 5.2 L/min during hard manual rib cage compression vs. 15.9 +/- 2.2 and 16.6 +/- 2.8 L/min without treatment and soft manual rib cage compression, respectively (p = 0.0006). During hard manual rib cage compression, mucus moved toward the glottis (1.01 +/- 2.37 mm/min); conversely, mucus moved toward the lungs during no treatment and soft manual rib cage compression, -0.28 +/- 0.61 and -0.15 +/- 0.95 mm/min, respectively (p = 0.0283). Soft manual rib cage compression slightly worsened static lung elastance and cardiac output (p = 0.0391). Conclusions: Hard manual rib cage compression improved mucus clearance in animals positioned in the anti-Trendelenburg position. The technique appeared to be safe. Conversely, soft manual rib cage compression was not effective and potentially unsafe. These findings corroborate the predominant role of peak expiratory flow on mucus clearance. (Crit Care Med 2013; 41:850-856) C1 [Daniel Marti, Joan; Li Bassi, Gianluigi; Rigol, Montserrat; Saucedo, Lina; Tavares Ranzani, Otavio; Esperatti, Mariano; Luque, Nestor; Ferrer, Miguel; Torres, Antoni] Hosp Clin Barcelona, Pulm & Crit Care Unit, Div Anim Experimentat, Thorax Inst, Barcelona, Spain. [Li Bassi, Gianluigi; Rigol, Montserrat; Ferrer, Miguel; Torres, Antoni] Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Li Bassi, Gianluigi; Ferrer, Miguel] Ctr Invest Biomed Red Enfermedades Resp, Mallorca, Spain. [Rigol, Montserrat; Torres, Antoni] Hosp Clin Barcelona, Dept Cardiol, Thorax Inst, Barcelona, Spain. [Tavares Ranzani, Otavio] Univ Sao Paulo, Fac Med, Resp Intens Care Unit, Pulm Div InCor, Sao Paulo, Brazil. [Vilaro, Jordi] FCS Blanquerna, Res Grp GReFis, Barcelona, Spain. [Kolobow, Theodor] NHLBI, Pulm & Crit Care Med Branch, Sect Pulm & Cardiac Assist Devices, NIH, Bethesda, MD 20892 USA. [Torres, Antoni] Univ Barcelona, Barcelona, Spain. Univ Barcelona, Anim Res Labs, E-08007 Barcelona, Spain. RP Torres, A (reprint author), Hosp Clin Barcelona, Pulm & Crit Care Unit, Div Anim Experimentat, Thorax Inst, Barcelona, Spain. EM atorres@clinic.ub.es RI Ranzani, Otavio/K-1196-2012; OI Ranzani, Otavio/0000-0002-4677-6862; Vilaro, Jordi/0000-0002-2150-8992 FU Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS); Ministerio de Ciencia e Innovacion [PS09/01249]; European Society of Intensive Care Medicine-ESICM; Fundacio Catalana de Pneumologia (FUCAP); SEPAR-ALAT fellowship, Sociedad Espanola, de Neumologia y Cirugia Toracica (SEPAR); Centro de Investigacion Biomedica En Red-Enfermedades Respiratorias (CIBERES); University of Barcelona; Covidien FX Supported by the Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Ministerio de Ciencia e Innovacion (PS09/01249); European Society of Intensive Care Medicine-ESICM (2009 Alain Harf Award on Applied Respiratory Physiology); Fundacio Catalana de Pneumologia (FUCAP); SEPAR-ALAT fellowship, Sociedad Espanola, de Neumologia y Cirugia Toracica (SEPAR); Centro de Investigacion Biomedica En Red-Enfermedades Respiratorias (CIBERES); and University of Barcelona.; Dr. Li Bassi received grant support from Covidien and royalties from the NIH. Dr. Torres has board membership with Astellas and has consulted for Bayer. He received grant support from Covidien. The remaining author have not disclosed any potential conflicts of interest. NR 28 TC 11 Z9 11 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2013 VL 41 IS 3 BP 850 EP 856 DI 10.1097/CCM.0b013e3182711b52 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 095BB UT WOS:000315308400017 PM 23314585 ER PT J AU Nguyen, R Perfetto, S Mahnke, YD Chattopadhyay, P Roederer, M AF Nguyen, Richard Perfetto, Stephen Mahnke, Yolanda D. Chattopadhyay, Pratip Roederer, Mario TI Quantifying spillover spreading for comparing instrument performance and aiding in multicolor panel design SO CYTOMETRY PART A LA English DT Article DE compensation; quality control; sensitivity; immunophenotyping ID FLOW-CYTOMETRY; COMPENSATION AB After compensation, the measurement errors arising from multiple fluorescences spilling into each detector become evident by the spreading of nominally negative distributions. Depending on the instrument configuration and performance, and reagents used, this spillover spreading (SS) affects sensitivity in any given parameter. The degree of SS had been predicted theoretically to increase with measurement error, i.e., by the square root of fluorescence intensity, as well as directly related to the spectral overlap matrix coefficients. We devised a metric to quantify SS between any pair of detectors. This metric is intrinsic, as it is independent of fluorescence intensity. The combination of all such values for one instrument can be represented as a spillover spreading matrix (SSM). Single-stained controls were used to determine the SSM on multiple instruments over time, and under various conditions of signal quality. SSM values reveal fluorescence spectrum interactions that can limit the sensitivity of a reagent in the presence of brightly-stained cells on a different color. The SSM was found to be highly reproducible; its non-trivial values show a CV of less than 30% across a 2-month time frame. In addition, the SSM is comparable between similarly-configured instruments; instrument-specific differences in the SSM reveal underperforming detectors. Quantifying and monitoring the SSM can be a useful tool in instrument quality control to ensure consistent sensitivity and performance. In addition, the SSM is a key element for predicting the performance of multicolor immunofluorescence panels, which will aid in the optimization and development of new panels. We propose that the SSM is a critical component of QA/QC in evaluation of flow cytometer performance. Published 2013 Wiley- Periodicals, Inc. C1 [Nguyen, Richard; Perfetto, Stephen] NIAID, Flow Cytometry Core, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Mahnke, Yolanda D.; Chattopadhyay, Pratip; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. EM roederer@nih.gov OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural Research Program of the National Institute for Allergy and Infectious Diseases of the National Institutes of Health FX Grant sponsor: Intramural Research Program of the National Institute for Allergy and Infectious Diseases of the National Institutes of Health NR 7 TC 12 Z9 13 U1 1 U2 9 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 MAR PY 2013 VL 83A IS 3 BP 306 EP 315 DI 10.1002/cyto.a.22251 PG 10 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 094XP UT WOS:000315299000009 PM 23389989 ER PT J AU Ward, MM AF Ward, Michael M. TI Sense of Control and Self-Reported Health in a Population-Based Sample of Older Americans: Assessment of Potential Confounding by Affect, Personality, and Social Support SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Sense of control; Affect; Personality; Social support; Self-reported health ID PSYCHOSOCIAL FACTORS; RISK-FACTORS; SOCIOECONOMIC DIFFERENCES; PERCEIVED CONTROL; PRIMARY-CARE; MORTALITY; OUTCOMES; ADULTS; LOCUS; LIFE AB Sense of control has been linked to improved health outcomes, but it is unclear if this association is independent of other psychosocial factors. The aim of this study is to test the strength of association between sense of control and self-reported health after adjustment for positive and negative affect, "Big 5" personality factors, and social support. Data on sense of control (measured by personal mastery, perceived constraints, and a health-specific rating of control), affect, personality, social support, and two measures of self-reported health (global rating of fair or poor health and presence of functional limitations) were obtained on 6,891 participants in the Health and Retirement Study, a population-based survey of older Americans. The cross-sectional association between sense of control measures and each measure of self-reported health was tested in hierarchical logistic regression models, before and after adjustment for affect, personality, and social support. Participants with higher personal mastery were less likely to report fair/poor health (odds ratio 0.76 per 1-point increase) while those with higher perceived constraints were more likely to report fair/poor health (odds ratio 1.37 per 1-point increase). Associations remained after adjustment for affect, but adjustment for affect attenuated the association of personal mastery by 37% and of perceived constraints by 67%. Further adjustment for personality and social support did not alter the strength of association. Findings were similar for the health-specific rating of control, and for associations with functional limitations. Sense of control is associated with self-reported health in older Americans, but this association is partly confounded by affect. C1 NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, Intramural Res Program, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [ZIA AR041153-07] NR 37 TC 7 Z9 7 U1 2 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD MAR PY 2013 VL 20 IS 1 BP 140 EP 147 DI 10.1007/s12529-011-9218-x PG 8 WC Psychology, Clinical SC Psychology GA 094NQ UT WOS:000315271400019 PM 22282403 ER PT J AU Robbins, PF AF Robbins, Paul F. TI Helping Tumor Cells To Die SO JOURNAL OF IMMUNOLOGY LA English DT Editorial Material ID METASTATIC MELANOMA PATIENTS; DISSEMINATED MURINE LEUKEMIA; CD8(+) T-CELLS; INFILTRATING LYMPHOCYTES; ADOPTIVE IMMUNOTHERAPY; CYCLOPHOSPHAMIDE; THERAPY; ELIMINATION; ERADICATION; REGRESSION C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Robbins, PF (reprint author), NCI, Surg Branch, CRC 3-5744,10 Ctr Dr, Bethesda, MD 20892 USA. EM paulrobbins@mail.nih.gov NR 21 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2013 VL 190 IS 5 BP 1897 EP 1898 DI 10.4049/jimmunol.1300045 PG 2 WC Immunology SC Immunology GA 091ZT UT WOS:000315089100003 PM 23417525 ER PT J AU Dillahunt, SE Sargent, JL Suzuki, R Proia, RL Gilfillan, A Rivera, J Olivera, A AF Dillahunt, Sandra E. Sargent, Jennifer L. Suzuki, Ryo Proia, Richard L. Gilfillan, Alasdair Rivera, Juan Olivera, Ana TI Usage of Sphingosine Kinase Isoforms in Mast Cells Is Species and/or Cell Type Determined SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; IN-VITRO; ACTIVATION; SPHINGOSINE-1-PHOSPHATE; 1-PHOSPHATE; CONTRIBUTES; DEGRANULATION; INFLAMMATION; EXPRESSION; RECEPTORS AB Fc epsilon RI engagement in mast cells (MCs) induces the activation of two distinct sphingosine kinase isoforms (SphK1 and SphK2) to produce sphingosine-1-phosphate, a mediator essential for MC responses. Whereas embryonic-derived SphK2-null MCs showed impaired responses to Ag, RNA silencing studies on other MC types indicated a dominant role for SphK1. Given the known functional heterogeneity of MCs, we explored whether the reported differences in SphK1 or SphK2 usage could be reflective of phenotypic differences between MC populations. Using lentiviral-based short hairpin RNA to silence SphK1 or SphK2, we found that SphK2 is required for murine MC degranulation, calcium mobilization, and cytokine and leukotriene production, irrespective of the tissue from which the MC progenitors were derived, the stage of MC granule maturity, or the conditions used for differentiation. This finding was consistent with the lack of a full allergic response in SphK2-null mice challenged to undergo passive cutaneous anaphylaxis. A redundant role for both SphKs was uncovered, however, in chemotaxis toward Ag in all MC types tested and in TNF-alpha production in certain MC types. In contrast, human MC responses were dependent only on SphK1, associating with a more robust expression of this isoform and a more varied representation of SphK variants relative to murine MCs. The findings show that the function of SphK1 and SphK2 can be interchangeable in MCs; however, an important determinant of SphK isoform usage is the species of origin and an influencing factor, the tissue from which MCs may be derived and/or their differentiation state. The Journal of Immunology, 2013, 190: 2058-2067. C1 [Dillahunt, Sandra E.; Sargent, Jennifer L.; Suzuki, Ryo; Rivera, Juan; Olivera, Ana] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Proia, Richard L.] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Gilfillan, Alasdair] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Olivera, A (reprint author), NIAMSD, Immunogenet Mol Lab, NIH, Bldg 10,Room 13C207, Bethesda, MD 20892 USA. EM oliveraa@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Office of Science and Technology, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health.; We acknowledge the support of the animal care program and the light image section of the Office of Science and Technology, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health. NR 63 TC 5 Z9 6 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2013 VL 190 IS 5 BP 2058 EP 2067 DI 10.4049/jimmunol.1201503 PG 10 WC Immunology SC Immunology GA 091ZT UT WOS:000315089100020 PM 23359503 ER PT J AU Dutta, M Kraus, ZJ Gomez-Rodriguez, J Hwang, SH Cannons, JL Cheng, J Lee, SY Wiest, DL Wakeland, EK Schwartzberg, PL AF Dutta, Mala Kraus, Zachary J. Gomez-Rodriguez, Julio Hwang, Sun-hee Cannons, Jennifer L. Cheng, Jun Lee, Sang-Yun Wiest, David L. Wakeland, Edward K. Schwartzberg, Pamela L. TI A Role for Ly108 in the Induction of Promyelocytic Zinc Finger Transcription Factor in Developing Thymocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NKT CELL-DEVELOPMENT; COMPLEX CLASS-I; CD4(+) T-CELLS; NEGATIVE SELECTION; GENE; MICE; RECEPTOR; SAP; DEFICIENT; MOLECULES AB The promyelocytic zinc finger transcription factor (PLZF) is required for the development of activated phenotypes in NKT and other innate T lymphocytes. Although strong TCR stimulation has been implicated in the induction of PLZF, the factors regulating PLZF expression are incompletely understood. We show in this study that costimulation of preselection double-positive thymocytes through the signaling lymphocyte activation molecule family receptor Ly108 markedly enhanced PLZF expression compared with that induced by TCR stimulation alone. Costimulation with Ly108 increased expression of early growth response protein (Egr)-2 and binding of Egr-2 to the promoter of Zbtb16, which encodes PLZF, and resulted in PLZF levels similar to those seen in NKT cells. In contrast, costimulation with anti-CD28 failed to enhance Egr-2 binding and Zbtb16 expression. Moreover, mice lacking Ly108 showed decreased numbers of PLZF-expressing CD4(+) T cells. Together, these results support a potential role for Ly108 in the induction of PLZF. The Journal of Immunology, 2013, 190: 2121-2128. C1 [Dutta, Mala; Kraus, Zachary J.; Gomez-Rodriguez, Julio; Cannons, Jennifer L.; Cheng, Jun; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Dutta, Mala] George Washington Univ, Sch Med, Inst Biomed Sci, Washington, DC 20052 USA. [Hwang, Sun-hee; Wakeland, Edward K.] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA. [Lee, Sang-Yun; Wiest, David L.] Fox Chase Canc Ctr, Immune Cell Dev & Host Def Program, Philadelphia, PA 19111 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, 49 Convent Dr,Room 4A38, Bethesda, MD 20892 USA. EM pams@mail.nih.gov OI Wiest, David/0000-0002-0792-3188 FU National Human Genome Research Institute, National Institutes of Health; National Institutes of Health [R01AI081314, AI045196] FX This work was supported by intramural funding of the National Human Genome Research Institute, National Institutes of Health (to P. L. S.), and National Institutes of Health Grants R01AI081314 (to D.L.W.) and AI045196 (to E.K.W.). NR 41 TC 16 Z9 16 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2013 VL 190 IS 5 BP 2121 EP 2128 DI 10.4049/jimmunol.1202145 PG 8 WC Immunology SC Immunology GA 091ZT UT WOS:000315089100026 PM 23355739 ER PT J AU Dey, R Dagur, PK Selvapandiyan, A McCoy, JP Salotra, P Duncan, R Nakhasi, HL AF Dey, Ranadhir Dagur, Pradeep K. Selvapandiyan, Angamuthu McCoy, J. Philip Salotra, Poonam Duncan, Robert Nakhasi, Hira L. TI Live Attenuated Leishmania donovani p27 Gene Knockout Parasites Are Nonpathogenic and Elicit Long-Term Protective Immunity in BALB/c Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN VISCERAL LEISHMANIASIS; AZAR DERMAL LEISHMANIASIS; REGULATORY T-CELLS; CUTANEOUS LEISHMANIASIS; L-MAJOR; MYCOBACTERIUM-TUBERCULOSIS; PERSISTENT PARASITES; MURINE MACROPHAGES; INTERFERON-GAMMA; CROSS-PROTECTION AB Leishmaniasis causes significant morbidity and mortality worldwide, and no vaccines against this disease are available. Previously, we had shown that the amastigote-specific protein p27 (Ldp27) is a component of an active cytochrome c oxidase complex in Leishmania donovani and that upon deletion of its gene the parasite had reduced virulence in vivo. In this study, we have shown that Ldp27(-/-) parasites do not survive beyond 20 wk in BALB/c mice and hence are safe as an immunogen. Upon virulent challenge, mice 12 wk postimmunization showed significantly lower parasite burden in the liver and spleen. When mice were challenged 20 wk postimmunization, a significant reduction in parasite burden was still noted, suggesting long-term protection by Ldp27(-/-) immunization. Immunization with Ldp27(-/-) induced both pro- and anti-inflammatory cytokine responses and activated splenocytes for enhanced leishmanicidal activity in association with NO production. Protection in both short- and long-term immunized mice after challenge with the wild-type parasite correlated with the stimulation of multifunctional Th1-type CD4 and CD8 T cells. Adoptive transfer of T cells from long-term immunized mice conferred protection against virulent challenge in naive recipient mice, suggesting involvement of memory T cell response in protection against Leishmania infection. Immunization of mice with Ldp27(-/-) also demonstrated cross-protection against Leishmania major and Leishmania braziliensis infection. Our data show that genetically modified live attenuated Ldp27(-/-) parasites are safe, induce protective immunity even in the absence of parasites, and can provide protection against homologous and heterologous Leishmania species. The Journal of Immunology, 2013, 190: 2138-2149. C1 [Dey, Ranadhir; Duncan, Robert; Nakhasi, Hira L.] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20892 USA. [Dagur, Pradeep K.; McCoy, J. Philip] NHLBI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. [Selvapandiyan, Angamuthu] Inst Mol Med, New Delhi 110020, India. [Salotra, Poonam] Indian Council Med Res, Inst Pathol, New Delhi 110029, India. RP Nakhasi, HL (reprint author), US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM Ranadhir.Dey@fda.hhs.gov; Hira.Nakhasi@fda.hhs.gov RI Duncan, Robert/I-8168-2015 OI Duncan, Robert/0000-0001-8409-2501 FU Critical Path Initiative of the Center for Biologics Evaluation and Research, Food and Drug Administration FX This work was supported by intramural funds and the Critical Path Initiative of the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 75 TC 28 Z9 29 U1 1 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2013 VL 190 IS 5 BP 2138 EP 2149 DI 10.4049/jimmunol.1202801 PG 12 WC Immunology SC Immunology GA 091ZT UT WOS:000315089100028 PM 23338240 ER PT J AU Macon, MB Fenton, SE AF Macon, Madisa B. Fenton, Suzanne E. TI Endocrine Disruptors and the Breast: Early Life Effects and Later Life Disease SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Review DE Endocrine disruption; Breast cancer; Mammary gland; Hormones ID MAMMARY-GLAND DEVELOPMENT; IN-UTERO EXPOSURE; BISPHENOL-A ALTERS; LONG-EVANS RATS; PERFLUOROOCTANOIC ACID EXPOSURE; ATRAZINE METABOLITE MIXTURE; FEMALE REPRODUCTIVE-SYSTEM; SPRAGUE-DAWLEY RATS; SOY PROTEIN ISOLATE; CANCER RISK AB Breast cancer risk has both heritable and environment/lifestyle components. The heritable component is a small contribution (5-27 %), leaving the majority of risk to environment (e.g., applied chemicals, food residues, occupational hazards, pharmaceuticals, stress) and lifestyle (e.g., physical activity, cosmetics, water source, alcohol, smoking). However, these factors are not well-defined, primarily due to the enormous number of factors to be considered. In both humans and rodent models, environmental factors that act as endocrine disrupting compounds (EDCs) have been shown to disrupt normal mammary development and lead to adverse lifelong consequences, especially when exposures occur during early life. EDCs can act directly or indirectly on mammary tissue to increase sensitivity to chemical carcinogens or enhance development of hyperplasia, beaded ducts, or tumors. Protective effects have also been reported. The mechanisms for these changes are not well understood. Environmental agents may also act as carcinogens in adult rodent models, directly causing or promoting tumor development, typically in more than one organ. Many of the environmental agents that act as EDCs and are known to affect the breast are discussed. Understanding the mechanism(s) of action for these compounds will be critical to prevent their effects on the breast in the future. C1 [Macon, Madisa B.] Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC USA. [Macon, Madisa B.; Fenton, Suzanne E.] NIEHS, NTP Labs, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Fenton, SE (reprint author), NIEHS, NTP Labs, Div Natl Toxicol Program, NIH, 111 TW Alexander Dr,Bldg 101,MD E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102785-03]; NIEHS NIH HHS [T32 ES007126] NR 164 TC 33 Z9 34 U1 4 U2 88 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD MAR PY 2013 VL 18 IS 1 SI SI BP 43 EP 61 DI 10.1007/s10911-013-9275-7 PG 19 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 096YW UT WOS:000315442000005 PM 23417729 ER PT J AU Hruby, A Ngwa, JS Renstrom, F Wojczynski, MK Ganna, A Hallmans, G Houston, DK Jacques, PF Kanoni, S Lehtimaki, T Lemaitre, RN Manichaikul, A North, KE Ntalla, I Sonestedt, E Tanaka, T van Rooij, FJA Bandinelli, S Djousse, L Grigoriou, E Johansson, I Lohman, KK Pankow, JS Raitakari, OT Riserus, U Yannakoulia, M Zillikens, MC Hassanali, N Liu, YM Mozaffarian, D Papoutsakis, C Syvanen, AC Uitterlinden, AG Viikari, J Groves, CJ Hofman, A Lind, L McCarthy, MI Mikkila, V Mukamal, K Franco, OH Borecki, IB Cupples, LA Dedoussis, GV Ferrucci, L Hu, FB Ingelsson, E Kahonen, M Kao, WHL Kritchevsky, SB Orho-Melander, M Prokopenko, I Rotter, JI Siscovick, DS Witteman, JCM Franks, PW Meigs, JB McKeown, NM Nettleton, JA AF Hruby, Adela Ngwa, Julius S. Renstrom, Frida Wojczynski, Mary K. Ganna, Andrea Hallmans, Goran Houston, Denise K. Jacques, Paul F. Kanoni, Stavroula Lehtimaki, Terho Lemaitre, Rozenn N. Manichaikul, Ani North, Kari E. Ntalla, Ioanna Sonestedt, Emily Tanaka, Toshiko van Rooij, Frank J. A. Bandinelli, Stefania Djousse, Luc Grigoriou, Efi. Johansson, Ingegerd Lohman, Kurt K. Pankow, James S. Raitakari, Olli T. Riserus, Ulf Yannakoulia, Mary Zillikens, M. Carola Hassanali, Neelam Liu, Yongmei Mozaffarian, Dariush Papoutsakis, Constantina Syvanen, Ann-Christine Uitterlinden, Andre G. Viikari, Jorma Groves, Christopher J. Hofman, Albert Lind, Lars McCarthy, Mark I. Mikkila, Vera Mukamal, Kenneth Franco, Oscar H. Borecki, Ingrid B. Cupples, L. Adrienne Dedoussis, George V. Ferrucci, Luigi Hu, Frank B. Ingelsson, Erik Kahonen, Mika Kao, W. H. Linda Kritchevsky, Stephen B. Orho-Melander, Marju Prokopenko, Inga Rotter, Jerome I. Siscovick, David S. Witteman, Jacqueline C. M. Franks, Paul W. Meigs, James B. McKeown, Nicola M. Nettleton, Jennifer A. TI Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies SO JOURNAL OF NUTRITION LA English DT Article ID TYPE-2 DIABETES-MELLITUS; WHOLE-GRAIN INTAKE; DOUBLE-BLIND; COFFEE CONSUMPTION; DIETARY MAGNESIUM; ENVIRONMENT INTERACTIONS; CARDIOVASCULAR-DISEASE; NONDIABETIC SUBJECTS; METABOLIC SYNDROME; PROSPECTIVE COHORT AB Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (In-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [beta = -0.009 mmol/L (95% CI: -0.013, -0.005), P< 0.0001] and insulin (-0.020 In-pmo/L (95% CI: -0.024, -0.017), P< 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P= 0.03) with glucose, and rs11558471 in SLC30A8and rs3740393 near CNNM2showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted. J. Nutr. 143: 345-353, 2013. C1 [Hruby, Adela; Jacques, Paul F.; McKeown, Nicola M.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Ngwa, Julius S.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Renstrom, Frida; Hu, Frank B.; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Renstrom, Frida; Sonestedt, Emily; Orho-Melander, Marju; Franks, Paul W.] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Renstrom, Frida; Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Wojczynski, Mary K.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Ganna, Andrea; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Houston, Denise K.; Kritchevsky, Stephen B.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Kanoni, Stavroula] Wellcome Trust Sanger Inst, Hinxton, England. [Kanoni, Stavroula; Grigoriou, Efi.; Yannakoulia, Mary; Papoutsakis, Constantina; Dedoussis, George V.] Harokopio Univ Athens, Dept Nutr & Dietet, Athens, Greece. [Lehtimaki, Terho] Fimlab Labs, Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Lehtimaki, Terho] Tampere Univ Hosp, Tampere, Finland. [Lemaitre, Rozenn N.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Manichaikul, Ani] Univ Virginia, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Charlottesville, VA USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Ntalla, Ioanna; Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [van Rooij, Frank J. A.; Zillikens, M. Carola; Uitterlinden, Andre G.; Hofman, Albert; Franco, Oscar H.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Rooij, Frank J. A.; Zillikens, M. Carola; Uitterlinden, Andre G.; Hofman, Albert; Franco, Oscar H.; Witteman, Jacqueline C. M.] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Djousse, Luc] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Djousse, Luc; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr, Boston, MA USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Ctr Geriatr Res Educ & Clin, Boston, MA USA. [Johansson, Ingegerd] Umea Univ, Dept Odontol, Umea, Sweden. [Lohman, Kurt K.] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Riserus, Ulf] Uppsala Univ, Dept Publ Hlth & Caring Sci Clin Nutr & Metab, Uppsala, Sweden. [Zillikens, M. Carola; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Hassanali, Neelam; Groves, Christopher J.; McCarthy, Mark I.; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Nutr, Boston, MA 02115 USA. [Mozaffarian, Dariush] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Syvanen, Ann-Christine] Uppsala Univ, Mol Med & Sci Life Lab, Dept Med Sci, Uppsala, Sweden. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Viikari, Jorma] Turku Univ Hosp, FIN-20520 Turku, Finland. [Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Mikkila, Vera] Univ Helsinki, Dept Food & Environm Sci, Helsinki, Finland. [Mukamal, Kenneth] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, FIN-33101 Tampere, Finland. [Kao, W. H. Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Clin Epidemiol Unit, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Diabet Res Unit, Boston, MA 02114 USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. RP McKeown, NM (reprint author), Tufts Univ, Friedman Sch Nutr Sci & Policy, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu RI Prokopenko, Inga/H-3241-2014; Sonestedt, Emily/I-3814-2016; Djousse, Luc/F-5033-2017; OI Prokopenko, Inga/0000-0003-1624-7457; Sonestedt, Emily/0000-0002-0747-4562; Djousse, Luc/0000-0002-9902-3047; Cupples, L. Adrienne/0000-0003-0273-7965; Kritchevsky, Stephen/0000-0003-3336-6781; Franks, Paul/0000-0002-0520-7604; Ganna, Andrea/0000-0002-8147-240X FU Pfizer Nutrition FX The full author list and affiliations are included in Supplemental Table 4 in the "Online Supporting Material" link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org. O.H.F. is the recipient of a grant from Pfizer Nutrition to establish a center for research on aging (ErasmusAGE). All other authors declared no conflicts of interest NR 40 TC 23 Z9 23 U1 1 U2 10 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 MAR PY 2013 VL 143 IS 3 BP 345 EP 353 DI 10.3945/jn.112.172049 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 093EC UT WOS:000315173500014 PM 23343670 ER PT J AU Xiao, YL Kash, JC Beres, SB Sheng, ZM Musser, JM Taubenberger, JK AF Xiao, Yong-Li Kash, John C. Beres, Stephen B. Sheng, Zong-Mei Musser, James M. Taubenberger, Jeffery K. TI High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded autopsy lung tissue sample from the 1918 influenza pandemic SO JOURNAL OF PATHOLOGY LA English DT Article DE influenza A virus; pandemic; 1918 influenza virus; formalin-fixed; paraffin-embedded tissue; NGS ID A H1N1 VIRUS; DUPLEX-SPECIFIC NUCLEASE; TUMOR SAMPLES; FORMALDEHYDE FIXATION; MESSENGER-RNA; COPY-NUMBER; GENE; INFECTION; EVOLUTION; PATHOLOGY AB Most biopsy and autopsy tissues are formalin-fixed and paraffin-embedded (FFPE), but this process leads to RNA degradation that limits gene expression analysis. The RNA genome of the 1918 pandemic influenza virus was previously determined in a 9-year effort by overlapping RT-PCR from post-mortem samples. Here, the full genome of the 1918 virus at 3000x coverage was determined in one high-throughput sequencing run of a library derived from total RNA of a 1918 FFPE sample after duplex-specific nuclease treatments. Bacterial sequences associated with secondary bacterial pneumonias were also detected. Host transcripts were well represented in the library. Compared to a 2009 pandemic influenza virus FFPE post-mortem library, the 1918 sample showed significant enrichment for host defence and cell death response genes, concordant with prior animal studies. This methodological approach should assist in the analysis of FFPE tissue samples isolated over the past century from a variety of diseases. C1 [Xiao, Yong-Li; Kash, John C.; Sheng, Zong-Mei; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Beres, Stephen B.; Musser, James M.] Methodist Hosp Syst, Ctr Mol & Translat Human Infect Dis Res, Dept Pathol & Genom Med, Houston, TX 77030 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 33 North Dr,Room 3E19A-2 MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU Intramural Research Program of the NIH; NIAID FX This work was supported by the Intramural Research Program of the NIH and the NIAID. NR 83 TC 15 Z9 16 U1 4 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD MAR PY 2013 VL 229 IS 4 BP 535 EP 545 DI 10.1002/path.4145 PG 11 WC Oncology; Pathology SC Oncology; Pathology GA 094ML UT WOS:000315267600005 PM 23180419 ER PT J AU Koek, W Cheng, K Rice, KC AF Koek, Wouter Cheng, Kejun Rice, Kenner C. TI Discriminative Stimulus Effects of the GABA(B) Receptor-Positive Modulator rac-BHFF: Comparison with GABA(B) Receptor Agonists and Drugs of Abuse SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ALCOHOL-PREFERRING RATS; PRECURSOR GAMMA-BUTYROLACTONE; ALLOSTERIC MODULATOR; IN-VIVO; DIFFERENTIAL ANTAGONISM; MOTIVATIONAL PROPERTIES; PHYSIOLOGICAL FUNCTIONS; HYDROXYBUTYRATE GHB; ACID(B) RECEPTORS; CGP7930 AB GABA(B) receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABA(B) receptor agonists, because selective enhancement of activated receptors could have effects different from nonselective activation of all receptors. To examine this, pigeons were trained to discriminate the GABA(B) receptor-positive modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle. The discriminative stimulus effects of rac-BHFF were not mimicked by the GABA(B) receptor agonists baclofen and gamma-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABA(B) receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABA(B) receptor antagonist 3-aminopropyl (diethoxymethyl) phosphinic acid CGP35348) but were attenuated by the less efficacious GABAB receptor-positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2dimethylpropyl) phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABA(B2) subunits of GABA(B) receptors. At a dose 10-fold lower than the training dose, rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB. This study provides evidence that the effects of GABA(B) receptor-positive modulators are not identical to those of GABA(B) receptor agonists. In addition, the results suggest that positive modulation of GABA(B) receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine. Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABA(B) receptors mediating the effects of baclofen and GHB are not identical. C1 [Koek, Wouter] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX USA. [Koek, Wouter] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Koek, W (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7703 Floyd Curl Dr,Mail Code 7792, San Antonio, TX USA. EM koek@uthscsa.edu FU National Institutes of Health National Institute on Drug Abuse [DA15692]; National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Intramural Research Programs of the National Institutes of Health National Institute on Drug Abuse FX This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA15692]; and also, in part, by the Intramural Research Programs of the National Institutes of Health National Institute on Drug Abuse and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism. NR 54 TC 11 Z9 12 U1 0 U2 16 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 MAR PY 2013 VL 344 IS 3 BP 553 EP 560 DI 10.1124/jpet.112.202226 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 093LD UT WOS:000315192500002 PM 23275067 ER PT J AU Loeb, S Carter, HB Berndt, SI Ricker, W Schaeffer, EM AF Loeb, Stacy Carter, H. Ballentine Berndt, Sonja I. Ricker, Winnie Schaeffer, Edward M. TI Is Repeat Prostate Biopsy Associated with a Greater Risk of Hospitalization? Data from SEER-Medicare SO JOURNAL OF UROLOGY LA English DT Article DE prostate; biopsy; infection; hospitalization; patient admission ID CANCER AB Purpose: We recently reported an increasing risk over time of hospitalization among Medicare participants after undergoing an initial prostate biopsy. Less is known about the relative risks of repeat prostate biopsies, which are frequently performed in prostate cancer screening and in active surveillance programs. We determined whether repeat biopsies are associated with an increased risk of hospitalization compared to the initial biopsy. Materials and Methods: Using SEER (Surveillance, Epidemiology and End Results)-Medicare linked data from 1991 to 2007 we identified 13,883 men who underwent a single prostate biopsy and 3,640 who had multiple biopsies. The 30-day hospitalization rates were compared between these groups, and with a randomly selected control population of 134,977. ICD-9 codes were then used to examine the frequency of serious infectious and noninfectious urological complications as the primary diagnosis for hospital admissions. Results: Initial and repeat biopsies were associated with a significantly increased risk of hospitalization within a 30-day period compared to randomly selected controls (p < 0.0001). However, the repeat biopsy session was not associated with a greater risk of infectious (OR 0.81, 95% 0.49-1.32, p = 0.39) or serious noninfectious urological complications (OR 0.94, 95% CI 0.54-1.62, p = 0.82) compared to the initial biopsy. Conclusions: Each biopsy was associated with a significant risk of complications compared to randomly selected controls. However, the repeat biopsy procedure itself was not associated with a greater risk of serious complications requiring hospital admission compared to the initial biopsy. C1 [Loeb, Stacy] NYU, Dept Urol, New York, NY 10016 USA. [Carter, H. Ballentine; Schaeffer, Edward M.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ricker, Winnie] Informat Management Serv Inc, Rockville, MD USA. RP Loeb, S (reprint author), NYU, Dept Urol, 550 1st Ave,VZ30 6th Floor 612, New York, NY 10016 USA. EM stacyloeb@gmail.com OI Loeb, Stacy/0000-0003-3933-9207 FU Division of Cancer Epidemiology and Genetics; Louis Feil Charitable Lead Trust; Howard Hughes Medical Institute; National Institutes of Health; AUA Foundation/Astellas Rising Star in Urology Award; Patrick C. Walsh Prostate Cancer Research Foundation FX Supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, Centers for Medicare & Medicaid Services; Information Management Services, Inc. and the SEER Program tumor registries in the creation of the SEER-Medicare database.; Supported by the Louis Feil Charitable Lead Trust.; Supported by the Howard Hughes Medical Institute, the National Institutes of Health, the AUA Foundation/Astellas Rising Star in Urology Award and the Patrick C. Walsh Prostate Cancer Research Foundation. NR 11 TC 28 Z9 28 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2013 VL 189 IS 3 BP 867 EP 870 DI 10.1016/j.juro.2012.10.005 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 092HB UT WOS:000315109600023 PM 23063634 ER PT J AU Zucali, PA Di Tommaso, L Petrini, I Battista, S Lee, HS Merino, M Lorenzi, E Voulaz, E De Vincenzo, F Simonelli, M Roncalli, M Giordano, L Alloisio, M Santoro, A Giaccone, G AF Zucali, P. A. Di Tommaso, L. Petrini, I. Battista, S. Lee, H. S. Merino, M. Lorenzi, E. Voulaz, E. De Vincenzo, F. Simonelli, M. Roncalli, M. Giordano, L. Alloisio, M. Santoro, A. Giaccone, G. TI Reproducibility of the WHO classification of thymomas: Practical implications SO LUNG CANCER LA English DT Article DE Thymomas; WHO classification; Reproducibility; Practical implications ID THYMIC EPITHELIAL TUMORS; HISTOLOGIC CLASSIFICATION; CARCINOMA; PROGNOSIS; NEOPLASMS; SURVIVAL AB Background: The WHO-classification was shown to be an independent prognostic marker in some but not all retrospective studies possibly due to lack of reproducibility. We investigated the reproducibility of the WHO-classification and its prognostic implication using a large series of resected thymomas. Methods: Four independent pathologists histologically classified a surgical series of 129 thymic tumors in a blinded fashion. Fleiss' kappa-coefficient was used to assess the pathologists' overall agreement, and Cohen-Kappa to assess the agreement between two observers. Disease-related-survival (DRS) and progression-free-survival (PFS) curves were generated by Kaplan-Meier method and compared by log-rank test. Results: In 63/129 (48.8%) cases there was a complete agreement; in 43/129 (33.3%) cases 3/4 pathological diagnoses were identical; in 15/129 (11.6%) cases the diagnoses were identical by pair; in 8/129 (6.2%) cases three different pathological diagnoses were on record. The Kappa-correlation coefficient was only moderate (0.53). A following web review carried out on the 23 cases with at least two different diagnoses reached a complete consensus. The histotype showed a statistically significant impact on PFS and DRS in the classification provided by only two pathologists. Conclusions: In this study, the agreement on WHO classification of thymomas was only moderate and this impacted on patients management Web consensus conference on the diagnosis, more stringent diagnostic criteria or the adoption of referral diagnostic centres may substantially reduce discrepancies. Published by Elsevier Ireland Ltd. C1 [Zucali, P. A.; Di Tommaso, L.; Battista, S.; Lorenzi, E.; Voulaz, E.; De Vincenzo, F.; Simonelli, M.; Roncalli, M.; Giordano, L.; Alloisio, M.; Santoro, A.] Humanitas Canc Ctr, I-20089 Milan, Italy. [Petrini, I.; Lee, H. S.; Merino, M.; Giaccone, G.] NCI, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Petrini, Iacopo/K-7316-2016; Giaccone, Giuseppe/E-8297-2017; OI Petrini, Iacopo/0000-0002-7752-6866; Giaccone, Giuseppe/0000-0002-5023-7562; di tommaso, luca/0000-0002-9013-4728; Giordano, Laura/0000-0002-9587-7870; Roncalli, Massimo/0000-0002-7901-8910; Simonelli, Matteo/0000-0002-5264-1251 FU Intramural NIH HHS [ZIA BC011269-01] NR 20 TC 13 Z9 13 U1 0 U2 2 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 MAR PY 2013 VL 79 IS 3 BP 236 EP 241 DI 10.1016/j.lungcan.2012.11.015 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 094BV UT WOS:000315238900007 PM 23279873 ER PT J AU Limburg, PJ Mandrekar, SJ Aubry, MC Ziegler, KLA Zhang, J Yi, JE Henry, M Tazelaar, HD Lam, S McWilliams, A Midthun, DE Edell, ES Rickman, OB Mazzone, P Tockman, M Beamis, JF Lamb, C Simoff, M Loprinzi, C Szabo, E Jett, J AF Limburg, Paul J. Mandrekar, Sumithra J. Aubry, Marie Christine Ziegler, Katie L. Allen Zhang, Jun Yi, Joanne E. Henry, Michael Tazelaar, Henry D. Lam, Stephen McWilliams, Annette Midthun, David E. Edell, Eric S. Rickman, Otis B. Mazzone, Peter Tockman, Melvyn Beamis, John F. Lamb, Carla Simoff, Michael Loprinzi, Charles Szabo, Eva Jett, James CA Canc Prevention Network TI Randomized phase II trial of sulindac for lung cancer chemoprevention SO LUNG CANCER LA English DT Article DE Lung cancer; Chemoprevention; Phase II clinical trial; Sulindac; NSAIDs ID WHITE-LIGHT BRONCHOSCOPY; FORMER SMOKERS; BRONCHIAL EPITHELIUM; CIGARETTE-SMOKING; UNITED-STATES; ASPIRIN; LESIONS; FLUORESCENCE; PREVENTION; DYSPLASIA AB Introduction: Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (>= 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). Methods: At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for 6 months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Results: Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p = 0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms,. but the difference between arms was not statistically significant (p = 0.92). Conclusions: Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention. (c) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Limburg, Paul J.; Mandrekar, Sumithra J.; Aubry, Marie Christine; Ziegler, Katie L. Allen; Zhang, Jun; Yi, Joanne E.; Henry, Michael; Midthun, David E.; Edell, Eric S.; Rickman, Otis B.; Loprinzi, Charles; Jett, James] Mayo Clin, Rochester, MN USA. [Tazelaar, Henry D.] Mayo Clin Arizona, Scottsdale, AZ USA. [Lam, Stephen; McWilliams, Annette] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Mazzone, Peter] Cleveland Clin, Cleveland, OH 44106 USA. [Tockman, Melvyn] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Beamis, John F.; Lamb, Carla] Lahey Clin Med Ctr, Burlington, MA 01803 USA. [Simoff, Michael] Henry Ford Hosp, Detroit, MI 48202 USA. [Szabo, Eva] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Limburg, PJ (reprint author), 200 1st St SW, Rochester, MN 55905 USA. EM limburg.paul@mayo.edu RI Rickman, Otis/D-8199-2014 OI Rickman, Otis/0000-0001-7222-6840 FU Mayo Clinic Clinical Research Unit [M01-RR00585]; National Cancer Institute, Division of Cancer Prevention [N01-CN-35000] FX The authors gratefully acknowledge the staff of the Mayo Clinic Clinical Research Unit (supported by grant M01-RR00585); Dr. Wilma Lingle, Cindy Fitting, Maria Resner, Colleen Garvey, and Sharon Kaufman for their assistance with study design, administration and manuscript preparation. This work was sponsored by the National Cancer Institute, Division of Cancer Prevention, contract N01-CN-35000. NR 41 TC 6 Z9 6 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD MAR PY 2013 VL 79 IS 3 BP 254 EP 261 DI 10.1016/j.lungcan.2012.11.011 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 094BV UT WOS:000315238900010 PM 23261228 ER PT J AU Li, X Xi, ZX Markou, A AF Li, Xia Xi, Zheng-Xiong Markou, Athina TI Metabotropic glutamate 7 (mGlu7) receptor: A target for medication development for the treatment of cocaine dependence SO NEUROPHARMACOLOGY LA English DT Review DE AMN082; Glutamate; Cocaine; Addiction; GABA ID VENTRAL TEGMENTAL AREA; BRAIN-STIMULATION REWARD; ALLOSTERIC MODULATOR AMN082; NUCLEUS-ACCUMBENS SHELL; DRUG-SEEKING BEHAVIOR; GROUP-II; NICOTINE DEPENDENCE; PARKINSONS-DISEASE; ANIMAL-MODELS; INDUCED REINSTATEMENT AB Brain glutamate has been shown to play an important role in reinstatement to drug seeking, a behavior considered to be of relevance to relapse to drug taking in humans. Therefore, glutamate receptors, in particular metabotropic glutamate (mGlu) receptors, have become important targets for medication development for the treatment of drug dependence. In this review article, we focus on the mGlu7 receptor subtype, and discuss recent findings with AMN082, a selective mGlu7 receptor allosteric agonist, in animal models with relevance to drug dependence. Systemic or local administration of AMN082 into the nucleus accumbens (NAc), a critical brain region involved in reward and drug dependence processes, inhibited the reinforcing and motivational effects of cocaine, heroin and ethanol, as assessed by the intravenous drug self-administration procedure. In addition, AMN082 inhibited the reward-enhancing effects induced by cocaine, as assessed in the intracranial self-stimulation procedure, and cocaine- or cue-induced reinstatement of drug-seeking behavior. In vivo microdialysis studies indicated that systemic or intra-NAc administration of AMN082 significantly decreased extracellular gamma-aminobutyric acid (GABA) and elevated extracellular glutamate, but had no effect on extracellular dopamine in the NAc, suggesting that a non-dopaminergic mechanism underlies the effects of AMN082 on the actions of cocaine. Further, data indicated that AMN082-induced changes in glutamate were the net effect of two actions: one is the direct inhibition of glutamate release by activation of mGlu7 receptors on glutamatergic neurons; another is the indirect increases of glutamate release mediated by decreases in GABA transmission. These increases in extracellular glutamate functionally antagonized cocaine-induced inhibition of NAc-ventral pallidum GABAergic neurotransmission, and therefore, the rewarding effects of cocaine. In addition, elevated extracellular glutamate activated presynaptic mGlu2/3 autoreceptors which in turn inhibited cocaine priming- or cue-induced enhancement of glutamate release and reinstatement of drug-seeking behavior. Taken together, these findings suggest that the mGlu7 receptor is an important target for medication development for the treatment of drug dependence. AMN082 or other mGlu7 receptor allosteric agonists may have potential as novel pharmacotherapies for cocaine addiction. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Li, Xia; Markou, Athina] Univ Calif San Diego, Sch Med, Dept Psychiat, La Jolla, CA 92093 USA. [Xi, Zheng-Xiong] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. RP Li, X (reprint author), Univ Calif San Diego, Sch Med, Dept Psychiat, M-C 0603,9500 Gilman Dr, La Jolla, CA 92093 USA. EM x9li@ucsd.edu FU Lundbeck; Bristol-Myers Squibb Co.; F. Hoffman-La Roche; Pfizer; Astra-Zeneca; Abbott GmbH and Company; Tobacco-Related Disease Research Program from the State of California [20KT-0064]; NIH [DA011946]; Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX AM has received contract research support from Lundbeck, Bristol-Myers Squibb Co., F. Hoffman-La Roche, Pfizer, and Astra-Zeneca, and honoraria/consulting fees from Abbott GmbH and Company, Astra-Zeneca, and Pfizer during the past 3 years. AM has a patent application on the use of metabotropic glutamate compounds for the treatment of nicotine dependence. The remaining authors report no financial conflicts of interests.; XL was supported by a new investigator award 20KT-0064 by the Tobacco-Related Disease Research Program from the State of California. AM was supported by NIH grant DA011946. Z-XX was supported by Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 120 TC 11 Z9 13 U1 0 U2 24 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 MAR PY 2013 VL 66 SI SI BP 12 EP 23 DI 10.1016/j.neuropharm.2012.04.010 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 092MC UT WOS:000315125700002 PM 22546614 ER PT J AU Lucas, SJ Bortolotto, ZA Collingridge, GL Lodge, D AF Lucas, Sarah J. Bortolotto, Zuner A. Collingridge, Graham L. Lodge, David TI Selective activation of either mGlu2 or mGlu3 receptors can induce LTD in the amygdala SO NEUROPHARMACOLOGY LA English DT Article DE Metabotropic glutamate receptors; mGlu3; mGlu2; Lateral amygdala; Long-term depression ID METABOTROPIC GLUTAMATE RECEPTORS; LONG-TERM DEPRESSION; HIPPOCAMPUS IN-VITRO; GROUP-II; DENTATE GYRUS; N-ACETYLASPARTYLGLUTAMATE; SYNAPTIC-TRANSMISSION; BASOLATERAL AMYGDALA; AGONIST; SYNAPSES AB Group II metabotropic glutamate (mGlu) receptors are known to induce a long-term depression (LTD) of synaptic transmission in many brain regions including the amygdala. However the roles of the individual receptor subtypes, mGlu2 and mGlu3, in LTD are not well understood. In particular, it is unclear whether activation of mGlu3 receptors is sufficient to induce LTD at synapses in the CNS. In the present study, advantage was taken of a Wistar rat strain not expressing mGlu2 receptors (Ceolin et al., 2011) to investigate the function of mGlu3 receptors in the amygdala. In this preparation, the group II agonist, DCG-IV induced an LTD of the cortical, but not the intra-nuclear, synaptic input to the lateral amygdala. This LTD was concentration dependent and was blocked by the group II mGlu receptor antagonist, LY341495. To investigate further the role of mGlu3 receptors, we used LY395756 (an mGlu2 agonist and mGlu3 antagonist), which acts as a pure mGlu3 receptor antagonist in this rat strain. This compound alone had no effect on basal synaptic transmission, but blocked the LTD induced by DCG-IV. Furthermore, we found that DCG-IV also induces LTD in mGlu2 receptor knock-out (KO) mice to a similar extent as in wild-type mice. This confirms that the activation of mGlu2 receptors alone is sufficient to induce LTD at this amygdala synapse. To address whether mGlu2 activation alone is also sufficient to induce LTD at this synapse we used LY541850 (the active enantiomer of LY395756) in wild-type mice. LY541850 induced a substantial LTD showing that either receptor alone is capable of inducing LTD in this pathway. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Lucas, Sarah J.; Bortolotto, Zuner A.; Collingridge, Graham L.; Lodge, David] Univ Bristol, MRC Ctr Synapt Plast, Bristol BS8 1TD, Avon, England. [Collingridge, Graham L.] Seoul Natl Univ, Coll Nat Sci, Dept Brain & Cognit Sci, Seoul, South Korea. RP Lucas, SJ (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Sarah.Lucas@nih.gov RI Collingridge, Graham/C-4605-2015; OI Collingridge, Graham/0000-0002-9572-5359; Lucas, Sarah/0000-0002-5577-763X FU MRC; Centre for Cognitive Neuroscience (Eli Lilly); WCU program through the KOSEF; MEST [R31-10089] FX Funded by the MRC and the Centre for Cognitive Neuroscience (Eli Lilly). SL was a MRC scholar. LY395756, LY541850 and the KO mice were kind gifts from Eli Lilly & Co. Ltd. GLC is a WCU International Scholar supported by the WCU program through the KOSEF funded by the MEST (R31-10089). NR 38 TC 5 Z9 5 U1 0 U2 8 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 MAR PY 2013 VL 66 SI SI BP 196 EP 201 DI 10.1016/j.neuropharm.2012.04.006 PG 6 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 092MC UT WOS:000315125700021 PM 22531751 ER PT J AU Bogenpohl, J Galvan, A Hu, X Wichmann, T Smith, Y AF Bogenpohl, James Galvan, Adriana Hu, Xing Wichmann, Thomas Smith, Yoland TI Metabotropic glutamate receptor 4 in the basal ganglia of parkinsonian monkeys: Ultrastructural localization and electrophysiological effects of activation in the striatopallidal complex SO NEUROPHARMACOLOGY LA English DT Article DE mGluR4; Basal ganglia; Parkinson's disease; Striatum; Globus pallidus; Monkey ID POSITIVE ALLOSTERIC MODULATORS; NIGRA PARS RETICULATA; GLOBUS-PALLIDUS; ALLEVIATES AKINESIA; DISEASE TREATMENT; NEURONS; MGLUR4; RATS; TRANSMISSION; PRIMATES AB Group III metabotropic glutamate receptors (mGluR4,7,8) are widely distributed in the basal ganglia. Injection of group III mGluR agonists into the striatopallidal complex alleviates parkinsonian symptoms in 6-hydroxydopamine-treated rats. In vitro rodent studies have suggested that this may be partly due to modulation of synaptic transmission at striatopallidal and corticostriatal synapses through mGluR4 activation. However, the in vivo electrophysiological effects of group III mGluRs activation upon basal ganglia neurons activity in nonhuman primates remain unknown. Thus, in order to examine the anatomical substrates and physiological effects of group III mGluRs activation upon striatal and pallidal neurons in monkeys, we used electron microscopy immunohistochemistry to localize mGluR4, combined with local administration of the group III mGluR agonist L-AP4, or the mGluR4 positive allosteric modulator VU0155041, to assess the effects of group III mGluR activation on the firing rate and pattern of striatal and pallidal neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. At the ultrastructural level, striatal mGluR4 immunoreactivity was localized in pre- (60%) and postsynaptic (30%) elements, while in the GPe, mGluR4 was mainly expressed pre-synaptically (90%). In the putamen, terminals expressing mGluR4 were evenly split between putative excitatory and inhibitory terminals, while in the GPe, most labeled terminals displayed the ultrastructural features of striatal-like inhibitory terminals, though putative excitatory boutons were also labeled. No significant difference was found between normal and parkinsonian monkeys. Extracellular recordings in awake MPTP-treated monkeys revealed that local microinjections of small volumes of L-AP4 resulted in increased firing rates in one half of striatal cells and one third of pallidal cells, while a significant number of neurons in both structures showed either opposite effects, or did not display any significant rate changes following L-AP4 application. VU0155041 administration had little effect on firing rates. Both compounds also had subtle effects on bursting and oscillatory properties, acting to increase the irregularity of firing. The occurrence of pauses in firing was reduced in the majority (80%) of GPe neurons after L-AP4 injection. Our findings indicate that glutamate can mediate multifarious physiological effects upon striatal and pallidal neurons through activation of pre-synaptic group III mGluRs at inhibitory and excitatory synapses in parkinsonian monkeys. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Bogenpohl, James; Galvan, Adriana; Hu, Xing; Wichmann, Thomas; Smith, Yoland] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Galvan, Adriana; Wichmann, Thomas; Smith, Yoland] Emory Univ, Dept Neurol, Sch Med, Atlanta, GA 30322 USA. [Bogenpohl, James; Galvan, Adriana; Hu, Xing; Wichmann, Thomas; Smith, Yoland] Emory Univ, NIH UDALL Ctr Excellence Parkinsons Dis Res, Atlanta, GA 30322 USA. RP Smith, Y (reprint author), Emory Univ, Yerkes Primate Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. EM ysmit01@emory.edu FU RJG Foundation; Michael J Fox Foundation; Udall Center for Parkinson's Disease Research [NIH P50 NS071669]; Yerkes National Primate Research Center [NIH P51 RR-000165] FX This work was supported by grants from the RJG Foundation, the Michael J Fox Foundation, the Udall Center for Parkinson's Disease Research (NIH P50 NS071669), and the Yerkes National Primate Research Center base grant (NIH P51 RR-000165). Many thanks are due to Jeff Conn, Colleen Niswender, Corey Hopkins and other members of the Vanderbilt Center for Neuroscience Drug Discovery for providing VU0155041, and to Jeff Pare and Susan Jenkins for technical support. NR 63 TC 14 Z9 14 U1 0 U2 4 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 MAR PY 2013 VL 66 SI SI BP 242 EP 252 DI 10.1016/j.neuropharm.2012.05.017 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 092MC UT WOS:000315125700026 PM 22634360 ER PT J AU Li, X Higley, A Song, R Xi, ZX AF Li, Xia Higley, Amanda Song, Rui Xi, Zheng-Xiong TI Effects of metabotropic glutamate receptor ligands on male sexual behavior in rats SO NEUROPHARMACOLOGY LA English DT Article DE mGluR2/3; mGluR5; mGluR7; LY379268; MPEP; AMN082; Sexual behavior ID MEDIAL PREOPTIC AREA; CUE-INDUCED REINSTATEMENT; MPEP DECREASED NICOTINE; AGONIST LY379268; COCAINE-SEEKING; IN-VIVO; VENTROMEDIAL HYPOTHALAMUS; CONDITIONED REINSTATEMENT; CONVENTIONAL REINFORCER; INDUCED RELAPSE AB Metabotropic glutamate receptors (mGluRs), particularly mGluR2/3, mGluR5 and mGluR7, have received much attention in medication development for the treatment of drug addiction and other neuropsychiatric diseases. However, little is known as to whether mGluR ligands also alter natural sexual behavior, a possible unwanted effect when used in humans. In the present study, we used classical copulatory behaviors to evaluate the effects of LY379268 (a selective mGluR2/3 agonist), MPEP (a selective mGluR5 antagonist) and AMN082 (a selective mGluR7 agonist), on male sexual performance in rats. We found that systemic administration of LY379268 (1, 3 mg/kg, i.p.) had no effect, while MPEP (20 mg/kg, but not 10 mg/kg, i.p.) and AMN082 (10, 20 mg/kg, but not 3 mg/kg) produced a significant and dose-dependent reduction in both sex-seeking and sex- performance behaviors, manifested as an increase in mount or intromission latency and time required for ejaculation, and a reduction in mount or intromission frequency. This inhibition lasted for about 30-60 min. These findings suggest that compounds that target mGluR5 or mGluR7, but not mGluR2/3, may have short-term inhibitory effects on male sexual performance. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. Published by Elsevier Ltd. C1 [Li, Xia; Higley, Amanda; Song, Rui; Xi, Zheng-Xiong] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Li, Xia] Univ Calif San Diego, Sch Med, Dept Psychiat, La Jolla, CA 92093 USA. RP Xi, ZX (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 73 TC 4 Z9 5 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD MAR PY 2013 VL 66 SI SI BP 373 EP 381 DI 10.1016/j.neuropharm.2012.08.006 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 092MC UT WOS:000315125700039 PM 22968089 ER PT J AU Soto, PL Katz, JL AF Soto, Paul L. Katz, Jonathan L. TI Interactions of cocaine with dopamine D-2-like antagonists in squirrel monkeys SO PSYCHOPHARMACOLOGY LA English DT Article DE Dopamine D-2 receptor; D-2 antagonist; Cocaine; Drug discrimination; Squirrel monkey ID DISCRIMINATIVE STIMULUS PROPERTIES; SUBSTITUTED BENZAMIDE DRUGS; RHESUS-MONKEYS; RECEPTOR SUBTYPES; LOCOMOTOR-ACTIVITY; RATS; HALOPERIDOL; SCH-23390; BLOCKADE; AGONISTS AB Studies investigating dopamine D-2 receptor antagonism of cocaine's discriminative stimulus effects have resulted in varied effects possibly due to the use of different antagonists, species, and procedures. The present study sought to further investigate D-2 antagonism of cocaine's discriminative stimulus effects using a variety of D-2 antagonists and multiple doses of the antagonists in combination with cocaine. The benzamide D-2 antagonists, eticlopride, raclopride, and sulpiride, and the butyrophenone D-2 antagonists haloperidol and spiperone were administered alone and in combination with cocaine in squirrel monkeys trained to discriminate cocaine from saline under a fixed-ratio food reinforcement procedure. All the D-2 antagonists, except haloperidol, antagonized the discriminative stimulus effects of the cocaine training dose. However, only the benzamide D-2 antagonists produced significant rightward shifts in the cocaine discriminative stimulus dose-effect curve and they only did so within a narrow dose range and time after administration. In contrast, the D-2 antagonists failed to antagonize the rate-suppressant effects of cocaine, and in some cases, cocaine appeared to antagonize the rate-suppressant effects of the antagonists. The present results suggest (1) that D-2 antagonism of cocaine's discriminative stimulus effects depends critically on the selected antagonist, antagonist dose, and time of administration, as well as how antagonism is assessed (i.e., in terms of effects on training dose or on the cocaine dose-effect curve), (2) that the maximal shift in cocaine's discriminative stimulus dose-effect curve possible with D-2 antagonists under these procedures is similar to two- to threefold, and (3) that different effects of cocaine are differentially sensitive to dopamine receptor antagonism. C1 [Soto, Paul L.] Johns Hopkins Univ, Sch Med, Div Behav Biol, Baltimore, MD 21224 USA. [Katz, Jonathan L.] NIDA, Medicat Discovery Res Branch, Psychobiol Sect, DHHS,NIH,IRP,BRC, Baltimore, MD 21224 USA. RP Soto, PL (reprint author), Johns Hopkins Univ, Sch Med, Div Behav Biol, 5510 Nathan Shock Dr,Suite 3000,Johns Hopkins Bay, Baltimore, MD 21224 USA. EM psoto@jhmi.edu; jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse FX We are grateful for the expert technical assistance of Eric Adams in conducting these studies. These studies were supported by the Intramural Research Program of the Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. NR 26 TC 2 Z9 2 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 MAR PY 2013 VL 226 IS 2 BP 393 EP 400 DI 10.1007/s00213-012-2914-7 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 096XR UT WOS:000315438700018 PM 23192312 ER PT J AU Little, MP Wakeford, R AF Little, Mark P. Wakeford, Richard TI How is the risk of radiation-induced cancer influenced by background risk factors? Invited commentary on "A method for determining weights for excess relative risk and excess absolute risk when applied in the calculation of lifetime risk of cancer from radiation exposure" by Walsh and Schneider (2012) SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Editorial Material ID ATOMIC-BOMB SURVIVORS; BREAST-CANCER; POOLED ANALYSIS; UNCERTAINTY; MORTALITY; SMOKING C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Rockville, MD 20852 USA. [Wakeford, Richard] Univ Manchester, Dalton Nucl Inst, Manchester M13 9PL, Lancs, England. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Rockville, MD 20852 USA. EM mark.little@nih.gov NR 24 TC 1 Z9 1 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2013 VL 52 IS 1 BP 147 EP 150 DI 10.1007/s00411-012-0442-9 PG 4 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 096DU UT WOS:000315385100014 PM 23180111 ER PT J AU Pawel, DJ Gilbert, ES AF Pawel, D. J. Gilbert, E. S. TI Invited commentary on "A method for determining weights for excess relative risk and excess absolute risk when applied in the calculation of lifetime risk of cancer from radiation exposure" by Walsh and Schneider (2012) SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Letter ID ATOMIC-BOMB SURVIVORS; SOLID CANCER C1 [Pawel, D. J.] US EPA, Washington, DC 20460 USA. [Gilbert, E. S.] NCI, Div Epidemiol & Genet, Bethesda, MD 20892 USA. RP Pawel, DJ (reprint author), US EPA, MC 6608J,1200 Penn Av NW, Washington, DC 20460 USA. EM Pawel.David@epamail.epa.gov NR 12 TC 0 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2013 VL 52 IS 1 BP 151 EP 153 DI 10.1007/s00411-012-0443-8 PG 3 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 096DU UT WOS:000315385100015 PM 23180112 ER PT J AU Little, MP Azizova, TV Bazyka, D Bouffler, SD Cardis, E Chekin, S Chumak, VV Cucinotta, FA de Vathaire, F Hall, P Harrison, JD Hildebrandt, G Ivanov, V Kashcheev, VV Klymenko, SV Laurent, O Ozasa, K Tapio, S Taylor, AM Tzoulaki, I Vandoolaeghe, WL Wakeford, R Zablotska, L Zhang, W Lipshultz, SE AF Little, Mark P. Azizova, Tamara V. Bazyka, Dimitry Bouffler, Simon D. Cardis, Elisabeth Chekin, Sergey Chumak, Vadim V. Cucinotta, Francis A. de Vathaire, Florent Hall, Per Harrison, John D. Hildebrandt, Guido Ivanov, Victor Kashcheev, Valeriy V. Klymenko, Sergiy V. Laurent, Olivier Ozasa, Kotaro Tapio, Soile Taylor, Andrew M. Tzoulaki, Ioanna Vandoolaeghe, Wendy L. Wakeford, Richard Zablotska, Lydia Zhang, Wei Lipshultz, Steven E. TI Comment on "Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors" (Radiat. Environ. Biophys (2012) 51:165-178) by Schollnberger et al. SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Letter ID CIRCULATORY DISEASE; IONIZING-RADIATION; EXPOSURE C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Rockville, MD 20852 USA. [Azizova, Tamara V.] Southern Urals Biophys Inst, Ozyorsk, Russia. [Bouffler, Simon D.; Chumak, Vadim V.; Klymenko, Sergiy V.] Res Ctr Radiat Med, Kiev, Ukraine. [Bouffler, Simon D.; Harrison, John D.; Zhang, Wei] Hlth Protect Agcy, Ctr Radiat Chem & Environm Hazards, Chilton, England. [Cardis, Elisabeth] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Chekin, Sergey; Ivanov, Victor; Kashcheev, Valeriy V.] Russian Acad Med Sci, Med Radiol Res Ctr, Obninsk, Russia. [Cucinotta, Francis A.] NASA, Lyndon B Johnson Space Ctr, Radiat Hlth Off, Houston, TX 77058 USA. [de Vathaire, Florent] Inst Gustave Roussy, INSERM, Unite U1018, Radiat Epidemiol Grp, F-94805 Villejuif, France. [Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hildebrandt, Guido] Univ Rostock, Dept Radiotherapy & Radiat Oncol, D-18055 Rostock, Germany. [Laurent, Olivier] Univ Calif Irvine, Coll Hlth Sci, Program Publ Hlth, Irvine, CA USA. [Laurent, Olivier] LEPID, SRBE, PRP HOM, IRSN,Lab Epidemiol, Fontenay Aux Roses, France. [Ozasa, Kotaro] Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima, Japan. [Tapio, Soile] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Radiat Biol ISB, Oberschleissheim, Germany. [Taylor, Andrew M.] UCL Inst Cardiovasc Sci, London, England. [Taylor, Andrew M.] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Tzoulaki, Ioanna; Vandoolaeghe, Wendy L.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Epidemiol & Biostat, London, England. [Wakeford, Richard] Univ Manchester, Dalton Nucl Inst, Manchester, Lancs, England. [Zablotska, Lydia] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Lipshultz, Steven E.] Univ Miami, Dept Pediat, Leonard M Miller Sch Med, Miami, FL 33152 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Executive Plaza South,6120 Executive Blvd MSC 723, Rockville, MD 20852 USA. EM mark.little@nih.gov RI Tapio, Soile/M-7358-2014; Kashcheev, Valeriy/L-7794-2015; Chumak, Vadim/N-6960-2015; Ivanov, Victor/R-9385-2016; Cardis, Elisabeth/C-3904-2017; OI Klymenko, Sergiy/0000-0002-9758-7316; Tapio, Soile/0000-0001-9860-3683; Little, Mark/0000-0003-0980-7567; Kashcheev, Valeriy/0000-0003-4108-9761; Chumak, Vadim/0000-0001-6045-9356; Ivanov, Victor/0000-0003-1372-0018; Bazyka, Dimitry/0000-0001-9982-5990; Wakeford, Richard/0000-0002-2934-0987 NR 10 TC 6 Z9 6 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD MAR PY 2013 VL 52 IS 1 BP 157 EP 159 DI 10.1007/s00411-012-0453-6 PG 3 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 096DU UT WOS:000315385100017 PM 23296519 ER PT J AU Huang, Q Purzycka, KJ Lusvarghi, S Li, DH LeGrice, SFJ Boeke, JD AF Huang, Qing Purzycka, Katarzyna J. Lusvarghi, Sabrina Li, Donghui LeGrice, Stuart F. J. Boeke, Jef D. TI Retrotransposon Ty1 RNA contains a 5 '-terminal long-range pseudoknot required for efficient reverse transcription SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE RNA structure; retrotransposon; reverse transcription; pseudoknot; SHAPE ID VIRUS-LIKE PARTICLES; SECONDARY STRUCTURE PREDICTION; PRIMER TRANSFER-RNA; TELOMERASE RNA; SACCHAROMYCES-CEREVISIAE; ELEMENT TRANSPOSITION; ESCHERICHIA-COLI; GENE-EXPRESSION; YEAST; PROTEIN AB Ty1 retrotransposon RNA has the potential to fold into a variety of distinct structures, mutation of which affects retrotransposition frequencies. We show here that one potential functional structure is located at the 5' end of the genome and can assume a pseudoknot conformation. Chemoenzymatic probing of wild-type and mutant mini-Ty1 RNAs supports the existence of such a structure, while molecular genetic analyses show that mutations disrupting pseudoknot formation interfere with retrotransposition, indicating that it provides a critical biological function. These defects are enhanced at higher temperatures. When these mutants are combined with compensatory changes, retrotransposition is restored, consistent with pseudoknot architecture. Analyses of mutants suggest a defect in Ty1 reverse transcription. Collectively, our data allow modeling of a three-dimensional structure for this novel critical cis-acting signal of the Ty1 genome. C1 [Huang, Qing; Li, Donghui; Boeke, Jef D.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Huang, Qing; Li, Donghui; Boeke, Jef D.] Johns Hopkins Univ, High Throughput Biol Ctr, Sch Med, Baltimore, MD 21205 USA. [Purzycka, Katarzyna J.; Lusvarghi, Sabrina; LeGrice, Stuart F. J.] Natl Canc Inst, Frederick, MD 21702 USA. [Purzycka, Katarzyna J.] Polish Acad Sci, Lab Struct Chem Nucle Acids, Inst Bioorgan Chem, PL-61704 Poznan, Poland. [Li, Donghui] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD 21205 USA. RP LeGrice, SFJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. EM legrices@mail.nih.gov; jboeke@jhmi.edu OI Boeke, Jef/0000-0001-5322-4946 FU NIH [GM36481] FX We thank Joan Curcio, David Garfinkel, Eric Bolton, Robert Yarrington, and Candice Coombes for helpful discussions, Lixin Dai and Zheng Kuang for advice on Q-PCR, Mariusz Popenda for advice on 3-D structure prediction, and Marty Taylor for help with immunoblots. The work was supported in part by NIH grant GM36481 to J.D.B. NR 62 TC 7 Z9 7 U1 2 U2 20 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 MAR PY 2013 VL 19 IS 3 BP 320 EP 332 DI 10.1261/rna.035535.112 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 093KF UT WOS:000315190100003 PM 23329695 ER PT J AU Tobian, AAR Grabowski, MK Kigozi, G Gravitt, PE Eaton, KP Serwadda, D Nalugoda, F Wawer, MJ Quinn, TC Gray, RH AF Tobian, Aaron A. R. Grabowski, Mary K. Kigozi, Godfrey Gravitt, Patti E. Eaton, Kevin P. Serwadda, David Nalugoda, Fred Wawer, Maria J. Quinn, Thomas C. Gray, Ronald H. TI High-risk human papillomavirus prevalence is associated with HIV infection among heterosexual men in Rakai, Uganda SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article ID SIMPLEX-VIRUS TYPE-2; MALE CIRCUMCISION; RANDOMIZED-TRIAL; NEGATIVE MEN; CONDOM USE; PREVENTION; CANCER; MALES; WOMEN AB Objectives Human papillomavirus (HPV) infection causes genital warts, penile cancer and cervical cancer. Africa has one of the highest rates of penile and cervical cancers, but there are little data on high-risk human papillomavirus (HR-HPV) prevalence in heterosexual men. Knowledge of HR-HPV prevalence, risk factors and genotype distribution among heterosexual men is important to establish risk-reduction prevention strategies. Methods 1578 uncircumcised men aged 15-49 years who enrolled in male circumcision trials in Rakai, Uganda, were evaluated for HR-HPV from swabs of the coronal sulcus/glans using Roche HPV Linear Array. Adjusted prevalence risk ratios (adjPRRs) were estimated using modified Poisson multivariable regression. Results HPV prevalence (either high risk or low risk) was 90.7% (382/421) among HIV-positive men and 60.9% (596/978) among HIV-negative men (PRR 1.49, 95% CI 1.40 to 1.58). HIV-positive men had a significantly higher risk of infection with three or more HR-HPV genotypes (PRR = 5.76, 95% CI 4.27 to 7.79). Among HIV-positive men, high-risk sexual behaviours were not associated with increased HR-HPV prevalence. Among HIV-negative men, HR-HPV prevalence was associated with self-reported genital warts (adjPRR 1.57, 95% CI 1.07 to 2.31). Among all men (both HIV negative and HIV positive), HR-HPV prevalence was associated with more than 10 lifetime sexual partners (adjPRR 1.30, 95% CI 1.01 to 1.66), consistent condom use (adjPRR 1.31, 95% CI 1.08 to 1.60) and HIV infection (adjPRR 1.80, 95% CI 1.60 to 2.02). HR-HPV prevalence was lower among men who reported no sexual partners during the past year (adjPRR 0.47, 95% CI 0.23 to 0.94). Conclusion The burden of HR-HPV infection is high among heterosexual men in sub-Saharan Africa and most pronounced among the HIV-infected individuals. C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Tobian, Aaron A. R.; Grabowski, Mary K.; Gravitt, Patti E.; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Kigozi, Godfrey; Serwadda, David; Nalugoda, Fred; Wawer, Maria J.; Gray, Ronald H.] Rakai Hlth Sci Program, Entebbe, Uganda. [Gravitt, Patti E.] Perdana Univ, Grad Sch Med, Serdang, Malaysia. [Eaton, Kevin P.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 667,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Bill and Melinda Gates Foundation [22006.02]; National Institutes of Health [U1AI51171]; NIH [U01-AI-068613, 3U01-AI075115-03S1, 1K23AI093152-01A1]; Doris Duke Charitable Foundation Clinician Scientist Development Award [22006.02]; Johns Hopkins University Clinician Scientist Award FX The trial was funded by the Bill and Melinda Gates Foundation (#22006.02) and the National Institutes of Health (#U1AI51171). The Fogarty International Center (#5D43TW001508 and #2D43TW000010-19-AITRP) contributed to training. National Institute of Allergy and Infectious Diseases (NIAID), NIH grants U01-AI-068613 and 3U01-AI075115-03S1 and the NIAID Intramural Program provided laboratory support. AART was supported by the NIH 1K23AI093152-01A1, Doris Duke Charitable Foundation Clinician Scientist Development Award (#22006.02) and the Johns Hopkins University Clinician Scientist Award. NR 30 TC 6 Z9 7 U1 0 U2 10 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD MAR PY 2013 VL 89 IS 2 BP 122 EP 127 DI 10.1136/sextrans-2012-050524 PG 6 WC Infectious Diseases SC Infectious Diseases GA 093QZ UT WOS:000315207800014 PM 22628661 ER PT J AU Nicholson, B Noble, J Forooghian, F Meyerle, C AF Nicholson, Benjamin Noble, Jason Forooghian, Farzin Meyerle, Catherine TI Central Serous Chorioretinopathy: Update on Pathophysiology and Treatment SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE central serous chorioretinopathy; diffuse retinal pigment epitheliopathy; photodynamic therapy; corticosteroids; indocyanine green angiography; fundus autofluorescence; optical coherence tomography ID OPTICAL COHERENCE TOMOGRAPHY; HALF-DOSE VERTEPORFIN; TERM-FOLLOW-UP; PIGMENT EPITHELIAL DETACHMENT; INDOCYANINE GREEN ANGIOGRAPHY; FLUENCE PHOTODYNAMIC THERAPY; OBSTRUCTIVE SLEEP-APNEA; CHOROIDAL NEOVASCULARIZATION SECONDARY; INTRAVITREAL BEVACIZUMAB INJECTION; SYSTEMIC CORTICOSTEROID TREATMENT AB Recent technological advances new pathophysiological insights, new imaging techniques for diagnosis and management, and new treatments have led to an improved understanding of central serous chorioretinopathy (CSC). The primary role of the choroid has become more widely accepted with widespread use of indocyanine green angiography. Optical coherence tomography (OCT), and particularly enhanced depth imaging OCT, demonstrate a thickened and engorged choroid. Adaptive optics, fundus autofluorescence, multifocal electroretinography, microperimetry, and contrast sensitivity testing reveal that patients with even a mild course suffer previously undetected anatomic and functional loss. Although focal laser and photodynamic therapy are the current standard of care for persistent subretinal fluid in CSC, they are not appropriate in all cases, and the optimal timing of intervention remains unclear. (Surv Ophthalmol 58:103-126, 2013. Published by Elsevier Inc.) C1 [Nicholson, Benjamin; Meyerle, Catherine] NEI, NIH, Bethesda, MD 20814 USA. [Noble, Jason] Univ Toronto, Toronto, ON, Canada. [Noble, Jason] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Forooghian, Farzin] Univ British Columbia, Dept Ophthalmol & Visual Sci, Vancouver, BC V5Z 1M9, Canada. RP Meyerle, C (reprint author), NEI, NIH, 10 Ctr Dr,Room 10C442, Bethesda, MD 20814 USA. EM meyerlec@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999] NR 243 TC 84 Z9 92 U1 1 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD MAR-APR PY 2013 VL 58 IS 2 BP 103 EP 126 DI 10.1016/j.survophthal.2012.07.004 PG 24 WC Ophthalmology SC Ophthalmology GA 095GW UT WOS:000315323700001 PM 23410821 ER PT J AU Fang, ZZ Cao, YF Hu, CM Hong, M Sun, XY Ge, GB Liu, Y Zhang, YY Yang, L Sun, HZ AF Fang, Zhong-Ze Cao, Yun-Feng Hu, Cui-Min Hong, Mo Sun, Xiao-Yu Ge, Guang-Bo Liu, Yong Zhang, Yan-Yan Yang, Ling Sun, Hong-Zhi TI Structure-inhibition relationship of ginsenosides towards UDP-glucuronosyltransferases (UGTs) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Ginsenosides; UDP-glucuronosyltransferases (UGTs); Ginseng-drug interaction ID DRUG-DRUG INTERACTIONS; HUMAN LIVER; GINSENG; WARFARIN; CYTOCHROME-P450; GLUCURONIDATION; METABOLISM; CONSTITUENTS; CODEINE; HUMANS AB The wide utilization of ginseng provides the high risk of herb-drug interaction (HDI) with many clinical drugs. The inhibition of ginsenosides towards drug-metabolizing enzymes (DMEs) has been regarded as an important reason for herb-drug interaction (HDI). Compared with the deep studies on the ginsenosides' inhibition towards cytochrome P450 (CYP), the inhibition of ginsenosides towards the important phase II enzymes UDP-glucuronosyltransferases (UGTs) remains to be unclear. The present study aims to evaluate the inhibition behavior of ginsenosides towards important UGT isoforms located in the liver and intestine using in vitro methods. The recombinant UGT isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as in vitro probe reaction. The results showed that structure-dependent inhibition existed for the inhibition of ginsenosides towards UGT isoforms. To clarify the possibility of in vivo herb-drug interaction induced by this kind of inhibition, the ginsenoside Rg(3) was selected as an example, and the inhibition kinetic type and parameters (IQ were determined. Rg(3) competitively inhibited UGT1A7, 2B7 and 2B15-catalyzed 4-MU glucuronidation reaction, and exerted noncompetitive inhibition towards UGT1A8-catalyzed 4-MU glucuronidation. The inhibition parameters (K-i values) were calculated to be 22.6, 7.9, 1.9, and 2.0 mu M for UGT1A7, 1A8, 2B7 and 2B15. Using human maximum plasma concentration of Rg(3) (400 ng/ml (0.5 mu M)) after intramuscular injection of 60 mg Rg(3), the area under the plasma concentration-time curve (AUC) was extrapolated to increase by 22%, 63%, 26.3%, and 25% for the co-administered drugs completely undergoing the metabolism catalyzed by UGT1A7, 1A8, 2B7 and 2B15, respectively. All these results indicated that the ginsenosides' inhibition towards UGT isoforms might be an important reason for ginseng-drug interaction. (C) 2013 Elsevier Inc. All rights reserved. C1 [Fang, Zhong-Ze; Sun, Hong-Zhi] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. [Cao, Yun-Feng] Shanghai Engineer & Technol Res Ctr Reprod Hlth D, Shanghai Inst Planned Parenthood Res, Key Lab Contracept & Devices Res NPFPC, Shanghai 200032, Peoples R China. [Fang, Zhong-Ze; Cao, Yun-Feng; Hong, Mo; Sun, Xiao-Yu] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Fang, Zhong-Ze; Cao, Yun-Feng; Hong, Mo; Sun, Xiao-Yu] 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. [Ge, Guang-Bo; Liu, Yong; Zhang, Yan-Yan; Yang, Ling] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China. RP Sun, HZ (reprint author), Liaoning Med Univ, Jinzhou, Liaoning, Peoples R China. EM zzfang228@gmail.com RI Liu, Yong/A-1289-2011 OI Liu, Yong/0000-0002-4638-0788 FU National Natural Science Foundation of China [81202586] FX This work was supported by the National Natural Science Foundation of China (no. 81202586). NR 26 TC 47 Z9 49 U1 7 U2 52 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 MAR 1 PY 2013 VL 267 IS 2 BP 149 EP 154 DI 10.1016/j.taap.2012.12.019 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 095WX UT WOS:000315366800002 PM 23306165 ER PT J AU Long, Y Lin, ZX Xia, MH Zheng, W Li, ZY AF Long, Yan Lin, Zuoxian Xia, Menghang Zheng, Wei Li, Zhiyuan TI Mechanism of HERG potassium channel inhibition by tetra-n-octylammonium bromide and benzethonium chloride SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Quaternary ammonium; Tetra-n-octylammonium bromide; Benzethonium chloride; HERG potassium channel; HERG channel blocker; Patch clamp ID RABBIT VENTRICULAR MYOCYTES; S6 TRANSMEMBRANE DOMAIN; USE-DEPENDENT BLOCK; DELAYED K+ CURRENT; MOLECULAR DETERMINANTS; DOFETILIDE BLOCK; XENOPUS OOCYTES; CELL-LINE; IN-VITRO; CISAPRIDE AB Tetra-n-octylammonium bromide and benzethonium chloride are synthetic quaternary ammonium salts that are widely used in hospitals and industries for the disinfection and surface treatment and as the preservative agent. Recently, the activities of HERG channel inhibition by these compounds have been found to have potential risks to induce the long QT syndrome and cardiac arrhythmia, although the mechanism of action is still elusive. This study was conducted to investigate the mechanism of HERG channel inhibition by these compounds by using whole-cell patch clamp experiments in a CHO cell line stably expressing HERG channels. Tetra-n-octylammonium bromide and benzethonium chloride exhibited concentration-dependent inhibitions of HERG channel currents with IC50 values of 4 nM and 17 nM, respectively, which were also voltage-dependent and use-dependent. Both compounds shifted the channel activation I-V curves in a hyperpolarized direction for 10-15 mV and accelerated channel activation and inactivation processes by 2-fold. In addition, tetra-n-octylammonium bromide shifted the inactivation I-V curve in a hyperpolarized direction for 24.4 mV and slowed the rate of channel deactivation by 2-fold, whereas benzethonium chloride did not. The results indicate that tetra-n-octylammonium bromide and benzethonium chloride are open-channel blockers that inhibit HERG channels in the voltage-dependent, use-dependent and state-dependent manners. (C) 2013 Elsevier Inc. All rights reserved. C1 [Long, Yan; Lin, Zuoxian; Li, Zhiyuan] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Peoples R China. [Xia, Menghang; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Li, ZY (reprint author), Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Kaiyuan Rd 190,Guangzhou Sci Pk, Guangzhou 510530, Peoples R China. EM li_zhiyuan@gibh.ac.cn RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Chinese Academy of Sciences FX This work was supported by the "Hundred Talents Program" of the Chinese Academy of Sciences. NR 56 TC 3 Z9 3 U1 1 U2 20 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 MAR 1 PY 2013 VL 267 IS 2 BP 155 EP 166 DI 10.1016/j.taap.2012.12.021 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 095WX UT WOS:000315366800003 PM 23313619 ER PT J AU Pettibone, KG Friend, KB Nargiso, JE Florin, P AF Pettibone, Kristianna G. Friend, Karen B. Nargiso, Jessica E. Florin, Paul TI Evaluating Environmental Change Strategies: Challenges and Solutions SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE Environmental change; Evaluation; Policy; Mixed methods; Substance abuse; Tobacco control ID HEALTH PROMOTION; COMMUNITY; PREVENTION; ALCOHOL; POLICY; PROGRAMS; TRIAL AB In this introductory article we define environmental change strategies (ECS), summarize the primary challenges associated with evaluating ECS, and provide an overview of the methods researchers have employed to begin to address these challenges. This special issue provides a range of examples, from researchers and practitioners in the field, of different approaches for addressing these challenges. These articles present new methods to understand and test how ECS are implemented and propose methods to evaluate their implementation. The content of the articles covers multiple public health issues, including substance abuse prevention, tobacco control, HIV prevention, and obesity prevention. This special issue is intended to build the evidence base for effective ECS, generate compelling discussion, critical analyses, and spur future research that will help improve the implementation and evaluation of ECS. C1 [Pettibone, Kristianna G.] NIEHS, NIH, Morrisville, NC 27650 USA. [Friend, Karen B.] Decis Sci Inst, Pacific Inst Res & Evaluat, Pawtucket, RI 02860 USA. [Friend, Karen B.; Nargiso, Jessica E.] Brown Univ, Ctr Alcohol & Addict Studies, Warren Alpert Med Sch, Providence, RI 02912 USA. [Florin, Paul] Univ Rhode Isl, Dept Psychol, Kingston, RI 02881 USA. RP Pettibone, KG (reprint author), NIEHS, NIH, 530 Davis Dr, Morrisville, NC 27650 USA. EM pettibonekg@niehs.nih.gov NR 31 TC 7 Z9 7 U1 1 U2 16 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0562 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD MAR PY 2013 VL 51 IS 1-2 BP 217 EP 221 DI 10.1007/s10464-012-9556-0 PG 5 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA 088KV UT WOS:000314834100018 PM 23054168 ER PT J AU Unick, JL Beavers, D Bond, DS Clark, JM Jakicic, JM Kitabchi, AE Knowler, WC Wadden, TA Wagenknecht, LE Wing, RR AF Unick, Jessica L. Beavers, Daniel Bond, Dale S. Clark, Jeanne M. Jakicic, John M. Kitabchi, Abbas E. Knowler, William C. Wadden, Thomas A. Wagenknecht, Lynne E. Wing, Rena R. CA Look AHEAD Res Grp TI The Long-term Effectiveness of a Lifestyle Intervention in Severely Obese Individuals SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cardiovascular disease risk; Diabetes; Lifestyle intervention; Severe obesity; Weight loss ID WEIGHT-LOSS MAINTENANCE; LOOK-AHEAD TRIAL; BARIATRIC SURGERY; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ADULTS; MORTALITY AB OBJECTIVE: Severe obesity (body mass index [BMI] >= 40 kg/m(2)) is a serious public health concern. Although bariatric surgery is an efficacious treatment approach, it is limited in reach; thus, nonsurgical treatment alternatives are needed. We examined the 4-year effects of an intensive lifestyle intervention on body weight and cardiovascular disease risk factors among severely obese, compared with overweight (25 <= BMI <= 30), class I (30 <= BMI <= 35), and class II obese (35 <= BMI <= 40) participants. METHODS: There were 5145 individuals with type 2 diabetes (45-76 years, BMI >= 25 kg/m(2)) randomized to an intensive lifestyle intervention or diabetes support and education. The lifestyle intervention group received a behavioral weight loss program that included group and individual meetings, a >= 10% weight loss goal, calorie restriction, and increased physical activity. Diabetes support and education received a less intense educational intervention. Four-year changes in body weight and cardiovascular disease risk factors were assessed. RESULTS: Across BMI categories, 4-year changes in body weight were significantly greater in lifestyle participants compared with diabetes support and education (Ps < .05). At year 4, severely obese lifestyle participants lost 4.9% +/- 8.5%, which was similar to class I (4.8% +/- 7.2%) and class II obese participants (4.4% +/- 7.6%), and significantly greater than overweight participants (3.4% +/- 7.0%; P < .05). Four-year changes in low-density-lipoprotein cholesterol, triglycerides, diastolic blood pressure, HbA 1c, and blood glucose were similar across BMI categories in lifestyle participants; however, the severely obese had less favorable improvements in high-density-lipoprotein cholesterol (3.1 +/- 0.4 mg/dL) and systolic blood pressure (-1.4 +/- 0.7 mm Hg) compared with the less obese (Ps < .05). CONCLUSION: Lifestyle interventions can result in important long-term weight losses and improvements in cardiovascular disease risk factors among a significant proportion of severely obese individuals. (C) 2013 Elsevier Inc. All rights reserved. The American Journal of Medicine (2013) 126, 236-242 C1 [Unick, Jessica L.; Bond, Dale S.; Wing, Rena R.] Brown Univ, Weight Control & Diabet Res Ctr, Miriam Hosp, Providence, RI 02903 USA. [Unick, Jessica L.; Bond, Dale S.; Wing, Rena R.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02903 USA. [Beavers, Daniel] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Clark, Jeanne M.] Johns Hopkins Univ, Baltimore, MD USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Phys Act & Weight Management Res Ctr, Pittsburgh, PA 15260 USA. [Kitabchi, Abbas E.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Knowler, William C.] NIDDKD, Phoenix, AZ USA. [Wadden, Thomas A.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wagenknecht, Lynne E.] Wake Forest Sch Med, Winston Salem, NC USA. RP Unick, JL (reprint author), Brown Univ, Warren Alpert Med Sch, Miriam Hosp, Weight Control & Diabet Res Ctr, 196 Richmond St, Providence, RI 02903 USA. EM junick@lifespan.org RI Beavers, Daniel/G-5338-2016 FU Department of Health and Human Services through National Institutes of Health [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; National Institutes of Health (NIH) Office of Research on Women's Health; Centers for Disease Control and Prevention; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center; Massachusetts Institute of Technology General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center (GCRC) [M01RR000056]; Clinical Translational Research Center (CTRC); Clinical & Translational Science Award [UL1 RR 024153]; NIH [DK 046204]; VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Bartter General Clinical Research Center [M01RR01346]; BodyMedia, Inc. FX This study is supported by the Department of Health and Human Services through the following cooperative agreements from the National Institutes of Health: DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992. The following federal agencies have contributed support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; National Institutes of Health (NIH) Office of Research on Women's Health; and the Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Indian Health Service (IHS) provided personnel, medical oversight, and use of facilities. The opinions expressed in this article are those of the authors and do not necessarily reflect the views of the IHS or other funding sources. Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (GCRC) (M01RR000056), the Clinical Translational Research Center (CTRC) funded by the Clinical & Translational Science Award (UL1 RR 024153) and NIH grant (DK 046204); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; and the Frederic C. Bartter General Clinical Research Center (M01RR01346). The following organizations have committed to make major contributions to Look AHEAD: FedEx Corporation; Health Management Resources; LifeScan, Inc., a Johnson & Johnson Company; OPTIFAST of Nestle HealthCare Nutrition, Inc.; Hoffmann-La Roche Inc.; Abbott Nutrition; and Slim-Fast Brand of Unilever North America.; Dr Jakicic reported serving on the scientific advisory board for Alere Wellbeing; he was the principal investigator on a research grant awarded to the University of Pittsburgh from BodyMedia, Inc., and he received an honorarium for a scientific presentation from Jenny Craig and Nestle Nutrition Institute. No other authors reported any other conflicts of interest or financial disclosures. NR 25 TC 35 Z9 38 U1 2 U2 77 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2013 VL 126 IS 3 BP 236 EP U92 DI 10.1016/j.amjmed.2012.10.010 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 088YM UT WOS:000314873800023 PM 23410564 ER PT J AU Liu, QY Salaverria, I Pittaluga, S Jegalian, AG Xi, LQ Siebert, R Raffeld, M Hewitt, SM Jaffe, ES AF Liu, Qingyan Salaverria, Itziar Pittaluga, Stefania Jegalian, Armin G. Xi, Liqiang Siebert, Reiner Raffeld, Mark Hewitt, Stephen M. Jaffe, Elaine S. TI Follicular Lymphomas in Children and Young Adults A Comparison of the Pediatric Variant With Usual Follicular Lymphoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE pediatric follicular lymphoma; follicular lymphoma; IRF4 (interferon regulatory factor 4); MUM1; BCL2; BCL6; fluorescence in situ hybridization (FISH); Waldeyer ring; testis ID B-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; EXPRESSION; TRANSLOCATION; CHILDHOOD; CLONALITY; ANTIBODY; PROTEIN; ENTITY AB Follicular lymphoma (FL), a common lymphoma in adults, occurs rarely in pediatric and young adult patients. Most pediatric cases have been described as grade 3, but the criteria to distinguish the pediatric variant of FL (PFL) from usual FL (UFL) seen in adults are not well defined. We undertook a study of FL in patients under the age of 30. We identified 63 cases, which were analyzed by morphology, immunohistochemistry, and polymerase chain reaction analysis of IGH@ and IGK@ clonality. These data were correlated with clinical findings including stage, treatment, and outcome. Among the 63 cases, 34 cases were classified as PFL: 22 presenting in lymph nodes, 8 in the Waldeyer ring, and 4 in the testis. Clonal immunoglobulin gene rearrangement was detected in 97% of PFL cases, but fluorescence in situ hybridization analysis showed an absence of the BCL2/IGH@ translocation in all cases tested. Twenty-nine cases were classified as UFL, 28 of which presented in lymph nodes. The nodal PFLs were observed exclusively in male patients in both children and young adults with a median age of 15 years. They showed marked head/neck predilection, blastoid cytologic features with a high proliferation rate, lack of BCL2 protein and t(14;18), low clinical stage at presentation, and good prognosis. PFLs involving the Waldeyer ring were distinguished by MUM1 expression, 50% (3/6) of which carried IRF4 breaks. BCL2 expression was common (63%) in the absence of BCL2/IGH@ translocation. UFLs were more common in female patients, exclusively in young adults (median age, 24 y), with no cases reported in patients under the age of 18. Twenty-five of 29 cases were of grade 1-2, and 4 cases were classified as grade 3A. They exhibited a higher clinical stage at presentation. Eighty-three percent expressed BCL2. Our results indicate that histologic and immunophenotypic criteria can reliably separate PFL and UFL and that UFL is exceptionally rare in the pediatric age group. PFL associated with particular anatomic sites have distinctive features and should be evaluated separately in future clinical and biological studies. C1 [Liu, Qingyan; Pittaluga, Stefania; Jegalian, Armin G.; Xi, Liqiang; Raffeld, Mark; Hewitt, Stephen M.; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Salaverria, Itziar; Siebert, Reiner] Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel, Germany. RP Jaffe, ES (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. EM ejaffe@mail.nih.gov RI Siebert, Reiner/A-8049-2010; SALAVERRIA, ITZIAR/L-2246-2015; OI SALAVERRIA, ITZIAR/0000-0002-2427-9822; Hewitt, Stephen/0000-0001-8283-1788; Jaffe, Elaine/0000-0003-4632-0301 FU intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Kinderkrebsinitative (KKI) Buchholz, Holm-Seppensen FX Supported by funding from the intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. R. S. is supported by the Kinderkrebsinitative (KKI) Buchholz, Holm-Seppensen. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 27 TC 29 Z9 30 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2013 VL 37 IS 3 BP 333 EP 343 DI 10.1097/PAS.0b013e31826b9b57 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA 092BY UT WOS:000315095000003 PM 23108024 ER PT J AU Liu, QY Galli, S Srinivasan, R Linehan, WM Tsokos, M Merino, MJ AF Liu, Qingyan Galli, Susanna Srinivasan, Ramaprasad Linehan, William Marston Tsokos, Maria Merino, Maria J. TI Renal Medullary Carcinoma Molecular, Immunohistochemistry, and Morphologic Correlation SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE renal medullary carcinoma; SMARCB1; loss of heterozygosity ID MALIGNANT RHABDOID TUMORS; CHROMATIN-REMODELING COMPLEX; INI1 PROTEIN; SUPPRESSOR; DIFFERENTIATION; CELLS; SNF5; EXPRESSION; SNF5/INI1; FEATURES AB Renal medullary carcinoma, a highly aggressive tumor mainly occurring in patients with sickle cell hemoglobinopathy, is characterized by advanced stage at the time of presentation and poor response to treatment. Currently, the pathogenesis of this tumor is not well understood. In this study, the clinicopathologic features and molecular changes of 15 renal medullary carcinoma cases were evaluated. These cases demonstrated male predominance (M:F = 2:1) with a median age of 26 years. The tumors occurred predominantly in the right kidney with an average size of 5.9 cm. Immunohistochemistry analysis showed that the neoplastic cells were positive for CEA (7/8), AE1/3 (8/8), CAM5.2 (7/7), CK7 (5/5), CK20 (4/6), and vimentin (6/6). Absence of SMARCB1 protein expression in tumor cells was demonstrated in all of the 7 cases analyzed. By polymerase chain reaction-based microsatellite analysis, loss of heterozygosity of SMARCB1 was identified in 9 of 10 cases. These data suggest that inactivation of SMARCB1 may play a role in the pathogenesis of renal medullary carcinoma. C1 NCI, Translat Surg Pathol Sect, Bethesda, MD 20892 USA. NCI, Urol Oncol Sect, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Translat Surg Pathol Sect, Pathol Lab, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 2B44, Bethesda, MD 20892 USA. EM mjmerino@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX Supported by funding from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 22 TC 27 Z9 30 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2013 VL 37 IS 3 BP 368 EP 374 DI 10.1097/PAS.0b013e3182770406 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 092BY UT WOS:000315095000006 PM 23348212 ER PT J AU Weisbrod, AB Webb, RC Mathur, A Barak, S Abraham, SB Nilubol, N Quezado, M Stratakis, CA Kebebew, E AF Weisbrod, Allison B. Webb, Richard C. Mathur, Aarti Barak, Stephanie Abraham, Smita Baid Nilubol, Naris Quezado, Martha Stratakis, Constantine A. Kebebew, Electron TI Adrenal Histologic Findings Show No Difference in Clinical Presentation and Outcome in Primary Hyperaldosteronism SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article DE Primary hyperaldosteronism; Adrenal vein sampling; Aldosterone producing adenoma ID MULTIPLE ADRENOCORTICAL MICRONODULES; ALDOSTERONE-PRODUCING ADENOMA; PRIMARY HYPER-ALDOSTERONISM; OF-THE-LITERATURE; UNILATERAL ADRENALECTOMY; LAPAROSCOPIC ADRENALECTOMY; ESSENTIAL-HYPERTENSION; BLOOD-PRESSURE; CONNS-SYNDROME; HYPERPLASIA AB Primary hyperaldosteronism is most commonly due to a solitary cortical adenoma. Thus, some surgeons have suggested a subtotal adrenalectomy is a reasonable approach when a mass can be identified. On the other hand, adrenal vein sampling (AVS) is being used more frequently to distinguish patients with unilateral disease for adrenalectomy, even if a discrete mass is not identified on axial imaging. In these cases, surgical pathology may reveal a cortical adenoma, a cortical adenoma with hyperplasia, or cortical hyperplasia. The goal of this study was to compare the presentation and outcome among patients undergoing adrenalectomy and found to have different histologic features. We performed a retrospective analysis of 136 patients with primary hyperaldosteronism. A total of 95 patients had an adrenalectomy for unilateral disease. The preoperative clinical and laboratory, and postoperative outcome of the three aforementioned histologic groups were compared. A total of 95 patients underwent an adrenalectomy. We found no significant difference in age, gender, body mass index, duration of hypertension, number of antihypertensive medications, serum aldosterone level, serum renin level, or adrenal vein sampling ratios among the three histologic categories. We also found no significant difference among the three categories in postoperative cure rate. The rate of unilateral hyperplasia in patients with primary hyperaldosteronism (16 %) is likely higher than previously reported, which may be due to the increasing use of AVS. The clinical presentation and outcome of patients regardless of the histologic findings are similar. Our data also suggests that subtotal adrenalectomy would not be appropriate in patients with primary hyperaldosteronism. C1 [Weisbrod, Allison B.; Webb, Richard C.; Mathur, Aarti; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Barak, Stephanie; Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Abraham, Smita Baid] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Weisbrod, AB (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM abweisbrod@gmail.com FU Intramural NIH HHS [ZIA BC011275-02] NR 48 TC 6 Z9 6 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD MAR PY 2013 VL 20 IS 3 BP 753 EP 758 DI 10.1245/s10434-012-2670-2 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 090RW UT WOS:000314998000009 PM 23090573 ER PT J AU Parks, CG D'Aloisio, AA Deroo, LA Huiber, K Rider, LG Miller, FW Sandler, DP AF Parks, Christine G. D'Aloisio, Aimee A. DeRoo, Lisa A. Huiber, Kirstin Rider, Lisa G. Miller, Frederick W. Sandler, Dale P. TI Childhood socioeconomic factors and perinatal characteristics influence development of rheumatoid arthritis in adulthood SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID LIFE-COURSE; BIRTH-WEIGHT; SOCIAL-CLASS; RISK; SMOKING; STRESS; RESPONSES; EXPOSURE; POSITION; DISEASES AB Background Rheumatoid arthritis (RA) has been associated with lower socioeconomic status (SES), but the reasons for this are not known. Objective To examine childhood SES measures, SES trajectory and other perinatal factors in relation to RA. Methods The sample included 50 884 women, aged 35-74 (84% non-Hispanic white) enrolled 2004-9 in a US national cohort study. In baseline questionnaires, cases (N=424, 0.8%) reported RA diagnosis after age 16, ever use of disease-modifying antirheumatic drugs or steroids for RA and >= 6 weeks bilateral joint swelling. Childhood SES measures are presented as OR and 95% CI adjusted for age and race/ethnicity. Analyses of perinatal factors also adjusted for childhood SES, and joint effects of childhood and adult SES and smoking exposures were evaluated. Results Patients with RA reported lower childhood household education (< 12 years vs college degree; OR=1.7; 95% CI 1.1 to 2.5), food insecurity (OR=1.5, 95% CI 1.1 to 2.0) and young maternal age (< 20 vs 20-34 years; OR=1.7, 95% CI 1.2 to 2.5), with a trend (p < 0.0001) for increasing number of adverse factors (OR=3.0; 95% CI 1.3 to 7.0; 4 vs 0 factors) compared with non-cases. High birth weight (> 4000 g) and preconception paternal smoking were independently associated with RA. Together, lower childhood SES and adult education (< college degree) were associated with RA (interaction p=0.03), with a joint effect magnitude similar to a history of paternal and adult smoking. Conclusions RA was associated with low childhood SES sustained into adulthood, with cumulative effects across multiple measures, suggesting the importance of other unmeasured factors linking SES and RA. C1 [Parks, Christine G.; D'Aloisio, Aimee A.; DeRoo, Lisa A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, Div Intramural Res, Durham, NC 27599 USA. [Huiber, Kirstin] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Rider, Lisa G.; Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, Bethesda, MD USA. RP Parks, CG (reprint author), NIEHS, Epidemiol Branch, Durham, NC 27599 USA. EM Parks1@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593; Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS [Z01 ES044005-09] NR 37 TC 13 Z9 13 U1 1 U2 11 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2013 VL 72 IS 3 BP 350 EP 356 DI 10.1136/annrheumdis-2011-201083 PG 7 WC Rheumatology SC Rheumatology GA 088BQ UT WOS:000314809200007 PM 22586176 ER PT J AU Weisman, MH Witter, JP Reveille, JD AF Weisman, Michael H. Witter, James P. Reveille, John D. TI The prevalence of inflammatory back pain: population-based estimates from the US National Health and Nutrition Examination Survey, 2009-10 SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID ANKYLOSING-SPONDYLITIS; CLINICAL HISTORY; CRITERIA; CLASSIFICATION AB Objective To estimate the current US inflammatory back pain (IBP) prevalence using four published case definitions. Methods Analysis of an IBP data collection instrument specifically designed for the 2009-10 National Health and Nutrition Examination Survey. Subjects were 5103 US adults ages 20-69 with complete data. IBP prevalence as determined by Calin et al criteria, European Spondylarthropathy Study Group (ESSG) criteria, and Berlin criteria 8a and 7b. Results Age-adjusted US prevalence of IBP by Calin criteria was 5.0% (95% CI 4.2% to 5.8%). Prevalence of IBP was 5.6% (95% CI 4.7% to 6.5%) by ESSG criteria, and 5.8% (95% CI 5.2% to 6.4%) and 6.0% (95% CI 4.9% to 7.1%) by Berlin Criteria 8a and 7b, respectively. IBP prevalence did not differ significantly by age groups or between men and women. IBP prevalence was significantly lower among non-Hispanic black persons compared with non-Hispanic white persons for the Calin and ESSG IBP criteria. For the ESSG and Berlin 7b criteria, non-Hispanic white persons had significantly higher IBP prevalences compared with Mexican Americans. Conclusions IBP is associated with spondyloarthritis. Awareness of the prevalence of IBP may be useful for planning future epidemiological studies as well as development and validation of diagnostic and classification criteria for specific clinically defined diseases. C1 [Weisman, Michael H.] Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA. [Witter, James P.] NIAMSD, Rheumat Dis Clin Program, NIH, Bethesda, MD 20892 USA. [Reveille, John D.] Univ Texas Houston, Div Rheumatol, Houston, TX USA. RP Weisman, MH (reprint author), Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA. EM michael.weisman@cshs.org FU SAA; SPARTAN FX An unrestricted grant to the CDC Foundation from the SAA and SPARTAN. NR 13 TC 15 Z9 15 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2013 VL 72 IS 3 BP 369 EP 373 DI 10.1136/annrheumdis-2012-201403 PG 5 WC Rheumatology SC Rheumatology GA 088BQ UT WOS:000314809200010 PM 22791746 ER PT J AU Peters, MJ Broer, L Willemen, HLDM Eiriksdottir, G Hocking, LJ Holliday, KL Horan, MA Meulenbelt, I Neogi, T Popham, M Schmidt, CO Soni, A Valdes, AM Amin, N Dennison, EM Eijkelkamp, N Harris, TB Hart, DJ Hofman, A Huygen, FJPM Jameson, KA Jones, GT Launer, LJ Kerkhof, HJM de Kruijf, M McBeth, J Kloppenburg, M Ollier, WE Oostra, B Payton, A Rivadeneira, F Smith, BH Smith, AV Stolk, L Teumer, A Thomson, W Uitterlinden, AG Wang, K van Wingerden, SH Arden, NK Cooper, C Felson, D Gudnason, V Macfarlane, GJ Pendleton, N Slagboom, PE Spector, TD Volzke, H Kavelaars, A van Duijn, CM Williams, FMK van Meurs, JBJ AF Peters, Marjolein J. Broer, Linda Willemen, Hanneke L. D. M. Eiriksdottir, Gudny Hocking, Lynne J. Holliday, Kate L. Horan, Michael A. Meulenbelt, Ingrid Neogi, Tuhina Popham, Maria Schmidt, Carsten O. Soni, Anushka Valdes, Ana M. Amin, Najaf Dennison, Elaine M. Eijkelkamp, Niels Harris, Tamara B. Hart, Deborah J. Hofman, Albert Huygen, Frank J. P. M. Jameson, Karen A. Jones, Gareth T. Launer, Lenore J. Kerkhof, Hanneke J. M. de Kruijf, Marjolein McBeth, John Kloppenburg, Margreet Ollier, William E. Oostra, Ben Payton, Antony Rivadeneira, Fernando Smith, Blair H. Smith, Albert V. Stolk, Lisette Teumer, Alexander Thomson, Wendy Uitterlinden, Andre G. Wang, Ke van Wingerden, Sophie H. Arden, Nigel K. Cooper, Cyrus Felson, David Gudnason, Vilmundur Macfarlane, Gary J. Pendleton, Neil Slagboom, P. Eline Spector, Tim D. Voelzke, Henry Kavelaars, Annemieke van Duijn, Cornelia M. Williams, Frances M. K. van Meurs, Joyce B. J. TI Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID O-METHYLTRANSFERASE GENE; ADULT TWIN REGISTRY; KNEE OSTEOARTHRITIS; FIBROMYALGIA SYNDROME; T102C POLYMORPHISM; NEUROPATHIC PAIN; COHORT PROFILE; RISK-FACTORS; POPULATION; SUSCEPTIBILITY AB Background and objectives Chronic widespread pain (CWP) is a common disorder affecting similar to 10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. Methods We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. Results The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2x10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7x10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4x10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7x10(-4)). Conclusions We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain. C1 [Peters, Marjolein J.; Kerkhof, Hanneke J. M.; de Kruijf, Marjolein; Rivadeneira, Fernando; Stolk, Lisette; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Peters, Marjolein J.; Kerkhof, Hanneke J. M.; de Kruijf, Marjolein; Rivadeneira, Fernando; Stolk, Lisette; Uitterlinden, Andre G.; Slagboom, P. Eline; van Meurs, Joyce B. J.] Netherlands Genom Initiat Sponsored Netherlands C, Leiden, Netherlands. [Broer, Linda; Amin, Najaf; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Wingerden, Sophie H.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Willemen, Hanneke L. D. M.; Kavelaars, Annemieke] Univ Med Ctr Utrecht, Lab Neuroimmunol & Dev Origins Dis, Utrecht, Netherlands. [Eiriksdottir, Gudny; Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Hocking, Lynne J.] Univ Aberdeen, Aberdeen Pain Res Collaborat Musculoskeletal Res, Aberdeen, Scotland. [Holliday, Kate L.; McBeth, John; Thomson, Wendy] Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Epidemiol Unit, Manchester, Lancs, England. [Horan, Michael A.; Pendleton, Neil] Univ Manchester, Sch Community Based Med, Mental Hlth & Neurodegenerat Grp, Manchester, Lancs, England. [Meulenbelt, Ingrid; Slagboom, P. Eline] Leiden Univ, Med Ctr, Sect Mol Epidemiol, Dept Med Stat & Bioinformat, Leiden, Netherlands. [Neogi, Tuhina; Wang, Ke; Felson, David] Boston Univ, Sch Med, Clin Epidemiol Unit, Boston, MA 02118 USA. [Popham, Maria; Valdes, Ana M.; Hart, Deborah J.; Spector, Tim D.; Williams, Frances M. K.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Schmidt, Carsten O.; Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Soni, Anushka] Univ Oxford, NIHR Musculoskeletal Biomed Res Unit, Oxford, England. [Dennison, Elaine M.; Jameson, Karen A.; Arden, Nigel K.; Cooper, Cyrus] Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Dennison, Elaine M.] Victoria Univ Wellington, Sch Biol Sci, Wellington, New Zealand. [Eijkelkamp, Niels] UCL, Mol Nocicept Grp, London, England. [Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Huygen, Frank J. P. M.; de Kruijf, Marjolein] Erasmus MC, Dept Anaesthesiol, Rotterdam, Netherlands. [Jones, Gareth T.; Macfarlane, Gary J.] Univ Aberdeen, Aberdeen Pain Res Collaborat Epidemiol Grp, Aberdeen, Scotland. [Kloppenburg, Margreet] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands. [Kloppenburg, Margreet] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. [Ollier, William E.; Payton, Antony] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England. [Oostra, Ben] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Smith, Blair H.] Univ Dundee, Med Res Inst, Dundee, Scotland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Dept Med, Reykjavik, Iceland. [Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Institute Funct Genom, Greifswald, Germany. [Arden, Nigel K.; Cooper, Cyrus] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, NIHR Biomed Res Unit, Oxford, England. RP van Meurs, JBJ (reprint author), Erasmus MC, Erasmus Med Ctr Rotterdam, Dept Internal Med, Genet Lab, Room Ee579B,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM j.vanmeurs@erasmusmc.nl RI Macfarlane, Gary/I-9521-2014; Pendleton, Neil/F-2333-2015; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Blair/G-2834-2012; Smith, Albert/K-5150-2015; Slagboom, P. Eline/R-4790-2016; OI McBeth, John/0000-0001-7047-2183; Macfarlane, Gary/0000-0003-2322-3314; Felson, David/0000-0002-2668-2447; Pendleton, Neil/0000-0003-0794-2386; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Blair/0000-0002-5362-9430; Smith, Albert/0000-0003-1942-5845; Slagboom, P. Eline/0000-0002-2875-4723; Thomson, Wendy/0000-0002-9022-5179; Hocking, Lynne J/0000-0002-2414-2826; Williams, Frances/0000-0002-2998-2744; Peters, Marjolein/0000-0003-3167-9063; Eijkelkamp, Niels/0000-0003-0039-7063; Neogi, Tuhina/0000-0002-9515-1711; Payton, Antony/0000-0003-0335-152X FU Arthritis Research UK; Biotechnology and Biological Sciences Research Council [BB/F022441/1]; Medical Research Council [G0100594, G0901461, G1001375, MC_U147585819, MC_UP_A620_1014]; NIA NIH HHS [R01 AG018393]; NIAMS NIH HHS [P60 AR047785]; NINDS NIH HHS [R01 NS073939, R01 NS074999]; Wellcome Trust NR 78 TC 37 Z9 38 U1 1 U2 31 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2013 VL 72 IS 3 BP 427 EP 436 DI 10.1136/annrheumdis-2012-201742 PG 10 WC Rheumatology SC Rheumatology GA 088BQ UT WOS:000314809200020 PM 22956598 ER PT J AU Rao, VA AF Rao, V. Ashutosh TI Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID MEDIATED DNA-DAMAGE; ADVANCED BREAST-CANCER; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; DOXORUBICIN-INDUCED CARDIOTOXICITY; MITOCHONDRIAL NADH DEHYDROGENASE; ISONICOTINOYL HYDRAZONE CLASS; SELECTIVE ANTITUMOR-ACTIVITY; ACUTE LYMPHOBLASTIC-LEUKEMIA; SILIBININ SUPPRESSES GROWTH; CONGESTIVE HEART-FAILURE AB Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2 alpha). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2 alpha inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 18, 930-955. C1 US FDA, Div Therapeut Prot, Biochem Lab, Off Biotechnol Prod,Off Pharmaceut Sci,Ctr Drug E, Bethesda, MD 20892 USA. RP Rao, VA (reprint author), US FDA, Div Therapeut Prot, Biochem Lab, Off Biotechnol Prod,Off Pharmaceut Sci,Ctr Drug E, HFD-122,NIH Bldg 29A,Room 2A-11, Bethesda, MD 20892 USA. EM ashutosh.rao@fda.hhs.gov FU Food and Drug Administration Critical Path Initiative; National Cancer Institute FX V.A.R. is thankful to the Food and Drug Administration Critical Path Initiative and the National Cancer Institute for research support. The author wishes to thank Drs. Emily Shacter (FDA), Eugene Herman (FDA), and Yves Pommier (NCI) for insightful discussions and encouragement. Drs. John Nittis (University of Illinois), Neil Osheroff (Vanderbilt University), and Tomas Simunek (Charles University in Prague) are acknowledged for graciously agreeing to allow an adaptation of their published figures. Drs. Jennifer Dickey (FDA) and Melanie Simpson (NCI) are thanked for their critical reading of the article. NR 308 TC 11 Z9 11 U1 2 U2 38 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD MAR PY 2013 VL 18 IS 8 BP 930 EP 955 DI 10.1089/ars.2012.4877 PG 26 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 079OO UT WOS:000314180300005 PM 22900902 ER PT J AU Tang, SC Wang, YC Li, YI Lin, HC Manzanero, S Hsieh, YH Phipps, S Hu, CJ Chiou, HY Huang, YS Yang, WS Mattson, MP Arumugam, TV Jeng, JS AF Tang, Sung-Chun Wang, Yu-Chi Li, Yu-I Lin, Hsiao-Ching Manzanero, Silvia Hsieh, Yu-Hsuan Phipps, Simon Hu, Chaur-Jong Chiou, Hung-Yi Huang, Yi-Shuian Yang, Wei-Shiung Mattson, Mark P. Arumugam, Thiruma V. Jeng, Jiann-Shing TI Functional Role of Soluble Receptor for Advanced Glycation End Products in Stroke SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE animal model; HMGB1; inflammation; ischemic stroke; sRAGE ID MOBILITY GROUP BOX-1; CORONARY-ARTERY-DISEASE; ACUTE ISCHEMIC-STROKE; CARDIOVASCULAR-DISEASE; PLASMA-LEVELS; BRAIN-INJURY; RAGE; EXPRESSION; HEART; SRAGE AB Objective-Little is known about the involvement of the soluble form of receptor for advanced glycation end products (sRAGE) in acute ischemic stroke (IS). Here, we aim to identify the role of plasma sRAGE and high mobility group box 1 (HMGB1) in imaging-confirmed IS patients, as well as mice subjected to focal ischemic stroke. Methods and Results-IS patients were recruited and plasma samples were collected for the measurement of sRAGE and HMGB1 after stroke. The relation of sRAGE and HMGB1 with acute IS was also investigated in a C57BL/6J mouse model of focal ischemic stroke and primary cortical neurons subjected to oxygen and glucose deprivation. Plasma levels of sRAGE and HMGB1 were both significantly increased within 48 hours after IS, and the sRAGE level was an independent predictor of functional outcome at 3 months poststroke. Immunoprecipitation assays revealed that the binding of plasma HMGB1 to sRAGE increased progressively after IS both in patients and mice. Administration of recombinant sRAGE significantly reduced infiltrating immune cells and improved the outcome of injury in mice, protected cultured neurons against oxygen and glucose deprivation-induced cell death, and ameliorated the detrimental effect of recombinant HMGB1. Conclusion-Early poststroke plasma sRAGE may play a protective role in IS by capturing HMGB1. Hence, recombinant sRAGE is a potential therapeutic agent in acute IS. (Arterioscler Thromb Vasc Biol. 2013;33:585-594.) C1 [Tang, Sung-Chun; Wang, Yu-Chi; Jeng, Jiann-Shing] Natl Taiwan Univ Hosp, Stroke Ctr, Taipei 10055, Taiwan. [Tang, Sung-Chun; Wang, Yu-Chi; Jeng, Jiann-Shing] Natl Taiwan Univ Hosp, Dept Neurol, Taipei 10055, Taiwan. [Li, Yu-I] Natl Taiwan Univ Hosp, Dept Pathol, Taipei 10055, Taiwan. [Yang, Wei-Shiung] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 10055, Taiwan. [Lin, Hsiao-Ching] Natl Taiwan Univ Hosp, Dept Neurol, Yun Lin Branch, Taipei 10055, Taiwan. [Manzanero, Silvia; Hsieh, Yu-Hsuan; Phipps, Simon; Arumugam, Thiruma V.] Univ Queensland, Sch Biomed Sci, St Lucia, Qld, Australia. [Hu, Chaur-Jong] Taipei Med Univ, Dept Neurol, Shuang Ho Hosp, Taipei, Taiwan. [Chiou, Hung-Yi] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan. [Huang, Yi-Shuian] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Jeng, JS (reprint author), Natl Taiwan Univ Hosp, Stroke Ctr, 7 Chung Shan S Rd, Taipei 10055, Taiwan. EM t.arumugam@uq.edu.au; jsjeng@ntu.edu.tw RI Arumugam, Thiruma/B-4898-2011; Phipps, Simon/F-9170-2010; OI LI, YU-I/0000-0002-9888-1541; Jeng, Jiann-Shing/0000-0002-1456-3686; Phipps, Simon/0000-0002-7388-3612; Tang, Sung-Chun/0000-0003-3731-5973; Manzanero, Silvia/0000-0002-5294-7082; YANG, WEI-SHIUNG/0000-0001-5087-373X FU Taiwan National Science Council [97-2314-B-002-127-MY2, 98-2314-B-002-115-MY3]; Australian Research Council Future Fellowship [FT100100427]; National Institute on Aging Intramural Research Program FX This work was supported by the Taiwan National Science Council grants (97-2314-B-002-127-MY2 and 98-2314-B-002-115-MY3), Australian Research Council Future Fellowship (FT100100427) awarded to T.V.A., and the National Institute on Aging Intramural Research Program. NR 52 TC 26 Z9 26 U1 0 U2 13 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 MAR PY 2013 VL 33 IS 3 BP 585 EP 594 DI 10.1161/ATVBAHA.112.300523 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 089DS UT WOS:000314890200024 PM 23288172 ER PT J AU Wang, XY Baek, SJ Eling, TE AF Wang, Xingya Baek, Seung Joon Eling, Thomas E. TI The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer SO BIOCHEMICAL PHARMACOLOGY LA English DT Review DE NAG-1; GDF15; Cancer; Tumor suppressor ID MACROPHAGE-INHIBITORY CYTOKINE-1; TGF-BETA SUPERFAMILY; GROWTH-FACTOR-BETA; PROSTATE-DERIVED FACTOR; LUNG-CARCINOMA CELLS; COLORECTAL-CANCER; COLON-CANCER; RECEPTOR-GAMMA; UP-REGULATION; P53-DEPENDENT MECHANISM AB Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1, NAG-1, is a divergent member of the transforming growth factor-beta (TGF-beta) superfamily that plays a complex but poorly understood role in several human diseases including cancer. NAG-1 expression is substantially increased during cancer development and progression especially in gastrointestinal, prostate, pancreatic, colorectal, breast, melanoma, and glioblastoma brain tumors. Aberrant increases in the serum levels of secreted NAG-1 correlate with poor prognosis and patient survival rates in some cancers. In contrast, the expression of NAG-1 is up-regulated by several tumor suppressor pathways including p53, GSK-3 beta, and EGR-1. NAG-1 expression is also induced by many drugs and dietary compounds which are documented to prevent the development and progression of cancer in mouse models. Studies with transgenic mice expressing human NAG-1 demonstrated that the expression of NAG-1 inhibits the development of intestinal tumors and prostate tumors in animal models. Laboratory and clinical evidence suggest that NAG-1, like other TGF-beta family members, may have different or pleiotropic functions in the early and late stages of carcinogenesis. Upon understanding the molecular mechanism and function of NAG-1 during carcinogenesis, NAG-I may serve as a potential biomarker for the diagnosis and prognosis of cancer and a therapeutic target for the inhibition and treatment of cancer development and progression. Published by Elsevier Inc. C1 [Wang, Xingya; Eling, Thomas E.] NIEHS, Eicosanoid Biochem Grp, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Baek, Seung Joon] Univ Tennessee, Coll Vet Med, Dept Biomed & Diagnost Sci, Knoxville, TN 37996 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov FU NIEHS, NIH Intramural research program [ES-010016-14]; National Institutes of Health [R01CA108975] FX This research was supported, in part, by NIEHS, NIH Intramural research program, project number ES-010016-14 and partially by grant from the National Institutes of Health (R01CA108975) to SJB. The authors wish to thank all the previous members of the laboratories who have made contributions to these investigations. We also wish to thanks Justin Kosak for his critical reading of the manuscript. NR 95 TC 39 Z9 40 U1 0 U2 25 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 MAR 1 PY 2013 VL 85 IS 5 SI SI BP 597 EP 606 DI 10.1016/j.bcp.2012.11.025 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 090UB UT WOS:000315004400002 PM 23220538 ER PT J AU Gakh, AA Sosnov, AV Krasavin, M Nguyen, TL Hamel, E AF Gakh, Andrei A. Sosnov, Andrey V. Krasavin, Mikhail Tam Luong Nguyen Hamel, Ernest TI Identification of diaryl 5-amino-1,2,4-oxadiazoles as tubulin inhibitors: The special case of 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID DESIGNED MULTIPLE LIGANDS; POTENTIAL THERAPEUTIC AGENTS; ANTICANCER AGENTS; PROSTATE-CANCER; MAGIC BULLETS; BINDING-SITE; DISCOVERY; COLCHICINE; TARGET; DRUGS AB The combination of experimental (inhibition of colchicine binding) and computational (COMPARE, docking studies) data unequivocally identified diaryl 5-amino-1,2,4-oxadiazoles as potent tubulin inhibitors. Good correlation was observed between tubulin binding and cytostatic properties for all tested compounds with the notable exception of the lead candidate, 3-(3-methoxyphenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500078). This compound was found to be substantially more active in our in vitro experiments than the monofluorinated title compound, 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500067/NSC 757486), which in turn demonstrated slightly better tubulin binding activity. Comparative SAR analysis of 25 diaryl 5-amino-1,2,4-oxadiazoles with other known tubulin inhibitors, such as combretastatin A-4 (CA-4) and colchicine, provides further insight into the specifics of their binding as well as a plausible mechanism of action. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Gakh, Andrei A.] Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. [Gakh, Andrei A.] Univ Virginia, Charlottesville, VA 22908 USA. [Gakh, Andrei A.] Discovery Chem Project, Bethesda, MD 20824 USA. [Sosnov, Andrey V.] ORCHIMED, Inst Physiologically Act Cpds, Chernogolovka 142432, Russia. [Krasavin, Mikhail] Griffith Univ, Nathan, Qld 4111, Australia. [Tam Luong Nguyen] SAIC Frederick Inc, Target Struct Based Drug Discovery Grp, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Gakh, AA (reprint author), Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. EM gakhaa@yahoo.com RI Krasavin, Mikhail/F-2343-2011; OI Krasavin, Mikhail/0000-0002-0200-4772 FU U.S. Department of Energy; NCI; UT-Battelle, LLC [DE-AC05-00OR22725]; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This letter is a contribution from the Discovery Chemistry Project funded in part by the U.S. Department of Energy in collaboration with NCI. Oak Ridge National Laboratory is managed and operated by UT-Battelle, LLC, under contract DE-AC05-00OR22725 for the U. S. Department of Energy. In addition, this work has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. 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. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 31 TC 8 Z9 8 U1 1 U2 15 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 MAR 1 PY 2013 VL 23 IS 5 BP 1262 EP 1268 DI 10.1016/j.bmcl.2013.01.007 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 086NZ UT WOS:000314693400021 PM 23385208 ER PT J AU Kumkhaek, C Liu, WL Rodgers, GP AF Kumkhaek, Chutima Liu, Wenli Rodgers, Griffin P. TI Identification and characterization of novel full-length cDNAs expressed during hematopoietic lineage-specific differentiation of cultured human peripheral blood mononuclear cells SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Letter ID TRANSCRIPTION FACTOR; STEM-CELLS; CARCINOMA; DISPLAY; GROWTH; GENE C1 [Kumkhaek, Chutima; Liu, Wenli; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NHLBI, Mol & Clin Hematol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM griffinr@extra.niddk.nih.gov FU Intramural NIH HHS NR 15 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR PY 2013 VL 50 IS 3 BP 154 EP 155 DI 10.1016/j.bcmd.2012.12.001 PG 2 WC Hematology SC Hematology GA 091UE UT WOS:000315074500002 PM 23266226 ER PT J AU Luo, JH Chlebowski, R Liu, SM McGlynn, KA Parekh, N White, DL Margolis, KL AF Luo, Juhua Chlebowski, Rowan Liu, Simin McGlynn, Katherine A. Parekh, Niyati White, Donna L. Margolis, Karen L. TI Diabetes mellitus as a risk factor for gastrointestinal cancers among postmenopausal women SO CANCER CAUSES & CONTROL LA English DT Article DE Diabetes; Gastrointestinal cancers; Esophagus; Stomach; Liver; Biliary; Pancreas; Colon and rectal ID BASE-LINE CHARACTERISTICS; POPULATION-BASED COHORT; PRIMARY LIVER-CANCER; HEPATOCELLULAR-CARCINOMA; NONALCOHOLIC STEATOHEPATITIS; COLORECTAL-CANCER; PANCREATIC-CANCER; PARTICIPANTS; MORTALITY; METAANALYSIS AB While diabetes has been linked to several cancers in the gastrointestinal (GI) tract, findings have been mixed for sites other than colorectal and liver cancer. We used the Women's Health Initiative (WHI) data and conducted a comprehensive assessment of associations between diabetes and GI malignancy (esophagus, stomach, liver, biliary, pancreas, colon, and rectal). A total of 145,765 postmenopausal women aged 50-79 enrolled in the WHI were followed for a mean 10.3 years. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between GI cancers and diagnosed diabetes, including its duration and treatment. Diabetes at enrollment was associated with increased risk of liver (HR = 2.97; 95 % CI, 1.66-5.32), pancreatic (HR = 1.62; 95 % CI, 1.15-2.30), colon (HR = 1.38; 95 % CI, 1.14-1.66), and rectal (HR = 1.87, 95 % CI: 1.22-2.85) cancer. Diabetes severity, assessed by duration or need for pharmacotherapy, appeared to have stronger links to risk of liver, pancreatic, and rectal cancer, but not colon cancer. There was no statistically significant association of diabetes with biliary, esophageal, and stomach cancers. Type 2 diabetes is associated with a significantly increased risk of cancers of the liver, pancreas, colon, and rectum in postmenopausal women. The suggestion that diabetes severity further increases these cancer risks requires future studies. C1 [Luo, Juhua] W Virginia Univ, Sch Med, Mary Babb Randolph Canc Ctr, Dept Community Med, Morgantown, WV 26506 USA. [Chlebowski, Rowan] Harbor UCLA Med Ctr, Los Angeles Res Inst, Los Angeles, CA USA. [Liu, Simin] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Parekh, Niyati] NYU, Dept Nutr Food Studies & Publ Hlth, New York, NY USA. [White, Donna L.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [White, Donna L.] Baylor Coll Med, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. [White, Donna L.] Houston VAHSR&D Ctr Excellence, Clin Epidemiol & Outcomes Program, Houston, TX USA. [Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN USA. RP Luo, JH (reprint author), W Virginia Univ, Sch Med, Mary Babb Randolph Canc Ctr, Dept Community Med, POB 9190, Morgantown, WV 26506 USA. EM Jiluo@hsc.wvu.edu RI Liu, Simin/I-3689-2014; OI Liu, Simin/0000-0003-2098-3844; parekh , niyati /0000-0002-1334-0528 FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. 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]; NIDDK Career Development Award [DK081736-01]; Houston VA HSR&D Center of Excellence [HFP90-20] FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. 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. A short list of WHI investigators is given in an Appendix. DW was supported by a NIDDK Career Development Award (DK081736-01) and the Houston VA HSR&D Center of Excellence (HFP90-20). NR 38 TC 7 Z9 8 U1 1 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2013 VL 24 IS 3 BP 577 EP 585 DI 10.1007/s10552-012-9996-8 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 090KC UT WOS:000314976900017 PM 22622863 ER PT J AU Leenders, M Bhattacharjee, S Vineis, P Stevens, V Bueno-de-Mesquita, H Shu, XO Amundadottir, L Gross, M Tobias, GS Wactawski-Wende, J Arslan, AA Duell, EJ Fuchs, CS Gallinger, S Hartge, P Hoover, RN Holly, EA Jacobs, EJ Klein, AP Kooperberg, C LaCroix, A Li, DH Mandelson, MT Olson, SH Petersen, G Risch, HA Yu, K Wolpin, BM Zheng, W Agalliu, I Albanes, D Boutron-Ruault, MC Bracci, PM Buring, JE Canzian, F Chang, K Chanock, SJ Cotterchio, M Gaziano, JM Giovanucci, EL Goggins, M Hallmans, G Hankinson, SE Hoffman-Bolton, JA Hunter, DJ Hutchinson, A Jacobs, KB Jenab, M Khaw, KT Kraft, P Krogh, V Kurtz, RC McWilliams, RR Mendelsohn, JB Patel, AV Rabe, KG Riboli, E Tjonneland, A Trichopoulos, D Virtamo, J Visvanathan, K Elena, JW Yu, H Zeleniuch-Jacquotte, A Stolzenberg-Solomon, RZ AF Leenders, Max Bhattacharjee, Samsiddhi Vineis, Paolo Stevens, Victoria Bueno-de-Mesquita, H. Bas Shu, Xiao-Ou Amundadottir, Laufey Gross, Myron Tobias, Geoffrey S. Wactawski-Wende, Jean Arslan, Alan A. Duell, Eric J. Fuchs, Charles S. Gallinger, Steven Hartge, Patricia Hoover, Robert N. Holly, Elizabeth A. Jacobs, Eric J. Klein, Alison P. Kooperberg, Charles LaCroix, Andrea Li, Donghui Mandelson, Margaret T. Olson, Sara H. Petersen, Gloria Risch, Harvey A. Yu, Kai Wolpin, Brian M. Zheng, Wei Agalliu, Ilir Albanes, Demetrius Boutron-Ruault, Marie-Christine Bracci, Paige M. Buring, Julie E. Canzian, Federico Chang, Kenneth Chanock, Stephen J. Cotterchio, Michelle Gaziano, J. Michael Giovanucci, Edward L. Goggins, Michael Hallmans, Goeran Hankinson, Susan E. Hoffman-Bolton, Judith A. Hunter, David J. Hutchinson, Amy Jacobs, Kevin B. Jenab, Mazda Khaw, Kay-Tee Kraft, Peter Krogh, Vittorio Kurtz, Robert C. McWilliams, Robert R. Mendelsohn, Julie B. Patel, Alpa V. Rabe, Kari G. Riboli, Elio Tjonneland, Anne Trichopoulos, Dimitrios Virtamo, Jarmo Visvanathan, Kala Elena, Joanne W. Yu, Herbert Zeleniuch-Jacquotte, Anne Stolzenberg-Solomon, Rachael Z. TI Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 SO CANCER CAUSES & CONTROL LA English DT Article DE Pancreatic cancer; One-carbon metabolism; Polymorphisms; Biomarkers; Epidemiology ID GENOME-WIDE ASSOCIATION; FOLATE INTAKE; DNA METHYLATION; RISK; METAANALYSIS; DIETARY; HOMOCYSTEINE; CARCINOGENESIS; SUSCEPTIBILITY; PROSTATE AB The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (< 0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis. C1 [Leenders, Max; Vineis, Paolo; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Leenders, Max; Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, NL-3508 GA Utrecht, Netherlands. [Bhattacharjee, Samsiddhi; Amundadottir, Laufey; Tobias, Geoffrey S.; Hartge, Patricia; Hoover, Robert N.; Yu, Kai; Albanes, Demetrius; Chanock, Stephen J.; Hutchinson, Amy; Jacobs, Kevin B.; Mendelsohn, Julie B.; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Vineis, Paolo] HuGeF Fdn, Turin, Italy. [Stevens, Victoria; LaCroix, Andrea; Patel, Alpa V.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Dept Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Amundadottir, Laufey; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gross, Myron] Univ Minnesota, Sch Med, Dept Lab Med Pathol, Minneapolis, MN 55455 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Arslan, Alan A.] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Barcelona, Spain. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Wolpin, Brian M.; Giovanucci, Edward L.; Hankinson, Susan E.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Fuchs, Charles S.; Wolpin, Brian M.; Buring, Julie E.; Gaziano, J. Michael; Giovanucci, Edward L.; Hankinson, Susan E.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Gallinger, Steven] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Holly, Elizabeth A.; Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Klein, Alison P.] Johns Hopkins Med Inst, Dept Epidemiol, Bloomberg Sch Publ Heath, Sol Goldman Pancreat Res Ctr, Baltimore, MD 21205 USA. [Kooperberg, Charles; Mandelson, Margaret T.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Mandelson, Margaret T.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Petersen, Gloria; Rabe, Kari G.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Risch, Harvey A.; Yu, Kai] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Agalliu, Ilir] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Boutron-Ruault, Marie-Christine] Univ Paris 11, Inst Gustave Roussy, INSERM, Villejuif, France. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Canzian, Federico] German Canc Res Ctr DFKZ, Div Canc Epidemiol, Heidelberg, Germany. [Chang, Kenneth] Univ Calif Irvine, Irvine Med Ctr, Comprehens Digest Dis Ctr, Orange, CA 92668 USA. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Phys Hlth Study, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Phys Hlth Study, Div Cardiovasc Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Phys Hlth Study, Div Prevent Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giovanucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Kraft, Peter; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovanucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Hallmans, Goeran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Hoffman-Bolton, Judith A.; Visvanathan, Kala] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hutchinson, Amy; Jacobs, Kevin B.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Jenab, Mazda] WHO, IARC, Lyon, France. [Khaw, Kay-Tee] Univ Cambridge, Addenbrookes Hosp, Dept Publ Hlth & Primary Care, Cambridge CB2 2QQ, England. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Krogh, Vittorio] Ist Nazl Tumori, Fdn Ist Recovero & Cura Carattere Sci IRCCS, Nutr Epidemiol Unit, I-20133 Milan, Italy. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [McWilliams, Robert R.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Elena, Joanne W.] NCI, Div Canc Prevent & Populat Control, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Leenders, M (reprint author), Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, F02-618,Postal Box 85500, NL-3508 GA Utrecht, Netherlands. EM M.Leenders-6@umcutrecht.nl RI Boutron Ruault, Marie-Christine/G-3705-2013; Gallinger, Steven/E-4575-2013; Boutron, Marie-Christine/K-8168-2013; Albanes, Demetrius/B-9749-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Krogh, Vittorio/K-2628-2016; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Krogh, Vittorio/0000-0003-0122-8624; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; Duell, Eric J/0000-0001-5256-0163 FU Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; World Cancer Research Fund [2008/51] FX This research was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. This study has been funded by the World Cancer Research Fund (Grant No. 2008/51 to PV). For full acknowledgments, please see electronic supplementary material. NR 32 TC 2 Z9 2 U1 0 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2013 VL 24 IS 3 BP 595 EP 602 DI 10.1007/s10552-012-0138-0 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 090KC UT WOS:000314976900019 PM 23334854 ER PT J AU Marchesi, C Rehman, A Rautureau, Y Kasal, DA Briet, M Leibowitz, A Simeone, SMC Ebrahimian, T Neves, MF Offermanns, S Gonzalez, FJ Paradis, P Schiffrin, EL AF Marchesi, Chiara Rehman, Asia Rautureau, Yohann Kasal, Daniel A. Briet, Marie Leibowitz, Avshalom Simeone, Stefania M. C. Ebrahimian, Talin Neves, Mario F. Offermanns, Stefan Gonzalez, Frank J. Paradis, Pierre Schiffrin, Ernesto L. TI Protective role of vascular smooth muscle cell PPAR gamma in angiotensin II-induced vascular disease SO CARDIOVASCULAR RESEARCH LA English DT Article DE Hypertension; Small arteries; Vascular protection; PPAR gamma; Angiotensin II ID ACTIVATED-RECEPTOR-GAMMA; IMPROVES ENDOTHELIAL FUNCTION; BLOOD-VESSELS; INDUCED HYPERTENSION; INSULIN-RESISTANCE; OXIDATIVE STRESS; DEFICIENT MICE; DYSFUNCTION; INFLAMMATION; EXPRESSION AB Vascular peroxisome proliferator-activated receptor (PPAR) activation improves vascular remodelling and endothelial function in hypertensive rodents. The goal of this study was to determine that vascular smooth muscle cell (VSMC) PPAR exerts a vascular protective role beyond its metabolic effects. We generated a model of adult inducible VSMC-specific Ppar inactivation to test the hypothesis that PPAR counteracts angiotensin (Ang) II-induced vascular remodelling and endothelial dysfunction. Inducible VSMC Ppar knockout mice were generated by crossing Ppar floxed mice with mice expressing a tamoxifen-inducible Cre recombinase Smooth muscle (Sm) myosin heavy chain promoter control. Eight-to-ten-week-old SmPpar(/) and control mice were infused with a nonpressor dose of Ang II for 7 days. Blood pressure was unaffected. Mesenteric arteries showed eutrophic remodelling in Ang II-infused control mice and hypertrophic remodelling in Ang II-infused SmPpar(/) mice. Endothelium-dependent relaxation to acetylcholine was reduced in SmPpar(/) mice and further impaired by Ang II infusion, and was unaffected by an inhibitor of NO synthase, suggesting a defect of NO-mediated relaxation. SmPpar deletion increased the sensitivity to Ang II-induced contraction. SmPpar(/) mice exhibited enhanced Ang II-induced vascular NADPH oxidase activity and adhesion molecule ICAM-1 and chemokine monocyte chemotactic protein-1 expression. The antioxidant Superoxide dismutase 3 expression was decreased by SmPpar deletion. Ang II infusion increased the expression of CD3 T-cell co-receptor chain and decreased Adiponectin in perivascular adipose tissue of SmPpar(/) mice. Inducible Ppar inactivation in VSMCs exacerbated Ang II-induced vascular remodelling and endothelial dysfunction via enhanced vascular oxidative stress and inflammation, revealing the protective role of VSMC PPAR in angiotensin II-induced vascular injury. C1 [Marchesi, Chiara; Rehman, Asia; Rautureau, Yohann; Kasal, Daniel A.; Briet, Marie; Leibowitz, Avshalom; Simeone, Stefania M. C.; Ebrahimian, Talin; Paradis, Pierre; Schiffrin, Ernesto L.] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. [Marchesi, Chiara] Univ Insubria, Dept Clin Med, Varese, Italy. [Kasal, Daniel A.; Neves, Mario F.] Univ Estado Rio De Janeiro, Rio De Janeiro, Brazil. [Briet, Marie] Hop Europeen Georges Pompidou, AP HP, Dept Pharmacol, F-75015 Paris, France. [Briet, Marie] Hop Europeen Georges Pompidou, AP HP, Inst Natl Sante & Rech Med, U970,PARCC, F-75015 Paris, France. [Leibowitz, Avshalom] Chaim Sheba Med Ctr, Dept Internal Med D, IL-52621 Tel Hashomer, Israel. [Leibowitz, Avshalom] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Offermanns, Stefan] Max Planck Inst Heart & Lung Res, Dept Pharmacol, Bad Nauheim, Germany. [Gonzalez, Frank J.] NCI, Lab Metab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. [Schiffrin, Ernesto L.] McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3T 1E2, Canada. RP Schiffrin, EL (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. EM ernesto.schiffrin@mcgill.ca RI Briet, Marie/K-7385-2015 FU Canadian Institutes of Health Research (CIHR) [37917, 82790]; Canada Research Chair (CRC) on Hypertension and Vascular Research by the CRC Government of Canada/CIHR Program; Canada Fund for Innovation (CFI); Pfizer Canada FX This work was supported by Canadian Institutes of Health Research (CIHR) grants 37917 and 82790, a Canada Research Chair (CRC) on Hypertension and Vascular Research by the CRC Government of Canada/CIHR Program, the Canada Fund for Innovation (CFI), and a grant from Pfizer Canada Competitive Cardiovascular Grants Program, all to E.L.S. NR 45 TC 19 Z9 19 U1 2 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 1 PY 2013 VL 97 IS 3 BP 562 EP 570 DI 10.1093/cvr/cvs362 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 091KM UT WOS:000315048200019 PM 23250918 ER PT J AU Wan, WZ Lionakis, MS Liu, Q Roffe, E Murphy, PM AF Wan, Wuzhou Lionakis, Michail S. Liu, Qian Roffe, Ester Murphy, Philip M. TI Genetic deletion of chemokine receptor Ccr7 exacerbates atherogenesis in ApoE-deficient mice SO CARDIOVASCULAR RESEARCH LA English DT Article DE Atherosclerosis; Inflammation; Leucocytes; Aorta ID T-CELL HOMEOSTASIS; ACCELERATES ATHEROSCLEROSIS; PERIPHERAL-TISSUES; IN-VIVO; DISEASE; INTERLEUKIN-12; INFLAMMATION; NEUTROPHILS; DISRUPTION; MECHANISMS AB Recent evidence suggests that both Ccr7 and its ligands, Ccl19 and Ccl21, are present in mouse and human atherosclerotic plaques; however, the role of Ccr7 in atherogenesis is still controversial. Here, we addressed this question by using the classic apolipoprotein E-deficient (ApoE(/)) mouse model of atherosclerosis. Ccr7(/)ApoE(/) double knockout mice and Ccr7(/)ApoE(/) littermates were generated and maintained on a high-fat Western diet for 8 weeks to induce atherosclerosis. Ccr7(/)ApoE(/) mice showed an approximate to 80 increase in atherosclerotic lesion size in the whole aorta and a two-fold increase in the aortic root compared with Ccr7(/)ApoE(/) mice. Ccr7(/)ApoE(/) mice had increased T cells in the blood, bone marrow, and spleen, as well as in atherosclerotic lesions. Competitive repopulation experiments revealed that T cells from Ccr7(/)ApoE(/) mice migrated poorly into lymph nodes but better into mouse aortas compared with T cells from Ccr7(/)ApoE(/) mice. Transplantation of the bone marrow from Ccr7(/)ApoE(/) mice into lethally irradiated Ccr7(/)ApoE(/) mice resulted in approximate to 60 more atherosclerotic lesions compared with Ccr7(/)ApoE(/) donor bone marrow, suggesting that exacerbation was mediated by a Ccr7 bone marrow-derived cell(s). Furthermore, in Ccr7(/)ApoE(/) mice the serum level of IL-12 was markedly increased, whereas the level of transforming growth factor beta (TGF-) was significantly decreased, suggesting an imbalance of T cell responses in these mice. Our data suggest that genetic deletion of Ccr7 exacerbates atherosclerosis by increasing T cell accumulation in atherosclerotic lesions. C1 [Wan, Wuzhou; Lionakis, Michail S.; Liu, Qian; Roffe, Ester; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike,Bldg 10,Rm11N113, Bethesda, MD 20892 USA. EM pmm@nih.gov RI Wan, Wuhzou/H-8556-2013; Roffe, Ester/H-4688-2012 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 33 TC 18 Z9 19 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 1 PY 2013 VL 97 IS 3 BP 580 EP 588 DI 10.1093/cvr/cvs349 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 091KM UT WOS:000315048200021 PM 23180724 ER PT J AU Hogan, M Bahta, M Cherry, S Lountos, GT Tropea, JE Zhao, BM Burke, TR Waugh, DS Ulrich, RG AF Hogan, Megan Bahta, Medhanit Cherry, Scott Lountos, George T. Tropea, Joseph E. Zhao, Bryan M. Burke, Terrence R., Jr. Waugh, David S. Ulrich, Robert G. TI Biomolecular Interactions of Small-molecule Inhibitors Affecting the YopH Protein Tyrosine Phosphatase SO CHEMICAL BIOLOGY & DRUG DESIGN LA English DT Article DE affinity screening; competitive binding assay; high-throughput screening; peptide microarray; phosphopeptide; protein tyrosine phosphatase; surface plasmon resonance; Yersinia pestis outer protein H ID SUBSTRATE-TRAPPING MUTANTS; YERSINIA-PESTIS; SH2 DOMAINS; BINDING; LIBRARY; DEPHOSPHORYLATION; IDENTIFICATION; SPECIFICITY; MECHANISM; DISCOVERY AB We have developed competitive and direct binding methods to examine small-molecule inhibitors of protein tyrosine phosphatase activity. Focusing on the Yersinia pestis outer protein H, a potent bacterial protein tyrosine phosphatase, we describe how an understanding of the kinetic interactions involving Yersinia pestis outer protein H, peptide substrates, and small-molecule inhibitors of protein tyrosine phosphatase activity can be beneficial for inhibitor screening, and we further translate these results into a microarray assay for high-throughput screening. C1 [Hogan, Megan; Zhao, Bryan M.; Ulrich, Robert G.] USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Bahta, Medhanit; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Cherry, Scott; Lountos, George T.; Tropea, Joseph E.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, NIH,Frederick Natl Lab, Ft Detrick, MD 21702 USA. [Lountos, George T.] SAIC Frederick Inc, Frederick Natl Lab, Basic Sci Program, Frederick, MD 21702 USA. RP Ulrich, RG (reprint author), USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. EM rulrich@bhsai.org RI Burke, Terrence/N-2601-2014; Lountos, George/B-3983-2015 FU Department of Defense; Joint Science and Technology Office; 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 This project was supported in part by an appointment of MH to the Research Participation Program for the U.S. Army Medical Research and Materiel Command, administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and the USAMRMC and by funding from: the Department of Defense, Joint Science and Technology Office; federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E; and 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 the mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. NR 31 TC 2 Z9 2 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-0277 J9 CHEM BIOL DRUG DES JI Chem. Biol. Drug Des. PD MAR PY 2013 VL 81 IS 3 BP 323 EP 333 DI 10.1111/cbdd.12097 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 090NM UT WOS:000314985900002 PM 23241354 ER PT J AU Chun, TW AF Chun, Tae-Wook TI Tracking replication-competent HIV reservoirs in infected individuals SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE highly active antiretroviral therapy; HIV; latency; quantitative coculture assay; viral reservoirs ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; IMMUNODEFICIENCY-VIRUS TYPE-1; BLOOD MONONUCLEAR-CELLS; VALPROIC ACID; LATENT RESERVOIR; PLASMA VIREMIA; COMBINATION THERAPY; ANTIVIRAL THERAPY; EXTENDED PERIODS AB Purpose of review Prolonged suppression of plasma viremia is now achievable in a majority of HIV-infected individuals receiving antiretroviral therapy (ART). However, ART alone cannot eradicate HIV in infected individuals. The purpose of this review is to discuss the importance of tracking levels of infected CD4(+) T cells carrying replication-competent HIV in basic and clinical research and how the use of this virologic marker could help determine the efficacy of ART and several novel therapeutic strategies that are being proposed for eliminating persistent viral reservoir in infected individuals receiving ART. Recent findings In recent years, there has been a growing interest within the HIV/AIDS scientific community to develop therapeutic strategies aimed at eliminating persistently infected CD4(+) T cells in order to achieve a cure for HIV in infected individuals receiving ART. These approaches include administration of HIV-activating agents, modification of the genetics of CD4(+) T cells, stem cell transplantation, and therapeutic vaccination. Such approaches would ultimately require careful and accurate assessments of the effect of therapeutic agents on HIV burden in infected individuals. Summary Given that the majority of infected CD4(+) T cells in vivo carry replication-defective HIV, longitudinal measurements of the frequency of cells carrying replication-competent HIV along with other quantitative virologic parameters, such as levels of plasma viremia and cell-associated viral nucleic acid, can provide critical insight into the dynamics of the persistent viral reservoirs. Information related to HIV pathogenesis and the feasibility of eradicating the virus in infected individuals receiving ART in combination with novel therapeutic agents can also be gained from these analyses. C1 [Chun, Tae-Wook] NIAID, NIH, Bethesda, MD 20892 USA. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A32,9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 52 TC 9 Z9 9 U1 1 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAR PY 2013 VL 8 IS 2 BP 111 EP 116 DI 10.1097/COH.0b013e32835d6e1c PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 088AU UT WOS:000314807000005 PM 23380652 ER PT J AU Bosch, RJ Zhang, XY Sandler, NG AF Bosch, Ronald J. Zhang, Xinyan Sandler, Netanya G. TI Study design issues in evaluating immune biomarkers SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE biomarker; clinical trials; measurement error; observational research; surrogate marker ID SURROGATE END-POINTS; AGE-RELATED COMORBIDITIES; HIV-INFECTED INDIVIDUALS; AIDS CLINICAL-TRIALS; ANTIRETROVIRAL TREATMENT; CELL COUNT; T-CELLS; RELIABLE ASSESSMENT; ACTIVATION MARKERS; MAJOR MORBIDITY AB Purpose of review The dramatic increase in the number and type of immune biomarkers that can be measured, particularly those assessing immune activation, has led to numerous investigations in HIV-infected individuals to explore pathogenesis and to assess therapeutic interventions that aim to attenuate immune activation. An overview is provided on study designs and related statistical and operational issues relevant to these investigations. Recent findings Cohort studies and nested case-control studies within these cohorts have identified multiple biomarkers that are associated with an increased risk of disease. Early-stage clinical trials of therapies to address these risks in HIV-infected individuals with viral suppression on antiretroviral therapy are a substantial focus of current HIV research. Summary Appropriate study design is essential in biomarker research. C1 [Bosch, Ronald J.; Zhang, Xinyan] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Sandler, Netanya G.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bosch, RJ (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 651 Huntington Ave,FXB 603, Boston, MA 02115 USA. EM rbosch@hsph.harvard.edu OI Utay, Netanya/0000-0002-6407-8670 FU AIDS Clinical Trials Group; National Institute of Allergy and Infectious Diseases [AI-68636, AI-68634]; intramural programme of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health grant [AI-76174]; [P01-AI074415] FX This work was supported in part by AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI-68636, AI-68634), by P01-AI074415 and by the intramural programme of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank the members of the Immune Activation Focus Group of the ACTG and the Cleveland Immunopathogenesis Consortium (BBC), funded by National Institutes of Health grant AI-76174, for stimulating and informative discussions. NR 65 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAR PY 2013 VL 8 IS 2 BP 147 EP 154 DI 10.1097/COH.0b013e32835d3259 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 088AU UT WOS:000314807000010 PM 23380656 ER PT J AU Amarnath, S Barrett, AJ AF Amarnath, Shoba Barrett, Austin J. TI Mesenchymal stromal cells: heroes or non-combatants? SO CYTOTHERAPY LA English DT Editorial Material ID VERSUS-HOST-DISEASE; PROLIFERATION IN-VITRO; STEM-CELLS; GRAFT FAILURE; MICE; VIVO; TRANSPLANTATION; REDUCE; RISK C1 [Amarnath, Shoba] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Barrett, Austin J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Amarnath, S (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM samarnath@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 15 TC 1 Z9 1 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD MAR PY 2013 VL 15 IS 3 BP 253 EP 254 DI 10.1016/j.jcyt.2013.01.001 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 092PC UT WOS:000315133500001 PM 23579057 ER PT J AU Pamphilon, D Selogie, E McKenna, D Cancelas-Peres, JA Szczepiorkowski, ZM Sacher, R McMannis, J Eichler, H Garritsen, H Takanashi, M van de Watering, L Stroncek, D Reems, JA AF Pamphilon, Derwood Selogie, Eileen McKenna, David Cancelas-Peres, Jose A. Szczepiorkowski, Zbigniew M. Sacher, Ron McMannis, John Eichler, Hermann Garritsen, Henk Takanashi, Minoko van de Watering, Leo Stroncek, David Reems, Jo-Anna TI Current practices and prospects for standardization of the hematopoietic colony-forming unit assay: a report by the cellular therapy team of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative SO CYTOTHERAPY LA English DT Article DE colony-forming-units; hematopoietic; hematopoietic progenitor cells; potency test ID UMBILICAL-CORD BLOOD; TRYPAN BLUE; MULTIPLE-MYELOMA; SINGLE-CENTER; VIABILITY; TRANSPLANTATION; ENGRAFTMENT; CELLS; EXCLUSION; POTENCY AB Background aims. Wide acceptance of the colony-forming unit (CFU) assay as a reliable potency test for stem cell products is hindered by poor inter-laboratory reproducibility. The goal of this study was to ascertain current laboratory practices for performing the CFU assay with an eye towards identifying practices that could be standardized to improve overall reproducibility. Methods. A survey to evaluate current laboratory practices for performing CFU assays was designed and internationally distributed. Results. There were 105 respondents to the survey, of whom 68% performed CFU assays. Most survey recipients specified that an automated rather than a manual cell count was performed on pre-diluted aliquots of stem cell products. Viability testing methods employed various stains, and when multiple sites used the same viability stain, the methods differed. Cell phenotype used to prepare working cell suspensions for inoculating the CFU assay differed among sites. Most respondents scored CFU assays at 14-16 days of incubation, but culture plates were read with various microscopes. Of 57 respondents, 42% had not performed a validation study or established assay linearity. Only 63% of laboratories had criteria for determining if a plate was overgrown with colonies. Conclusions. Survey results revealed inconsistent inter-laboratory practices for performing the CFU assay. The relatively low number of centers with validated CFU assays raises concerns about assay accuracy and emphasizes a need to establish central standards. The survey results shed light on numerous steps of the methodology that could be targeted for standardization across laboratories. C1 [McKenna, David] Univ Minnesota, St Paul, MN 55108 USA. [Cancelas-Peres, Jose A.; Sacher, Ron] Hoxworth Blood Ctr, Cincinnati, OH USA. [Szczepiorkowski, Zbigniew M.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Selogie, Eileen; McMannis, John] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Eichler, Hermann] Saarland Univ Hosp, Inst Clin Hemostaseol & Transfus Med, Homburg, Germany. [Garritsen, Henk] Staedt Klinikum Braunschweig gGMbH, Braunschweig, Germany. [Takanashi, Minoko] Japanese Red Cross Kanto Koshinetsu Block Blood C, Tokyo, Japan. [van de Watering, Leo] LUMC Jon J van Rood Ctr Clin Transfus Res, Leiden, Netherlands. [Stroncek, David] NIH, Bethesda, MD 20892 USA. [Reems, Jo-Anna] Univ Washington, Seattle, WA 98195 USA. [Selogie, Eileen] ENet Answers, Manhattan Beach, CA USA. RP Reems, JA (reprint author), Univ Utah, 676 Arapeen Dr,Suite 300, Salt Lake City, UT 84108 USA. EM joanna.reems@hsc.utah.edu RI Szczepiorkowski, Zbigniew/A-1359-2007 OI Szczepiorkowski, Zbigniew/0000-0003-2357-9564 FU BEST; Puget Sound Blood Center FX We would like to thank members of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative cellular therapy team. This work was supported in part by the BEST Collaborative and the Puget Sound Blood Center. NR 18 TC 6 Z9 6 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD MAR PY 2013 VL 15 IS 3 BP 255 EP 262 DI 10.1016/j.jcyt.2012.11.013 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 092PC UT WOS:000315133500002 PM 23579058 ER PT J AU Shardell, M Simonsick, EM Hicks, GE Resnick, B Ferrucci, L Magaziner, J AF Shardell, Michelle Simonsick, Eleanor M. Hicks, Gregory E. Resnick, Barbara Ferrucci, Luigi Magaziner, Jay TI Sensitivity Analysis for Nonignorable Missingness and Outcome Misclassification from Proxy Reports SO EPIDEMIOLOGY LA English DT Article ID PATTERN-MIXTURE-MODELS; MULTIVARIATE INCOMPLETE DATA; LONGITUDINAL BINARY DATA; PROPENSITY SCORE; LOGISTIC-REGRESSION; HIP-FRACTURE; BIAS; DISABILITY; INFERENCE; AREAS AB Researchers often recruit proxy respondents, such as relatives or caregivers, for epidemiologic studies of older adults when study participants are unable to provide self-reports (eg, because of illness or cognitive impairment). In most studies involving proxy-reported outcomes, proxies are recruited only to report on behalf of participants who have missing self-reported outcomes; thus, either a proxy report or participant self-report, but not both, is available for each participant. When outcomes are binary and investigators conceptualize participant self-reports as gold standard measures, substituting proxy reports in place of missing participant self-reports in statistical analysis can introduce misclassification error and lead to biased parameter estimates. However, excluding observations from participants with missing self-reported outcomes may also lead to bias. We propose a pattern-mixture model that uses error-prone proxy reports to reduce selection bias from missing outcomes, and we describe a sensitivity analysis to address bias from differential outcome misclassification. We perform model estimation with high-dimensional (eg, continuous) covariates using propensity-score stratification and multiple imputation. We apply the methods to the Second Cohort of the Baltimore Hip Studies, a study of elderly hip fracture patients, to assess the relation between type of surgical treatment and perceived physical recovery. Simulation studies show that the proposed methods perform well. We provide SAS programs in the eAppendix (http://links.lww.com/EDE/A646) to enhance the methods' accessibility. (Epidemiology 2013;24: 215-223) C1 [Shardell, Michelle; Magaziner, Jay] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Baltimore, MD USA. [Resnick, Barbara] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. RP Shardell, M (reprint author), Univ Maryland, Sch Med, 660 W Redwood St, Baltimore, MD 21201 USA. EM mshardel@epi.umaryland.edu FU NIH [K25 AG034216, R01 AG06322, R01 AG09902] FX Supported by NIH grants K25 AG034216 (M.S.), R01 AG06322 (J.M.), and R01 AG09902 (J.M.). NR 44 TC 2 Z9 2 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2013 VL 24 IS 2 BP 215 EP 223 DI 10.1097/EDE.0b013e31827f4fa9 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 086ZB UT WOS:000314728000008 PM 23348065 ER PT J AU D'Aloisio, AA DeRoo, LA Baird, DD Weinberg, CR Sandler, DP AF D'Aloisio, Aimee A. DeRoo, Lisa A. Baird, Donna D. Weinberg, Clarice R. Sandler, Dale P. TI Prenatal and Infant Exposures and Age at Menarche SO EPIDEMIOLOGY LA English DT Article ID BREAST-CANCER RISK; BODY-SIZE; POSTNATAL-GROWTH; BIRTH-WEIGHT; REPRODUCTIVE-TRACT; SECULAR TRENDS; CD-1 MICE; US GIRLS; IN-UTERO; DIETHYLSTILBESTROL AB Background: Early menarche is related to increased risk of breast cancer. The number of established factors that contribute to early menarche is limited. We studied prenatal and infant exposures in relation to age at menarche in a nationwide cohort of women who have a family history of breast cancer. Methods: The study comprised 33,501 women in the Sister Study who were 35-59 years of age at baseline (2003-2009). We used polytomous logistic regression to estimate separate relative risk ratios (rRRs) and 95% confidence intervals (CIs) for associations of self-reported exposures with menarche at <= 10, 11, 14, and >= 15 years relative to menarche at 12-13 years. Results: Early menarche (<= 10 or 11 years) was associated with having low birth weight, having had a teenage mother, being first-born, and specific prenatal exposures: mother's smoking, diethylstilbestrol (DES), prepregnancy diabetes, and pregnancy-related hypertensive disorder. Prenatal exposures most strongly associated with very early menarche (<= 10 years) were DES (rRR = 1.56 [95% CI = 1.24-1.96]), maternal prepregnancy diabetes (2.24 [1.37-3.68]), and pregnancy-related hypertensive disorder (1.45 [1.18-1.79]). Soy formula was associated with both very early menarche (1.21 [0.94-1.54]) and late menarche (14 years: 1.17 [0.98-1.40] or >= 15 years: 1.28 [1.06-1.56]). Conclusions: Although menarche is only one marker of pubertal development, it is a commonly used surrogate. The observed associations of prenatal DES and soy formula exposure with age at menarche are consistent with animal data on exogenous estrogens and pubertal timing. Early-life exposures may confound associations between age at menarche and hormonally dependent outcomes in adults. (Epidemiology 2013; 24: 277-284) C1 [D'Aloisio, Aimee A.; DeRoo, Lisa A.; Baird, Donna D.; Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Weinberg, Clarice R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP D'Aloisio, AA (reprint author), NIEHS, Epidemiol Branch, POB 12233,Mail Drop A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM daloisio@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Sandler, Dale/0000-0002-6776-0018 FU NIH, National Institute of Environmental Health Sciences [Z01 ES044005] FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044005). NR 56 TC 24 Z9 25 U1 3 U2 27 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2013 VL 24 IS 2 BP 277 EP 284 DI 10.1097/EDE.0b013e31828062b7 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 086ZB UT WOS:000314728000016 PM 23348069 ER PT J AU Hammer, MB Eleuch-Fayache, G Gibbs, JR Arepalli, SK Chong, SB Sassi, C Bouhlal, Y Hentati, F Amouri, R Singleton, AB AF Hammer, M. B. Eleuch-Fayache, G. Gibbs, J. R. Arepalli, S. K. Chong, S. B. Sassi, C. Bouhlal, Y. Hentati, F. Amouri, R. Singleton, A. B. TI Exome sequencing: an efficient diagnostic tool for complex neurodegenerative disorders SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE APOB; ataxia; exome sequencing; mutation; SACS; SPG11 ID RECESSIVE SPASTIC ATAXIA; CHARLEVOIX-SAGUENAY; HEREDITARY ATAXIAS; CORPUS-CALLOSUM; HYPERTRIGLYCERIDEMIA; CLASSIFICATION; PARAPLEGIAS; SPG11 AB Background and purpose: Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. We studied three families diagnosed with ARCA. Methods: To determine the gene lesions responsible for their disorders, we performed high-density single-nucleotide polymorphism genotyping and exome sequencing. Results: We identified a new mutation in the SACS gene and a known mutation in SPG11. Notably, we also identified a homozygous variant in APOB, a gene previously associated with ataxia. Conclusions: These findings demonstrate that exome sequencing is an efficient and direct diagnostic tool for identifying the causes of complex and genetically heterogeneous neurodegenerative diseases, early-stage disease or cases with limited clinical data. C1 [Hammer, M. B.; Eleuch-Fayache, G.; Hentati, F.; Amouri, R.] Natl Inst Neurol, Dept Mol Neurobiol & Neuropathol, Tunis, Tunisia. [Hammer, M. B.; Gibbs, J. R.; Arepalli, S. K.; Chong, S. B.; Sassi, C.; Singleton, A. B.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Gibbs, J. R.; Sassi, C.] UCL, Reta Lilla Weston Labs, Inst Neurol, London, England. [Gibbs, J. R.; Sassi, C.] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Bouhlal, Y.] UCSF, Inst Human Genet, San Francisco, CA USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, 35 Convent Dr,Room 1A1014, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services [ZIA AG000958-09] FX The authors thank Jeffrey Hammer and Marguerite Meitzler for their contribution in the correction of the manuscript. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services. Project Number ZIA AG000958-09. NR 22 TC 14 Z9 14 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD MAR PY 2013 VL 20 IS 3 BP 486 EP 492 DI 10.1111/j.1468-1331.2012.03883.x PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 090RX UT WOS:000314998100018 PM 23043354 ER PT J AU Lungu, C Considine, E Zahir, S Ponsati, B Arrastia, S Hallett, M AF Lungu, C. Considine, E. Zahir, S. Ponsati, B. Arrastia, S. Hallett, M. TI Pilot study of topical acetyl hexapeptide-8 in the treatment for blepharospasm in patients receiving botulinum toxin therapy SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE blepharospasm; botulinum; dystonia; therapy; topical ID MECHANISM AB Background and purpose: Injectable botulinum neurotoxin (BoNT) is the principal effective treatment for blepharospasm (BSP). This trial explores the safety and efficacy of topical acetyl hexapeptide-8 (AH8), a competitive SNAP25 inhibitor, as a potential new therapy in BSP. Methods: Double-blind, placebo-controlled, randomized trial of daily topical application of AH8 in 24 patients with BSP. The primary outcome was time to return to baseline Jankovic Blepharospasm Rating Scale (JBRS) after a BoNT injection simultaneously with the initiation of AH8. Patients displaying a strictly regular pattern of response to 3-monthly injections of BoNT were included. Results: There were no significant adverse events. There was a trend for longer time until return to baseline JBRS after injection in the active group compared to placebo (3.7 months vs. 3.0 months), and for better scores in the active group. One-third (4/12) of the patients in the active group had a considerable extension of symptom control after BoNT (range: 3.3-7.1 months). Conclusions: Topical AH8 is safe and promising for extending the duration of action of BoNT therapy for BSP. C1 [Lungu, C.; Zahir, S.] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Considine, E.; Hallett, M.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Ponsati, B.; Arrastia, S.] BCN Peptides SA, Barcelona, Spain. RP Lungu, C (reprint author), NIH Med Neurol, Bldg 10,Rm 7D37,MSC 1428,10 Ctr Dr, Bethesda, MD 20892 USA. EM lunguci@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003032-08] NR 12 TC 10 Z9 11 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD MAR PY 2013 VL 20 IS 3 BP 515 EP 518 DI 10.1111/ene.12009 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 090RX UT WOS:000314998100022 PM 23146065 ER PT J AU Chukmaitov, A Bradley, CJ Dahman, B Siangphoe, U Warren, JL Klabunde, CN AF Chukmaitov, Askar Bradley, Cathy J. Dahman, Bassam Siangphoe, Umaporn Warren, Joan L. Klabunde, Carrie N. TI Association of polypectomy techniques, endoscopist volume, and facility type with colonoscopy complications SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID PRIMARY-CARE PHYSICIANS; COLORECTAL-CANCER; OUTPATIENT COLONOSCOPY; RISK-ADJUSTMENT; ADVERSE EVENTS; PERFORATION; PERFORMANCE; POPULATION; DELIVERY; QUALITY AB Background and Objective: Serious GI adverse events in the outpatient setting were examined by polypectomy technique, endoscopist volume, and facility type (ambulatory surgery center and hospital outpatient department). Design: Retrospective follow-up study. Setting: Ambulatory surgery and hospital discharge datasets from Florida (1997-2004) were used. Patients: A total of 2,315,126 outpatient colonoscopies performed in patients of all ages and payers were examined. Main Outcome: Thirty-day hospitalizations because of colonic perforations and GI bleeding, measured as cumulative and specific outcomes, were investigated. Results: Compared with simple colonoscopy, the adjusted risks of cumulative adverse events were greater with the use of cold forceps (1.21 [95% CI, 1.01-1.44]), ablation (3.75 [95% CI, 2.97-4.72]), hot forceps (5.63 [95% CI, 4.97-6.39]), snares (7.75 [95% CI, 6.95-8.64]), or complex colonoscopy (8.83 [95% CI, 7.70-10.12]). Low-volume endoscopists had higher risks of adverse events (1.18 [95% CI, 1.07-1.30]). A higher risk of adverse events was associated with procedures performed in ambulatory surgery centers (1.27 [95% CI, 1.16-1.40]). Important findings were also reported for the analyses stratified by specific outcomes and procedures. Limitation: The study was constrained by limitations inherent in administrative data pertaining to a single state. Conclusions: As the complexity of polypectomy increases, a higher risk of adverse events is reported. Using lower risk procedures when clinically appropriate or referring patients to high-volume endoscopists can reduce the rates of perforations and GI bleeding. Given the large number of colonoscopies performed in the United States, it is critical that the rates of adverse events be considered when choosing procedures. (Gastrointest Endosc 2013;77:436-46.) C1 [Chukmaitov, Askar; Bradley, Cathy J.; Dahman, Bassam; Siangphoe, Umaporn] Virginia Commonwealth Univ, Dept Healthcare Policy & Res, Sch Med, Richmond, VA 23298 USA. [Warren, Joan L.; Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Chukmaitov, A (reprint author), Virginia Commonwealth Univ, Dept Healthcare Policy & Res, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM achukmaitov@vcu.edu FU Virginia Commonwealth University Massey Cancer Center pilot grant FX The authors disclosed no financial relationships relevant to this publication. This study (Dr Chukmaitov) is supported by the Virginia Commonwealth University Massey Cancer Center pilot grant. NR 27 TC 26 Z9 26 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAR PY 2013 VL 77 IS 3 BP 436 EP 446 DI 10.1016/j.gie.2012.11.012 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 088JT UT WOS:000314831000015 PM 23290773 ER PT J AU Laiyemo, AO Doubeni, C Brim, H Ashktorab, H Schoen, RE Gupta, S Charabaty, A Lanza, E Smoot, DT Platz, E Cross, AJ AF Laiyemo, Adeyinka O. Doubeni, Chyke Brim, Hassan Ashktorab, Hassan Schoen, Robert E. Gupta, Samir Charabaty, Aline Lanza, Elaine Smoot, Duane T. Platz, Elizabeth Cross, Amanda J. TI Short- and long-term risk of colorectal adenoma recurrence among whites and blacks SO GASTROINTESTINAL ENDOSCOPY LA English DT Article; Proceedings Paper CT 53rd Annual Meeting of the Society-for-Surgery-of-the-Alimentary-Tract (SSAT) / Digestive Disease Week (DDW) / Meeting of the Pancreas-Club CY MAY 17-22, 2012 CL San Diego, CA SP Amer Assoc Study Liver Dis (AASLD), Amer Gastroenterol Assoc (AGA), Amer Soc Gastrointestinal Endoscopy (ASGE), Soc Surg Alimentary Tract (SSAT), Pancreas Club ID RACIAL-DIFFERENCES; AMERICAN-COLLEGE; TASK-FORCE; HIGH-FIBER; LOW-FAT; CANCER; RACE; SURVIVAL; TRIAL; COLON AB Background: It is unclear whether the higher burden from colorectal cancer among blacks is due to an increased biological susceptibility. Objective: To determine whether non-Hispanic blacks (blacks) have a higher risk of adenoma recurrence than non-Hispanic whites (whites) after removal of colorectal adenoma. Design: Secondary analysis of the Polyp Prevention Trial (PPT) data. Setting: United States. Patients: Patients were 1668 self-identified whites and 153 blacks who completed the 4-year trial. Of these, 688 whites and 55 blacks enrolled in a posttrial, passive Polyp Prevention Trial Continued Follow-up Study (PPT-CFS) and underwent another colonoscopy. Main Outcome Measurements: Recurrence and location of the adenoma and advanced adenoma by race-ethnicity during PPT and cumulative recurrence over a mean follow-up of 8.3 years (range, 4.9-12.4 years) among PPT-CFS enrollees. Results: Blacks had similar risk of recurrence of adenoma (39.2% vs 39.4%; incidence risk ratio [RR] = .98; 95% CI,.80-1.20) and advanced adenoma (8.5% vs 6.4%; RR = 1.18; 95% CI, .68-2.05) as whites at the end of PPT. Recurrence risk did not differ by colon subsite. Among PPT-CFS enrollees, the cumulative recurrence rate over a maximal follow-up period of 12 years was similar for blacks and whites for adenoma (67.3% vs 67.0%; RR = 1.01; 95% CI, .84-1.21) and advanced adenoma (14.5% vs 16.9%; RR = 1.03; 95% CI, .60-1.79). Limitation: There were few blacks in the long-term follow-up study. Conclusions: Adenoma and advanced adenoma recurrence did not differ by race. Our study does not support more frequent surveillance colonoscopies for blacks with a personal history of adenoma as an intervention to reduce colorectal cancer disparity. (Gastrointest Endosc 2013;77:447-54.) C1 [Laiyemo, Adeyinka O.; Ashktorab, Hassan] Howard Univ Hosp, Dept Med, Washington, DC USA. [Laiyemo, Adeyinka O.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Doubeni, Chyke] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Brim, Hassan] Howard Univ Hosp, Dept Pathol, Washington, DC USA. [Schoen, Robert E.] Univ Pittsburgh, Dept Med & Epidemiol, Pittsburgh, PA USA. [Gupta, Samir] Univ Texas SW Med Ctr Dallas, Div Gastroenterol, Dallas, TX 75390 USA. [Charabaty, Aline] Georgetown Univ, Dept Med, Div Gastroenterol, Washington, DC USA. [Lanza, Elaine] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Smoot, Duane T.] Meharry Med Ctr, Dept Med, Nashville, TN USA. [Platz, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Cross, Amanda J.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Laiyemo, AO (reprint author), Howard Univ, Coll Med, Div Gastroenterol, Dept Med, 2041 Georgia Ave NW, Washington, DC 20060 USA. EM adeyinka.laiyemo@howard.edu OI Doubeni, Chyke/0000-0001-7495-0285 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [P30 CA006973, U54 CA091431, 5K01CA127118, K01 CA127118, 5U54CA091431-09 S1] NR 31 TC 10 Z9 10 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAR PY 2013 VL 77 IS 3 BP 447 EP 454 DI 10.1016/j.gie.2012.11.027 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 088JT UT WOS:000314831000016 PM 23337636 ER PT J AU David, A Bennink, JR Yewdell, JW AF David, Alexandre Bennink, Jack R. Yewdell, Jonathan W. TI Emetine optimally facilitates nascent chain puromycylation and potentiates the ribopuromycylation method (RPM) applied to inert cells SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE Ribopuromycylation; Puromycin; Translation; Ribosome ID INHIBITORS; COMPLEXES; PROTEIN AB We previously described the ribopuromyclation method (RPM) to visualize and quantitate translating ribosomes in fixed and permeabilized cells by standard immunofluorescence. RPM is based on puromycylation of nascent chains bound to translating ribosomes followed by detection of puromycylated nascent chains with a puromycin-specific mAb. We now demonstrate that emetine optimally enhances nascent chain puromycylation, and describe a modified RPM protocol for identifying ribosome-bound nascent chains in metabolically inert permeabilized cells. C1 [David, Alexandre; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [David, Alexandre] CNRS, INSERM, U661, Inst Genom Fonct,UMR5203, F-34094 Montpellier, France. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@nih.gov OI David, Alexandre/0000-0003-3365-1339 FU Division of Intramural Research, NIAID FX Glennys Reynoso provided outstanding technical support. This work was generously supported by the Division of Intramural Research, NIAID. NR 11 TC 8 Z9 8 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0948-6143 J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD MAR PY 2013 VL 139 IS 3 BP 501 EP 504 DI 10.1007/s00418-012-1063-8 PG 4 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA 090IF UT WOS:000314972000009 PM 23229864 ER PT J AU Humble, MM Young, MJ Foley, JF Pandiri, AR Travlos, GS Copeland, WC AF Humble, Margaret M. Young, Matthew J. Foley, Julie F. Pandiri, Arun R. Travlos, Greg S. Copeland, William C. TI Polg2 is essential for mammalian embryogenesis and is required for mtDNA maintenance SO HUMAN MOLECULAR GENETICS LA English DT Article ID DNA-POLYMERASE-GAMMA; P55 ACCESSORY SUBUNIT; DROSOPHILA EMBRYOS; DISEASE; REPLICATION; MUTATIONS; DELETION; CLONING; HEALTH; REPAIR AB Mammalian mitochondrial DNA (mtDNA) is replicated by the heterotrimeric Pol comprised of a single catalytic subunit, encoded by Polg, and a homodimeric accessory subunit encoded by the Polg2 gene. While the catalytic subunit has been shown to be essential for embryo development, genetic data regarding the accessory subunit are lacking in mammalian systems. Here, we describe the generation of heterozygous (Polg2(/)) and homozygous (Polg2(/)) knockout (KO) mice. Polg2(/) mice are haplosufficient and develop normally with no discernable difference in mitochondrial function through 2 years of age. In contrast, the Polg2(/) is embryonic lethal at day 8.08.5 p.c. with concomitant loss of mtDNA and mtDNA gene products. Electron microscopy shows severe ultra-structural defects and loss of organized cristae in mitochondria of the Polg2(/) embryos as well as an increase in lipid accumulation compared with both wild-type (WT) and Polg2(/) embryos. Our data indicate that Polg2 function is critical to mammalian embryogenesis and mtDNA replication, and that a single copy of Polg2 is sufficient to sustain life. C1 [Humble, Margaret M.; Young, Matthew J.; Copeland, William C.] NIEHS, Mitochondrial DNA Replicat Grp, Mol Genet Lab, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Foley, Julie F.] NIEHS, Special Tech Grp, Cellular & Mol Pathol Branch, Natl Toxicol Program,NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.] NIEHS, Expt Pathol Labs Inc, CMPB, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.] NIEHS, Expt Pathol Labs Inc, NTP, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Travlos, Greg S.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, NIH,DHHS, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, 111T W Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES 065078, ES 065080] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ES 065078 and ES 065080). NR 35 TC 18 Z9 18 U1 0 U2 8 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 MAR 1 PY 2013 VL 22 IS 5 BP 1017 EP 1025 DI 10.1093/hmg/dds506 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 089GB UT WOS:000314897600015 PM 23197651 ER PT J AU Holmans, P Moskvina, V Jones, L Sharma, M Vedernikov, A Buchel, F Sadd, M Bras, JM Bettella, F Nicolaou, N Simon-Sanchez, J Mittag, F Gibbs, JR Schulte, C Durr, A Guerreiro, R Hernandez, D Brice, A Stefansson, H Majamaa, K Gasser, T Heutink, P Wood, NW Martinez, M Singleton, AB Nalls, MA Hardy, J Morris, HR Williams, NM AF Holmans, Peter Moskvina, Valentina Jones, Lesley Sharma, Manu Vedernikov, Alexey Buchel, Finja Sadd, Mohamad Bras, Jose M. Bettella, Francesco Nicolaou, Nayia Simon-Sanchez, Javier Mittag, Florian Gibbs, J. Raphael Schulte, Claudia Durr, Alexandra Guerreiro, Rita Hernandez, Dena Brice, Alexis Stefansson, Hreinn Majamaa, Kari Gasser, Thomas Heutink, Peter Wood, Nicholas W. Martinez, Maria Singleton, Andrew B. Nalls, Michael A. Hardy, John Morris, Huw R. Williams, Nigel M. CA IPDGC TI A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinsons disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; UBIQUITIN-PROTEIN LIGASE; ALPHA-SYNUCLEIN; MULTIPLE-SCLEROSIS; RISK-FACTORS; PINK1; DJ-1; MUTATIONS; DEGRADATION; VARIANTS AB Parkinsons disease (PD) is the second most common neurodegenerative disease affecting 12 in people 60 and 34 in people 80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P 1 10(16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P 0.014 and P 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P 0.001), implicating genes involved in the oregulation of leucocyte/lymphocyte activity' and also ocytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated. C1 [Holmans, Peter; Moskvina, Valentina; Jones, Lesley; Vedernikov, Alexey; Morris, Huw R.; Williams, Nigel M.] Cardiff Univ, Dept Psychol Med & Neurol, Inst Psychol Med & Clin Neurosci, MRC,Ctr Neuropsychiat Genet & Genom,Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Gibbs, J. Raphael; Hernandez, Dena; Singleton, Andrew B.; Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Buchel, Finja; Mittag, Florian] Univ Tubingen, Ctr Bioinformat Tuebingen ZBIT, Tubingen, Germany. [Sharma, Manu; Schulte, Claudia; Gasser, Thomas] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany. [Sadd, Mohamad; Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Bras, Jose M.; Gibbs, J. Raphael; Guerreiro, Rita; Hernandez, Dena; Wood, Nicholas W.; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Wood, Nicholas W.] UCL, UCL Genet Inst, London, England. [Bettella, Francesco; Stefansson, Hreinn] DeCODE Genet, Sci Serv, IS-101 Reykjavik, Iceland. [Nicolaou, Nayia; Simon-Sanchez, Javier; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [Sharma, Manu; Schulte, Claudia; Gasser, Thomas] German Ctr Neurodegenerat Dis, DZNE Deutsch Zentrum Neurodegenerat Erkrangungen, Tubingen, Germany. [Durr, Alexandra; Brice, Alexis] Univ Paris 06, INSERM, CRICM, UMRS975,CNRS UMR 7225, F-75013 Paris, France. [Durr, Alexandra; Brice, Alexis] Univ Paris 06, UMRS975, F-75013 Paris, France. [Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France. [Brice, Alexis] Inst Cerveau & Moelle Epiniere, F-75013 Paris, France. [Majamaa, Kari] Univ Oulu, Dept Med Biochem & Mol Biol, FIN-90014 Oulu, Finland. RP Williams, NM (reprint author), Cardiff Univ, Dept Psychol Med & Neurol, Inst Psychol Med & Clin Neurosci, MRC,Ctr Neuropsychiat Genet & Genom,Sch Med, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM williamsnm@cf.ac.uk RI Singleton, Andrew/C-3010-2009; Morris, Huw/B-8527-2008; Hardy, John/C-2451-2009; Charlesworth, Gavin/B-5895-2011; Bras, Jose/A-1428-2011; Deloukas, Panos/B-2922-2013; Guerreiro, Rita/A-1327-2011; Deuschl, Gunther/A-7986-2010; Scheffer, Hans/E-4644-2012; Cooper, J Mark/D-5826-2013; Lees, Andrew/A-6605-2009; Traynor, Bryan/G-5690-2010; Holmans, Peter/F-4518-2015; Wood, Nicholas/C-2505-2009; van de Warrenburg, Bart/D-1935-2010; Martinez, Maria/B-3111-2013; corvol, jean-christophe/I-6387-2012; Revesz, Tamas/A-8732-2010; Trabzuni, Daniah/C-4034-2012 OI Morris, Huw/0000-0002-5473-3774; Deloukas, Panos/0000-0001-9251-070X; Scheffer, Hans/0000-0002-2986-0915; Cooper, J Mark/0000-0002-3007-3054; Plagnol, Vincent/0000-0002-5597-9215; Stefansson, Hreinn/0000-0002-9331-6666; Bhatia, Kailash/0000-0001-8185-286X; Holmans, Peter/0000-0003-0870-9412; Wood, Nicholas/0000-0002-9500-3348; Martinez, Maria/0000-0003-2180-4537; corvol, jean-christophe/0000-0001-7325-0199; Revesz, Tamas/0000-0003-2501-0259; Bras, Jose/0000-0001-8186-0333; Escott-Price, Valentina/0000-0003-1784-5483; Schulte, Claudia/0000-0003-4006-1265; Trabzuni, Daniah/0000-0003-4826-9570 FU Parkinson's UK [K0906, 8047, J-0804]; Department of Health NIHR Biomedical Research Centre; Medical Research Council [G0700943]; German National Genome Network (NGFNplus) [01GS08134]; German Ministry for Education and Research; Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000949-06, Z01 AG000950-10]; Hersenstichting Nederland; Neuroscience Campus Amsterdam; section of Medical genomics; Prinses Beatrix Fonds FX This work was supported by Parkinson's UK (formerly The PD society) (ref no K0906). Additionally, part of the study was undertaken at UCLH/UCL, using funding through a Department of Health NIHR Biomedical Research Centre. This work was also supported by Parkinson's UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). The German work was also supported by the German National Genome Network (NGFNplus #01GS08134; German Ministry for Education and Research). This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project numbers Z01 AG000949-06 and Z01 AG000950-10. The French GWA scan work was supported by the French National Agency of Research (http://www.agence-nationale-recherche.fr, ANR-08-MNP-012) and by the National Research Funding Agency (ANR-08-NEUR-004-01) in the ERA-NET NEURON framework (http://www.neuron-eranet.eu). We also want to thank the Hersenstichting Nederland (http://www.hersenstichting.nl), the Neuroscience Campus Amsterdam and the section of Medical genomics, the Prinses Beatrix Fonds (http://www.prinsesbeatrixfonds.nl) for sponsoring this work. NR 47 TC 32 Z9 32 U1 2 U2 48 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 MAR 1 PY 2013 VL 22 IS 5 BP 1039 EP 1049 DI 10.1093/hmg/dds492 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 089GB UT WOS:000314897600017 PM 23223016 ER PT J AU Duncan, WC Sarasso, S Ferrarelli, F Selter, J Riedner, BA Hejazi, NS Yuan, PX Brutsche, N Manji, HK Tononi, G Zarate, CA AF Duncan, Wallace C., Jr. Sarasso, Simone Ferrarelli, Fabio Selter, Jessica Riedner, Brady A. Hejazi, Nadia S. Yuan, Peixiong Brutsche, Nancy Manji, Husseini K. Tononi, Giulio Zarate, Carlos A., Jr. TI Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE biomarker; brain derived neurotrophic factor; major depressive disorder; N-methyl-D-aspartate receptor; sleep slow wave activity ID D-ASPARTATE ANTAGONIST; NEUROTROPHIC FACTOR; CORTICAL SYNCHRONIZATION; SYNAPTIC POTENTIATION; DOUBLE-BLIND; RAT-BRAIN; IN-VIVO; EEG; HOMEOSTASIS; RILUZOLE AB The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electro-encephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Asberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response. C1 [Duncan, Wallace C., Jr.; Selter, Jessica; Hejazi, Nadia S.; Brutsche, Nancy; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Sarasso, Simone; Ferrarelli, Fabio; Riedner, Brady A.; Tononi, Giulio] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. [Yuan, Peixiong] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. RP Zarate, CA (reprint author), 10 Ctr Dr CRC,Unit 7 SE,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI Sarasso, Simone/C-7817-2012 OI Sarasso, Simone/0000-0001-9984-4710 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); NIMH-NIH; Phillips Respironics FX Dr Duncan, Ms Selter, Dr Hejazi, Dr Yuan, Ms Brutsche, and Dr Zarate gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), and thank the 7SE Research Unit of the NIMH-NIH for their support. Ioline Henter (NIMH) provided invaluable editorial assistance.; This study was supported in part by the IRP-NIMH-NIH. The author(s) declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 yr for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Drs Zarate and Manji are listed as co-inventors on a patent application for the use of ketamine in major depression. Drs Zarate and Manji have assigned their rights on the patent to the US Government but will share a percentage of any royalties that may be received by the government. Dr Tononi has consulted for Sanofi-Aventis and Takeda and is currently the David P. White Chair in Sleep Medicine at the University of Wisconsin Madison, endowed by Phillips Respironics. Dr Tononi has also received unrelated research support from Phillips Respironics. Dr Riedner is financially supported in part by the research funds given to Dr Tononi by Philips Respironics. NR 46 TC 38 Z9 41 U1 1 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAR PY 2013 VL 16 IS 2 BP 301 EP 311 DI 10.1017/S1461145712000545 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 090RF UT WOS:000314996100007 PM 22676966 ER PT J AU Bergman, J Roof, RA Furman, CA Conroy, JL Mello, NK Sibley, DR Skolnick, P AF Bergman, Jack Roof, Rebecca A. Furman, Cheryse A. Conroy, Jennie L. Mello, Nancy K. Sibley, David R. Skolnick, Phil TI Modification of cocaine self-administration by buspirone (buspar (R)): potential involvement of D-3 and D-4 dopamine receptors SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Buspirone; cocaine addiction; D-3 receptor antagonist; D-4 receptor antagonist; i.v. self-administration; medications development ID PLACEBO-CONTROLLED TRIAL; RHESUS-MONKEYS; D-AMPHETAMINE; SUBJECTIVE RESPONSES; HEALTHY-VOLUNTEERS; ACTIVE METABOLITE; DRUG-ADDICTION; DOUBLE-BLIND; PHARMACOKINETICS; ANTAGONIST AB Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D-1 nor D-2 receptor antagonists have proven effective, medications acting at two other potential targets, D-3 and D-4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D-3 and D-4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D-3 and D-4 receptors (similar to 98 and similar to 29 nM respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D-3 and D-4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose-effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction. C1 [Bergman, Jack; Mello, Nancy K.] Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. [Roof, Rebecca A.; Furman, Cheryse A.; Conroy, Jennie L.; Sibley, David R.] Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Skolnick, Phil] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. RP Bergman, J (reprint author), Harvard Univ, McLean Hosp, Sch Med, 115 Mill St, Belmont, MA 02478 USA. EM jbergman@hms.harvard.edu FU Intramural Program of NINDS/NIH; [DA8-8876] FX The authors acknowledge support of the present work, in part, by contract DA8-8876 (N. K. Mello, P. I.) as well as the Intramural Program of NINDS/NIH. The authors also acknowledge the invaluable assistance toward completing this project that has been provided by Dr Jane Acri at NIDA/NIH. NR 55 TC 37 Z9 37 U1 0 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAR PY 2013 VL 16 IS 2 BP 445 EP 458 DI 10.1017/S1461145712000661 PG 14 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 090RF UT WOS:000314996100018 PM 22827916 ER PT J AU Boukheris, H Stovall, M Gilbert, ES Stratton, KL Smith, SA Weathers, R Hammond, S Mertens, AC Donaldson, SS Armstrong, GT Robison, LL Neglia, JP Inskip, PD AF Boukheris, Houda Stovall, Marilyn Gilbert, Ethel S. Stratton, Kayla L. Smith, Susan A. Weathers, Rita Hammond, Sue Mertens, Ann C. Donaldson, Sarah S. Armstrong, Gregory T. Robison, Leslie L. Neglia, Joseph P. Inskip, Peter D. TI Risk of Salivary Gland Cancer After Childhood Cancer: A Report From the Childhood Cancer Survivor Study SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID LONG-TERM SURVIVORS; BONE-MARROW-TRANSPLANTATION; ATOMIC-BOMB SURVIVORS; MALIGNANT NEOPLASMS; HODGKINS-DISEASE; PAROTID-GLAND; TUMORS; NECK; HEAD AB Purpose: To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS). Methods and Materials: Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology, and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking, and alcohol consumption. Results: During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR = 39.4; 95% CI = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking, or alcohol intake. Conclusion: Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies. (C) 2013 Elsevier Inc. C1 [Boukheris, Houda; Gilbert, Ethel S.; Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Stovall, Marilyn; Smith, Susan A.; Weathers, Rita] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Stratton, Kayla L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Hammond, Sue] Ohio State Univ, Sch Med, Dept Pathol, Columbus, OH 43210 USA. [Mertens, Ann C.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Donaldson, Sarah S.] Stanford Univ, Med Ctr, Dept Radiat Oncol, Stanford, CA 94305 USA. [Armstrong, Gregory T.; Robison, Leslie L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Neglia, Joseph P.] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. RP Inskip, PD (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7052, Bethesda, MD 20892 USA. EM inskippe@mail.nih.gov FU National Cancer Institute [U24 CA55727]; Lance Armstrong Foundation [147149]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The Childhood Cancer Survivor Study (CCSS) is a collaborative, multi-institutional project, funded as a resource by the National Cancer Institute, of individuals who survived 5 or more years after diagnosis of childhood cancer. The CCSS study population is a retrospectively ascertained cohort of 20,346 childhood cancer survivors diagnosed before age 21 between 1970 and 1986 and approximately 4000 siblings of survivors, who serve as a control group. The cohort was assembled through the efforts of 26 participating clinical research centers in the United States and Canada. Information on how to access and use the CCSS resource is available at www.stjude.org/ccss.; Supported by National Cancer Institute grant # U24 CA55727 to St. Jude Children's Research Hospital, the Lance Armstrong Foundation grant 147149, and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 26 TC 7 Z9 7 U1 1 U2 10 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 MAR 1 PY 2013 VL 85 IS 3 BP 776 EP 783 DI 10.1016/j.ijrobp.2012.06.006 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 086MA UT WOS:000314687000044 PM 22836059 ER PT J AU Chung, C Jalali, S Foltz, W Burrell, K Wildgoose, P Lindsay, P Graves, C Camphausen, K Milosevic, M Jaffray, D Zadeh, G Menard, C AF Chung, Caroline Jalali, Shahrzad Foltz, Warren Burrell, Kelly Wildgoose, Petra Lindsay, Patricia Graves, Christian Camphausen, Kevin Milosevic, Michael Jaffray, David Zadeh, Gelareh Menard, Cynthia TI Imaging Biomarker Dynamics in an Intracranial Murine Glioma Study of Radiation and Antiangiogenic Therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID MOUSE MODEL; 9.4 T; ADC; ANGIOGENESIS; GLIOBLASTOMA; SUNITINIB; CANCER; TUMORS; MRI AB Purpose: There is a growing need for noninvasive biomarkers to guide individualized spatio-temporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI). Methods and Materials: Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhanced T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K-trans, K-ep). Results: Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K-trans reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K-ep reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of -0.878 (P=.002) and -0.80 (P=.01), respectively. Conclusions: Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future. (C) 2013 Elsevier Inc. C1 [Chung, Caroline; Foltz, Warren; Wildgoose, Petra; Lindsay, Patricia; Milosevic, Michael; Jaffray, David; Menard, Cynthia] Univ Hlth Network Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. [Jalali, Shahrzad; Burrell, Kelly] SickKids Hosp, Brain Tumor Res Ctr, Toronto, ON, Canada. [Graves, Christian; Camphausen, Kevin] NCI, Dept Radiat Oncol, Bethesda, MD 20892 USA. [Zadeh, Gelareh] Univ Hlth Network Toronto Western Hosp, Toronto, ON, Canada. RP Chung, C (reprint author), 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM caroline.chung@rmp.uhn.on.ca FU Rapid Astrazeneca; CARO Evaluation of Radio-modifers (RAZCER) grant from Canadian Association of Radiation Oncology (CARO) FX This research was supported by a Rapid Astrazeneca and CARO Evaluation of Radio-modifers (RAZCER) grant from Canadian Association of Radiation Oncology (CARO). NR 15 TC 20 Z9 21 U1 0 U2 13 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 MAR 1 PY 2013 VL 85 IS 3 BP 805 EP 812 DI 10.1016/j.ijrobp.2012.07.005 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 086MA UT WOS:000314687000048 PM 22929856 ER PT J AU O'Reilly, EA Sharma, S Klinger, R Harrison, M Weiner-Gorzel, K Kelly, C Maguire, A McCormack, J Conlon, S Aherne, S Beggan, C Bambury, R Lyons, T Dorsey, TH Ambs, S O'Connor, D Quinn, C McCaffrey, J Salman, R Glynn, SA Furlong, F McCann, A Kell, M AF O'Reilly, Elma A. Sharma, Shiva Klinger, Rut Harrison, Michele Weiner-Gorzel, Karolina Kelly, Ciara Maguire, Aoife McCormack, Janet Conlon, Susie Aherne, Susan Beggan, Caitlin Bambury, Richard Lyons, Tomas Dorsey, Tiffany H. Ambs, Stefan O'Connor, Darran Quinn, Cecily McCaffrey, John Salman, Reem Glynn, Sharon A. Furlong, Fiona McCann, Amanda Kell, Malcolm TI Cellular fate assessment in triple negative breast cancer (TNBC) predictchemoresponse and patient outcome SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [O'Reilly, Elma A.; Sharma, Shiva; Klinger, Rut; Weiner-Gorzel, Karolina; O'Connor, Darran; Furlong, Fiona; McCann, Amanda] UCD Sch Med & Med Sci, UCD Conway Inst Biomol & Biomed Res, Dublin, Ireland. [O'Reilly, Elma A.; Sharma, Shiva; Salman, Reem; Kell, Malcolm] Mater Misericordiae Univ Hosp, Dept Surg, Dublin 7, Ireland. [Harrison, Michele; Conlon, Susie; Beggan, Caitlin] Mater Misericordiae Univ Hosp, Dept Pathol, Dublin 7, Ireland. [Kelly, Ciara; Bambury, Richard; Lyons, Tomas; McCaffrey, John] Mater Misericordiae Univ Hosp, Dept Oncol, Dublin 7, Ireland. [Maguire, Aoife; Aherne, Susan; Quinn, Cecily] St Vincents Univ Hosp, Dept Pathol, Dublin 4, Ireland. [Dorsey, Tiffany H.; Ambs, Stefan] NCI, Bethesda, MD 20892 USA. [Glynn, Sharon A.] NUI Galway, Prostate Canc Inst, Galway, Ireland. RI Glynn, Sharon/D-7136-2013 OI Glynn, Sharon/0000-0003-1459-2580 NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2013 VL 182 SU 2 BP S31 EP S32 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 092AJ UT WOS:000315090900004 ER PT J AU Carballido-Gamio, J Harnish, R Saeed, I Streeper, T Sigurdsson, S Amin, S Atkinson, EJ Therneau, TM Siggeirsdottir, K Cheng, XG Melton, LJ Keyak, J Gudnason, V Khosla, S Harris, TB Lang, TF AF Carballido-Gamio, Julio Harnish, Roy Saeed, Isra Streeper, Timothy Sigurdsson, Sigurdur Amin, Shreyasee Atkinson, Elizabeth J. Therneau, Terry M. Siggeirsdottir, Kristin Cheng, Xiaoguang Melton, L. Joseph, III Keyak, Joyce Gudnason, Vilmundur Khosla, Sundeep Harris, Tamara B. Lang, Thomas F. TI Proximal femoral density distribution and structure in relation to age and hip fracture risk in women SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSTEOPOROSIS; PROXIMAL FEMUR; STATISTICAL PARAMETRIC MAPPING; AGE; FRACTURE ID VOXEL-BASED MORPHOMETRY; QUANTITATIVE COMPUTED-TOMOGRAPHY; GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; FINITE-ELEMENT-ANALYSIS; ADULT RHESUS-MONKEY; CORTICAL BONE; ODANACATIB TREATMENT; STRENGTH; GEOMETRY; BRAIN AB Hip fracture risk rises exponentially with age, but there is little knowledge about how fracture-related alterations in hip structure differ from those of aging. We employed computed tomography (CT) imaging to visualize the three-dimensional (3D) spatial distribution of bone mineral density (BMD) in the hip in relation to age and incident hip fracture. We used intersubject image registration to integrate 3D hip CT images into a statistical atlas comprising women aged 21 to 97 years (n=349) and a group of women with (n=74) and without (n=148) incident hip fracture 4 to 7 years after their imaging session. Voxel-based morphometry was used to generate Student's t test statistical maps from the atlas, which indicated regions that were significantly associated with age or with incident hip fracture. Scaling factors derived from intersubject image registration were employed as measures of bone size. BMD comparisons of young, middle-aged, and older American women showed preservation of load-bearing cortical and trabecular structures with aging, whereas extensive bone loss was observed in other trabecular and cortical regions. In contrast, comparisons of older Icelandic fracture women with age-matched controls showed that hip fracture was associated with a global cortical bone deficit, including both the superior cortical margin and the load-bearing inferior cortex. Bone size comparisons showed larger dimensions in older compared to younger American women and in older Icelandic fracture women compared to controls. The results indicate that older Icelandic women who sustain incident hip fracture have a structural phenotype that cannot be described as an accelerated pattern of normal age-related loss. The fracture-related cortical deficit noted in this study may provide a biomarker of increased hip fracture risk that may be translatable to dual-energy X-ray absorptiometry (DXA) and other clinical images. (c) 2013 American Society for Bone and Mineral Research. C1 [Carballido-Gamio, Julio; Harnish, Roy; Saeed, Isra; Streeper, Timothy; Lang, Thomas F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Sigurdsson, Sigurdur; Siggeirsdottir, Kristin; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Amin, Shreyasee; Melton, L. Joseph, III] Mayo Clin, Coll Med, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Amin, Shreyasee] Mayo Clin, Coll Med, Div Rheumatol, Dept Internal Med, Rochester, MN USA. [Atkinson, Elizabeth J.; Therneau, Terry M.] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Cheng, Xiaoguang] Beijing Ji Shui Tan Hosp, Dept Radiol, Beijing, Peoples R China. [Melton, L. Joseph, III; Khosla, Sundeep] Mayo Clin, Coll Med, Dept Internal Med, Div Endocrinol Diabet Metab & Nutr, Rochester, MN USA. [Keyak, Joyce] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92717 USA. [Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Harris, Tamara B.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Lang, TF (reprint author), 185 Berry St,Suite 350, San Francisco, CA 94143 USA. EM Thomas.Lang@ucsf.edu RI Lang, Thomas/B-2685-2012; Gudnason, Vilmundur/K-6885-2015; OI Lang, Thomas/0000-0002-3720-8038; Gudnason, Vilmundur/0000-0001-5696-0084; Khosla, Sundeep/0000-0002-2936-4372 FU NIH/NIA [R01AG028832]; NIH/NIAMS [R01AR46197, R01AR027065, M01-RR00585/UL1-RR024150]; NIH/NIA Professional Services [HHSN311200900345P]; NIH [N01-AG-12100]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study was supported by the NIH/NIA R01AG028832, NIH/NIAMS R01AR46197, NIH/NIA Professional Services Contract HHSN311200900345P, NIH/NIAMS R01AR027065, and M01-RR00585/UL1-RR024150 (Center for Translational Science Activities). The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. NR 37 TC 23 Z9 23 U1 1 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD MAR PY 2013 VL 28 IS 3 BP 537 EP 546 DI 10.1002/jbmr.1802 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 092FZ UT WOS:000315106300014 PM 23109068 ER PT J AU Sabatino, SA Thompson, TD Smith, JL Rowland, JH Forsythe, LP Pollack, L Hawkins, NA AF Sabatino, Susan A. Thompson, Trevor D. Smith, Judith Lee Rowland, Julia H. Forsythe, Laura P. Pollack, Loria Hawkins, Nikki A. TI Receipt of cancer treatment summaries and follow-up instructions among adult cancer survivors: results from a national survey SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Cancer survivors; Treatment summaries; Cancer follow-up care; Survivorship care plans ID PRIMARY-CARE PHYSICIANS; BREAST-CANCER; CHILDHOOD-CANCER; PERSPECTIVES; PREVALENCE; KNOWLEDGE; QUALITY AB The purpose of this study is to examine reporting of treatment summaries and follow-up instructions among cancer survivors. Using the 2010 National Health Interview Survey, we created logistic regression models among cancer survivors not in treatment (n = 1,345) to determine characteristics associated with reporting treatment summaries and written follow-up instructions, adjusting for sociodemographic, access, and cancer-related factors. Findings are presented for all survivors and those recently diagnosed (a parts per thousand currency sign4 years). We also examined unadjusted associations between written instructions and subsequent surveillance and screening. Among those recently diagnosed, 38 % reported receiving treatment summaries and 58 % reported written instructions. Among all survivors, approximately one third reported summaries and 44 % reported written instructions. After adjustment, lower reporting of summaries was associated with cancer site, race, and number of treatment modalities among those recently diagnosed, and white vs. black or Hispanic race/ethnicity, breast vs. colorectal cancer, > 10 vs. a parts per thousand currency sign5 years since diagnosis, no clinical trials participation, and better than fair health among all survivors. For instructions, lower reporting was associated with no trials participation and lower income among those recently diagnosed, and increasing age, white vs. black race, lower income, > 10 vs. a parts per thousand currency sign5 years since diagnosis, 1 vs. a parts per thousand yen2 treatment modalities, no trials participation, and at least good vs. fair/poor health among all survivors. Written instructions were associated with reporting provider recommendations for breast and cervical cancer surveillance, and recent screening mammograms. Many recently diagnosed cancer survivors did not report receiving treatment summaries and written follow-up instructions. Opportunities exist to examine associations between use of these documents and recommended care and outcomes, and to facilitate their adoption. Cancer survivors who have completed therapy should ask their providers for treatment summaries and written follow-up instructions, and discuss with them how their cancer and therapy impact their future health care. C1 [Sabatino, Susan A.; Thompson, Trevor D.; Smith, Judith Lee; Hawkins, Nikki A.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA 30341 USA. [Rowland, Julia H.; Forsythe, Laura P.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Forsythe, Laura P.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, Bethesda, MD 20892 USA. [Pollack, Loria] Ctr Dis Control & Prevent, Div Appl Sci, Off Surveillance Epidemiol & Lab Serv, Atlanta, GA 30341 USA. RP Sabatino, SA (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, MS K55,4770 Buford Highway, Atlanta, GA 30341 USA. EM SSabatino@cdc.gov NR 35 TC 22 Z9 22 U1 1 U2 9 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 MAR PY 2013 VL 7 IS 1 BP 32 EP 43 DI 10.1007/s11764-012-0242-x PG 12 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 087GL UT WOS:000314749200003 PM 23179495 ER PT J AU Buzaglo, JS Miller, SM Kendall, J Stanton, AL Wen, KY Scarpato, J Zhu, F Lyle, J Rowland, J AF Buzaglo, Joanne S. Miller, Suzanne M. Kendall, Jeffery Stanton, Annette L. Wen, Kuang-Yi Scarpato, John Zhu, Fang Lyle, Jennifer Rowland, Julia TI Evaluation of the efficacy and usability of NCI's Facing Forward booklet in the cancer community setting SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Survivorship; Cancer control; Psychosocial interventions; Facing Forward ID BREAST-CANCER; INFORMATION-SEEKING; AFRICAN-AMERICANS; SUPPORT GROUPS; SURVIVORS; CARE; SYMPTOMS; NEEDS; ASSOCIATION; PEOPLE AB The NCI developed the print-based educational brochure, Facing Forward, to fill a gap in helping cancer patients meet the challenges of transitioning from active treatment to survivorship; however, little research has been conducted on its efficacy. The aims of this study were to evaluate the efficacy of Facing Forward in promoting the uptake of recommended behaviors (e.g., ways to manage physical changes) and to explore its usability. At the last treatment appointment, early-stage breast, prostate, colorectal, and thoracic cancer patients (N = 340) recruited from community clinical oncology practices and an academic medical center completed a baseline assessment and were randomized to receive either Facing Forward (n = 175) or an attention control booklet about the NCI's Cancer Information Service (n = 165). Patients completed follow-up assessments at 8 weeks and 6 months post-baseline. The reported uptake of recommended stress management behaviors was greater among intervention than control participants at both 8 weeks post-baseline (p = 0.016) and 6 months post-baseline (p = 0.017). At 8 weeks post-baseline, the intervention control group difference was greater among African-American than Caucasian participants (p < 0.03) and significant only among the former (p < 0.003); attendance at a cancer support group was also greater among the intervention than control group participants (p < 0.02). There were no significant intervention control group differences in the reported uptake of recommended behaviors in three other categories (p > 0.025). Intervention participants rated Facing Forward as understandable and helpful and indicated a high level of intention to try the behaviors recommended. Facing Forward can enhance early-stage survivors' reported ability to manage stress and increase support group use during the reentry period. Facing Forward can help survivors meet the challenges of the reentry period. C1 [Buzaglo, Joanne S.] Res & Training Inst, Philadelphia, PA 19131 USA. [Miller, Suzanne M.; Wen, Kuang-Yi; Scarpato, John] Fox Chase Canc Ctr, Psychosocial & Biobehav Med Dept, Philadelphia, PA 19111 USA. [Kendall, Jeffery] UT SW Simmons Canc Ctr, Psychosocial Oncol Program, Dallas, TX 75390 USA. [Stanton, Annette L.] Univ Calif Los Angeles, Dept Psychol, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. [Stanton, Annette L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. [Zhu, Fang] Fox Chase Canc Ctr, Biostat & Bioinformat Facil, Philadelphia, PA 19111 USA. [Lyle, Jennifer] Natl Comprehens Canc Network, Ft Washington, PA 19034 USA. [Rowland, Julia] NCI, Off Canc Survivorship, NIH, DHHS, Bethesda, MD 20892 USA. RP Miller, SM (reprint author), Fox Chase Canc Ctr, Psychosocial & Biobehav Med Dept, Robert C Young Pavil,4th Floor,333 Cottman Ave, Philadelphia, PA 19111 USA. EM Suzanne.MillerHalegoua@fccc.edu FU National Institute of Health [R01 CA104979, 5P01 CA057586]; Fox Chase Cancer Center Behavioral Research Core Facility [P30 CA06927]; Department of Defense [DAMD 17-0-101-1-0238, DAMD 17-02-1-0382]; LAF [PT07-07020] FX This work was supported in part by National Institute of Health grants R01 CA104979, 5P01 CA057586, and the Fox Chase Cancer Center Behavioral Research Core Facility P30 CA06927, as well as Department of Defense grants DAMD 17-0-101-1-0238 and DAMD 17-02-1-0382 and the LAF PT07-07020 grant. We are indebted to Mary Anne Ryan for her technical assistance. NR 48 TC 7 Z9 7 U1 1 U2 7 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 MAR PY 2013 VL 7 IS 1 BP 63 EP 73 DI 10.1007/s11764-012-0245-7 PG 11 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 087GL UT WOS:000314749200006 PM 23229087 ER PT J AU Brinkman, TM Ullrich, NJ Zhang, N Green, DM Zeltzer, LK Lommel, KM Brouwers, P Srivastava, DK Jain, N Robison, LL Krull, KR AF Brinkman, Tara M. Ullrich, Nicole J. Zhang, Nan Green, Daniel M. Zeltzer, Lonnie K. Lommel, Karen M. Brouwers, Pim Srivastava, Deo Kumar Jain, Neelam Robison, Leslie L. Krull, Kevin R. TI Prevalence and predictors of prescription psychoactive medication use in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Psychoactive medication; Quality of life; Survivorship ID QUALITY-OF-LIFE; LONG-TERM SURVIVORS; CHRONIC PAIN; ANTIDEPRESSANT MEDICATION; FOLLOW-UP; LEUKEMIA; BRAIN; LAMOTRIGINE; TOPIRAMATE; DEPRESSION AB Childhood cancer survivors are at risk for late effects which may be managed pharmacologically. The purposes of this study were to estimate and compare the prevalence of psychoactive medication use of adult survivors of childhood cancer and sibling controls, identify predictors of medication use in survivors, and investigate associations between psychoactive medications and health-related quality of life (HRQOL). Psychoactive medication use from 1994 to 2010 was evaluated in 10,378 adult survivors from the Childhood Cancer Survivor Study. A randomly selected subset of 3,206 siblings served as a comparison group. Multivariable logistic regression models were used to calculate odds ratios (OR) for baseline and new onset of self-reported psychoactive medication use and HRQOL. Survivors were significantly more likely to report baseline (22 vs. 15 %, p < 0.001) and new onset (31 vs. 25 %, p < 0.001) psychoactive medication use compared to siblings, as well as use of multiple medications (p < 0.001). In multivariable models, controlling for pain and psychological distress, female survivors were significantly more likely to report baseline and new onset use of antidepressants (OR = 2.66, 95 % CI = 2.01-3.52; OR = 2.02, 95 % CI = 1.72-2.38, respectively) and multiple medications (OR = 1.80, 95 % CI = 1.48-2.19; OR = 1.77, 95 % CI = 1.48-2.13, respectively). Non-cranial radiation and amputation predicted incident use of analgesics > 15 years following diagnosis. Antidepressants were associated with impairment across all domains of HRQOL, with the exception of physical function. Prevalence of psychoactive medication use was higher among survivors for most medication classes, as was the use of multiple medications. Clinicians should be aware of the possible contribution of psychoactive medications to HRQOL. Survivors of childhood cancer are more likely to be prescribed psychoactive medication than their sibling counterparts, though use of such medication does not appear to normalize quality of life. Survivors are encouraged to consider additional interventions, including psychosocial support and physical exercise. C1 [Brinkman, Tara M.; Green, Daniel M.; Robison, Leslie L.; Krull, Kevin R.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Ullrich, Nicole J.] Childrens Hosp Boston, Dept Neurol, Boston, MA USA. [Zhang, Nan; Srivastava, Deo Kumar] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Zeltzer, Lonnie K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Lommel, Karen M.] Univ Kentucky, Coll Med, Dept Psychiat, Lexington, KY USA. [Lommel, Karen M.] Univ Kentucky, Coll Med, Dept Pediat, Lexington, KY USA. [Brouwers, Pim] NIMH, Div AIDS Res, Rockville, MD 20857 USA. [Jain, Neelam] Germantown Psychol Associates, Germantown, TN USA. RP Brinkman, TM (reprint author), St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 262 Danny Thomas Pl,MS 735, Memphis, TN 38105 USA. EM tara.brinkman@stjude.org OI Zeltzer, Lonnie/0000-0001-9306-9450 FU NCI NIH HHS [U24 CA055727]; NICHD NIH HHS [P30 HD018655] NR 38 TC 9 Z9 9 U1 2 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 MAR PY 2013 VL 7 IS 1 BP 104 EP 114 DI 10.1007/s11764-012-0250-x PG 11 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 087GL UT WOS:000314749200010 PM 23224753 ER PT J AU Yang, JY Brooks, S Meyer, JA Blakesley, RR Zelazny, AM Segre, JA Snitkin, ES AF Yang, Joy Y. Brooks, Shelise Meyer, Jennifer A. Blakesley, Robert R. Zelazny, Adrian M. Segre, Julia A. Snitkin, Evan S. TI Pan-PCR, a Computational Method for Designing Bacterium-Typing Assays Based on Whole-Genome Sequence Data SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RESISTANT ACINETOBACTER-BAUMANNII; CARE-ASSOCIATED INFECTIONS; ESCHERICHIA-COLI; ARBITRARY PRIMERS; GENETIC DIVERSITY; MULTIPLEX PCR; STRAINS; IDENTIFICATION; POPULATIONS; SALMONELLA AB With increasing rates of antibiotic resistance, bacterial infections have become more difficult to treat, elevating the importance of surveillance and prevention. Effective surveillance relies on the availability of rapid, cost-effective, and informative typing methods to monitor bacterial isolates. PCR-based typing assays are fast and inexpensive, but their utility is limited by the lack of targets which are capable of distinguishing between strains within a species. To identify highly informative PCR targets from the growing base of publicly available bacterial genome sequences, we developed pan-PCR. This computer algorithm uses existing genome sequences for isolates of a species of interest and identifies a set of genes whose patterns of presence or absence provide the best discrimination between strains in this species. A set of PCR primers targeting the identified genes is then designed, with each PCR product being of a different size to allow multiplexing. These target DNA regions and PCR primers can then be utilized to type bacterial isolates. To evaluate pan-PCR, we designed an assay for the emerging pathogen Acinetobacter baumannii. Taking as input a set of 29 previously sequenced genomes, pan-PCR identified 6 genetic loci whose presence or absence was capable of distinguishing all the input strains. This assay was applied to a set of patient isolates, and its discriminatory power was compared to that of multilocus sequence typing (MLST) and whole-genome optical maps. We found that the pan-PCR assay was capable of making clinically relevant distinctions between strains with identical MLST profiles and showed a discriminatory power similar to that of optical maps. Pan-PCR represents a tool capable of exploiting available genome sequence data to design highly discriminatory PCR assays. The ease of design and implementation makes this approach feasible for diagnostic facilities of all sizes. C1 [Yang, Joy Y.; Meyer, Jennifer A.; Segre, Julia A.; Snitkin, Evan S.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Brooks, Shelise; Blakesley, Robert R.] NIH, NIH Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Zelazny, Adrian M.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov; snitkines@mail.nih.gov FU NHGRI; NIHCC; NIGMS FX Research support came from NHGRI and NIHCC intramural research programs. E. S. S. is supported by a Pharmacology Research Associate Training Fellowship, NIGMS. NR 41 TC 9 Z9 9 U1 1 U2 10 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 MAR PY 2013 VL 51 IS 3 BP 752 EP 758 DI 10.1128/JCM.02671-12 PG 7 WC Microbiology SC Microbiology GA 092LA UT WOS:000315121700004 PM 23254127 ER PT J AU Samuel, A Nayak, B Paldurai, A Xiao, S Aplogan, GL Awoume, KA Webby, RJ Ducatez, MF Collins, PL Samal, SK AF Samuel, Arthur Nayak, Baibaswata Paldurai, Anandan Xiao, Sa Aplogan, Gilbert L. Awoume, Kodzo A. Webby, Richard J. Ducatez, Mariette F. Collins, Peter L. Samal, Siba K. TI Phylogenetic and Pathotypic Characterization of Newcastle Disease Viruses Circulating in West Africa and Efficacy of a Current Vaccine SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID VIRULENT-STRAINS; FUSION PROTEIN; OUTBREAKS; POULTRY; LINEAGE AB Newcastle disease (ND) is a deadly avian disease worldwide. In Africa, ND is enzootic and causes large economic losses, but little is known about the Newcastle disease virus (NDV) strains circulating in African countries. In this study, 27 NDV isolates collected from apparently healthy chickens in live-bird markets of the West African countries Benin and Togo in 2009 were characterized. All isolates had polybasic fusion (F)-protein cleavage sites and were shown to be highly virulent in standard pathogenicity assays. Infection of 2-week-old chickens with two of the isolates resulted in 100% mortality within 4 days. Phylogenetic analysis of the 27 isolates based on a partial F-protein gene sequence identified three clusters: one containing all the isolates from Togo and one from Benin (cluster 2), one containing most isolates from Benin (cluster 3), and an outlier isolate from Benin (cluster 1). All the three clusters are related to genotype VII strains of NDV. In addition, the cluster of viruses from Togo contained a recently identified 6-nucleotide insert between the hemagglutinin-neuraminidase (HN) and large polymerase (L) genes in a complete genome of an NDV isolate from this geographical region. Multiple strains that include this novel element suggest local emergence of a new genome length class. These results reveal genetic diversity within and among local NDV populations in Africa. Sequence analysis showed that the F and HN proteins of six West African isolates share 83.2 to 86.6% and 86.5 to 87.9% identities, respectively, with vaccine strain LaSota, indicative of considerable diversity. A vaccine efficacy study showed that the LaSota vaccine protected birds from morbidity and mortality but did not prevent shedding of West African challenge viruses. C1 [Samuel, Arthur; Nayak, Baibaswata; Paldurai, Anandan; Xiao, Sa; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Aplogan, Gilbert L.] LADISERO, Lab Diagnost Vet & Serosurveillance, Parakou, Benin. [Awoume, Kodzo A.] Lab Vet Lome, Lome, Togo. [Webby, Richard J.; Ducatez, Mariette F.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU NIAID [N01A060009]; NIAID, NIH; National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services [HHSN266200700005C]; American Lebanese Syrian Associated Charities (ALSAC) FX This work was supported by NIAID contract N01A060009 (85% support) and the NIAID, NIH, Intramural Research Program (15% support).; R. J. Webby, M. F. Ducatez, G. L. Aplogan, and K. A. Awoume were supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services, under contract no. HHSN266200700005C and by the American Lebanese Syrian Associated Charities (ALSAC). NR 28 TC 17 Z9 20 U1 0 U2 8 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 MAR PY 2013 VL 51 IS 3 BP 771 EP 781 DI 10.1128/JCM.02750-12 PG 11 WC Microbiology SC Microbiology GA 092LA UT WOS:000315121700006 PM 23254128 ER PT J AU Lau, AF Drake, SK Calhoun, LB Henderson, CM Zelazny, AM AF Lau, Anna F. Drake, Steven K. Calhoun, Leslie B. Henderson, Christina M. Zelazny, Adrian M. TI Development of a Clinically Comprehensive Database and a Simple Procedure for Identification of Molds from Solid Media by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID INVASIVE ASPERGILLOSIS; ANAEROBIC-BACTERIA; SP NOV.; NEOSARTORYA; FUMIGATUS; DISEASE; DERMATOPHYTE; FUSARIUM; SYSTEM; FUNGI AB Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is a powerful tool for the rapid and highly accurate identification of clinical pathogens but has not been utilized extensively in clinical mycology due to challenges in developing an effective protein extraction method and the limited databases available. Here, we developed an alternate extraction procedure and constructed a highly stringent database comprising 294 individual isolates representing 76 genera and 152 species. To our knowledge, this is the most comprehensive clinically relevant mold database developed to date. When challenged with 421 blinded clinical isolates from our institution, by use of the BioTyper software, accurate species-level (score of >= 2.0) and genus-level (score of >= 1.7) identifications were obtained for 370 (88.9%) and 18 (4.3%) isolates, respectively. No isolates were misidentified. Of the 33 isolates (7.8%) for which there was no identification (score of <1.7), 25 were basidiomycetes not associated with clinical disease and 8 were Penicillium species that were not represented in the database. Our library clearly outperformed the manufacturer's database that was obtained with the instrument, which identified only 3 (0.7%) and 26 (6.2%) isolates at species and genus levels, respectively. Identification was not affected by different culture conditions. Implementation into our routine workflow has revolutionized our mycology laboratory efficiency, with improved accuracy and decreased time for mold identification, eliminating reliance on traditional phenotypic features. C1 [Lau, Anna F.; Calhoun, Leslie B.; Henderson, Christina M.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Drake, Steven K.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Lau, AF (reprint author), NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM Anna.Lau@nih.gov FU NIH Clinical Center, Department of Laboratory Medicine FX The Intramural Research Program of the NIH Clinical Center, Department of Laboratory Medicine, supported this research. NR 28 TC 59 Z9 62 U1 0 U2 14 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 MAR PY 2013 VL 51 IS 3 BP 828 EP 834 DI 10.1128/JCM.02852-12 PG 7 WC Microbiology SC Microbiology GA 092LA UT WOS:000315121700014 PM 23269728 ER PT J AU Durbin, AP Whitehead, SS AF Durbin, Anna P. Whitehead, Stephen S. TI The Dengue Human Challenge Model: Has the Time Come to Accept This Challenge? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE dengue vaccine; live attenuated tetravalent; clinical tria ID HUMAN VOLUNTEERS; PROTECTIVE EFFICACY; VACCINE; SAFETY; IMMUNOGENICITY; ATTENUATION; RECOMBINANT; INFECTIONS; CANDIDATE; SEVERITY C1 [Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Whitehead, Stephen S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Durbin, AP (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 624 N Broadway,Rm 251, Baltimore, MD 21205 USA. EM adurbin@jhsph.edu NR 15 TC 16 Z9 16 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 MAR 1 PY 2013 VL 207 IS 5 BP 697 EP 699 DI 10.1093/infdis/jis749 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 089FD UT WOS:000314894600001 PM 23225898 ER PT J AU Viboud, C Eisenstein, J Reid, AH Janczewski, TA Morens, DM Taubenberger, JK AF Viboud, Cecile Eisenstein, Jana Reid, Ann H. Janczewski, Thomas A. Morens, David M. Taubenberger, Jeffery K. TI Age- and Sex-Specific Mortality Associated With the 1918-1919 Influenza Pandemic in Kentucky SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE pandemic; influenza; mortality; age patterns; gender; immunity; military ID EPIDEMIOLOGIC EVIDENCE; BACTERIAL PNEUMONIA; UNITED-STATES; DEATHS; VIRUS; WAVE; PREPAREDNESS; COPENHAGEN; RESPONSES; INSIGHTS AB Background. The reasons for the unusual age-specific mortality patterns of the 1918-1919 influenza pandemic remain unknown. Here we characterize pandemic-related mortality by single year of age in a unique statewide Kentucky data set and explore breakpoints in the age curves. Methods. Individual death certificates from Kentucky during 1911-1919 were abstracted by medically trained personnel. Pandemic-associated excess mortality rates were calculated by subtracting observed rates during pandemic months from rates in previous years, separately for each single year of age and by sex. Results. The age profile of excess mortality risk in fall 1918 was characterized by a maximum among infants, a minimum at ages 9-10 years, a maximum at ages 24-26 years, and a second minimum at ages 56-59 years. The excess mortality risk in young adults had been greatly attenuated by winter 1919. The age breakpoints of mortality risk did not differ between males and females. Conclusions. The observed mortality breakpoints in male and female cohorts born during 1859-1862, 18921894, and 1908-1909 did not coincide with known dates of historical pandemics. The atypical age mortality patterns of the 1918-1919 pandemic cannot be explained by military crowding, war-related factors, or prior immunity alone and likely result from a combination of unknown factors. C1 [Viboud, Cecile] Fogarty Int Ctr, Bethesda, MD USA. [Eisenstein, Jana] NCI, Bethesda, MD 20892 USA. [Morens, David M.; Taubenberger, Jeffery K.] NIAID, NIH, Bethesda, MD 20892 USA. [Reid, Ann H.; Janczewski, Thomas A.] Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Taubenberger, JK (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,Rm 3E19A-2,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU Fogarty International Center (in-house research program); National Institute for Allergy and Infectious Diseases, National Institutes of Health; International Influenza Unit, Office of Global Affairs, US Department of Health and Human Services; Armed Forces Institute of Pathology FX This work was supported by the Fogarty International Center (in-house research program); the National Institute for Allergy and Infectious Diseases, National Institutes of Health (intramural research program); the International Influenza Unit, Office of Global Affairs, US Department of Health and Human Services (to the Fogarty International Center); and the Armed Forces Institute of Pathology (to J. K. T.). NR 50 TC 15 Z9 16 U1 0 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2013 VL 207 IS 5 BP 721 EP 729 DI 10.1093/infdis/jis745 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 089FD UT WOS:000314894600004 PM 23230061 ER PT J AU Graham, SM Casenghi, M Jean-Philippe, P Hatherill, M Hesseling, AC Nachman, S Starke, JR Swaminathan, S Cuevas, LE AF Graham, Stephen M. Casenghi, Martina Jean-Philippe, Patrick Hatherill, Mark Hesseling, Anneke C. Nachman, Sharon Starke, Jeffrey R. Swaminathan, Soumya Cuevas, Luis E. TI Untitled Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID INTRATHORACIC TUBERCULOSIS; DIAGNOSTICS; CONSENSUS C1 [Graham, Stephen M.] Univ Melbourne, Ctr Int Child Hlth, Dept Paediat, Melbourne, Vic, Australia. [Graham, Stephen M.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Casenghi, Martina] Med Sans Frontieres, Geneva, Switzerland. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn, Maternal Adolescent Pediat Res Branch, Div Aids,NIH, Bethesda, MD 20892 USA. [Nachman, Sharon] SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. [Starke, Jeffrey R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Hatherill, Mark] Univ Cape Town, S African TB Vaccine Initiat, Sch Child & Adolescent Hlth, ZA-7925 Cape Town, South Africa. [Hesseling, Anneke C.] Univ Stellenbosch, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Cuevas, Luis E.] Univ Liverpool, Sch Trop Med, Liverpool L69 3BX, Merseyside, England. RP Graham, SM (reprint author), Univ Melbourne, Ctr Int Child Hlth, Dept Paediat, Royal Childrens Hosp, Flemington Rd, Parkville, Vic 3052, Australia. EM steve.graham@rch.org.au NR 3 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 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2013 VL 207 IS 5 BP 871 EP U179 DI 10.1093/infdis/jis769 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 089FD UT WOS:000314894600022 PM 23242541 ER PT J AU Ameri, P Canepa, M Milaneschi, Y Spallarossa, P Leoncini, G Giallauria, F Strait, JB Lakatta, EG Brunelli, C Murialdo, G Ferrucci, L AF Ameri, P. Canepa, M. Milaneschi, Y. Spallarossa, P. Leoncini, G. Giallauria, F. Strait, J. B. Lakatta, E. G. Brunelli, C. Murialdo, G. Ferrucci, L. TI Relationship between vitamin D status and left ventricular geometry in a healthy population: results from the Baltimore Longitudinal Study of Aging SO JOURNAL OF INTERNAL MEDICINE LA English DT Article DE heart; left ventricular mass; left ventricular remodelling; population; vitamin D ID CONGESTIVE-HEART-FAILURE; D DEFICIENCY; HEMODIALYSIS-PATIENTS; D SUPPLEMENTATION; SECONDARY HYPERPARATHYROIDISM; CARDIOVASCULAR-DISEASE; CARDIAC-HYPERTROPHY; EJECTION FRACTION; CONTROLLED-TRIAL; KIDNEY-DISEASE AB Ameri P, Canepa M, Milaneschi Y, Spallarossa P, Leoncini G, Giallauria F, Strait JB, Lakatta EG, Brunelli C, Murialdo G, Ferrucci L (University of Genova, Genova, Italy; Clinical Research Branch, National Institute on Aging, NIH, Baltimore, MD, USA; National Institute on Aging, NIH, Baltimore, MD, USA; and VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands). Relationship between vitamin D status and left ventricular geometry in a healthy population: results from the Baltimore Longitudinal Study of Aging. J Intern Med 2013; 273: 253-262. Objectives The effects of vitamin D on the heart have been studied in patients with cardiac disease, but not in healthy persons. We investigated the relation between vitamin D status and left ventricular (LV) structure and function in community-dwelling subjects without heart disease. Design The relationship between concentrations of 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D reserve, and LV transthoracic echocardiography measures was analysed in 711 participants in the Baltimore Longitudinal Study of Aging who were without cardiac disease. Results Mean 25(OH)D in the study population was 32.3 +/- 11.4ngmL1; only 15.5% of subjects had moderate or severe vitamin D deficiency [25(OH)D<20ngmL1]. Adjusting for age, body mass index, cardiovascular disease risk factors, physical activity, calcium and parathyroid hormone, 25(OH)D was positively correlated with LV thickness ( 0.095, SE 0.039, P<0.05) and LV mass index ( 7.5, SE 2.6, P<0.01). A significant nonlinear relation between 25(OH)D and LV concentric remodelling was observed. LV remodelling was more likely in participants with 25(OH)D levels <30ngmL1 [odds ratio (OR) 1.24; 95% confidence interval (CI) 0.831.85] or 38ngmL1 (OR 1.73; 95% CI 1.132.65), compared with those with 3037ngmL1 25(OH)D. Consistently, LV relative wall thickness was significantly lower (P for trend=0.05), and LV diastolic internal diameter index (P for trend<0.05) and end-diastolic volume index (P for trend<0.05) were significantly higher in subjects with 3037ngmL1 25(OH)D compared to the rest of the study population. There was a significant interaction between 25(OH)D and hypertension on the risk of LV hypertrophy (P<0.05). Conclusions In a population-based sample of predominantly vitamin D-sufficient subjects without heart disease, LV geometry was most favourable at intermediate 25(OH)D concentrations. C1 [Ameri, P.; Canepa, M.; Spallarossa, P.; Leoncini, G.; Brunelli, C.; Murialdo, G.] Univ Genoa, Dept Internal Med, I-16132 Genoa, Italy. [Canepa, M.; Milaneschi, Y.; Giallauria, F.; Strait, J. B.; Ferrucci, L.] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Canepa, M.; Strait, J. B.; Lakatta, E. G.] NIA, Lab Cardiovasc Sci, Human Cardiovasc Studies Unit, NIH, Baltimore, MD 21224 USA. [Milaneschi, Y.] Vrije Univ Amsterdam, Dept Psychiat, Med Ctr GGZ InGeest, Amsterdam, Netherlands. RP Ameri, P (reprint author), Univ Genoa, Dept Internal Med, Viale Benedetto 15,6, I-16132 Genoa, Italy. EM pietroameri@unige.it; marco.canepa@nih.gov RI Giallauria, Francesco/B-5681-2013 OI Giallauria, Francesco/0000-0003-4119-9397 FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 38 TC 15 Z9 16 U1 1 U2 14 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 MAR PY 2013 VL 273 IS 3 BP 253 EP 262 DI 10.1111/joim.12007 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 092DC UT WOS:000315098100005 PM 23061475 ER PT J AU Menazza, S Wong, R Nguyen, T Wang, GH Gucek, M Murphy, E AF Menazza, Sara Wong, Renee Tiffany Nguyen Wang, Guanghui Gucek, Marjan Murphy, Elizabeth TI CypD(-/-) hearts have altered levels of proteins involved in Krebs cycle, branch chain amino acid degradation and pyruvate metabolism SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Cyclophilin D; Mitochondrial permeability transition pore; Heart; Proteomics analysis; Metabolomics changes ID MITOCHONDRIAL PERMEABILITY TRANSITION; ACUTE MYOCARDIAL-INFARCTION; CYCLOPHILIN-D; REPERFUSION INJURY; OXIDANT STRESS; CELL-DEATH; PORE; MICE; CYCLOSPORINE; INTERACTS AB Cyclophilin D (CypD) is a mitochondrial chaperone that has been shown to regulate the mitochondrial permeability transition pore (MPTP). MPTP opening is a major determinant of mitochondrial dysfunction and cardiomyocyte death during ischemia/reperfusion (I/R) injury. Mice lacking CypD have been widely used to study regulation of the MPTP, and it has been shown recently that genetic depletion of CypD correlates with elevated levels of mitochondrial Ca2+. The present study aimed to characterize the metabolic changes in CypD(-/-) hearts. Initially, we used a proteomics approach to examine protein changes in CypD(-/-) mice. Using pathway analysis, we found that CypD(-/-) hearts have alterations in branched chain amino acid metabolism, pyruvate metabolism and the Krebs cycle. We tested whether these metabolic changes were due to inhibition of electron transfer from these metabolic pathways into the electron transport chain. As we found decreased levels of succinate dehydrogenase and electron transfer flavoprotein in the proteomics analysis, we examined whether activities of these enzymes might be altered. However, we found no alterations in their activities. The proteomics study also showed a 23% decrease in carnitine-palmitoyltransferase 1 (CPTI), which prompted us to perform a metabolomics analysis. Consistent with the decrease in CPT1, we found a significant decrease in C4/Ci4, C5-OH/C3-DC, C12:1, C14:1, C16:1, and C20:3 acyl carnitines in hearts from CypD(-/-) mice. In summary, CypD(-/-) hearts exhibit changes in many metabolic pathways and caution should be used when interpreting results from these mice as due solely to inhibition of the MPTP. Published by Elsevier Ltd. C1 [Menazza, Sara; Wong, Renee; Tiffany Nguyen; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, NIH, Bldg 10,Room 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU Intramural Program of the National Heart, Lung, and Blood Institute, NIH FX We thank the Sanford Burnham Metabolomics core facility for the metabolomics measurements. This work was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, NIH. NR 32 TC 21 Z9 21 U1 1 U2 24 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 MAR PY 2013 VL 56 BP 81 EP 90 DI 10.1016/j.yjmcc.2012.12.004 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 090YS UT WOS:000315016500010 PM 23262437 ER PT J AU Havelka, GE Moreira, ES Rodriguez, MP Tsihlis, ND Wang, Z Martinez, J Hrabie, JA Kiefer, LK Kibbe, MR AF Havelka, George E. Moreira, Edward S. Rodriguez, Monica P. Tsihlis, Nick D. Wang, Zheng Martinez, Janet Hrabie, Joseph A. Kiefer, Larry K. Kibbe, Melina R. TI Nitric oxide delivery via a permeable balloon catheter inhibits neointimal growth after arterial injury SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Neointimal hyperplasia; Restenosis; Nitric oxide; Adventitia; Media; Intima; Inflammation; Macrophage; Endoluminal ID PORCINE CORONARY-ARTERIES; RAT CAROTID ARTERIES; INTIMAL HYPERPLASIA; L-ARGININE; IN-VIVO; ANGIOGRAPHIC RESTENOSIS; SYNTHASE GENE; VEIN GRAFTS; NO DONOR; ANGIOPLASTY AB Background: Neointimal hyperplasia limits the longevity of vascular interventions. Nitric oxide (NO) is well known to inhibit neointimal hyperplasia. However, delivery of NO to the vasculature is challenging. Our study aims to evaluate the efficacy of delivering NO to the site of injury using a permeable balloon catheter. Our hypothesis is that ultra-short duration NO delivery using a permeable balloon catheter will inhibit neointimal hyperplasia. Materials and methods: Ten-week-old male Sprague-Dawley rats underwent carotid artery balloon injury. Groups included: (1) control, (2) injury, (3) injury + periadventitial NO, and (4) injury + endoluminal NO via permeable balloon catheter. The catheter was inflated to 5 atm pressure for 5 min. Arteries were harvested 2 wk following injury. Morphometric assessment for neointimal hyperplasia and immunohistochemical staining for inflammatory markers were performed. Results: Injury increased neointimal hyperplasia compared with control (intima/media area [I/M] ratio 1.07 versus 0.11, respectively, P < 0.001). Periadventitial delivery of NO reduced the I/M area ratio compared with injury alone (55% decrease, P < 0.001). Endoluminal delivery of NO also reduced the I/M area ratio compared with injury alone (65% decrease; P < 0.001). Both endoluminal and periadventitial NO affected the I/M ratio by reducing the intimal area (64% and 46%, respectively, P < 0.001) whereas neither affected the medial area. Periadventitial NO delivery increased lumen area (P < 0.05), whereas endoluminal NO delivery increased circumference (P < 0.05). Periadventitial NO delivery inhibited macrophage intimal infiltration compared with injury alone (P < 0.05). Conclusions: These data demonstrate that short-duration endoluminal NO delivery via permeable balloon catheters inhibits neointimal hyperplasia following arterial interventions. Endoluminal delivery of NO could become a focus for future clinical interventions. Published by Elsevier Inc. C1 [Havelka, George E.; Moreira, Edward S.; Rodriguez, Monica P.; Tsihlis, Nick D.; Wang, Zheng; Martinez, Janet; Kibbe, Melina R.] Northwestern Univ, Div Vasc Surg, Chicago, IL 60611 USA. [Havelka, George E.; Moreira, Edward S.; Rodriguez, Monica P.; Tsihlis, Nick D.; Wang, Zheng; Martinez, Janet; Kibbe, Melina R.] Northwestern Univ, Inst BioNanotechnol Med, Chicago, IL 60611 USA. [Havelka, George E.] Univ Illinois, Dept Surg, Chicago, IL 60680 USA. [Hrabie, Joseph A.; Kiefer, Larry K.] NCI, Biol Chem Lab, Frederick, MD 21701 USA. [Kibbe, Melina R.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. RP Kibbe, MR (reprint author), Northwestern Univ, Div Vasc Surg, 676 N St Clair,650, Chicago, IL 60611 USA. EM mkibbe@nmh.org OI Bahnson, Edward/0000-0001-8578-0517; Tsihlis, Nick/0000-0002-0410-0143 FU National Institutes of Health [T32 HL094293-01]; Society for Vascular Surgery Foundation; Northwestern Memorial Foundation Collaborative Development Initiative; Center for Limb Preservation; Northwestern University Institute for BioNanotechnology in Medicine FX This work was supported by funding from the National Institutes of Health (T32 HL094293-01, GEH, MPR), the Society for Vascular Surgery Foundation (MRK), and Northwestern Memorial Foundation Collaborative Development Initiative, Center for Limb Preservation, the generosity of Mrs. Hilda Rosenbloom and Mrs. Eleanor Baldwin and the Northwestern University Institute for BioNanotechnology in Medicine. NR 34 TC 11 Z9 11 U1 2 U2 6 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 MAR PY 2013 VL 180 IS 1 BP 35 EP 42 DI 10.1016/j.jss.2012.10.048 PG 8 WC Surgery SC Surgery GA 089LQ UT WOS:000314912400013 PM 23164361 ER PT J AU Strasberg, HR Del Fiol, G Cimino, JJ AF Strasberg, Howard R. Del Fiol, Guilherme Cimino, James J. TI Terminology challenges implementing the HL7 context-aware knowledge retrieval ('Infobutton') standard SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID INFORMATION NEEDS; CLINICAL QUESTIONS; PHYSICIANS AB Point-of-care information needs are common and frequently unmet. One solution to this problem is the use of Infobuttons, which are context-sensitive links from electronic health records (EHR) to knowledge resources, sometimes involving an intermediate broker known as an Infobutton Manager. Health Level Seven (HL7) has developed the Context-Aware Knowledge Retrieval (Infobutton) standard to standardize the integration between EHR systems and knowledge resources. While the standard specifies a set of context attributes and standard terminologies, it leaves to knowledge resources the flexibility to decide how to use these attributes and terminologies to retrieve the most relevant content. This paper describes some of the challenges faced by knowledge resources in trying to locate the most relevant content based on the attribute values for a given Infobutton request. Various approaches to content retrieval are discussed, including the role of indexing with standardized codes, the role of text-based search engines together with their ranking algorithms, and the role of hybrid approaches. Knowledge resource developers must carefully consider business rules, heuristics, and precision/recall tradeoffs when implementing the HL7 Infobutton standard. C1 [Strasberg, Howard R.] Wolters Kluwer Hlth, Sunnyvale, CA USA. [Del Fiol, Guilherme] Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA. [Cimino, James J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. RP Strasberg, HR (reprint author), 3830 Valley Ctr Dr,Ste 705,PMB 461, San Diego, CA 92130 USA. EM howard.strasberg@wolterskluwer.com OI Del Fiol, Guilherme/0000-0001-9954-6799; Cimino, James/0000-0003-4101-1622 FU Agency for Healthcare Research and Quality [K01HS018352]; NIH Clinical Center; National Library of Medicine FX This project was supported in part by grant number K01HS018352 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. This research was also supported in part by intramural research funds from the NIH Clinical Center and the National Library of Medicine. NR 21 TC 1 Z9 1 U1 1 U2 16 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 MAR PY 2013 VL 20 IS 2 BP 218 EP 223 DI 10.1136/amiajnl-2012-001251 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 088YX UT WOS:000314875100002 PM 23077131 ER PT J AU Escaffre, O Le Nouen, C Amelot, M Ambroggio, X Ogden, KM Guionie, O Toquin, D Muller, H Islam, MR Eterradossi, N AF Escaffre, Olivier Le Nouen, Cyril Amelot, Michel Ambroggio, Xavier Ogden, Kristen M. Guionie, Olivier Toquin, Didier Mueller, Hermann Islam, Mohammed R. Eterradossi, Nicolas TI Both Genome Segments Contribute to the Pathogenicity of Very Virulent Infectious Bursal Disease Virus SO JOURNAL OF VIROLOGY LA English DT Article ID DEPENDENT RNA-POLYMERASE; DOUBLE-STRANDED-RNA; CAPSID PROTEIN; ANTIGENIC CHARACTERIZATION; NONSTRUCTURAL PROTEIN; MOLECULAR-DYNAMICS; DIFFERENT STRAINS; BIRNAVIRUS VP1; AMINO-ACIDS; IN-VITRO AB Infectious bursal disease virus (IBDV) causes an economically significant disease of chickens worldwide. Very virulent IBDV (vvIBDV) strains have emerged and induce as much as 60% mortality. The molecular basis for vvIBDV pathogenicity is not understood, and the relative contributions of the two genome segments, A and B, to this phenomenon are not known. Isolate 94432 has been shown previously to be genetically related to vvIBDVs but exhibits atypical antigenicity and does not cause mortality. Here the full-length genome of 94432 was determined, and a reverse genetics system was established. The molecular clone was rescued and exhibited the same antigenicity and reduced pathogenicity as isolate 94432. Genetically modified viruses derived from 94432, whose vvIBDV consensus nucleotide sequence was restored in segment A and/or B, were produced, and their pathogenicity was assessed in specific-pathogen-free chickens. We found that a valine (position 321) that modifies the most exposed part of the capsid protein VP2 critically modified the antigenicity and partially reduced the pathogenicity of 94432. However, a threonine (position 276) located in the finger domain of the virus polymerase (VP1) contributed even more significantly to attenuation. This threonine is partially exposed in a hydrophobic groove on the VP1 surface, suggesting possible interactions between VP1 and another, as yet unidentified molecule at this amino acid position. The restored vvIBDV-like pathogenicity was associated with increased replication and lesions in the thymus and spleen. These results demonstrate that both genome segments influence vvIBDV pathogenicity and may provide new targets for the attenuation of vvIBDVs. C1 [Escaffre, Olivier; Le Nouen, Cyril; Guionie, Olivier; Toquin, Didier; Eterradossi, Nicolas] Anses French Agcy Food Environm & Occupat Hlth &, Immunol & Parasitol Unit VIPAC, OIE Reference Lab Infect Bursal Dis, Ploufragan, France. [Amelot, Michel] Anses French Agcy Food Environm & Occupat Hlth &, Expt Poultry & Rabbit Unit SELEAC, Ploufragan, France. [Ambroggio, Xavier] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Ogden, Kristen M.] NIAID, Infect Dis Lab, Rotavirus Mol Biol Sect, NIH, Bethesda, MD 20892 USA. [Mueller, Hermann] Univ Leipzig, Inst Virol, Fac Vet Med, D-04109 Leipzig, Germany. [Islam, Mohammed R.] Bangladesh Agr Univ, Dept Pathol, Mymensingh, Bangladesh. RP Eterradossi, N (reprint author), Anses French Agcy Food Environm & Occupat Hlth &, Immunol & Parasitol Unit VIPAC, OIE Reference Lab Infect Bursal Dis, Ploufragan, France. EM nicolas.eterradossi@anses.fr FU French Agency for Food, Environmental and Occupational Health and Safety (Anses) [2002-7]; COST Action [839]; Conseil General des Cotes d'Armor FX This work was supported by research grant 2002-7 from the French Agency for Food, Environmental and Occupational Health and Safety (Anses), by COST Action 839 "Immunosuppressive Viral Diseases of Chickens," and by the Conseil General des Cotes d'Armor. NR 72 TC 17 Z9 22 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 MAR PY 2013 VL 87 IS 5 BP 2767 EP 2780 DI 10.1128/JVI.02360-12 PG 14 WC Virology SC Virology GA 088ZL UT WOS:000314876900036 PM 23269788 ER PT J AU Rubinson, L Mutter, R Viboud, C Hupert, N Uyeki, T Creanga, A Finelli, L Iwashyna, TJ Carr, B Merchant, R Katikineni, D Vaughn, F Clancy, C Lurie, N AF Rubinson, Lewis Mutter, Ryan Viboud, Cecile Hupert, Nathaniel Uyeki, Timothy Creanga, Andreea Finelli, Lyn Iwashyna, Theodore J. Carr, Brendan Merchant, Raina Katikineni, Devi Vaughn, Frances Clancy, Carolyn Lurie, Nicole TI Impact of the Fall 2009 Influenza A(H1N1)pdm09 Pandemic on US Hospitals SO MEDICAL CARE LA English DT Article DE pandemic influenza; hospital surge capacity; emergency department ID A H1N1 VIRUS; ACUTE MYOCARDIAL-INFARCTION; UNITED-STATES; INFECTION; BURDEN AB Background: Understanding how hospitals functioned during the 2009 influenza A(H1N1)pdm09 pandemic may improve future public health emergency response, but information about its impact on US hospitals remains largely unknown. Research Design: We matched hospital and emergency department (ED) discharge data from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project with community-level influenza-like illness activity during each hospital's pandemic period in fall 2009 compared with a corresponding calendar baseline period. We compared inpatient mortality for sentinel conditions at high-surge versus nonsurge hospitals. Results: US hospitals experienced a doubling of pneumonia and influenza ED visits during fall 2009 compared with prior years, along with an 18% increase in overall ED visits. Although no significant increase in total inpatient admissions occurred overall, approximately 10% of all study hospitals experienced high surge, associated with higher acute myocardial infarction and stroke case fatality rates. These hospitals had similar characteristics to other US hospitals except that they had higher mortality for acute cardiac illnesses before the pandemic. After adjusting for 2008 case fatality rates, the association between high-surge hospitals and increased mortality for acute myocardial infarction and stroke patients persisted. Conclusions: The fall 2009 pandemic period substantially impacted US hospitals, mostly through increased ED visits. For a small proportion of hospitals that experienced a high surge in inpatient admissions, increased mortality from selected clinical conditions was associated with both prepandemic outcomes and surge, highlighting the linkage between daily hospital operations and disaster preparedness. C1 [Rubinson, Lewis; Vaughn, Frances; Lurie, Nicole] US Dept HHS, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. [Mutter, Ryan; Clancy, Carolyn] Agcy Healthcare Res & Qual, Rockville, MD 20850 USA. [Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Hupert, Nathaniel] Weill Cornell Med Ctr, New York, NY USA. [Uyeki, Timothy; Finelli, Lyn] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Creanga, Andreea] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Iwashyna, Theodore J.] Univ Michigan Hlth Syst, Dept Internal Med, Ann Arbor, MI USA. [Carr, Brendan; Merchant, Raina] Univ Penn, Perelman Sch Med, Dept Emergency Med, Philadelphia, PA 19104 USA. [Katikineni, Devi] Social & Sci Syst Inc, Silver Spring, MD USA. RP Mutter, R (reprint author), Agcy Healthcare Res & Qual, Ctr Delivery Org & Markets, 540 Gaither Rd, Rockville, MD 20850 USA. EM Ryan.Mutter@ahrq.hhs.gov OI Iwashyna, Theodore/0000-0002-4226-9310 NR 23 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2013 VL 51 IS 3 BP 259 EP 265 DI 10.1097/MLR.0b013e31827da8ea PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 090NE UT WOS:000314985100009 PM 23295577 ER PT J AU Vedell, PT Lu, Y Grubbs, CJ Yin, YX Jiang, H Bland, KI Muccio, DD Cvetkovic, D You, M Lubet, R AF Vedell, Peter T. Lu, Yan Grubbs, Clinton J. Yin, Yuxin Jiang, Hui Bland, Kirby I. Muccio, Donald D. Cvetkovic, Dusica You, Ming Lubet, Ronald TI Effects on Gene Expression in Rat Liver after Administration of RXR Agonists: UAB30, 4-Methyl-UAB30, and Targretin (Bexarotene) SO MOLECULAR PHARMACOLOGY LA English DT Article ID INDUCED MAMMARY CARCINOGENESIS; RETINOIC ACID ANALOGS; LUNG-CANCER; PREVENTION; RECEPTORS; 9CUAB30; MODELS; INDOLE-3-CARBINOL; VARIANCE; GLAND AB Examination of three retinoid X receptor (RXR) agonists [Targretin (TRG), UAB30, and 4-methyl-UAB30 (4-Me-UAB30)] showed that all inhibited mammary cancer in rodents and two (TRG and 4-Me-UAB30) strikingly increased serum triglyceride levels. Agents were administered in diets to female Sprague-Dawley rats. Liver RNA was isolated and micro-arrayed on the Affymetrix GeneChip Rat Exon 1.0 ST array. Statistical tests identified genes that exhibited differential expression and fell into groups, or modules, with differential expression among agonists. Genes in specific modules were changed by one, two, or all three agonists. An interactome analysis assessed the effects on genes that heterodimerize with known nuclear receptors. For proliferator-activated receptor alpha/RXR-activated genes, the strongest response was TRG > 4-Me-UAB30 > UAB30. Many liver X receptor/RXR-related genes (e. g., Scd-1 and Srebf1, which are associated with increased triglycerides) were highly expressed in TRG and 4-Me-UAB30- but not UAB30-treated livers. Minimal expression changes were associated with retinoic acid receptor or vitamin D receptor heterodimers by any of the agonists. UAB30 unexpectedly and uniquely activated genes associated with the aryl hydrocarbon hydroxylase (Ah) receptor (Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1). Based on the Ah receptor activation, UAB30 was tested for its ability to prevent dimethylbenzanthracene (DMBA)-induced mammary cancers, presumably by inhibiting DMBA activation, and was highly effective. Gene expression changes were determined by reverse transcriptase-polymerase chain reaction in rat livers treated with Targretin for 2.3, 7, and 21 days. These showed similar gene expression changes at all three time points, arguing some steady-state effect. Different patterns of gene expression among the agonists provided insight into molecular differences and allowed one to predict certain physiologic consequences of agonist treatment. C1 [Vedell, Peter T.; Lu, Yan; Yin, Yuxin; Jiang, Hui; Bland, Kirby I.; You, Ming] Med Coll Wisconsin, Ctr Canc, Dept Pharmacol Toxicol, Milwaukee, WI 53226 USA. [Grubbs, Clinton J.; Bland, Kirby I.; Muccio, Donald D.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Grubbs, Clinton J.; Bland, Kirby I.; Muccio, Donald D.] Univ Alabama Birmingham, Dept Chem, Birmingham, AL 35294 USA. [Cvetkovic, Dusica] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Lubet, Ronald] NCI, Bethesda, MD 20892 USA. RP Grubbs, CJ (reprint author), Univ Alabama Birmingham, Chemoprevent Ctr, 1670 Univ Blvd,VH-G-78-D Box 800, Birmingham, AL 35294 USA. EM clinton.grubbs@ccc.uab.edu RI Yin, Yuxin/G-2694-2014 OI Yin, Yuxin/0000-0002-1639-285X FU National Institutes of Health National Cancer Institute [P50 CA089019, HHSN261200433001C]; Intramural Research Program of the National Institutes of Health (National Cancer Institute) FX This research was supported by the National Institutes of Health National Cancer Institute [Grant P50 CA089019 and contract number HHSN261200433001C]. This research was also supported in part by the Intramural Research Program of the National Institutes of Health (National Cancer Institute). NR 33 TC 12 Z9 12 U1 0 U2 12 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 MAR PY 2013 VL 83 IS 3 BP 698 EP 708 DI 10.1124/mol.112.082404 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 092VU UT WOS:000315151900015 PM 23292798 ER PT J AU James, LI Barsyte-Lovejoy, D Zhong, N Krichevsky, L Korboukh, VK Herold, JM MacNevin, CJ Norris, JL Sagum, CA Tempel, W Marcon, E Guo, HB Gao, C Huang, XP Duan, SL Emili, A Greenblatt, JF Kireev, DB Jin, J Janzen, WP Brown, PJ Bedford, MT Arrowsmith, CH Frye, SV AF James, Lindsey I. Barsyte-Lovejoy, Dalia Zhong, Nan Krichevsky, Liubov Korboukh, Victoria K. Herold, J. Martin MacNevin, Christopher J. Norris, Jacqueline L. Sagum, Cari A. Tempel, Wolfram Marcon, Edyta Guo, Hongbo Gao, Cen Huang, Xi-Ping Duan, Shili Emili, Andrew Greenblatt, Jack F. Kireev, Dmitri B. Jin, Jian Janzen, William P. Brown, Peter J. Bedford, Mark T. Arrowsmith, Cheryl H. Frye, Stephen V. TI Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain SO NATURE CHEMICAL BIOLOGY LA English DT Article ID LYSINE BINDING-PROTEINS; POLYCOMB PROTEIN; STRUCTURAL BASIS; DNA-REPAIR; PHD FINGER; METHYLATION; RECOGNITION; CHROMATIN; INHIBITION; MBT AB We describe the discovery of UNC1215, a potent and selective chemical probe for the methyllysine (Kme) reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin-interacting transcriptional repressors. UNC1215 binds L3MBTL3 with a K-d of 120 nM, competitively displacing mono- or dimethyllysine-containing peptides, and is greater than 50-fold more potent toward L3MBTL3 than other members of the MBT family while also demonstrating selectivity against more than 200 other reader domains examined. X-ray crystallography identified a unique 2:2 polyvalent mode of interaction between UNC1215 and L3MBTL3. In cells, UNC1215 is nontoxic and directly binds L3MBTL3 via the Kme-binding pocket of the MBT domains. UNC1215 increases the cellular mobility of GFP-L3MBTL3 fusion proteins, and point mutants that disrupt the Kme-binding function of GFP-L3MBTL3 phenocopy the effects of UNC1215 on localization. Finally, UNC1215 was used to reveal a new Kme-dependent interaction of L3MBTL3 with BCLAF1, a protein implicated in DNA damage repair and apoptosis. C1 [James, Lindsey I.; Korboukh, Victoria K.; Herold, J. Martin; MacNevin, Christopher J.; Norris, Jacqueline L.; Gao, Cen; Kireev, Dmitri B.; Jin, Jian; Janzen, William P.; Frye, Stephen V.] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Barsyte-Lovejoy, Dalia; Zhong, Nan; Krichevsky, Liubov; Tempel, Wolfram; Brown, Peter J.; Arrowsmith, Cheryl H.] Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada. [Krichevsky, Liubov; Arrowsmith, Cheryl H.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Krichevsky, Liubov; Duan, Shili; Arrowsmith, Cheryl H.] Univ Toronto, Ontario Canc Inst, Campbell Family Canc Res Inst, Toronto, ON, Canada. [MacNevin, Christopher J.; Huang, Xi-Ping] Univ N Carolina, Dept Pharmacol, Chapel Hill Med Sch, Chapel Hill, NC USA. [Sagum, Cari A.; Bedford, Mark T.] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA. [Marcon, Edyta; Guo, Hongbo; Emili, Andrew; Greenblatt, Jack F.] Donnelly Ctr, Banting & Best Dept Med Res, Toronto, ON, Canada. [Huang, Xi-Ping] Univ N Carolina, Chapel Hill Med Sch, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC USA. RP Frye, SV (reprint author), Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. EM carrow@uhnres.utoronto.ca; svfrye@email.unc.edu FU US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; US National Institute of General Medical Sciences; US National Institutes of Health [RC1GM090732, R01GM100919]; Carolina Partnership; University Cancer Research Fund; University of North Carolina at Chapel Hill; Center for Environmental and Molecular Carcinogenesis at the M.D. Anderson Cancer Center; National Institute of Mental Health Psychoactive Drug Screening Program; Ontario Research Fund [ORF-GL2]; Natural Sciences and Engineering Research Council of Canada; Ontario Ministry of Health and Long-Term Care; American Cancer Society [119169-PF-10-183-01-TBE]; Structural Genomics Consortium; Canadian Institutes of Health Research [1097737]; Eli Lilly Canada; Genome Canada; GlaxoSmithKline; Ontario Ministry of Economic Development and Innovation; Novartis Research Foundation; Pfizer; Abbott; Takeda; Wellcome Trust; US National Institute of Environmental Health Sciences [ES007784]; Cancer Prevention Research Institute of Texas [RP110471] FX We thank M. Vedadi, G. Wasney and F. Li for support with the protein lysine methyltransferase selectivity screening; O. Fedorov for support with the bromodomain selectivity screening; A. Tumber for support with the lysine demethylase selectivity screening; E. Hull-Ryde for support with the CellTiter-Glo cell viability assay; K. Hahn (University of North Carolina (UNC)) for providing mero76; B. Roth for helpful discussion regarding the GPCR selectivity studies; and G. Wang (UNC) for providing PHF23 and JARID1 proteins. Results shown in this report are derived from work performed at the Structural Biology Center at the Advanced Photon Source at Argonne National Laboratory. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. The research described here was supported by the US National Institute of General Medical Sciences; US National Institutes of Health (grant RC1GM090732 and R01GM100919); the Carolina Partnership and the University Cancer Research Fund; University of North Carolina at Chapel Hill; the Center for Environmental and Molecular Carcinogenesis at the M.D. Anderson Cancer Center; the National Institute of Mental Health Psychoactive Drug Screening Program; the Ontario Research Fund (grant ORF-GL2); the Natural Sciences and Engineering Research Council of Canada; the Ontario Ministry of Health and Long-Term Care; the American Cancer Society (C.J.M.; 119169-PF-10-183-01-TBE); and the Structural Genomics Consortium, which is a registered charity (number 1097737) that receives funds from Canadian Institutes of Health Research; Eli Lilly Canada; Genome Canada; GlaxoSmithKline; the Ontario Ministry of Economic Development and Innovation; the Novartis Research Foundation; Pfizer; Abbott; Takeda; and the Wellcome Trust. M.T.B. is supported by an institutional grant from the US National Institute of Environmental Health Sciences (ES007784) and Cancer Prevention Research Institute of Texas funding (RP110471). C.H.A. holds a Canada Research Chair in Structural Genomics. NR 38 TC 62 Z9 63 U1 1 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD MAR PY 2013 VL 9 IS 3 BP 184 EP 191 DI 10.1038/NCHEMBIO.1157 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 092OW UT WOS:000315132900014 PM 23292653 ER PT J AU Wynn, TA AF Wynn, Thomas A. TI Myeloid-cell differentiation redefined in cancer SO NATURE IMMUNOLOGY LA English DT Editorial Material ID IDENTIFICATION AB The differentiation of monocytes is altered in cancer, which results in the unexpected conversion of a large proportion of monocytic myeloid-derived suppressor cells into polymorphonuclear myeloid-derived suppressor cells. C1 [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Program Tissue Immun & Repair, NIH, Bethesda, MD 20892 USA. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Program Tissue Immun & Repair, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov FU Intramural NIH HHS [ZIA AI001019-06] NR 12 TC 4 Z9 4 U1 0 U2 7 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 MAR PY 2013 VL 14 IS 3 BP 197 EP 199 PG 3 WC Immunology SC Immunology GA 091QR UT WOS:000315065400006 PM 23416669 ER PT J AU Baumann, MH Partilla, JS Lehner, KR Thorndike, EB Hoffman, AF Holy, M Rothman, RB Goldberg, SR Lupica, CR Sitte, HH Brandt, SD Tella, SR Cozzi, NV Schindler, CW AF Baumann, Michael H. Partilla, John S. Lehner, Kurt R. Thorndike, Eric B. Hoffman, Alexander F. Holy, Marion Rothman, Richard B. Goldberg, Steven R. Lupica, Carl R. Sitte, Harald H. Brandt, Simon D. Tella, Srihari R. Cozzi, Nicholas V. Schindler, Charles W. TI Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive 'Bath Salts' Products SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE designer drug; dopamine; cathinone; monoamine transporter; uptake blocker ID MONOAMINE UPTAKE INHIBITORS; NUCLEUS-ACCUMBENS; LOCOMOTOR-ACTIVITY; DOPAMINE OVERFLOW; D-AMPHETAMINE; LEGAL HIGHS; TRANSPORTERS; DRUGS; SEROTONIN; RATS AB The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of [H-3]dopamine (IC50=4.1 nM) and [H-3]norepinephrine (IC50=26 nM) with high potency but has weak effects on uptake of [H-3]serotonin (IC50=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations. Neuropsychopharmacology (2013) 38, 552-562; doi:10.1038/npp.2012.204; published online 17 October 2012 C1 [Baumann, Michael H.; Partilla, John S.; Lehner, Kurt R.; Rothman, Richard B.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Thorndike, Eric B.; Goldberg, Steven R.; Schindler, Charles W.] NIDA, Preclin Pharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Hoffman, Alexander F.; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Holy, Marion; Sitte, Harald H.] Med Univ Vienna, Inst Pharmacol, Ctr Physiol & Pharmacol, Vienna, Austria. [Brandt, Simon D.] Liverpool John Moores Univ, Sch Pharm & Biomol Sci, Liverpool L3 5UX, Merseyside, England. [Tella, Srihari R.] Drug Enforcement Adm, Off Div Control, Drug & Chem Evaluat Sect, Springfield, VA USA. [Cozzi, Nicholas V.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Neuropharmacol Lab, Madison, WI USA. RP Baumann, MH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 333 Cassell Dr,Suite 4500, Baltimore, MD 21224 USA. EM mbaumann@mail.nih.gov RI Sitte, Harald/N-2681-2013; Hoffman, Alexander/H-3035-2012; OI Sitte, Harald/0000-0002-1339-7444; Hoffman, Alexander/0000-0002-2676-0628; Brandt, Simon/0000-0001-8632-5372 FU Austrian Science Fund/FWF [SFB3506] FX We thank Mario A. Ayestas Jr. for helpful technical assistance. This research was generously supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, USA, and by the Austrian Science Fund/FWF, SFB3506. The views expressed herein are those of the authors and do not necessarily represent the views of the Drug Enforcement Administration, the United States Department of Justice or an officer or entity of the United States. NR 54 TC 107 Z9 108 U1 3 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2013 VL 38 IS 4 BP 552 EP 562 DI 10.1038/npp.2012.204 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 091OX UT WOS:000315060800002 PM 23072836 ER PT J AU Fantegrossi, WE Gannon, BM Zimmerman, SM Rice, KC AF Fantegrossi, William E. Gannon, Brenda M. Zimmerman, Sarah M. Rice, Kenner C. TI In vivo Effects of Abused 'Bath Salt' Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE designer drug; cathinone; behavior; thermoregulation; locomotor activity ID SELF-INJURIOUS-BEHAVIOR; KNOCKOUT MICE; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; NONLINEAR PHARMACOKINETICS; AMBIENT-TEMPERATURE; UPTAKE INHIBITORS; DOPAMINE RELEASE; SQUIRREL-MONKEYS; D-AMPHETAMINE; METHAMPHETAMINE AB In recent years, synthetic analogues of naturally occurring cathinone have emerged as psychostimulant-like drugs of abuse in commercial 'bath salt' preparations. 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these illicit products, and its structural similarities to the more well-known drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) suggest that it may have similar in vivo effects to these substances. In these studies, adult male NIH Swiss mice were trained to discriminate 0.3 mg/kg MDPV from saline, and the interoceptive effects of a range of substitution doses of MDPV, MDMA, and METH were then assessed. In separate groups of mice, surgically implanted radiotelemetry probes simultaneously monitored thermoregulatory and locomotor responses to various doses of MDPV and MDMA, as a function of ambient temperature. We found that mice reliably discriminated the MDPV training dose from saline and that cumulative doses of MDPV, MDMA, and METH fully substituted for the MDPV training stimulus. All three drugs had similar ED50 values in this procedure. Stimulation of motor activity was observed following administration of a wide range of MDPV doses (1-30 mg/kg), and the warm ambient temperature potentiated motor activity and elicited profound stereotypy and self-injurious behavior at 30 mg/kg. In contrast, MDPV-induced hyperthermic effects were observed in only the warm ambient environment. This pattern of effects is in sharp contrast to MDMA, where ambient temperature interacts with thermoregulation, but not locomotor activity. These studies suggest that although the interoceptive effects of MDPV are similar to those of MDMA and METH, direct effects on thermoregulatory processes and locomotor activity are likely mediated by different mechanisms than those of MDMA. Neuropsychopharmocology (2013) 38, 563-573; doi:10.1038/npp.2012.233; published online 5 December 2012 C1 [Fantegrossi, William E.; Gannon, Brenda M.; Zimmerman, Sarah M.] Univ Arkansas Med Sci, Coll Med, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. [Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, Bethesda, MD USA. RP Fantegrossi, WE (reprint author), Univ Arkansas Med Sci, Coll Med, Dept Pharmacol & Toxicol, 4301 W Markham St,Mail Slot 638, Little Rock, AR 72205 USA. EM WEFantegrossi@uams.edu FU National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX We thank William S Hyatt for helpful technical assistance, and the UAMS Division of Laboratory Animal Medicine for expert husbandry services. This research was generously supported by the UAMS Center for Translational Neuroscience (RR020146) and the UAMS Translational Research Institute (RR029884). A portion of this work was supported by the Intramural Research Programs of National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. The views expressed herein are those of the authors and do not necessarily represent the views of the University of Arkansas for Medical Sciences or the National Institute on Drug Abuse. NR 57 TC 40 Z9 40 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2013 VL 38 IS 4 BP 563 EP 573 DI 10.1038/npp.2012.233 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 091OX UT WOS:000315060800003 PM 23212455 ER PT J AU Hiranita, T Mereu, M Soto, PL Tanda, G Katz, JL AF Hiranita, Takato Mereu, Maddalena Soto, Paul L. Tanda, Gianluigi Katz, Jonathan L. TI Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE sigma receptor; cocaine; dopamine; drug reinforcement history; reinforcement mechanisms; drug self-administration ID CONDITIONED PLACE PREFERENCE; RATS DISCRIMINATING COCAINE; RECEPTOR AGONISTS; EXTRACELLULAR DOPAMINE; PROTEIN EXPRESSION; NUCLEUS-ACCUMBENS; UPTAKE INHIBITORS; METHAMPHETAMINE; INVOLVEMENT; LIGANDS AB Sigma(1) receptors (sigma(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective sigma R-1 agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either sigma R-1 agonist. In contrast, after subjects self-administered cocaine sigma R-1 agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both sigma R-1 agonists, extinguished when injections were discontinued, and reconditioned when sigma R-1 agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of sigma R-1 agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the sigma R antagonist, BD 1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive sigma R-1 agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced sigma R-1 mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse. Neuropsychopharmacology (2013) 38, 605-615; doi:10.1038/npp.2012.224; published online 28 November 2012 C1 [Hiranita, Takato; Mereu, Maddalena; Tanda, Gianluigi; Katz, Jonathan L.] NIDA, Psychobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,US Dept HHS,NIH, Baltimore, MD 21224 USA. [Soto, Paul L.] Johns Hopkins Univ, Sch Med, Behav Biol Res Ctr, Baltimore, MD USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,US Dept HHS,NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov RI Tanda, Gianluigi/B-3318-2009; Hiranita, Takato/G-6567-2011; OI Tanda, Gianluigi/0000-0001-9526-9878; Katz, Jonathan/0000-0002-1068-1159 FU Intramural Research Program of the National Institute on Drug Abuse FX We thank Patty Ballerstadt for administrative assistance and Drs Tsung-Ping Su, Teruo Hayashi, James H. Woods, and James E. Barrett for advice on these studies and the preparation of the manuscript. The work reported herein was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 53 TC 13 Z9 13 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2013 VL 38 IS 4 BP 605 EP 615 DI 10.1038/npp.2012.224 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 091OX UT WOS:000315060800007 PM 23187725 ER PT J AU Wheeler, DC Burstyn, I Vermeulen, R Yu, K Shortreed, SM Pronk, A Stewart, PA Colt, JS Baris, D Karagas, MR Schwenn, M Johnson, A Silverman, DT Friesen, MC AF Wheeler, David C. Burstyn, Igor Vermeulen, Roel Yu, Kai Shortreed, Susan M. Pronk, Anjoeka Stewart, Patricia A. Colt, Joanne S. Baris, Dalsu Karagas, Margaret R. Schwenn, Molly Johnson, Alison Silverman, Debra T. Friesen, Melissa C. TI Inside the black box: starting to uncover the underlying decision rules used in a one-by-one expert assessment of occupational exposure in case-control studies SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID MATRIX AB Objectives Evaluating occupational exposures in population-based case-control studies often requires exposure assessors to review each study participant's reported occupational information job-by-job to derive exposure estimates. Although such assessments likely have underlying decision rules, they usually lack transparency, are time consuming and have uncertain reliability and validity. We aimed to identify the underlying rules to enable documentation, review and future use of these expert-based exposure decisions. Methods Classification and regression trees (CART, predictions from a single tree) and random forests (predictions from many trees) were used to identify the underlying rules from the questionnaire responses, and an expert's exposure assignments for occupational diesel exhaust exposure for several metrics: binary exposure probability and ordinal exposure probability, intensity and frequency. Data were split into training (n=10 488 jobs), testing (n=2247) and validation (n=2248) datasets. Results The CART and random forest models' predictions agreed with 92-94% of the expert's binary probability assignments. For ordinal probability, intensity and frequency metrics, the two models extracted decision rules more successfully for unexposed and highly exposed jobs (86-90% and 57-85%, respectively) than for low or medium exposed jobs (7-71%). Conclusions CART and random forest models extracted decision rules and accurately predicted an expert's exposure decisions for the majority of jobs, and identified questionnaire response patterns that would require further expert review if the rules were applied to other jobs in the same or different study. This approach makes the exposure assessment process in case-control studies more transparent, and creates a mechanism to efficiently replicate exposure decisions in future studies. C1 [Friesen, Melissa C.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Friesen, MC (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8106,MSC 7240, Bethesda, MD 20892 USA. EM friesenmc@mail.nih.gov RI Friesen, Melissa/A-5362-2009; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The research was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 28 TC 12 Z9 12 U1 0 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD MAR PY 2013 VL 70 IS 3 BP 203 EP 210 DI 10.1136/oemed-2012-100918 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 088HG UT WOS:000314824000009 PM 23155187 ER PT J AU Parikh, H Jia, JP Zhang, XJ Chung, CC Jacobs, KB Yeager, M Boland, J Hutchinson, A Burdett, L Hoskins, J Risch, HA Stolzenberg-Solomon, RZ Chanock, SJ Wolpin, BM Petersen, GM Fuchs, CS Hartge, P Amundadottir, L AF Parikh, Hemang Jia, Jinping Zhang, Xijun Chung, Charles C. Jacobs, Kevin B. Yeager, Meredith Boland, Joseph Hutchinson, Amy Burdett, Laura Hoskins, Jason Risch, Harvey A. Stolzenberg-Solomon, Rachael Z. Chanock, Stephen J. Wolpin, Brian M. Petersen, Gloria M. Fuchs, Charles S. Hartge, Patricia Amundadottir, Laufey TI A Resequence Analysis of Genomic Loci on Chromosomes 1q32.1, 5p15.33, and 13q22.1 Associated With Pancreatic Cancer Risk SO PANCREAS LA English DT Article DE pancreatic cancer; targeted resequencing; GWAS; susceptibility loci; SNP; 1000G ID COHORT-CONSORTIUM PANSCAN; SUSCEPTIBILITY LOCI; WIDE ASSOCIATION; POOLED-ANALYSIS; TERT-CLPTM1L LOCUS; VARIANTS; LUNG; PROSTATE; HISTORY AB Objective: The objective of this study was to fine-map common pancreatic cancer susceptibility regions. Methods: We conducted targeted Roche-454 resequencing across 428 kb in 3 genomic regions identified in genome-wide association studies (GWAS) of pancreatic cancer, on chromosomes 1q32.1, 5p15.33, and 13q22.1. Results: An analytical pipeline for calling genotypes was developed using HapMap samples sequenced on chr5p15.33. Concordance to 1000 Genomes data for chr5p15.33 was greater than 96%. The concordance for chr1q32.1 and chr13q22.1 with pancreatic cancer GWAS data was greater than 99%. Between 9.2% and 19.0% of variants detected were not present in 1000 Genomes for the respective continental population. The majority of completely novel single-nucleotide polymorphisms (SNPs) were less common (minor allele frequency [MAF], <= 5%) or rare (MAF, <= 2%), illustrating the value of enlarging test sets for discovery of less common variants. Using the data set, we examined haplotype blocks across each region using a tag SNP analysis (r(2) > 0.8 for MAF of >= 5%) and determined that at least 196, 243, and 63 SNPs are required for fine-mapping chr1q32.1, chr5p15.33, and chr13q22.1, respectively, in European populations. Conclusions: We have characterized germline variation in 3 regions associated with pancreatic cancer risk and show that targeted resequencing leads to the discovery of novel variants and improves the completeness of germline sequence variants for fine-mapping GWAS susceptibility loci. C1 [Parikh, Hemang; Jia, Jinping; Chung, Charles C.; Hoskins, Jason; Chanock, Stephen J.; Amundadottir, Laufey] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Parikh, Hemang; Jia, Jinping; Zhang, Xijun; Chung, Charles C.; Jacobs, Kevin B.; Yeager, Meredith; Boland, Joseph; Hutchinson, Amy; Burdett, Laura; Hoskins, Jason; Stolzenberg-Solomon, Rachael Z.; Chanock, Stephen J.; Hartge, Patricia; Amundadottir, Laufey] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zhang, Xijun; Jacobs, Kevin B.; Yeager, Meredith; Boland, Joseph; Hutchinson, Amy; Burdett, Laura] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Risch, Harvey A.] Yale Univ, Sch Med, Sch Publ Hlth, New Haven, CT USA. [Wolpin, Brian M.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wolpin, Brian M.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Wolpin, Brian M.; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. RP Amundadottir, L (reprint author), NIH, Lab Translat Genom, Div Canc Epidemiol & Genet, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM amundadottirl@mail.nih.gov RI Hoskins, Jason/F-5672-2012; Amundadottir, Laufey/L-7656-2016 OI Hoskins, Jason/0000-0001-6944-1996; Amundadottir, Laufey/0000-0003-1859-8971 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E] FX This work was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH) under contract no. HHSN261200800001E. NR 37 TC 4 Z9 4 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD MAR PY 2013 VL 42 IS 2 BP 209 EP 215 DI 10.1097/MPA.0b013e318264cea5 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 090JL UT WOS:000314975200005 PM 23295781 ER PT J AU Langan, RC Gill, F Raiji, MT Mullinax, JE Pittaluga, S Pandalai, P Davis, J Perkins, K Avital, I AF Langan, Russell C. Gill, Fred Raiji, Manish T. Mullinax, John E. Pittaluga, Stefania Pandalai, Prakash Davis, Joie Perkins, Katie Avital, Itzhak TI Autoimmune Pancreatitis in the Autoimmune Lymphoproliferative Syndrome (ALPS) A Sheep in Wolves' Clothing? SO PANCREAS LA English DT Letter ID DIAGNOSTIC-CRITERIA; MANAGEMENT C1 [Langan, Russell C.; Raiji, Manish T.; Mullinax, John E.; Pandalai, Prakash] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Gill, Fred] NIH, Internal Med Consultat Serv, Ctr Clin, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Davis, Joie; Perkins, Katie] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD USA. [Avital, Itzhak] Bon Secours Canc Inst, Richmond, VA USA. RP Langan, RC (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Russell.Langan@gmail.com RI Mullinax, John/L-2509-2014 FU Intramural NIH HHS [ZIA BC011267-02, ZIA BC011267-01] NR 10 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2013 VL 42 IS 2 BP 363 EP 366 DI 10.1097/MPA.0b013e3182648778 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 090JL UT WOS:000314975200030 PM 23407489 ER PT J AU Hobday, T Qin, R Reidy, D Moore, M Strosberg, J Kaubisch, A Shah, M Kindler, H Lenz, HJ Chen, H Erlichman, C AF Hobday, Timothy Qin, Rui Reidy, Diane Moore, Malcolm Strosberg, Jonathan Kaubisch, Andreas Shah, Manisha Kindler, Hedy Lenz, Heinz-Joseph Chen, Helen Erlichman, Charles TI Multi-Center Phase II Trial of Temsirolimus (TEM) and Bevacizumab (BEV) in Pancreatic Neuroendocrine Tumor (PNET): Results of a Planned Interim Efficacy Analysis SO PANCREAS LA English DT Meeting Abstract C1 [Hobday, Timothy; Qin, Rui; Erlichman, Charles] Mayo Clin Coll Med, Rochester, MN USA. [Reidy, Diane] Mem Sloan Kettering Canc Ctr MMSK, New York, NY USA. [Moore, Malcolm] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Strosberg, Jonathan] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Kaubisch, Andreas] Montefiore Med Ctr, Bronx, NY 10467 USA. [Shah, Manisha] Ohio State Univ, Columbus, OH 43210 USA. [Kindler, Hedy] Univ Chicago, Chicago, IL 60637 USA. [Lenz, Heinz-Joseph] Univ So Calif, Los Angeles, CA USA. [Chen, Helen] NCI, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2013 VL 42 IS 2 BP 375 EP 376 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 090JL UT WOS:000314975200059 ER PT J AU Mahmoud, AM Sandoval, C Teng, BY Schnermann, JB Martin, KH Mustafa, SJ Mukdadi, OM AF Mahmoud, Ahmed M. Sandoval, Cesar Teng, Bunyen Schnermann, Jurgen B. Martin, Karen H. Mustafa, S. Jamal Mukdadi, Osama M. TI High-resolution vascular tissue characterization in mice using 55 MHz ultrasound hybrid imaging SO ULTRASONICS LA English DT Article DE High resolution ultrasound; Tissue characterization; Atherosclerosis; Signal and image processing ID BACKSCATTER INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC LESIONS; INTEGRATED BACKSCATTER; IN-VIVO; KNOCKOUT MICE; MOUSE; TOMOGRAPHY; ADENOSINE; PLAQUES; IMAGES AB Ultrasound and Duplex ultrasonography in particular are routinely used to diagnose cardiovascular disease (CVD), which is the leading cause of morbidity and mortality worldwide. However, these techniques may not be able to characterize vascular tissue compositional changes due to CVD. This work describes an ultrasound-based hybrid imaging technique that can be used for vascular tissue characterization and the diagnosis of atherosclerosis. Ultrasound radiofrequency (RF) data were acquired and processed in time, frequency, and wavelet domains to extract six parameters including time integrated backscatter (T-IB), time variance (T-var), time entropy (T-E), frequency integrated backscatter (F-IB), wavelet root mean square value (W-rms), and wavelet integrated backscatter (W-IB). Each parameter was used to reconstruct an image co-registered to morphological B-scan. The combined set of hybrid images were used to characterize vascular tissue in vitro and in vivo using three mouse models including control (C57BL/6), and atherosclerotic apolipoprotein E-knockout (APOE-KO) and APOE/A(1) adenosine receptor double knockout (DKO) mice. The technique was tested using high-frequency ultrasound including single-element (center frequency = 55 MHz) and commercial array (center frequency = 40 MHz) systems providing superior spatial resolutions of 24 mu m and 40 mu m, respectively. Atherosclerotic vascular lesions in the APOE-KO mouse exhibited the highest values (contrast) of -10.11 +/- 1.92 dB, -12.13 +/- 2.13 dB, -7.54 +/- 1.45 dB, -5.10 +/- 1.06 dB, -5.25 +/- 0.94 dB, and -10.23 +/- 2.12 dB in T-IB, T-var, T-E, F-IB, W-rms, W-IB hybrid images (n = 10, p < 0.05), respectively. Control segments of normal vascular tissue showed the lowest values of -20.20 +/- 2.71 dB, -22.54 +/- 4.54 dB, -14.94 +/- 2.05 dB, -9.64 +/- 1.34 dB, -10.20 +/- 1.27 dB, and -19.36 +/- 3.24 dB in same hybrid images (n = 6, p < 0.05). Results from both histology and optical images showed good agreement with ultrasound findings within a maximum error of 3.6% in lesion estimation. This study demonstrated the feasibility of a high-resolution hybrid imaging technique to diagnose atherosclerosis and characterize plaque components in mouse. In the future, it can be easily implemented on commercial ultrasound systems and eventually translated into clinics as a screening tool for atherosclerosis and the assessment of vulnerable plaques. (C) 2012 Elsevier B. V. All rights reserved. C1 [Mahmoud, Ahmed M.] Univ Pittsburgh, Inst Heart & Vasc, Ctr Ultrasound Mol Imaging & Therapeut, Pittsburgh, PA 15261 USA. [Mahmoud, Ahmed M.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15261 USA. [Mahmoud, Ahmed M.] Cairo Univ, Dept Biomed Engn, Giza 12613, Egypt. [Sandoval, Cesar; Mukdadi, Osama M.] W Virginia Univ, Dept Mech & Aerosp Engn, Morgantown, WV 26506 USA. [Teng, Bunyen; Martin, Karen H.; Mustafa, S. Jamal; Mukdadi, Osama M.] W Virginia Univ, Ctr Cardiovasc & Resp Sci, Morgantown, WV 26506 USA. [Schnermann, Jurgen B.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Mahmoud, AM (reprint author), Univ Pittsburgh, Inst Heart & Vasc, Ctr Ultrasound Mol Imaging & Therapeut, Pittsburgh, PA 15261 USA. EM Mahmouda@upmc.edu FU Research Funding Development Grant of West Virginia University; NIH [S10 RR026378]; [NIH-DE019561]; [NIH-HL027339]; [HL094447] FX This work was supported by NIH-DE019561 to OMM, in part by NIH-HL027339 and HL094447 to SJM, Research Funding Development Grant of West Virginia University to BT, and NIH Instrumentation grant S10 RR026378 by KHM. Authors would like to thank Ms. Sarah McLaughlin for her help performing the ultrasound in vivo scanning and animal procedures. NR 37 TC 2 Z9 2 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0041-624X EI 1874-9968 J9 ULTRASONICS JI Ultrasonics PD MAR PY 2013 VL 53 IS 3 BP 727 EP 738 DI 10.1016/j.ultras.2012.10.017 PG 12 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 088YD UT WOS:000314872900014 PM 23218908 ER PT J AU Obara, CJ Dowd, KA Ledgerwood, JE Pierson, TC AF Obara, Christopher J. Dowd, Kimberly A. Ledgerwood, Julie E. Pierson, Theodore C. TI Impact of viral attachment factor expression on antibody-mediated neutralization of flaviviruses SO VIROLOGY LA English DT Article DE West Nile virus; Dengue virus; Antibody neutralization; Stoichiometric threshold; Attachment factor ID WEST-NILE-VIRUS; BORNE ENCEPHALITIS-VIRUS; HUMAN DENDRITIC CELLS; PROTEIN DOMAIN-III; DENGUE VIRUS; ENVELOPE PROTEIN; DC-SIGN; STRUCTURAL BASIS; CELLULAR CYTOTOXICITY; DEPENDENT ENHANCEMENT AB Neutralization of flaviviruses requires engagement of the virion by antibodies with a stoichiometry that exceeds a required threshold. Factors that modulate the number of antibodies bound to an individual virion when it contacts target cells impact neutralization potency. However, the contribution of cellular factors to the potency of neutralizing antibodies has not been explored systematically. Here we investigate the relationship between expression level of a viral attachment factor on cells and the neutralizing potency of antibodies. Analysis of the attachment factor DC-SIGNR on cells in neutralization studies failed to identify a correlation between DC-SIGNR expression and antibody-mediated protection. Furthermore, neutralization potency was equivalent on a novel Jurkat cell line induced to express DC-SIGNR at varying levels. Finally, blocking virus-attachment factor interactions had no impact on neutralization activity. Altogether, our studies suggest that cellular attachment factor expression is not a significant contributor to the potency of neutralizing antibodies to flaviviruses. (c) 2012 Elsevier Inc. All rights reserved. C1 [Obara, Christopher J.; Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20852 USA. [Ledgerwood, Julie E.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20852 USA. [Obara, Christopher J.] Georgetown Univ, Dept Microbiol & Immunol, Washington, DC 20057 USA. RP Pierson, TC (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, 33 North Dr,Bldg 33,Room 2E19A-2, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU intramural research program of the National Institute of Allergy and Infectious Diseases; NIH Office of AIDS Research FX We would like to thank Dr. Michael S. Diamond for providing all the antibodies used in this study and for stimulating discussions, and Drs. Barney S. Graham and Heather D. Hickman for critical comments on the manuscript. This study was funded by the intramural research program of the National Institute of Allergy and Infectious Diseases and the NIH Office of AIDS Research. The funding sources had no role in study design; collection, analysis, or interpretation of the data; writing the report; or the decision to publish. NR 61 TC 3 Z9 3 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2013 VL 437 IS 1 BP 20 EP 27 DI 10.1016/j.virol.2012.11.016 PG 8 WC Virology SC Virology GA 089JY UT WOS:000314908000003 PM 23312596 ER PT J AU Gomez-Lopez, N Vega-Sanchez, R Castillo-Castrejon, M Romero, R Cubeiro-Arreola, K Vadillo-Ortega, F AF Gomez-Lopez, Nardhy Vega-Sanchez, Rodrigo Castillo-Castrejon, Marisol Romero, Roberto Cubeiro-Arreola, Karen Vadillo-Ortega, Felipe TI Evidence for a Role for the Adaptive Immune Response in Human Term Parturition SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Review DE Chemokines; choriodecidua; chorion; cytokines; decidua; labor; leukocytes; memory T cells; pregnancy; T cells ID REGULATORY T-CELLS; MATERNAL-FETAL INTERFACE; HUMAN DECIDUAL MACROPHAGES; PRETERM PREMATURE RUPTURE; ACTIVATING-FACTOR ACETYLHYDROLASE; TRIMESTER TROPHOBLAST CELLS; NORMAL HUMAN-PREGNANCY; TOLL-LIKE RECEPTORS; PERIPHERAL-BLOOD; CHRONIC CHORIOAMNIONITIS AB Problem Spontaneous labor at term involves leukocyte recruitment and infiltration into the choriodecidua; yet, characterization of these leukocytes and their immunological mediators is incomplete. The purpose of this study was to characterize the immunophenotype of choriodecidual leukocytes as well as the expression of inflammatory mediators in human spontaneous parturition at term. Method of study Choriodecidual leukocytes were analyzed by FACS, immunohistochemistry, and RT-PCR in three different groups: (i) preterm gestation delivered for medical indications without labor; (ii) term pregnancy without labor; and (iii) term pregnancy after spontaneous labor. Results Two T-cell subsets of memory-like T cells (CD3+CD4+CD45RO+ and CD3+CD4CD8CD45RO+ cells) were identified in the choriodecidua of women who had spontaneous labor. Evidence for an extensive immune signaling network composed of chemokines (CXCL8 and CXCL10), chemokine receptors (CXCR1-3), cytokines (IL-1 and TNF-), cell adhesion molecules, and MMP-9 was identified in these cells during spontaneous labor at term. Conclusions The influx of memory-like T cells in the choriodecidua and the evidence that they are active by producing chemokines and cytokines, and expressing chemokine receptors, cell adhesion molecules, and a matrix-degrading enzyme provides support for the participation of the adaptive immune system in the mechanisms of spontaneous parturition at term. C1 [Gomez-Lopez, Nardhy; Vega-Sanchez, Rodrigo] Inst Nacl Perinatol Isidro Espinosa de los Reyes, Res Direct, Mexico City, DF, Mexico. [Gomez-Lopez, Nardhy; Vega-Sanchez, Rodrigo] Inst Nacl Perinatol Isidro Espinosa de los Reyes, Dept Nutr Res, Mexico City, DF, Mexico. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Gomez-Lopez, Nardhy; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Castillo-Castrejon, Marisol; Vadillo-Ortega, Felipe] Univ Nacl Autonoma Mexico, Fac Med, Unidad Vinculac, Inst Nacl Med Genom, Mexico City 04510, DF, Mexico. [Cubeiro-Arreola, Karen] Inst Politecn Nacl, Escuela Nacl Ciencias Biol, Mexico City, DF, Mexico. RP Vadillo-Ortega, F (reprint author), Univ Nacl Autonoma Mexico, Fac Med, Dept Biochem, Av Univ 3000,Ciudad Univ,Torre Invest 3Er Piso, Mexico City 04510, DF, Mexico. EM nardhy.gomez-lopez@wayne.edu; felipe.vadillo@gmail.com RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU CONACyT-SALUD [7036, 69353]; Molly Towell Perinatal Research Foundation; Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS FX F.V-O was supported by CONACyT-SALUD 7036 and 69353. N.G-L was sponsored by the Molly Towell Perinatal Research Foundation. This work was supported, in part, by the Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS (R.R). NR 195 TC 29 Z9 29 U1 0 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD MAR PY 2013 VL 69 IS 3 BP 212 EP 230 DI 10.1111/aji.12074 PG 19 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 085HI UT WOS:000314605500004 PM 23347265 ER PT J AU Diaz, M AF Diaz, Marilyn TI The role of activation-induced deaminase in Lupus Nephritis SO AUTOIMMUNITY LA English DT Review DE AID; somatic mutation; lupus; glomerulonephritis; antibodies ID CLASS-SWITCH RECOMBINATION; PRIMARY IMMUNODEFICIENCY DISEASES; ANTIBODY-INDEPENDENT ROLE; HYPER-IGM SYNDROME; DNA B-CELLS; MRL/LPR MICE; SOMATIC HYPERMUTATION; IMMUNE-RESPONSE; MURINE LUPUS; AUTOIMMUNE-DISEASE AB High affinity autoreactive IgG antibodies have been implicated in the development of lupus nephritis and other autoimmune disorders. With the discovery of activation-induced deaminase (AID), this question could be finally tested by examining the impact of AID deficiency in autoimmune-prone mice like the MLR/lpr strain. We have recently shown that AID-deficient MRL/lpr mice experienced a complete abrogation of lupus nephritis, and increased survival despite a dramatic increase in autoreactive IgM. Subsequent studies demonstrated that anti-dsDNA IgM is not pathogenic and in fact protects MRL/lpr from glomerulonephritis. AID-deficiency is also associated with decreased antibody-independent B cell-mediated autoimmunity likely through the loss of high affinity receptors through somatic hypermutation. Combined these results directly implicate AID in the development of B cell mediated autoimmunity. However, studies with hyper IgM AID-deficient patients indicate an increase in the incidence of certain autoimmunities. These results, likely the result of the immunodeficiency associated with AID deficiency, suggest caution in therapeutic approaches based in AID inhibition. C1 NIEHS, Somat Hypermutat Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Diaz, M (reprint author), NIEHS, Somat Hypermutat Grp, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM diaz@niehs.nih.gov FU Division of Intramural Research of the NIH, NIEHS [Z01 ES101603] FX The author reports no conflicts of interest. This work was supported by Project Z01 ES101603, from the Division of Intramural Research of the NIH, NIEHS. The author is responsible for the content and writing of this manuscript. NR 50 TC 5 Z9 5 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0891-6934 J9 AUTOIMMUNITY JI Autoimmunity PD MAR PY 2013 VL 46 IS 2 BP 115 EP 120 DI 10.3109/08916934.2012.750303 PG 6 WC Immunology SC Immunology GA 085XL UT WOS:000314647500004 PM 23215788 ER PT J AU Thambisetty, M Beason-Held, LL An, Y Kraut, M Nalls, M Hernandez, DG Singleton, AB Zonderman, AB Ferrucci, L Lovestone, S Resnick, SM AF Thambisetty, Madhav Beason-Held, Lori L. An, Yang Kraut, Michael Nalls, Michael Hernandez, Dena G. Singleton, Andrew B. Zonderman, Alan B. Ferrucci, Luigi Lovestone, Simon Resnick, Susan M. TI Alzheimer Risk Variant CLU and Brain Function During Aging SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alzheimer's disease; cerebral blood flow; clusterin; memory; O-15-water PET; single nucleotide polymorphism ID MILD COGNITIVE IMPAIRMENT; GENOME-WIDE ASSOCIATION; IDENTIFIES VARIANTS; PLASMA CLUSTERIN; GENETIC RISK; OLDER-ADULTS; DISEASE; APOE; GENOTYPE; PICALM AB Background: We examined the effect of the novel Alzheimer's disease (AD) risk variant rs11136000 single nucleotide polymorphism in the clusterin gene (CLU) on longitudinal changes in resting state regional cerebral blood flow (rCBF) during normal aging and investigated its influence on cognitive decline in presymptomatic stages of disease progression. Methods: Subjects were participants in the Baltimore Longitudinal Study of Aging. A subset of 88 cognitively normal older individuals had longitudinal O-15-water positron emission tomography measurements of rCBF at baseline and up to eight annual follow-up visits. We also analyzed trajectories of cognitive decline among CLU risk carriers and noncarriers in individuals who remained cognitively normal (n = 599), as well as in those who subsequently converted to mild cognitive impairment or AD (n = 95). Results: Cognitively normal carriers of the CLU risk allele showed significant and dose-dependent longitudinal increases in resting state rCBF in brain regions intrinsic to memory processes. There were no differences in trajectories of memory performance between CLU risk carriers and noncarriers who remained cognitively normal. However, in cognitively normal individuals who eventually converted to mild cognitive impairment or AD, CLU risk carriers showed faster rates of decline in memory performance relative to noncarriers in the presymptomatic stages of disease progression. Conclusions: The AD risk variant CLU influences longitudinal changes in brain function in asymptomatic individuals and is associated with faster cognitive decline in presymptomatic stages of disease progression. These results suggest mechanisms underlying the role of CLU in AD and may be important in monitoring disease progression in at-risk elderly. C1 [Thambisetty, Madhav; Beason-Held, Lori L.; An, Yang; Zonderman, Alan B.; Resnick, Susan M.] NIA, NIH, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Kraut, Michael] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Nalls, Michael; Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Lovestone, Simon] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. RP Thambisetty, M (reprint author), NIA, NIH, Lab Behav Neurosci, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov RI Singleton, Andrew/C-3010-2009; OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, National Institutes of Health [N01-AG-3-2124]; MedStar Research Institute; Johnson Johnson; GlaxoSmithKline; Proteome Sciences; Merck Millipore FX This work was supported, in part, by research and development contract N01-AG-3-2124 from the Intramural Research Program, National Institute on Aging, National Institutes of Health and by a research and development contract with MedStar Research Institute.; Dr. Thambisetty is named as an inventor on a patent application filed by his previous employer, Kings College London (KCL), on biomarkers for Alzheimer's disease. Dr. Lovestone is an inventor on patents held by KCL for biomarkers of Alzheimer's disease. He is a research collaborator on studies funded by Johnson & Johnson, GlaxoSmithKline, Proteome Sciences, and Merck Millipore. He is a member of the Lundbeck Neurocience speaker panel. He does not report any personal financial rewards from the above entities. The other authors report no biomedical financial interests or potential conflicts of interest. NR 32 TC 30 Z9 31 U1 0 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2013 VL 73 IS 5 BP 399 EP 405 DI 10.1016/j.biopsych.2012.05.026 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 085SP UT WOS:000314634900004 PM 22795969 ER PT J AU Thambisetty, M An, Y Nalls, M Sojkova, J Swaminathan, S Zhou, Y Singleton, AB Wong, DF Ferrucci, L Saykin, AJ Resnick, SM AF Thambisetty, Madhav An, Yang Nalls, Michael Sojkova, Jitka Swaminathan, Shanker Zhou, Yun Singleton, Andrew B. Wong, Dean F. Ferrucci, Luigi Saykin, Andrew J. Resnick, Susan M. CA Baltimore Longitudinal Study Aging Alzheimer's Dis Neuroimaging TI Effect of Complement CR1 on Brain Amyloid Burden During Aging and Its Modification by APOE Genotype SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alzheimer's disease; amyloid; APOE; CR1; single nucleotide polymorphism; C-11-PiB PET ID GENOME-WIDE ASSOCIATION; PITTSBURGH COMPOUND-B; ALZHEIMERS-DISEASE; IDENTIFIES VARIANTS; A-BETA; CLU; PICALM; CORE; RISK; INDIVIDUALS AB Background: The rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in nondemented older individuals. Methods: We used C-11-Pittsburgh Compound-B positron emission tomography to quantify brain amyloid burden in 57 nondemented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed C-11-Pittsburgh Compound-B positron emission tomography data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset. Results: Risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE epsilon 4 individuals showed significantly higher brain amyloid burden relative to APOE epsilon 4 noncarriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample. Conclusions: Our findings suggest complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain A beta in nondemented individuals at risk for AD and suggest that clinical outcomes of such treatments might be influenced by complex gene-gene interactions. C1 [Thambisetty, Madhav; An, Yang; Sojkova, Jitka; Resnick, Susan M.] NIA, Lab Behav Neurosci, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Sojkova, Jitka; Zhou, Yun; Wong, Dean F.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Nalls, Michael; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Swaminathan, Shanker; Saykin, Andrew J.] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Ctr Neuroimaging, Indianapolis, IN USA. RP Thambisetty, M (reprint author), NIA, NIH, Room 4B-317,BRC Bldg,251 Bayview Blvd, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov RI Saykin, Andrew/A-1318-2007; Singleton, Andrew/C-3010-2009 OI Saykin, Andrew/0000-0002-1376-8532; FU National Institute on Aging, National Institutes of Health [N01-AG-3-2124]; National Institutes of Health [NIH] [U01 AG024904, RC2AG036535]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences; AstraZeneca; Bayer HealthCare; BioClinica; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; F. Hoffmann-La Roche; Genentech; GE Healthcare; Innogenetics, N.V.; IXICO; Janssen Alzheimer Immunotherapy Research and Development; Johnson and Johnson Pharmaceutical Research and Development; Medpace; Merck and Company; Meso Scale Diagnostics; Novartis Pharmaceuticals Corporation; Pfizer; Servier; Synarc; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; NIH [P30AG010129, K01AG030514] FX This work was supported in part by research and development contract N01-AG-3-2124 from the Intramural Research Program, National Institute on Aging, National Institutes of Health. The replication analysis in this report was based on data from the ADNI study (National Institutes of Health [NIH] Grant U01 AG024904; RC2AG036535). The ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences; AstraZeneca; Bayer HealthCare; BioClinica; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; F. Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics, N.V.; IXICO; Janssen Alzheimer Immunotherapy Research and Development; Johnson and Johnson Pharmaceutical Research and Development; Medpace; Merck and Company; Meso Scale Diagnostics; Novartis Pharmaceuticals Corporation; Pfizer; Servier; Synarc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH Grants P30AG010129 and K01AG030514. NR 36 TC 26 Z9 26 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2013 VL 73 IS 5 BP 422 EP 428 DI 10.1016/j.biopsych.2012.08.015 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 085SP UT WOS:000314634900007 PM 23022416 ER PT J AU Kochunov, P Glahn, DC Rowland, LM Olvera, RL Winkler, A Yang, YH Sampath, H Carpenter, WT Duggirala, R Curran, J Blangero, J Hong, LE AF Kochunov, Peter Glahn, David C. Rowland, Laura M. Olvera, Rene L. Winkler, Anderson Yang, Yi-Hong Sampath, Hemalatha Carpenter, Will T. Duggirala, Ravindranath Curran, Joanne Blangero, John Hong, L. Elliot TI Testing the Hypothesis of Accelerated Cerebral White Matter Aging in Schizophrenia and Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Accelerated aging; brain integrity; diffusion tensor imaging; fractional anisotropy; major depressive disorder; schizophrenia; white matter aging ID NONAFFECTIVE PSYCHOSIS; CARDIOVASCULAR-DISEASE; FRACTIONAL ANISOTROPY; SPATIAL STATISTICS; CIGARETTE-SMOKING; PREFRONTAL CORTEX; EXCESS MORTALITY; MOOD DISORDERS; DIFFUSION; BRAIN AB Background: Elevated rate of aging-related biological and functional decline, termed "accelerated aging," is reported in patients with schizophrenia (SCZ) and major depressive disorder (MDD). We used diffusion tensor imaging derived fractional anisotropy (FA) as a biomarker of aging-related decline in white matter (WM) integrity to test the hypotheses of accelerated aging in SCZ and MDD. Methods: The SCZ cohort comprised 58 SCZ patients and 60 controls (aged 20-60 years). The MDD cohort comprised 136 MDD patients and 351 controls (aged 20-79 years). The main outcome measures were the diagnosis-by-age interaction on whole-brain-averaged WM FA values and FA values from 12 major WM tracts. Results: Diagnosis-by-age interaction for the whole-brain average FA was significant for the SCZ (p=.04) but not the MDD (p=.80) cohort. Diagnosis-by-age interaction was nominally significant (p<.05) for five WM tracts for SCZ and for none of the tracts in the MDD cohort. Tract-specific heterochronicity of the onset of age-related decline in SCZ demonstrated strong negative correlations with the age-of-peak myelination and the rates of age-related decline obtained from normative sample (r = -.61 and -.80, p<.05, respectively). No such trends existed for MDD cohort. Conclusions: Cerebral WM showed accelerated aging in SCZ but not in MDD, suggesting some difference in the pathophysiology underlying their WM aging changes. Tract-specific heterochronicity of WM development modulated presentation of accelerated aging in SCZ: WM tracts that matured later in life appeared more sensitive to the pathophysiology of SCZ and demonstrated more susceptibility to disorder-related accelerated decline in FA values with age. This trend was not observed in MDD cohort. C1 [Kochunov, Peter; Rowland, Laura M.; Sampath, Hemalatha; Carpenter, Will T.; Hong, L. Elliot] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Kochunov, Peter; Glahn, David C.; Duggirala, Ravindranath; Curran, Joanne; Blangero, John] SW Fdn Biomed Res, San Antonio, TX 78284 USA. [Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. Olin Neuropsychiat Res Ctr, New Haven, CT USA. [Glahn, David C.; Winkler, Anderson] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Olvera, Rene L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Yang, Yi-Hong] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. RP Kochunov, P (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. EM pkochunov@mprc.umaryland.edu RI Winkler, Anderson/P-7773-2016 OI Winkler, Anderson/0000-0002-4169-9781 FU National Institute of Health [K01EB006395, R01EB015611, R37MH059490, R01MH078111, R01MH0708143, R01MH083824, R01DA027680, R01MH085646]; National Institute on Drug Abuse Intramural Research Program FX This research was supported by National Institute of Health Grant Nos. K01EB006395 and R01EB015611 to PK, R37MH059490 and R01MH078111 to JB, R01MH0708143 and R01MH083824 to DG, and R01DA027680 and R01MH085646 to LEH and by the National Institute on Drug Abuse Intramural Research Program. NR 60 TC 31 Z9 31 U1 1 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2013 VL 73 IS 5 BP 482 EP 491 DI 10.1016/j.biopsych.2012.10.002 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 085SP UT WOS:000314634900014 PM 23200529 ER PT J AU Mak, M Hallett, M AF Mak, Margaret Hallett, Mark TI Effect of cued training on motor evoked potential and cortical silent period in people with Parkinson's disease SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Parkinson's disease; Primary motor cortex; Motor evoked potential; Silent period; Visual cue ID TRANSCRANIAL MAGNETIC STIMULATION; SIT-TO-STAND; INTRACORTICAL INHIBITION; CORTICOCORTICAL INHIBITION; CORTEX EXCITABILITY; TMS; MECHANISMS; MOVEMENT; GAIT; FACILITATION AB Objective: To examine whether training under visual cues could enhance motor cortical excitability and intracortical inhibition in individuals with Parkinson's disease (PD). Methods: This was a single blinded cross-over study. Eight individuals with PD received two sessions of 30-min pinch-grip training with and without visual cues. The visual cue was given in form of an arrow that indicated the pre-set force level on a computer screen. Outcome measures consisted of peak motor evoked potential (MEP) and cortical silent period (CSP) of the first dorsal interosseus as well as behavioural tests including Purdue pegboard test, tapping speed in 30 s, and the maximum pinch grip force exerted by the thumb and index finger. Results: After cued training, there were significant increases in the peak MEP, CSP duration and tapping speed (all p < 0.05). In contrast, there was no change in all outcome measures after training under the non-cued condition. Conclusions: Thirty minutes of pinch-grip training with visual cues could enhance motor cortical excitability and intracortical inhibition in individuals with PD. Significance: The findings on the neurophysiological changes after cued-training may inform further clinical application of visual cues to maximize motor improvement and corticomotor plasticity in people with PD. (C) 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Mak, Margaret] Hong Kong Polytech Univ, Dept Rehabil Sci, Hong Kong, Hong Kong, Peoples R China. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Mak, M (reprint author), Hong Kong Polytech Univ, Dept Rehabil Sci, Hong Kong, Hong Kong, Peoples R China. EM rsmmak@inet.polyu.edu.hk FU Internal Competitive Research Grants, Hong Kong Polytechnic University [ZH61] FX The study was supported by the Internal Competitive Research Grants #ZH61, The Hong Kong Polytechnic University. NR 52 TC 4 Z9 4 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD MAR PY 2013 VL 124 IS 3 BP 545 EP 550 DI 10.1016/j.clinph.2012.08.017 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 086DN UT WOS:000314663700017 PM 23010693 ER PT J AU Ward, RE Boudreau, RM Vinik, AI Zivkovic, SA Njajou, OT Satterfield, S Harris, TB Newman, AB Strotmeyer, ES AF Ward, Rachel E. Boudreau, Robert M. Vinik, Aaron I. Zivkovic, Sasa A. Njajou, Omer T. Satterfield, Suzanne Harris, Tamara B. Newman, Anne B. Strotmeyer, Elsa S. TI Reproducibility of peroneal motor nerve conduction measurement in older adults SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Motor nerve conduction; Aging; Peripheral nerve function; Reproducibility; Diabetes ID DIABETIC PERIPHERAL NEUROPATHY; BODY-COMPOSITION; SENSORY FUNCTION; BLACK ADULTS; AGE; HEALTH; POPULATION; MELLITUS; FALLS; POLYNEUROPATHY AB Objective: While neuropathy is common in the elderly, nerve conduction (NC) reproducibility in older adults is not well-established. We sought to evaluate intraobserver reproducibility of peroneal motor NC measures in a diverse sample of older adults. Methods: We measured peroneal motor NC amplitude and velocity in a subset of participants (mean age = 82.9 +/- 2.7, n = 62, 50% female, 51.6% black, 35.5% DM) in the Health, Aging, and Body Composition Study. Using coefficients of variation (CVs), intraclass correlation coefficients (ICCs), and Bland Altman Plots, we compared two sets of measurements taken by the same examiner hours apart on the same day. Results: Low CVs (2.15-4.24%) and moderate to high ICCs (0.75-0.99) were observed. No systematic variation was found across measures. Despite small numbers in some subgroups, we found no differences in reproducibility by diabetes, race or study site. Conclusion: NC measures have moderate to high intraobsever reproducibility in older adults and are not affected by diabetes, race, or gender. Significance: These data provide evidence to support use of these measures in aging research. (C) 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland All rights reserved. C1 [Ward, Rachel E.; Boudreau, Robert M.; Newman, Anne B.; Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Vinik, Aaron I.] Eastern Virginia Med Sch, Dept Neurobiol, Norfolk, VA 23501 USA. [Zivkovic, Sasa A.] VA Pittsburgh HCS, Pittsburgh, PA USA. [Zivkovic, Sasa A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Njajou, Omer T.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, Lab Epidemiol Demog & Biometry, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP Strotmeyer, ES (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 N Bellefield Ave,Rm 515, Pittsburgh, PA 15213 USA. EM StrotmeyerE@edc.pitt.edu RI Strotmeyer, Elsa/F-3015-2014; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Strotmeyer, Elsa/0000-0002-4093-6036; Boudreau, Robert/0000-0003-0162-5187 FU Intramural Research Program of the NIH, National Institute on Aging; Ward RE, NIA Aging Training Grant [T32-AG-000181]; Strotmeyer ES, NIH/NIA [R01-AG 028050-01]; Health ABC, NIH/NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; Ward RE, K. Leroy Irvis Fellowship; University of Pittsburgh; University of Pittsburgh Claude D. Pepper Center Older Americans Independence Center [P30-AG024827] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging; Ward RE, NIA Aging Training Grant: T32-AG-000181; Strotmeyer ES, NIH/NIA R01-AG 028050-01; Health ABC, NIH/NIA N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; Ward RE, K. Leroy Irvis Fellowship, University of Pittsburgh; University of Pittsburgh Claude D. Pepper Center Older Americans Independence Center, P30-AG024827. We would like to acknowledge Chris Taylor, PhD and Mei Yang, MS for their work in data management, Amy Schorr for data collection (CT, MY and AS from the Department of Epidemiology, University of Pittsburgh), and Health ABC participants, staff and investigators. NR 42 TC 6 Z9 6 U1 0 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD MAR PY 2013 VL 124 IS 3 BP 603 EP 609 DI 10.1016/j.clinph.2012.07.027 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 086DN UT WOS:000314663700025 PM 23022036 ER PT J AU Forsberg, JA Sjoberg, D Chen, QR Vickers, A Healey, JH AF Forsberg, Jonathan Agner Sjoberg, Daniel Chen, Qing-Rong Vickers, Andrew Healey, John H. TI Treating Metastatic Disease: Which Survival Model Is Best Suited for the Clinic? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID CANCER-PATIENTS; PREDICTION; PROGNOSIS; SURGERY; CURVE; CARE AB To avoid complications associated with under- or overtreatment of patients with skeletal metastases, doctors need accurate survival estimates. Unfortunately, prognostic models for patients with skeletal metastases of the extremities are lacking, and physician-based estimates are generally inaccurate. We developed three types of prognostic models and compared them using calibration plots, receiver operating characteristic (ROC) curves, and decision curve analysis to determine which one is best suited for clinical use. A training set consisted of 189 patients who underwent surgery for skeletal metastases. We created models designed to predict 3- and 12-month survival using three methods: an Artificial Neural Network (ANN), a Bayesian Belief Network (BBN), and logistic regression. We then performed crossvalidation and compared the models in three ways: calibration plots plotting predicted against actual risk; area under the ROC curve (AUC) to discriminate the probability that a patient who died has a higher predicted probability of death compared to a patient who did not die; and decision curve analysis to quantify the clinical consequences of over- or undertreatment. All models appeared to be well calibrated, with the exception of the BBN, which underestimated 3-month survival at lower probability estimates. The ANN models had the highest discrimination, with an AUC of 0.89 and 0.93, respectively, for the 3- and 12-month models. Decision analysis revealed all models could be used clinically, but the ANN models consistently resulted in the highest net benefit, outperforming the BBN and logistic regression models. Our observations suggest use of the ANN model to aid decisions about surgery would lead to better patient outcomes than other alternative approaches to decision making. Level II, prognostic study. See Instructions for Authors for a complete description of levels of evidence. C1 [Forsberg, Jonathan Agner] USN, Med Res Ctr, Silver Spring, MD 20910 USA. [Forsberg, Jonathan Agner] Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Sect Orthopaed & Sports Med, Stockholm, Sweden. [Sjoberg, Daniel; Vickers, Andrew] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Chen, Qing-Rong] NCI, Ctr Bioinformat & Informat Technol, Rockville, MD USA. [Healey, John H.] Cornell Univ, Mem Sloan Kettering Canc Ctr, Dept Surg, Orthopaed Surg Serv, New York, NY 10021 USA. [Healey, John H.] Cornell Univ, Weill Coll Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Forsberg, JA (reprint author), USN, Med Res Ctr, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM jaforsberg@me.com OI Vickers, Andrew/0000-0003-1525-6503 FU NCI NIH HHS [P30 CA008748] NR 23 TC 8 Z9 8 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD MAR PY 2013 VL 471 IS 3 BP 843 EP 850 DI 10.1007/s11999-012-2577-z PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 084EC UT WOS:000314518500021 PM 22983682 ER PT J AU Tennant, BR Robertson, AG Kramer, M Li, L Zhang, X Beach, M Thiessen, N Chiu, R Mungall, K Whiting, CJ Sabatini, PV Kim, A Gottardo, R Marra, MA Lynn, FC Jones, SJM Hoodless, PA Hoffman, BG AF Tennant, B. R. Robertson, A. G. Kramer, M. Li, L. Zhang, X. Beach, M. Thiessen, N. Chiu, R. Mungall, K. Whiting, C. J. Sabatini, P. V. Kim, A. Gottardo, R. Marra, M. A. Lynn, F. C. Jones, S. J. M. Hoodless, P. A. Hoffman, B. G. TI Identification and analysis of murine pancreatic islet enhancers SO DIABETOLOGIA LA English DT Article DE ChIP-seq; Enhancer; H3K4me1; lncRNA; Pancreas; Transcription factor ID TRANSCRIPTION FACTOR-BINDING; EPIGENOMIC ANALYSIS; GENE-EXPRESSION; NONCODING RNAS; BETA-CELLS; MOUSE; GENOME; LIVER; SEQ; CHROMATIN AB The paucity of information on the epigenetic barriers that are blocking reprogramming protocols, and on what makes a beta cell unique, has hampered efforts to develop novel beta cell sources. Here, we aimed to identify enhancers in pancreatic islets, to understand their developmental ontologies, and to identify enhancers unique to islets to increase our understanding of islet-specific gene expression. We combined H3K4me1-based nucleosome predictions with pancreatic and duodenal homeobox 1 (PDX1), neurogenic differentiation 1 (NEUROD1), v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MAFA) and forkhead box A2 (FOXA2) occupancy data to identify enhancers in mouse islets. We identified 22,223 putative enhancer loci in in vivo mouse islets. Our validation experiments suggest that nearly half of these loci are active in regulating islet gene expression, with the remaining regions probably poised for activity. We showed that these loci have at least nine developmental ontologies, and that islet enhancers predominately acquire H3K4me1 during differentiation. We next discriminated 1,799 enhancers unique to islets and showed that these islet-specific enhancers have reduced association with annotated genes, and identified a subset that are instead associated with novel islet-specific long non-coding RNAs (lncRNAs). Our results indicate that genes with islet-specific expression and function tend to have enhancers devoid of histone methylation marks or, less often, that are bivalent or repressed, in embryonic stem cells and liver. Further, we identify a subset of enhancers unique to islets that are associated with novel islet-specific genes and lncRNAs. We anticipate that these data will facilitate the development of novel sources of functional beta cell mass. C1 [Tennant, B. R.; Kramer, M.; Beach, M.; Whiting, C. J.; Sabatini, P. V.; Kim, A.; Lynn, F. C.; Hoffman, B. G.] British Columbia Childrens Hosp, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada. [Tennant, B. R.; Kramer, M.; Beach, M.; Whiting, C. J.; Sabatini, P. V.; Kim, A.; Lynn, F. C.; Hoffman, B. G.] Sunny Hill Hlth Ctr, Vancouver, BC V5Z 4H4, Canada. [Robertson, A. G.; Thiessen, N.; Chiu, R.; Mungall, K.; Marra, M. A.; Jones, S. J. M.] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Li, L.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Zhang, X.] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1W5, Canada. [Gottardo, R.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Marra, M. A.; Jones, S. J. M.; Hoodless, P. A.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Lynn, F. C.; Hoffman, B. G.] Univ British Columbia, Dept Surg, Vancouver, BC V6T 1W5, Canada. [Jones, S. J. M.] Simon Fraser Univ, Dept Mol Biol & Biochem, Vancouver, BC, Canada. [Hoodless, P. A.] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. RP Hoffman, BG (reprint author), British Columbia Childrens Hosp, Child & Family Res Inst, Room A4-185,950 W28th Ave, Vancouver, BC V5Z 4H4, Canada. EM brad.hoffman@ubc.ca RI Tang, Macy/B-9798-2014; zhang, xuekui/C-5105-2015; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; OI Hoodless, Pamela/0000-0003-1371-0725 FU NIH, National Institute of Environmental Health Sciences [Z01-ES-101765]; NIH [HG005692]; NSERC-CGS fellowship; Canadian Institutes for Health Research [MOP-102628, RMF-111626, MOP-111010]; Juvenile Diabetes Research Foundation [2-2011-91, 5-2011-85]; Genome Canada; Genome British Columbia; Child and Family Research Institute; Common Wealth Insurance; Canucks for Kids Foundation FX M.A. Marra, P.A. Hoodless and S.J.M. Jones are Senior Scholars of the Michael Smith Foundation for Health Research. L. Li was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-101765). R. Gottardo was supported by NIH grant HG005692. X. Zhang was supported by an NSERC-CGS fellowship. F.C. Lynn was supported by the Canadian Institutes for Health Research (MOP-102628 and RMF-111626) and the Juvenile Diabetes Research Foundation (2-2011-91). Funding was provided by Genome Canada, Genome British Columbia, the Child and Family Research Institute, the Juvenile Diabetes Research Foundation (5-2011-85), Common Wealth Insurance, the Canadian Institutes for Health Research (MOP-111010), and the Canucks for Kids Foundation, with infrastructure support provided by the British Columbia Cancer Foundation. NR 43 TC 16 Z9 16 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2013 VL 56 IS 3 BP 542 EP 552 DI 10.1007/s00125-012-2797-5 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 084IH UT WOS:000314531700013 PM 23238790 ER PT J AU Lee-Young, RS Bonner, JS Mayes, WH Iwueke, I Barrick, BA Hasenour, CM Kang, L Wasserman, DH AF Lee-Young, R. S. Bonner, J. S. Mayes, W. H. Iwueke, I. Barrick, B. A. Hasenour, C. M. Kang, L. Wasserman, D. H. TI AMP-activated protein kinase (AMPK)alpha 2 plays a role in determining the cellular fate of glucose in insulin-resistant mouse skeletal muscle SO DIABETOLOGIA LA English DT Article DE AICAR; Glucose metabolism; Glycogen synthesis; Skeletal muscle ID NITRIC-OXIDE SYNTHASE; TYPE-2 DIABETIC-PATIENTS; EXERCISE IN-VIVO; GLYCOGEN-SYNTHASE; DOSE-RESPONSE; RATS; METABOLISM; INFUSION; MICE; METFORMIN AB We determined whether: (1) an acute lipid infusion impairs skeletal muscle AMP-activated protein kinase (AMPK)alpha 2 activity, increases inducible nitric oxide synthase (iNOS) and causes peripheral insulin resistance in conscious, unstressed, lean mice; and (2) restoration of AMPK alpha 2 activity during the lipid infusion attenuates the increase in iNOS and reverses the defect in insulin sensitivity in vivo. Chow-fed, 18-week-old C57BL/6J male mice were surgically catheterised. After 5 days they received: (1) a 5 h infusion of 5 ml kg(-1) h(-1) Intralipid + 6 U/h heparin (Lipid treatment) or saline (Control); (2) Lipid treatment or Control, followed by a 2 h hyperinsulinaemic-euglycaemic clamp (insulin clamp; 4 mU kg(-1) min(-1)); and (3) infusion of the AMPK activator, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR) (1 mg kg(-1) min(-1)), or saline during Lipid treatment, followed by a 2 h insulin clamp. In a separate protocol, mice producing a muscle-specific kinase-dead AMPK alpha 2 subunit (alpha 2-KD) underwent an insulin clamp to determine the role of AMPK alpha 2 in insulin-mediated muscle glucose metabolism. Lipid treatment decreased AMPK alpha 2 activity, increased iNOS abundance/activation and reduced whole-body insulin sensitivity in vivo. AICAR increased AMPK alpha 2 activity twofold; this did not suppress iNOS or improve whole-body or tissue-specific rates of glucose uptake during Lipid treatment. AICAR caused a marked increase in insulin-mediated glycogen synthesis in skeletal muscle. Consistent with this latter result, lean alpha 2-KD mice exhibited impaired insulin-stimulated glycogen synthesis even though muscle glucose uptake was not affected. Acute induction of insulin resistance via lipid infusion in healthy mice impairs AMPK alpha 2, increases iNOS and causes insulin resistance in vivo. However, these changes do not appear to be interrelated. Rather, a functionally active AMPK alpha 2 subunit is required for insulin-stimulated muscle glycogen synthesis. C1 [Lee-Young, R. S.] Baker IDI Heart & Diabet Inst, Div Metab & Obes, Cellular & Mol Metab Lab, Melbourne, Vic 3004, Australia. [Lee-Young, R. S.; Bonner, J. S.; Mayes, W. H.; Iwueke, I.; Barrick, B. A.; Hasenour, C. M.; Kang, L.; Wasserman, D. H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. [Lee-Young, R. S.; Wasserman, D. H.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. RP Lee-Young, RS (reprint author), Baker IDI Heart & Diabet Inst, Div Metab & Obes, Cellular & Mol Metab Lab, 75 Commercial Rd, Melbourne, Vic 3004, Australia. EM robert.lee-young@bakeridi.edu.au FU National Institutes of Health [DK054902, DK059637]; American Diabetes Association FX This work was supported by National Institutes of Health Grants DK054902 and DK059637 (to D.H. Wasserman). R.S. Lee-Young was supported by a mentor-based fellowship from the American Diabetes Association. NR 49 TC 10 Z9 11 U1 2 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2013 VL 56 IS 3 BP 608 EP 617 DI 10.1007/s00125-012-2787-7 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 084IH UT WOS:000314531700020 PM 23224579 ER PT J AU Yauk, CL Bishop, J Dearfield, KL Douglas, GR Hales, BF Luijten, M O'Brien, JM Robaire, B Sram, R van Benthem, J Wade, MG White, PA Marchetti, F AF Yauk, Carole L. Bishop, Jack Dearfield, Kerry L. Douglas, George R. Hales, Barbara F. Luijten, Mirjam O'Brien, Jason M. Robaire, Bernard Sram, Radim van Benthem, Jan Wade, Mike G. White, Paul A. Marchetti, Francesco TI The development of adverse outcome pathways for mutagenic effects for the organization for economic co-operation and development SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Editorial Material DE germ cells; mutagenesis; genotoxicity testing ID GERM-CELL MUTAGENS; CHALLENGES; GUIDELINES; REACH C1 [Yauk, Carole L.; Douglas, George R.; O'Brien, Jason M.; Wade, Mike G.; White, Paul A.; Marchetti, Francesco] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. [Bishop, Jack] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Dearfield, Kerry L.] US Food Safety & Inspect Serv, USDA, Washington, DC 20250 USA. [Hales, Barbara F.; Robaire, Bernard] McGill Univ, Dept Obstet & Gynecol, Dept Pharmacol & Therapeut, Montreal, PQ H3A 2T5, Canada. [Luijten, Mirjam; van Benthem, Jan] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Sram, Radim] Acad Sci Czech Republic, Inst Expt Med, Prague, Czech Republic. RP Yauk, CL (reprint author), Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. EM carole.yauk@hc-sc.gc.ca RI Sram, Radim/H-2455-2014; OI Sram, Radim/0000-0003-4256-3816; Marchetti, Francesco/0000-0002-9435-4867; Wade, Michael/0000-0002-7331-3839; Yauk, Carole/0000-0003-4919-876X; white, paul/0000-0001-5853-4759 NR 14 TC 4 Z9 4 U1 0 U2 14 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 MAR PY 2013 VL 54 IS 2 BP 79 EP 81 DI 10.1002/em.21757 PG 3 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 085EB UT WOS:000314595400001 PM 23355186 ER PT J AU Fei, CY DeRoo, LA Sandler, DP Weinberg, CR AF Fei, Chunyuan DeRoo, Lisa A. Sandler, Dale P. Weinberg, Clarice R. TI Menopausal symptoms and the risk of young-onset breast cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Breast cancer; Case-control; Menopausal symptoms; Young-onset cancer ID HORMONE-LEVELS; MIDLIFE WOMEN; POLYMORPHISMS; TRANSITION AB Background: Women with menopausal symptoms have been reported to have reduced risk of breast cancer, possibly reflecting differences in endogenous hormone levels. We examined the associations between menopausal symptoms and breast cancer in women under age 50. Methods: We carried out a sister-controlled case-control study, the Two Sister Study, comparing 1422 women with breast cancer diagnosed before age 50 and their 1669 sisters who were free of breast cancer and had enrolled in the prospective Sister Study cohort. History and age at first occurrence of menopause-associated symptoms (e.g. hot flashes, poor sleep or night sweats) were ascertained using computer-assisted telephone interviews. To equalise opportunity for exposure, we assessed exposures in relation to a sibship-based index age (the minimum of the age at diagnosis of the case sister and the age at interview of her control sister(s)), and estimated odds ratios using conditional logistic regression with adjustment for menopausal status and birth order. Findings: Having had menopause-associated symptoms (n = 706) prior to the index age was associated with reduced risk of young-onset breast cancer (odds ratio (OR), 0.49; 95% confidence interval (CI), 0.40-0.61). Similar results were seen for hot flashes and for "other" menopausal symptoms. The association between menopausal symptoms and breast cancer risk was somewhat stronger for oestrogen receptor positive tumours than for oestrogen receptor negative tumours (heterogeneity p = 0.07). Menopausal status, age at menopause, BMI and hormone replacement therapy did not modify the associations, but the inverse association between menopausal symptoms and breast cancer attenuated with increasing index age (p < 0.01). Interpretation: Menopause-associated symptoms were associated with markedly reduced risk of young-onset breast cancer. Further studies are needed to confirm the association and elucidate possible pathways. Published by Elsevier Ltd. C1 [Fei, Chunyuan; Weinberg, Clarice R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [DeRoo, Lisa A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, POB 12233,Mail Drop A3-03, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) [Z01-ES044005, Z01-ES102245]; Susan G. Komen for the Cure [FAS0703856] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) (project numbers Z01-ES044005 [C.R.W.] and Z01-ES102245 [D.P.S.]), with additional funding from Susan G. Komen for the Cure (Grant number FAS0703856 to C.R.W.). We thank Dr. Donna Baird and Dr. Hazel B. Nichols of NIEHS for helpful comments on the paper and Jean Keller of Westat for assistance with analysis. NR 11 TC 4 Z9 4 U1 0 U2 8 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 MAR PY 2013 VL 49 IS 4 BP 798 EP 804 DI 10.1016/j.ejca.2012.08.030 PG 7 WC Oncology SC Oncology GA 088QB UT WOS:000314849300005 PM 23021929 ER PT J AU Nagababu, E Mohanty, JG Friedman, JS Rifkind, JM AF Nagababu, E. Mohanty, J. G. Friedman, J. S. Rifkind, J. M. TI Role of peroxiredoxin-2 in protecting RBCs from hydrogen peroxide-induced oxidative stress SO FREE RADICAL RESEARCH LA English DT Article DE red blood cells; Peroxiredoxin-2; superoxide dismutase; hydrogen peroxide; heme degradation; deformability; oxidative stress ID RED-BLOOD-CELLS; HEME DEGRADATION-PRODUCTS; GLUTATHIONE-PEROXIDASE; HUMAN ERYTHROCYTES; SUPEROXIDE; HEMOGLOBIN; MEMBRANE; AUTOXIDATION; DEFICIENCY; CATALASE AB The role of peroxiredoxin-2 (PRDX2) in preventing hydrogen peroxide-induced oxidative stress in the red blood cell was investigated by comparing blood from PRDX2 knockout mice with superoxide dismutase-1 (SOD1) knockout and control mice. Loss of PRDX2 increased basal levels of methemoglobin and heme degradation (a marker for oxidative stress), and reduced red blood cell deformability. In vitro incubation under normoxic conditions, both with and without inhibition of catalase, resulted in a lag phase during which negligible heme degradation occurred followed by a more rapid rate of heme degradation in the absence of PRDX2. The appreciable basal increase in heme degradation for PRDX2 knockout mice, together with the lag during in vitro incubation, implies that PRDX2 neutralizes hydrogen peroxide generated in vivo under the transient hypoxic conditions experienced as the cells pass through the microcirculation. C1 [Nagababu, E.; Mohanty, J. G.; Rifkind, J. M.] NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. [Friedman, J. S.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, Rm 5B129,251 Bayview Blvd, Baltimore, MD 21224 USA. EM rifkindj@mail.nih.gov FU intramural research program of National Institutes on Aging, National Institute of Health; NIH [R21 DK075763]; US Army [W81XWH-10-2-0059] FX This research was supported by intramural research program of National Institutes on Aging, National Institute of Health and to JS Friedman-NIH grant R21 DK075763 and US Army grant W81XWH-10-2-0059. NR 52 TC 13 Z9 13 U1 1 U2 18 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1071-5762 J9 FREE RADICAL RES JI Free Radic. Res. PD MAR PY 2013 VL 47 IS 3 BP 164 EP 171 DI 10.3109/10715762.2012.756138 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 085XV UT WOS:000314648500004 PM 23215741 ER PT J AU Jackson, JM DeFor, TA Crain, AL Kerby, T Strayer, L Lewis, CE Whitlock, E Williams, S Bonds, DE Vitolins, MZ Rodabough, RJ Margolis, KL AF Jackson, Jody M. DeFor, Terese A. Crain, A. Lauren Kerby, Tessa Strayer, Lori Lewis, Cora E. Whitlock, Evelyn Williams, Selvi Bonds, Denise E. Vitolins, Mara Z. Rodabough, Rebecca J. Margolis, Karen L. TI Self-reported diabetes is a valid outcome in pragmatic clinical trials and observational studies SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Letter ID HEALTH; GLUCOSE C1 [Jackson, Jody M.; DeFor, Terese A.; Crain, A. Lauren; Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN 55440 USA. [Kerby, Tessa] HealthPartners, Hlth Improvement & Care Innovat, St Paul, MN USA. [Strayer, Lori] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Whitlock, Evelyn; Williams, Selvi] Kaiser Permanente, Ctr Hlth Res NW, Portland, OR USA. [Bonds, Denise E.] NHLBI, Prevent & Populat Sci Program, Bethesda, MD 20892 USA. [Vitolins, Mara Z.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Rodabough, Rebecca J.] Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat WHI, Cent Coordinating Ctr CCC, Seattle, WA 98104 USA. RP Jackson, JM (reprint author), HealthPartners Res Fdn, POB 1524,MS 21111R, Minneapolis, MN 55440 USA. EM jody.m.jackson@healthpartners.com NR 7 TC 16 Z9 16 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD MAR PY 2013 VL 66 IS 3 BP 349 EP 350 DI 10.1016/j.jclinepi.2012.01.013 PG 2 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 083SV UT WOS:000314486400015 PM 22564498 ER PT J AU Topping, V Romero, R Than, NG Tarca, AL Xu, ZH Kim, SY Wang, B Yeo, L Kim, CJ Hassan, SS Kim, JS AF Topping, Vanessa Romero, Roberto Than, Nandor Gabor Tarca, Adi L. Xu, Zhonghui Kim, Sun Young Wang, Bing Yeo, Lami Kim, Chong Jai Hassan, Sonia S. Kim, Jung-Sun TI Interleukin-33 in the human placenta SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Alarmin; chorioamnionitis; interleukin-1 family; pregnancy; preterm birth; preterm labor ID INFLAMMATORY RESPONSE SYNDROME; TUMOR-NECROSIS-FACTOR; MATERNAL-FETAL INTERFACE; VERSUS-HOST-DISEASE; INDUCED PRETERM PARTURITION; MOLECULAR-PATTERNS DAMPS; IL-1-LIKE CYTOKINE IL-33; HUMAN MYOMETRIAL CELLS; AMNIOTIC-FLUID SLUDGE; TOLL-LIKE RECEPTORS AB Objective: Interleukin-33 (IL-33) is the newest member of the IL-1 cytokine family, a group of key regulators of inflammation. The purpose of this study was to determine whether IL-33 is expressed in the human placenta and to investigate its expression in the context of acute and chronic chorioamnionitis. Methods: Placental tissues were obtained from five groups of patients: 1) normal pregnancy at term without labor (n = 10); 2) normal pregnancy at term in labor (n = 10); 3) preterm labor without inflammation (n = 10); 4) preterm labor with acute chorioamnionitis and funisitis (n = 10); and 5) preterm labor with chronic chorioamnionitis (n = 10). Immunostaining was performed to determine IL-33 protein expression patterns in the placental disk, chorioamniotic membranes, and umbilical cord. mRNA expression of IL-33 and its receptor IL1RL1 (ST2) was measured in primary amnion epithelial and mesenchymal cells (AECs and AMCs, n = 4) and human umbilical vein endothelial cells (HUVECs, n = 4) treated with IL-1 beta (1 and 10 ng/ml) and CXCL10 (0.5 and 1 or 5 ng/ml). Results: 1) Nuclear IL-33 expression was found in endothelial and smooth muscle cells in the placenta, chorioamniotic membranes, and umbilical cord; 2) IL-33 was detected in the nucleus of CD14+ macrophages in the chorioamniotic membranes, chorionic plate, and umbilical cord, and in the cytoplasm of myofibroblasts in the Wharton's jelly; 3) acute (but not chronic) chorioamnionitis was associated with the presence of IL-33+ macrophages in the chorioamniotic membranes and umbilical cord; 4) expression of IL-33 or IL1RL1 (ST2) mRNA in AECs was undetectable; 5) IL-33 mRNA expression increased in AMCs and HUVECs after IL-1 beta treatment but did not change with CXCL10 treatment; and 6) IL1RL1 (ST2) expression decreased in AMCs and increased in HUVECs after IL-1 beta but not CXCL10 treatment. Conclusions: IL-33 is expressed in the nucleus of placental endothelial cells, CD14+ macrophages, and myofibroblasts in the Wharton's jelly. IL-1 beta can induce the expression of IL-33 and its receptor. Protein expression of IL-33 is detectable in macrophages of the chorioamniotic membranes in acute (but not chronic) chorioamnionitis. C1 [Topping, Vanessa; Romero, Roberto; Than, Nandor Gabor; Tarca, Adi L.; Xu, Zhonghui; Kim, Sun Young; Wang, Bing; Yeo, Lami; Kim, Chong Jai; Hassan, Sonia S.; Kim, Jung-Sun] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Topping, Vanessa; Romero, Roberto; Than, Nandor Gabor; Tarca, Adi L.; Xu, Zhonghui; Kim, Sun Young; Wang, Bing; Yeo, Lami; Kim, Chong Jai; Hassan, Sonia S.; Kim, Jung-Sun] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Than, Nandor Gabor; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. [Kim, Chong Jai] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. [Kim, Jung-Sun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,4 Brush, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU 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 report no declarations of interest. This work was supported by 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 158 TC 9 Z9 11 U1 0 U2 16 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 MAR PY 2013 VL 26 IS 4 BP 327 EP 338 DI 10.3109/14767058.2012.735724 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 084IY UT WOS:000314533600001 PM 23039129 ER PT J AU Ziats, MN Rennert, OM AF Ziats, Mark N. Rennert, Owen M. TI Aberrant Expression of Long Noncoding RNAs in Autistic Brain SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Noncoding RNA; Long noncoding RNA; Genomics; Autistic disorder; Gene expression ID SPECTRUM DISORDERS; TRANSCRIPTOME; MICRORNAS; CORTEX; GENES AB The autism spectrum disorders (ASD) have a significant hereditary component, but the implicated genetic loci are heterogeneous and complex. Consequently, there is a gap in understanding how diverse genomic aberrations all result in one clinical ASD phenotype. Gene expression studies from autism brain tissue have demonstrated that aberrantly expressed protein-coding genes may converge onto common molecular pathways, potentially reconciling the strong heritability and shared clinical phenotypes with the genomic heterogeneity of the disorder. However, the regulation of gene expression is extremely complex and governed by many mechanisms, including noncoding RNAs. Yet no study in ASD brain tissue has assessed for changes in regulatory long noncoding RNAs (lncRNAs), which represent a large proportion of the human transcriptome, and actively modulate mRNA expression. To assess if aberrant expression of lncRNAs may play a role in the molecular pathogenesis of ASD, we profiled over 33,000 annotated lncRNAs and 30,000 mRNA transcripts from postmortem brain tissue of autistic and control prefrontal cortex and cerebellum by microarray. We detected over 200 differentially expressed lncRNAs in ASD, which were enriched for genomic regions containing genes related to neurodevelopment and psychiatric disease. Additionally, comparison of differences in expression of mRNAs between prefrontal cortex and cerebellum within individual donors showed ASD brains had more transcriptional homogeneity. Moreover, this was also true of the lncRNA transcriptome. Our results suggest that further investigation of lncRNA expression in autistic brain may further elucidate the molecular pathogenesis of this disorder. C1 [Ziats, Mark N.; Rennert, Owen M.] NICHHD, Lab Clin & Dev Genom, NIH, Bethesda, MD 20814 USA. [Ziats, Mark N.] Baylor Coll Med MSTP, Houston, TX USA. [Ziats, Mark N.] NIH Univ Cambridge Biomed Scholars Program, Cambridge, England. RP Ziats, MN (reprint author), NICHHD, Lab Clin & Dev Genom, NIH, 49 Convent Dr,Bldg 49,Room 2C08, Bethesda, MD 20814 USA. EM ziatsm@mail.nih.gov; rennerto@mail.nih.gov FU Intramural Research Program at the National Institute of Child Health and Human Development; Baylor College of Medicine MSTP; NIH-University of Cambridge Biomedical Scholars Program FX The Intramural Research Program at the National Institute of Child Health and Human Development supported this work. MNZ was also supported by Baylor College of Medicine MSTP and the NIH-University of Cambridge Biomedical Scholars Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 59 Z9 62 U1 3 U2 32 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD MAR PY 2013 VL 49 IS 3 BP 589 EP 593 DI 10.1007/s12031-012-9880-8 PG 5 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 086QN UT WOS:000314701300020 PM 22949041 ER PT J AU Lai, C Dunleavy, K AF Lai, Catherine Dunleavy, Kieron TI Tackling Burkitt lymphoma in older patients: novel strategies and the promise of targeted agents SO LEUKEMIA & LYMPHOMA LA English DT Editorial Material ID CELL LYMPHOMA; CYTARABINE; RITUXIMAB C1 [Lai, Catherine; Dunleavy, Kieron] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Metab Branch, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov NR 10 TC 0 Z9 1 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR PY 2013 VL 54 IS 3 BP 443 EP 444 DI 10.3109/10428194.2012.739689 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 084KR UT WOS:000314538600002 PM 23098086 ER PT J AU Cherry, BM Korde, N Kwok, M Roschewski, M Landgren, O AF Cherry, Benjamin M. Korde, Neha Kwok, Mary Roschewski, Mark Landgren, Ola TI Evolving therapeutic paradigms for multiple myeloma: back to the future SO LEUKEMIA & LYMPHOMA LA English DT Review DE Multiple myeloma; maintenance; extended dosing; lenalidomide; thalidomide ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; HIGH-DOSE MELPHALAN; TERM-FOLLOW-UP; RANDOMIZED CONTROLLED-TRIAL; UNDETERMINED SIGNIFICANCE MGUS; BORTEZOMIB PLUS MELPHALAN; INTERFERON-ALPHA THERAPY; SOUTHWEST-ONCOLOGY-GROUP; ELDERLY-PATIENTS AB Multiple myeloma (MM) is an ancient disease, but until the alkylating agent melphalan was found to have anti-myeloma properties in the 1950s there was virtually no effective therapy. By the late 1960s, extended dosing with melphalan and prednisone tripled survival from diagnosis and became the standard of care for newly diagnosed MM. "Maintenance therapy" to prolong survival through sustained disease control following induction chemotherapy was sought by 1970, but early strategies were ineffective and toxic. Subsequent applications of high-dose therapy (HDT)/autologous stem cell transplant (ASCT) changed the treatment paradigm for MM from extended dosing to an intensive strategy designed to eradicate the malignant cells in a single course of treatment. Although HDT-ASCT resulted in prolonged duration of remission and improved survival, the vast majority of patients still relapsed. Interferon (IFN) and glucocorticoid maintenance therapies demonstrated marginal improvements in outcomes but significant adverse effects. Novel agents introduced over the last decade have prolonged survival when given for maintenance following HDT-ASCT, but have also challenged the HDT-ASCT paradigm by achieving comparable remission rates when used alone as extended frontline therapy. This article reviews the evolution of therapeutic strategies for MM and discusses future questions facing MM investigators. C1 [Cherry, Benjamin M.; Korde, Neha; Kwok, Mary; Roschewski, Mark; Landgren, Ola] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov OI Roschewski, Mark/0000-0003-0278-2635 NR 122 TC 7 Z9 7 U1 0 U2 13 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR PY 2013 VL 54 IS 3 BP 451 EP 463 DI 10.3109/10428194.2012.717277 PG 13 WC Oncology; Hematology SC Oncology; Hematology GA 084KR UT WOS:000314538600006 PM 22880935 ER PT J AU Zhu, PX Degheidy, HA Marti, GE Li, SH Abbasi, F Wiestner, A Amstutz, P Tang, CM AF Zhu, Peixuan Degheidy, Heba A. Marti, Gerald E. Li, Shuhong Abbasi, Fatima Wiestner, Adrian Amstutz, Platte Tang, Cha-Mei TI Quantitative detection of zeta-chain-associated protein 70 expression in chronic lymphocytic leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE Chronic lymphocytic leukemia (CLL); ZAP-70; flow cytometry; immunomagnetic fluorescence assay; Signalyte-II spectrofluorometer ID GENE MUTATION STATUS; ZAP70 MESSENGER-RNA; ZAP-70 EXPRESSION; CD38 EXPRESSION; GENOMIC ABERRATIONS; PROGNOSTIC MARKER; B-CELLS; PROGRESSION; MICRORNA; REVEALS AB Overexpression of zeta-chain-associated protein 70 (ZAP-70) was recently recognized as an independent prognostic marker for the aggressive form of chronic lymphocytic leukemia (CLL). The objective of this study was to demonstrate the feasibility and implementation of quantitative detection of ZAP-70 protein in B cells to clearly distinguish patients with CLL with the aggressive form of the disease. B cells were isolated from patient blood and lysed. Released ZAP-70 protein was detected using an immunomagnetic fluorescence assay. The assay protocol was developed using Jurkat cells and recombinant ZAP-70 (rZAP-70). The limit of detection was determined to be lower than 125 Jurkat cells and 39 pg of rZAP-70 protein. The signal response was linear over a wide dynamic range, from 125 to 40 000 Jurkat cells per test (R-2 = 0.9987) and from 0 to 40 000 pg rZAP-70 protein per test (R-2 = 0.9928). The results from 20 patients with CLL correlated strongly with flow cytometry analysis. Concordance between the two methods for positive and negative results was 100% (7/7) and 92% (12/13), respectively, while the overall concordance between the two methods was 95%. The assay reported here is a simple, reliable and reproducible method for quantitative detection of ZAP-70 in patient leukemic cells, without the need for cell fixation or permeabilization. The ZAP-70 signal was linear over a wide dynamic range, which we believe enables quantitative assessment of small changes in ZAP-70 expression over the course of the disease and in response to therapeutic intervention. C1 [Zhu, Peixuan; Li, Shuhong; Amstutz, Platte; Tang, Cha-Mei] Creatv MicroTech Inc, Potomac, MD 20854 USA. [Degheidy, Heba A.; Marti, Gerald E.; Abbasi, Fatima] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. RP Zhu, PX (reprint author), Creatv MicroTech Inc, 11609 Lake Potomac Dr, Potomac, MD 20854 USA. EM pzhu@creatvmicrotech.com FU NHLBI, NIH; National Institutes of Health [R44 CA094430-02] FX The authors thank Susan Soto in Dr. Wiestner's laboratory for assistance in the collection of CLL blood samples and Yong-Qiang Wang for assistance in preparation of PBMCs from the samples. This research was supported in part by the intramural research program of NHLBI, NIH.; This work was supported by a grant R44 CA094430-02 from the National Institutes of Health. NR 33 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR PY 2013 VL 54 IS 3 BP 579 EP 586 DI 10.3109/10428194.2012.715349 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 084KR UT WOS:000314538600024 PM 22839722 ER PT J AU Kimlin, LC Casagrande, G Virador, VM AF Kimlin, Lauren C. Casagrande, Giovanna Virador, Victoria M. TI In vitro three-dimensional (3D) models in cancer research: An update SO MOLECULAR CARCINOGENESIS LA English DT Review DE 3D; coculture; carcinogenesis; tumor cells; invasion; metastasis; microenvironment; cancer stem cells; reactive stroma ID SQUAMOUS-CELL CARCINOMA; MULTICELLULAR TUMOR SPHEROIDS; EPITHELIAL-MESENCHYMAL TRANSITION; HUMAN COLORECTAL CARCINOMAS; ACUTE MYELOID-LEUKEMIA; STEM-CELLS; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; ORGAN-CULTURE; ENDOMETRIAL CARCINOMA AB Tissues are three-dimensional (3D) entities as is the tumor that arises within them. Though disaggregated cancerous tissues have produced numerous cell lines for basic and applied research, it is generally agreed that these lines are poor models of in vivo phenomena. In this review we focus on in vitro 3D models used in cancer research, particularly their contribution to molecular studies of the early stages of metastasis, angiogenesis, the tumor microenvironment, and cancer stem cells. We present a summary of the various formats used in the field of tissue bioengineering as they apply to mechanistic modeling of cancer stages or processes. In addition we list studies that model specific types of malignancies, highlight drastic differences in results between 3D in vitro models and classical monolayer culturing techniques, and establish the need for standardization of 3D models for meaningful preclinical and therapeutic testing. (c) 2011 Wiley Periodicals, Inc. C1 [Kimlin, Lauren C.; Casagrande, Giovanna; Virador, Victoria M.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Virador, VM (reprint author), Bldg 10-12C206,10 Ctr Dr,Mail Stop 1906, Bethesda, MD 20892 USA. NR 171 TC 77 Z9 78 U1 7 U2 188 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAR PY 2013 VL 52 IS 3 BP 167 EP 182 DI 10.1002/mc.21844 PG 16 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 084KF UT WOS:000314537300001 PM 22162252 ER PT J AU Hauser, DN Hastings, TG AF Hauser, David N. Hastings, Teresa G. TI Mitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism SO NEUROBIOLOGY OF DISEASE LA English DT Review DE Parkinson's disease; Mitochondria; Oxidative stress; Dopamine oxidation ID RAT-BRAIN MITOCHONDRIA; COMPLEX-I DEFICIENCY; NIGRAL GLUTATHIONE DEFICIENCY; RESOLUTION CRYSTAL-STRUCTURE; UBIQUITIN-PROTEASOME SYSTEM; CYSTEINE-SULFINIC ACID; SUBSTANTIA-NIGRA; ALPHA-SYNUCLEIN; PROTEIN DJ-1; DOPAMINERGIC-NEURONS AB The pathogenic mechanisms that underlie Parkinson's disease remain unknown. Here, we review evidence from both sporadic and genetic forms of Parkinson's disease that implicate both mitochondria and oxidative stress as central players in disease pathogenesis. A systemic deficiency in complex I of the mitochondrial electron transport chain is evident in many patients with the disease. Oxidative stress caused by reactive metabolites of dopamine and alterations in the levels of iron and glutathione in the substantia nigra accompany this mitochondrial dysfunction. Recent evidence from studies on the genetic forms of parkinsonism with particular stress on DJ-1, parkin, and PINK-1 also suggest the involvement of mitochondria and oxidative stress. (C) 2012 Elsevier Inc. All rights reserved. C1 [Hauser, David N.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hauser, David N.] Brown Univ, NIH, Grad Partnership Program, Dept Neurosci, Providence, RI 02912 USA. [Hastings, Teresa G.] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15260 USA. [Hastings, Teresa G.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Hastings, Teresa G.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. RP Hastings, TG (reprint author), Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15260 USA. EM hastingst@upmc.edu RI Hauser, David/I-4933-2012 OI Hauser, David/0000-0002-9500-5255 FU Intramural Research Program of the NIH, National Institute on Aging; NIH [NS059806] FX The authors would like to extend their gratitude to Dr. Mark R Cookson for careful reading and comments on this manuscript. D.N.H. is supported by the Intramural Research Program of the NIH, National Institute on Aging. T.G.H. is supported by NIH grant NS059806. NR 134 TC 110 Z9 118 U1 10 U2 103 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAR PY 2013 VL 51 SI SI BP 35 EP 42 DI 10.1016/j.nbd.2012.10.011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 085PQ UT WOS:000314627100005 PM 23064436 ER PT J AU Chang, C Metzger, CD Glover, GH Duyn, JH Heinze, HJ Walter, M AF Chang, Catie Metzger, Coraline D. Glover, Gary H. Duyn, Jeff H. Heinze, Hans-Jochen Walter, Martin TI Association between heart rate variability and fluctuations in resting-state functional connectivity SO NEUROIMAGE LA English DT Article DE Resting state fMRI; Spontaneous activity; Functional connectivity; Heart rate variability; Autonomic nervous system; Vigilance ID MIDBRAIN PERIAQUEDUCTAL GRAY; PREFRONTAL CORTICAL PROJECTIONS; DEFAULT MODE NETWORK; CINGULATE CORTEX; RHESUS-MONKEY; CARDIOVASCULAR-RESPONSES; AUTONOMIC CONTROL; MACAQUE MONKEYS; BRAIN MEDIATORS; BLOOD-PRESSURE AB Functional connectivity has been observed to fluctuate across the course of a resting state scan, though the origins and functional relevance of this phenomenon remain to be shown. The present study explores the link between endogenous dynamics of functional connectivity and autonomic state in an eyes-closed resting condition. Using a sliding window analysis on resting state fMRI data from 35 young, healthy male subjects, we examined how heart rate variability (HRV) covaries with temporal changes in whole-brain functional connectivity with seed regions previously described to mediate effects of vigilance and arousal (amygdala and dorsal anterior cingulate cortex: dACC). We identified a set of regions, including brainstem, thalamus, putamen, and dorsolateral prefrontal cortex, that became more strongly coupled with the dACC and amygdala seeds during states of elevated HRV. Effects differed between high and low frequency components of HRV, suggesting specific contributions of parasympathetic and sympathetic tone on individual connections. Furthermore, dynamics of functional connectivity could be separated from those primarily related to BOLD signal fluctuations. The present results contribute novel information about the neural basis of transient changes of autonomic nervous system states, and suggest physiological and psychological components of the recently observed non-stationarity in resting state functional connectivity. (C) 2012 Elsevier Inc. All rights reserved. C1 [Chang, Catie; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Chang, Catie; Glover, Gary H.] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Chang, Catie; Glover, Gary H.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Metzger, Coraline D.; Walter, Martin] Otto von Guericke Univ, Clin Affect Neuroimaging Lab, Ctr Behav Brain Sci, Magdeburg, Germany. [Heinze, Hans-Jochen; Walter, Martin] Otto von Guericke Univ, Leibniz Inst Neurobiol, Magdeburg, Germany. [Metzger, Coraline D.; Walter, Martin] Otto von Guericke Univ, Dept Psychiat, Magdeburg, Germany. [Heinze, Hans-Jochen; Walter, Martin] Otto von Guericke Univ, Dept Neurol, Magdeburg, Germany. RP Walter, M (reprint author), Ctr Behav & Brain Sci, Clin Affect Neuroimaging Lab CANLAB, ZENIT Bldg,Leipziger Str 44, D-39120 Magdeburg, Germany. EM martin.walter@med.ovgu.de FU NIH [F31-AG032168, P41-RR09784]; Intramural Research Program of the National Institute of Neurological Disorders and Stroke; BMBF-SuppHab; OvGU research stipend; SFB [779] FX The authors gratefully acknowledge support from NIH grants F31-AG032168 (CC), P41-RR09784 (GHG), and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (CC, JHD), as well as SFB 779 (CDM, MW), BMBF-SuppHab (MW) and an OvGU research stipend (CDM). NR 76 TC 58 Z9 58 U1 11 U2 57 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2013 VL 68 BP 93 EP 104 DI 10.1016/j.neuroimage.2012.11.038 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 083VG UT WOS:000314492700011 PM 23246859 ER PT J AU Conway, DL Hansen, NI Dudley, DJ Parker, CB Reddy, UM Silver, RM Bukowski, R Pinar, H Stoll, BJ Varner, MW Saade, GR Hogue, C Willinger, M Coustan, D Koch, MA Goldenberg, RL AF Conway, Deborah L. Hansen, Nellie I. Dudley, Donald J. Parker, Corette B. Reddy, Uma M. Silver, Robert M. Bukowski, Radek Pinar, Halit Stoll, Barbara J. Varner, Michael W. Saade, George R. Hogue, Carol Willinger, Marian Coustan, Donald Koch, Matthew A. Goldenberg, Robert L. CA Eunice Kennedy Shriver Natl Inst TI An Algorithm for the Estimation of Gestational Age at the Time of Fetal Death SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE stillbirth; fetal death; gestational age; algorithms ID FOOT LENGTH; STILLBORN FETUSES; HISTOLOGIC EVALUATION; MENSTRUAL AGE; PARAMETERS; AUTOPSY; GROWTH AB Background Accurate assignment of gestational age (GA) at time of fetal death is important for research and clinical practice. An algorithm to estimate GA at fetal death was developed and evaluated. Methods The algorithm developed by the Stillbirth Collaborative Research Network (SCRN) incorporated clinical and post-mortem data. The SCRN conducted a population-based casecontrol study of women with stillbirths and livebirths from 2006 to 2008 in five geographical catchment areas. Rules were developed to estimate a due date, identify an interval during which death likely occurred, and estimate GA at the time of fetal death. Reliability of using fetal foot length to estimate GA at death was assessed. Results The due date estimated for 620 singleton stillbirths studied was considered clinically reliable for 87%. Only 25.2% of stillbirths were documented alive within 2 days before diagnosis and 47.6% within 1 week of diagnosis. The algorithm-derived estimate of GA at time of fetal death was one or more weeks earlier than the GA at delivery for 43.5% of stillbirths. GA estimated from fetal foot length agreed with GA by algorithm within 2 weeks for 75% within a subset of well-dated stillbirths. Conclusions Precise assignment of GA at death, defined as reliable dating criteria and a short interval (1 week) during which fetal death was known to have occurred, was possible in 46.6% of cases. Fetal foot length is a relatively accurate measure of GA at death and should be collected in all stillbirth cases. C1 [Conway, Deborah L.; Dudley, Donald J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Hansen, Nellie I.; Parker, Corette B.; Koch, Matthew A.] RTI Int, Res Triangle Pk, NC USA. [Reddy, Uma M.; Willinger, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Silver, Robert M.; Varner, Michael W.] Univ Utah, Sch Med & Intermt Hlth Care, Salt Lake City, UT USA. [Bukowski, Radek; Saade, George R.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Pinar, Halit; Coustan, Donald] Brown Univ, Sch Med, Providence, RI 02912 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Atlanta, GA USA. [Hogue, Carol] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Goldenberg, Robert L.] Columbia Univ, Med Ctr, New York, NY USA. RP Dudley, DJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM dudleyd@uthscsa.edu RI Hogue, Carol/H-5442-2012; Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01-HD045954, U10-HD045953, U10-HD045925, U10-HD045952, U10-HD045955, U10-HD045944] FX The authors gratefully acknowledge the cooperation of the study participants, the staff members of the participating hospitals, and the members of the NICHD Scientific Advisory and Safety Monitoring Board, including: Reverend Phillip Cato, PhD; James W. Collins, Jr., MD, MPH; Terry Dwyer, MD, MPH; William P. Fifer, PhD; John Ilekis, PhD; Marc Incerpi, MD; George Macones, MD, MSCE; Richard M. Pauli, MD, PhD; Raymond W. Redline, MD; Elizabeth Thom, PhD (chair). This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Cooperative Agreement mechanism (U01-HD045954, U10-HD045953, U10-HD045925, U10-HD045952, U10-HD045955, U10-HD045944). NR 19 TC 7 Z9 7 U1 3 U2 7 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 MAR PY 2013 VL 27 IS 2 BP 145 EP 157 DI 10.1111/ppe.12037 PG 13 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 085AM UT WOS:000314583000005 PM 23374059 ER PT J AU Korzeniewski, SJ Pinto-Martin, JA Whitaker, AH Feldman, JF Lorenz, JM Levy, SE Movsas, TZ Pappas, A Paneth, N AF Korzeniewski, Steven J. Pinto-Martin, Jennifer A. Whitaker, Agnes H. Feldman, Judith F. Lorenz, John M. Levy, Susan E. Movsas, Tammy Z. Pappas, Athina Paneth, Nigel TI Association Between Transient Hypothyroxinaemia of Prematurity and Adult Autism Spectrum Disorder in a Low-Birthweight Cohort: An Exploratory Study SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE autism spectrum disorders; preterm; infants; thyroxine; transient hypothyroxinaemia of prematurity ID EPIDEMIOLOGIC ANALYSES; ADOLESCENTS AB Background Transient hypothyroxinaemia of prematurity (THOP) is associated with increased risk of cerebral palsy and lower IQ in low-birthweight infants. This study explores whether THOP is also associated with increased risk of autism spectrum disorders (ASD). Methods This secondary analysis uses data from a birth cohort of newborns weighing 5002000g (n=1105) who were followed to age 21 years, when they were assessed for ASD in the second of a two-stage process. Of the 187 assessed at age 21, 14 had ASD. Neonatal thyroxine results were available for 12/14 and 165/173 participants diagnosed with and without ASD, respectively. THOP was defined as thyroxine z-score <2.6. Unadjusted relative risks (RR) and confidence intervals (CI) were calculated. Results The mean neonatal thyroxine z-score in young adults diagnosed with ASD was 0.5 SD lower [95% CI 0.16, 1.06] than in those without ASD. Participants with THOP were at 2.5-fold greater risk of ASD (RR 2.5 [95% CI 0.7, 8.4]). While neither of these differences was statistically significant, in a secondary subgroup analysis of those whose mothers did not have hypertension during pregnancy, THOP significantly increased the RR for ASD (5.0 [95% CI 1.2, 20.5]). Conclusion While the primary relation between THOP and ASD found here is not statistically significant, the magnitude of association and significant relationship observed in the subgroup whose mothers did not have hypertension during pregnancy suggest that it is worthy of further investigation. C1 [Korzeniewski, Steven J.; Movsas, Tammy Z.; Pappas, Athina] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Korzeniewski, Steven J.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Pappas, Athina] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Paneth, Nigel] Michigan State Univ, Coll Human Med, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Paneth, Nigel] Michigan State Univ, Coll Human Med, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. [Pinto-Martin, Jennifer A.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Pinto-Martin, Jennifer A.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Levy, Susan E.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Whitaker, Agnes H.; Feldman, Judith F.] Columbia Univ, Div Child & Adolescent Psychiat, Dept Psychiat, Med Ctr,New York State Psychiat Inst, New York, NY 10027 USA. [Lorenz, John M.] Columbia Univ, Div Neonatol, Dept Pediat, Med Ctr, New York, NY 10027 USA. RP Korzeniewski, SJ (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Hutzel Womens Hosp, 4 Brush,Off 4817,3990 John R, Detroit, MI 48201 USA. EM skorzeni@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; NIMH [5 R01 MH57514]; March of Dimes [12-FY03-46]; Columbia University; [R01MH073807]; [NS-20713] 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, NIH, DHHS. Funding for the original study of the prevalence of ASD in a low-birthweight cohort was from R01MH073807 Pinto-Martin, J (PI); 03/01/2009 to 02/28/2010 (Pinto-Martin, Levy); Subcontract: Whitaker A. (PI), Columbia University (Lorenz, Feldman); Paneth (PI), Michigan State. Additional funding came from NS-20713 (P. I. Nigel Paneth, NBH birth data collection), NIMH grant # 5 R01 MH57514 (Agnes Whitaker, age 16 follow-up) and March of Dimes Grant # 12-FY03-46 (P. I. Agnes Whitaker, age 16 follow-up). NR 20 TC 2 Z9 2 U1 0 U2 7 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 MAR PY 2013 VL 27 IS 2 BP 182 EP 187 DI 10.1111/ppe.12034 PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 085AM UT WOS:000314583000009 PM 23374063 ER PT J AU Karlsson, RM Kircher, DM Shaham, Y O'Donnell, P AF Karlsson, Rose-Marie Kircher, Daniel M. Shaham, Yavin O'Donnell, Patricio TI Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia SO PSYCHOPHARMACOLOGY LA English DT Article DE Addiction; Schizophrenia; Dual diagnosis; Relapse; Animal model; Cocaine self-administration ID VENTRAL HIPPOCAMPAL LESION; DUAL DIAGNOSIS SCHIZOPHRENIA; SELF-ADMINISTERED COCAINE; PREFRONTAL CORTEX; ANIMAL-MODEL; DRUG-SEEKING; ADULT RATS; BEHAVIOR; RELAPSE; WITHDRAWAL AB Patients with schizophrenia exhibit high comorbidity for substance abuse, but the biological underpinnings of this dual-diagnosis condition are still unclear. Previous studies have shown that rats with a neonatal ventral hippocampal lesion (NVHL), a widely used developmental animal model of schizophrenia, exhibit increased cocaine and methamphetamine self-administration and cocaine-induced reinstatement. Here, we assessed whether a NVHL would also potentiate cue-induced reinstatement of cocaine seeking and the time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving) in adult rats. Rats were trained to self-administer cocaine (3 or 6 h/day with 0.75 mg kg(-1) infusion(-1) paired with a tone-light cue) for 10 days, followed by extinction training (3 h/day) and cue-induced reinstatement of cocaine seeking. Other rats were tested for incubation of cocaine craving, assessed in extinction tests 1 and 30 days after the last self-administration session. Although there was no significant difference in cocaine intake between NVHL and sham controls, NVHL rats took significantly longer to reach an a priori set extinction criterion and exhibited enhanced cue-induced reinstatement. However, while cue-induced cocaine seeking was higher after 30 days than after 1 day of withdrawal (incubation of cocaine craving), the NVHL had no effect on this incubation. These data confirm previous reports on enhanced resistance to extinction after NVHL and demonstrate that NVHL rats exhibit enhanced cue-induced reinstatement of cocaine seeking after extinction, a measure of drug relapse. C1 [Karlsson, Rose-Marie; Kircher, Daniel M.; O'Donnell, Patricio] Univ Maryland, Sch Med, Dept Anat & Neurobiol, HSFII, Baltimore, MD 21201 USA. [Shaham, Yavin] NIDA, Behav Neurosci Branch, NIH, Baltimore, MD USA. [O'Donnell, Patricio] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP O'Donnell, P (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, HSFII, 20 Penn St,Room S251, Baltimore, MD 21201 USA. EM podon002@umaryland.edu RI shaham, yavin/G-1306-2014; OI O'Donnell, Patricio/0000-0001-7788-624X FU NIH [R01 DA014020]; Swedish Research Council [524-2009-621]; NIDA intramural research program FX The work was supported by a NIH grant (R01 DA014020; PO'D), by the Swedish Research Council (524-2009-621) to RMK, and by NIDA intramural research program to YS. NR 47 TC 8 Z9 8 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2013 VL 226 IS 1 BP 45 EP 51 DI 10.1007/s00213-012-2882-y PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 088PQ UT WOS:000314848000005 PM 23010798 ER PT J AU Gao, ZG Wei, Q Jayasekara, MPS Jacobson, KA AF Gao, Zhan-Guo Wei, Qiang Jayasekara, M. P. Suresh Jacobson, Kenneth A. TI The role of P2Y(14) and other P2Y receptors in degranulation of human LAD2 mast cells SO PURINERGIC SIGNALLING LA English DT Article DE P2Y; Mast cells; Uracil nucleotide; Degranulation; GPCR; G protein-coupled receptors ID FC-EPSILON-RI; ACTIVATION; ATP; HISTAMINE; RELEASE; SELECTIVITY; ANTAGONIST; EXPRESSION; AGONIST; HMC-1 AB Mast cell degranulation affects many conditions, e.g., asthma and urticaria. We explored the potential role of the P2Y(14) receptor (P2Y(14)R) and other P2Y subtypes in degranulation of human LAD2 mast cells. All eight P2YRs were expressed at variable levels in LAD2 cells (quantitative real-time RT-PCR). Gene expression levels of ADP receptors, P2Y(1)R, P2Y(12)R, and P2Y(13)R, were similar, and P2Y(11)R and P2Y(4)R were highly expressed at 5.8- and 3.8-fold of P2Y(1)R, respectively. Least expressed P2Y(2)R was 40-fold lower than P2Y(1)R, and P2Y(6)R and P2Y(14)R were a parts per thousand currency sign50 % of P2Y(1)R. None of the native P2YR agonists alone induced beta-hexosaminidase (beta-Hex) release, but some nucleotides significantly enhanced beta-Hex release induced by C3a or antigen, with a rank efficacy order of ATP > UDPG a parts per thousand yenaEuro parts per thousand ADP >> UDP, UTP. Although P2Y(11)R and P2Y(4)R are highly expressed, they did not seem to play a major role in degranulation as neither P2Y(4)R agonist UTP nor P2Y(11)R agonists ATP gamma S and NF546 had a substantial effect. P2Y(1)R-selective agonist MRS2365 enhanced degranulation, but similar to 1,000-fold weaker compared to its P2Y(1)R potency, and the effect of P2Y(6)R agonist 3-phenacyl-UDP was negligible. The enhancement by ADP and ATP appears mediated via multiple receptors. Both UDPG and a synthetic agonist of the P2Y(14)R, MRS2690, enhanced C3a-induced beta-Hex release, which was inhibited by a P2Y(14)R antagonist, specific P2Y(14)R siRNA and pertussis toxin, suggesting a role of P2Y(14)R activation in promoting human mast cell degranulation. C1 [Gao, Zhan-Guo; Wei, Qiang; Jayasekara, M. P. Suresh; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gao, ZG (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM zg21o@nih.gov; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK Intramural Research Program, National Institutes of Health FX This work is supported by the NIDDK Intramural Research Program, National Institutes of Health. We thank Drs. Arnold Kirshenbaum and Dean Metcalfe (NIAID, NIH, Bethesda, MD, USA) for providing LAD2 cells. We thank Prof. Mortimer M. Civan (University of Pennsylvania) for helpful discussions. NR 33 TC 17 Z9 18 U1 0 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAR PY 2013 VL 9 IS 1 BP 31 EP 40 DI 10.1007/s11302-012-9325-4 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 086XQ UT WOS:000314723400005 PM 22825617 ER PT J AU Walder, DJ Holtzman, CW Addington, J Cadenhead, K Tsuang, M Cornblatt, B Cannon, TD McGlashan, TH Woods, SW Perkins, DO Seidman, LJ Heinssen, R Walker, EF AF Walder, Deborah J. Holtzman, Carrie W. Addington, Jean Cadenhead, Kristin Tsuang, Ming Cornblatt, Barbara Cannon, Tyrone D. McGlashan, Thomas H. Woods, Scott W. Perkins, Diana O. Seidman, Larry J. Heinssen, Robert Walker, Elaine F. TI Sexual dimorphisms and prediction of conversion in the NAPLS psychosis prodrome SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Sex differences; Adolescence; At-risk; Prognosis; Vulnerability ID PREMORBID ADJUSTMENT SCALE; ULTRA-HIGH-RISK; GENDER-DIFFERENCES; 1ST-EPISODE SCHIZOPHRENIA; 1ST PSYCHOSIS; YOUNG-ADULTS; DISORDERS; VALIDITY; INDIVIDUALS; ASSOCIATION AB Sex differences in age at onset, symptomatology, clinical course (see Walker et al., 2002) and functional impairment (Thorup et al., 2007) are well documented in psychosis. The general pattern of findings is that males manifest an earlier onset, more severe symptoms and poorer prognosis than females. Limited studies examining individuals at clinical high-risk (CHR) suggest a similar pattern of sexual dimorphism (Holtzman et al., in review; Corcoran et al., 2011). As part of the North American Prodrome Longitudinal Study (NAPLS), the current study prospectively examined sexual dimorphisms in relationships among CHR symptoms, childhood (premorbid) academic and social functioning, baseline social and role functioning, and conversion to psychosis. Subjects included 276 (113F/163M) CHR NAPLS participants (ages 12-36.8 years). All measures/criteria were assessed at baseline except conversion status, assessed at 6-month intervals up to 30 months. Results show sex differences in baseline social and role functioning (though not in early childhood adjustment) that predate psychosis onset, with sexually dimorphic patterns in relation to prodromal symptoms. Among male (but not female) CHRs, baseline social functioning and positive prodromal symptoms predicted conversion. These findings help elucidate early course of vulnerability for, and maximally sensitive and specific etiological and prediction models of, psychosis conversion. Findings highlight the importance of considering sexually differentiated predictors of longitudinal course and outcome, in the context of emerging risk profiles. This may optimize efforts at early identification and individually tailored preventive interventions targeting different neurobiological markers/systems and/or cognitive-behavioral approaches. We speculate a contemporary, multidimensional model of psychosis risk that posits a role of sexually dimorphic, genetically linked influences that converge with a modulating role of gonadal hormones (see Walder et al., 2012) across a temporally sensitive neurodevelopmental trajectory towards conferring risk. (C) 2012 Elsevier B.V. All rights reserved. C1 [Walder, Deborah J.] CUNY Brooklyn Coll, Brooklyn, NY 11210 USA. [Walder, Deborah J.] CUNY, Grad Ctr, New York, NY USA. [Holtzman, Carrie W.; Walker, Elaine F.] Emory Univ, Atlanta, GA 30322 USA. [Addington, Jean] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Cadenhead, Kristin; Tsuang, Ming] Univ Calif San Diego, San Diego, CA 92103 USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Heinssen, Robert] NIMH, Bethesda, MD 20892 USA. RP Walder, DJ (reprint author), CUNY Brooklyn Coll, Dept Psychol, Room 5315 James Hall,2900 Bedford Ave, Brooklyn, NY 11210 USA. EM DWalder@brooklyn.cuny.edu FU Eli Lilly; Bristol Myers Squibb; Pfizer; NIMH [U01MH082022] FX Scott Woods: Self. NIMH: U01MH082022, grants from Eli Lilly, Bristol Myers Squibb, Pfizer. Consultant. Merck. NR 42 TC 19 Z9 19 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2013 VL 144 IS 1-3 BP 43 EP 50 DI 10.1016/j.schres.2012.11.039 PG 8 WC Psychiatry SC Psychiatry GA 088GI UT WOS:000314821400007 PM 23340377 ER PT J AU Ribbens, J Whiteley, G Furuya, H Southall, N Hu, X Marugan, J Ferrer, M Maegawa, GHB AF Ribbens, Jameson Whiteley, Grace Furuya, Hirokazu Southall, Noel Hu, Xin Marugan, Juan Ferrer, Marc Maegawa, Gustavo H. B. TI A high-throughput screening assay using Krabbe disease patient cells SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE beta-Galactocerebrosidase; High-throughput screening; Small molecules; Krabbe disease ID PHARMACOLOGICAL CHAPERONE; GAUCHER-DISEASE; LEUKODYSTROPHY; GALACTOCEREBROSIDASE; MUTATIONS; SUBSTRATE; DIAGNOSIS; THERAPY AB Globoid cell leukodystrophy (GLD) or Krabbe disease is a lysosomal disease caused by beta-galactocerebrosidase (GALC) deficiency resulting in a rapidly progressive neurodegenerative disorder. Unfortunately, the only available treatment is hematopoietic bone marrow transplantation, which prevents its fulminant manifestation but without treating further neurological manifestations. Here, we describe the development of a cellular high-throughput screening (HIS) assay using GLD patient fibroblasts to screen for small molecules that enhance the residual mutant GALC enzymatic activity. Small molecules have substantial therapeutic potential in GLD because they are more prone to cross the blood-brain barrier, reaching the neuronal affected cells. The transformation of primary skin fibroblasts with SV40 large T antigen has been shown to maintain the biochemical characteristics of the GLD cells and generates sufficient cells for the HTS. Using a specific fluorescent substrate, residual GALC activity from an SV40-transformed GLD patient fibroblast was measurable in high-density microplates. The pilot quantitative HTS against a small compound collection showed robust statistics. The small molecules that showed active concentration-response curves were further studied in primary GLD fibroblasts. This cell-based HTS assay demonstrates the feasibility of employing live GLD patient cells to identify therapeutic agents that can potentially be used for the treatment of this progressive neurodegenerative disease. (C) 2012 Elsevier Inc. All rights reserved. C1 [Ribbens, Jameson; Maegawa, Gustavo H. B.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Whiteley, Grace; Southall, Noel; Hu, Xin; Marugan, Juan; Ferrer, Marc] NIH, Natl Ctr Translat Therapeut, Rockville, MD 20850 USA. [Furuya, Hirokazu] NHO Omuta Hosp, Dept Neurol, Omuta, Fukuoka 8370911, Japan. [Maegawa, Gustavo H. B.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Maegawa, GHB (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. EM gmaegaw1@jhmi.edu RI Southall, Noel/H-8991-2012; OI Southall, Noel/0000-0003-4500-880X; Maegawa, Gustavo/0000-0001-6933-4138 FU Kennedy Krieger Intellectual and Developmental Disabilities Research Center; NIH Common Fund Molecular Libraries and Imaging Program [U54 MH084681]; G. Gaslini Institute - Telethon Genetic Biobank Network [GTB07001] FX We are in dept with Elizabeth Wohler B.Sc. and Denise Batista Ph.D. who assisted in locating the cell lines in Cell Bank from Kennedy Krieger Institute, which is funded by Kennedy Krieger Intellectual and Developmental Disabilities Research Center. This study was partly supported by the NIH Common Fund Molecular Libraries and Imaging Program, Grant U54 MH084681. We are grateful for the assistance of Cassandra Obie B.Sc. and David Valle M.D. for initial assistance to establish the cultured fibroblast lines. One of the cell lines used from patients affected by Krabbe disease was obtained from G. Gaslini Institute - Telethon Genetic Biobank Network (Project No. GTB07001). We are also thankful for Mirella Filocamo Ph.D., Head of Lab Diagnosi Pre e Post-natale Malattie Metaboliche, Coordinator, Telethon Genetic Biobank Network and Gaslini Institute, Genova, Italy. NR 29 TC 17 Z9 17 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 1 PY 2013 VL 434 IS 1 BP 15 EP 25 DI 10.1016/j.ab.2012.10.034 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 082FR UT WOS:000314378200004 PM 23138179 ER PT J AU Haginaka, J Kitabatake, T Hirose, I Matsunaga, H Moaddel, R AF Haginaka, Jun Kitabatake, Tomoko Hirose, Iyo Matsunaga, Hisami Moaddel, Ruin TI Interaction of cepharanthine with immobilized heat shock protein 90 alpha (Hsp90 alpha) and screening of Hsp90 alpha inhibitors SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Heat shock protein; Frontal affinity chromatography; Cepharanthine; Berbamine; Isotetrandrine; Cycleanine ID ANTITUMOR-ACTIVITY; IN-VITRO; HSP90; CANCER; HEAT-SHOCK-PROTEIN-90; MECHANISM; BINDING; CLIENT; GROWTH; VIVO AB Heat shock protein 90 alpha (Hsp90 alpha) immobilized on aminopropyl silica gels was prepared via the N- or C-terminal, which was termed Hsp90 alpha-NT or Hsp90 alpha-CT, respectively. Binding interactions of biscoclaurine alkaloids (cepharanthine (CEP), berbamine (BBM), isotetrandrine (ITD), and cycleanine (CCN)) with Hsp90 alpha were examined using the Hsp90 alpha-NT or -CT columns by frontal and zonal chromatography studies. The dissociation constants of CEP, BBM, ITD, and CCN to Hsp90 alpha-NT were estimated to be 5.3, 18.6, 46.3, and 159 mu M, respectively, by frontal chromatography techniques. Similar results were obtained with the Hsp90 alpha-CT column. These data suggest that these biscoclaurine alkaloids interact with the middle domain of Hsp90 alpha. This was confirmed by demonstrating that CEP competed with endothelial nitric oxide synthase at the middle domain of Hsp90 alpha, where it was shown to have a dissociation constant of 15 nM. Furthermore, the Hsp90 alpha-NT column was applied for preliminary screening of natural Hsp90 alpha inhibitors by zonal chromatography studies.(C) 2012 Elsevier Inc. All rights reserved. C1 [Haginaka, Jun; Kitabatake, Tomoko; Hirose, Iyo; Matsunaga, Hisami] Mukogawa Womens Univ, Sch Pharm & Pharmaceut Sci, Nishinomiya, Hyogo 6638179, Japan. [Moaddel, Ruin] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Haginaka, J (reprint author), Mukogawa Womens Univ, Sch Pharm & Pharmaceut Sci, 11-68 Koshien Kyuban Cho, Nishinomiya, Hyogo 6638179, Japan. EM haginaka@mukogawa-u.ac.jp FU Intramural Research Program at the National Institute on Aging, NIH FX This research was supported in part by the Intramural Research Program at the National Institute on Aging, NIH (R.M.). NR 20 TC 8 Z9 9 U1 0 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 1 PY 2013 VL 434 IS 1 BP 202 EP 206 DI 10.1016/j.ab.2012.11.010 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 082FR UT WOS:000314378200032 PM 23219559 ER PT J AU Kessler, RS Purcell, EP Glasgow, RE Klesges, LM Benkeser, RM Peek, CJ AF Kessler, Rodger S. Purcell, E. Peyton Glasgow, Russell E. Klesges, Lisa M. Benkeser, Rachel M. Peek, C. J. TI What Does It Mean to "Employ" the RE-AIM Model? SO EVALUATION & THE HEALTH PROFESSIONS LA English DT Article DE RE-AIM; evaluation; fidelity; model testing; methodology; review criteria ID PUBLIC-HEALTH IMPACT; EXTERNAL VALIDITY; CHILDHOOD OBESITY; INTERVENTIONS; TRANSLATION; FRAMEWORK AB Many grant proposals identify the use of a given evaluation model or framework but offer little about how such models are implemented. The authors discuss what it means to employ a specific model, RE-AIM, and key dimensions from this model for program planning, implementation, evaluation, and reporting. The authors report both conceptual and content specifications for the use of the RE-AIM model and a content review of 42 recent dissemination and implementation grant applications to National Institutes of Health that proposed the use of this model. Outcomes include the extent to which proposals addressed the overall RE-AIM model and specific items within the five dimensions in their methods or evaluation plans. The majority of grants used only some elements of the model (less than 10% contained thorough measures across all RE-AIM dimensions). Few met criteria for "fully developed use" of RE-AIM and the percentage of key issues addressed varied from, on average, 45% to 78% across the RE-AIM dimensions. The results and discussion of key criteria should help investigators in their use of RE-AIM and illuminate the broader issue of comprehensive use of evaluation models. C1 [Kessler, Rodger S.] Univ Vermont, Dept Family Med, Burlington, VT USA. [Purcell, E. Peyton; Glasgow, Russell E.; Benkeser, Rachel M.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. [Klesges, Lisa M.] Univ Memphis, Sch Publ Hlth, Memphis, TN 38152 USA. [Peek, C. J.] Univ Minnesota, Dept Family Med & Community Hlth, Minneapolis, MN USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 6144, Rockville, MD 20892 USA. EM glasgowre@mail.nih.gov NR 18 TC 44 Z9 45 U1 3 U2 28 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 MAR PY 2013 VL 36 IS 1 BP 44 EP 66 DI 10.1177/0163278712446066 PG 23 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 082BN UT WOS:000314366800002 PM 22615498 ER PT J AU McLeod, CC Klabunde, CN Willis, GB Stark, D AF McLeod, Caroline C. Klabunde, Carrie N. Willis, Gordon B. Stark, Debra TI Health Care Provider Surveys in the United States, 2000-2010: A Review SO EVALUATION & THE HEALTH PROFESSIONS LA English DT Review DE survey; health care provider; physicians; medical groups; health services research ID RESPONSE RATES; PHYSICIAN RESPONSE; PEDIATRICIANS; STRATEGIES; DESIGN; MAIL AB Surveys of health care providers (e. g., physicians and other health care professionals) are an important tool for assessing health care practices and the settings in which care is delivered. Although multiple methods are used to increase survey data quality, little is known about which methods are most commonly implemented. We reviewed 117 large surveys described in literature published between 2000 and 2010, examining descriptions of survey design features, survey implementation, and response rates. Despite wide variation, the typical provider survey selected practicing physicians as respondents, used the American Medical Association Masterfile as sample frame, included mail as both mode of initial contact and questionnaire administration mode, and offered monetary incentives to respondents. Our review revealed inconsistency of documentation concerning procedures used, and a variety of response rate calculation methods, such that it was difficult to determine practices that maximize response rate. We recommend that reports provide more comprehensive documentation concerning key methodological features to improve assessment of survey data quality. C1 [McLeod, Caroline C.; Stark, Debra] NOVA Res Co, Bethesda, MD USA. [Klabunde, Carrie N.; Willis, Gordon B.] NCI, Bethesda, MD 20892 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 23 TC 44 Z9 44 U1 1 U2 18 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 MAR PY 2013 VL 36 IS 1 BP 106 EP 126 DI 10.1177/0163278712474001 PG 21 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 082BN UT WOS:000314366800006 PM 23378504 ER PT J AU Middelton, LA AF Middelton, Lindsay A. TI Birt-Hogg-Dube: beyond the clinical manifestations SO FAMILIAL CANCER LA English DT Article DE Renal cancer; Birt-Hogg-Dube; Pneumothorax; Fibrofolliculoma; Psycho-social AB Clinicians and scientists understand the medical implications of BHD; however, what may not be apparent to clinicians and scientists are the psycho-social aspects of living with BHD. Although medical reality differs among people who have Birt-Hogg-Dub,, they often share multiple non-medical ramifications ranging from economic and physical insecurity to interruptions in familial communication patterns and relationships. Physicians cognizant of the psycho-social aspects of having BHD are in a position to offer enhanced and meaningful non-medical interventions and care to their patient with BHD. 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 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 0 TC 3 Z9 3 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD MAR PY 2013 VL 12 IS 1 BP 97 EP 99 DI 10.1007/s10689-012-9583-x PG 3 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 082QZ UT WOS:000314408700012 PM 23179794 ER PT J AU Orr, SL Le, D Long, JM Sobieszczuk, P Ma, B Tian, H Fang, XQ Paulson, JC Marth, JD Varki, N AF Orr, Sally L. Le, Dzung Long, Jeffrey M. Sobieszczuk, Peter Ma, Bo Tian, Hua Fang, Xiaoqun Paulson, James C. Marth, Jamey D. Varki, Nissi TI A phenotype survey of 36 mutant mouse strains with gene-targeted defects in glycosyltransferases or glycan-binding proteins SO GLYCOBIOLOGY LA English DT Article DE glycan-binding protein; glycosyltransferase; homozygous mutant mice; knock-out mice; mouse phenotype ID C-TYPE LECTIN; GENETICALLY ALTERED MICE; DC-SIGN; DENDRITIC CELLS; N-ACETYLGLUCOSAMINYLTRANSFERASE; CHONDROITIN SULFATES; PATHOGEN RECOGNITION; IMMUNE-RESPONSES; MANIC FRINGE; T-CELLS AB The consortium for functional glycomics (CFG) was a large research initiative providing networking and resources for investigators studying the role of glycans and glycan-binding proteins in health and disease. Starting in 2001, six scientific cores were established to generate data, materials and new technologies. By the end of funding in 2011, the mouse phenotype core (MPC) submitted data to a website from the phenotype screen of 36 mutant mouse strains deficient in a gene for either a glycan-binding protein (GBP) or glycosyltransferase (GT). Each mutant strain was allotted three months for analysis and screened by standard phenotype assays used in the fields of immunology, histology, hematology, coagulation, serum chemistry, metabolism and behavior. Twenty of the deficient mouse strains had been studied in other laboratories, and additional tests were performed on these strains to confirm previous observations and discover new data. The CFG constructed 16 new homozygous mutant mouse strains and completed the initial phenotype screen of the majority of these new mutant strains. In total, > 300 phenotype changes were observed, but considering the over 100 assays performed on each strain, most of the phenotypes were unchanged. Phenotype differences include abnormal testis morphology in GlcNAcT9- and Siglec-H-deficient mice and lethality in Pomgnt1-deficient mice. The numerous altered phenotypes discovered, along with the consideration of the significant findings of normality, will provide a platform for future characterization to understand the important roles of glycans and GBPs in the mechanisms of health and disease. C1 [Le, Dzung; Varki, Nissi] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Ma, Bo; Tian, Hua; Fang, Xiaoqun; Paulson, James C.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Ma, Bo; Tian, Hua; Fang, Xiaoqun; Paulson, James C.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Long, Jeffrey M.] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Sobieszczuk, Peter] Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc, Res Ctr, Auckland 1, New Zealand. [Orr, Sally L.; Marth, Jamey D.] Univ Calif Santa Barbara, Sanford Burnham Med Res Inst, Ctr Nanomed, Santa Barbara, CA 93106 USA. RP Varki, N (reprint author), Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. EM nvarki@ucsd.edu FU National Institute of General Medical Science, Glue Grant [U54 GM62116]; Intramural Research Program of the National Institute on Aging FX This work was supported by The National Institute of General Medical Science, Glue Grant, U54 GM62116 ( J.C.P.). Part of this research ( J.L.) was supported by the Intramural Research Program of the National Institute on Aging. NR 72 TC 17 Z9 17 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD MAR PY 2013 VL 23 IS 3 BP 363 EP 380 DI 10.1093/glycob/cws150 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 079DW UT WOS:000314151500010 PM 23118208 ER PT J AU Hoeben, A Martin, D Clement, PM Cools, J Gutkind, JS AF Hoeben, A. Martin, D. Clement, P. M. Cools, J. Gutkind, J. S. TI Role of GRB2-associated binder 1 in epidermal growth factor receptor-induced signaling in head and neck squamous cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE signal transduction; EGFR; head and neck cancer; EGFR-inhibitors; Akt; ERK; mTOR ID EGFR GENE; HUMAN-PAPILLOMAVIRUS; PLUS CETUXIMAB; CANCER; RECURRENT; EXPRESSION; CHEMOTHERAPY; POLYMORPHISM; MUTATIONS; BIOLOGY AB The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Despite the high expression of EGFR in HNSCC, EGFR inhibitors have only limited success as monotherapy. The Grb2-associated binder (GAB) family of adaptor proteins acts as docking/scaffolding molecules downstream of tyrosine kinase receptors. We hypothesized that GAB1 may amplify EGFR-induced signaling in HNSCCs and therefore could play a role in the reduced sensitivity of HNSCC to EGFR inhibitors. We used representative human HNSCC cell lines overexpressing wild type EGFR, and expressing GAB1 but not GAB2. We demonstrated that baseline Akt and MAPK signaling were reduced in HNSCC cells in which GAB1 expression was reduced. Furthermore, the maximal EGF-induced activation of the Akt and MAPK pathway was reduced and delayed, and the duration of the EGF-induced activation of these pathways was reduced in cells with GAB1 knock-down. In agreement with this, HNSCC cells in which GAB1 levels were reduced showed an increased sensitivity to the EGFR inhibitor gefitinib. Our work demonstrates that GAB1 plays an important role as part of the mechanism of by which EGFR induces induced activation of the MAPK and AKT pathway. Our results identify GAB1 as an amplifier of the EGFR-initiated signaling, which may also interfere with EGFR degradation. These findings support the emerging notion that reducing GAB1 function may sensitize HNSCC to EGFR inhibitors, hence representing a new therapeutic target HNSCC treatment in combination with EGFR targeting agents. C1 [Hoeben, A.; Clement, P. M.] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Martin, D.; Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Cools, J.] VIB, Dept Mol & Dev Genet, Louvain, Belgium. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov OI Cools, Jan/0000-0001-6626-5843 FU Intramural NIH HHS [ZIA DE000558-20] NR 41 TC 9 Z9 11 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2013 VL 132 IS 5 BP 1042 EP 1050 DI 10.1002/ijc.27763 PG 9 WC Oncology SC Oncology GA 078AU UT WOS:000314071300006 PM 22865653 ER PT J AU Duggan, C Wang, CY Neuhouser, ML Xiao, LR Smith, AW Reding, KW Baumgartner, RN Baumgartner, KB Bernstein, L Ballard-Barbash, R McTiernan, A AF Duggan, Catherine Wang, Ching-Yun Neuhouser, Marian L. Xiao, Liren Smith, Ashley Wilder Reding, Kerryn W. Baumgartner, Richard N. Baumgartner, Kathy B. Bernstein, Leslie Ballard-Barbash, Rachel McTiernan, Anne TI Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE IGF-1; IGFBP-3; breast cancer survival; mortality ID I IGF-I; CIRCULATING LEVELS; C-PEPTIDE; RISK; CARCINOGENESIS; PROGNOSIS; TAMOXIFEN; APOPTOSIS; SURVIVORS; HORMONES AB Elevated circulating insulin-like growth factor-1 (IGF-1), a breast epithelial cell mitogen, is associated with breast cancer development. However, its association with breast cancer survival is not established. Circulating concentrations of IGF-1 are controlled via binding proteins, including IGF Binding Protein-3 (IGFBP-3), that may modulate the association of IGF-1 with breast-cancer outcomes. We measured IGF-1 and IGFBP-3 concentrations in serum from 600 women enrolled in the health, eating, activity, and lifestyle (HEAL) study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between IGF-1 and IGFBP-3, and as a ratio, modeled using quintile cut-points, with risk of breast cancer-specific (n = 42 deaths) and all-cause mortality (n 5 87 deaths) using Cox proportional hazards models. In models adjusted for body mass index, ethnicity, tamoxifen use at time of blood draw, treatment received at diagnosis and IGFBP-3, women in the highest quintile of IGF-1 level had an increased risk of all-cause mortality (Hazard Ratio (HR) = 3.10, 95% CI 1.21-7.93, p = 0.02), although no dose-response association was evident. The IGF-1/IGFBP-3 ratio, an indicator of free IGF-I levels, was significantly associated with increasing risk of all-cause mortality (HR = 2.83, 95% CI 1.25-6.36 p(trend) = 0.01, upper vs. lower quintile) in a fully adjusted model. In conclusion, high serum levels of IGF-1 and the IGF1/IGFBP-3 ratio were associated with increased risk of all-cause mortality in women with breast cancer. These results need to be confirmed in larger breast cancer survivor cohorts. C1 [Duggan, Catherine; Wang, Ching-Yun; Neuhouser, Marian L.; Xiao, Liren; Reding, Kerryn W.; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Smith, Ashley Wilder; Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Reding, Kerryn W.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Baumgartner, Richard N.; Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Populat Hlth, Sch Publ Hlth & Informat Sci, Louisville, KY 40292 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Div Populat Sci, Duarte, CA 91010 USA. RP Duggan, C (reprint author), Fred Hutchinson Canc Res Ctr, MD B306, Seattle, WA USA. EM cduggan@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute [N01-CN-75036-20, N01-CN-05228, N01-PC-67010, U54-CA116847, U54CA116848, R25-CA94880]; National Institutes of Health [M01-RR-00037]; University of New Mexico [NCRR M01-RR-0997]; National Institute of Child Health and Human Development [N01-HD-3-3175]; California Department of Health Services [050Q-8709-S1528] FX Grant sponsor: National Cancer Institute; Grant numbers: N01-CN-75036-20, N01-CN-05228, N01-PC-67010, U54-CA116847, U54CA116848, R25-CA94880; Grant sponsor: National Institutes of Health; Grant number: M01-RR-00037; Grant sponsor: University of New Mexico; Grant number: NCRR M01-RR-0997; Grant sponsor: National Institute of Child Health and Human Development; Grant number: N01-HD-3-3175; Grant sponsor: California Department of Health Services; Grant number: 050Q-8709-S1528 NR 38 TC 20 Z9 21 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2013 VL 132 IS 5 BP 1191 EP 1200 DI 10.1002/ijc.27753 PG 10 WC Oncology SC Oncology GA 078AU UT WOS:000314071300022 PM 22847383 ER PT J AU Furukawa, K Preston, D Funamoto, S Yonehara, S Ito, M Tokuoka, S Sugiyama, H Soda, M Ozasa, K Mabuchi, K AF Furukawa, Kyoji Preston, Dale Funamoto, Sachiyo Yonehara, Shuji Ito, Masahiro Tokuoka, Shoji Sugiyama, Hiromi Soda, Midori Ozasa, Kotaro Mabuchi, Kiyohiko TI Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE thyroid cancer; radiation effects; epidemiological cohort study ID IONIZING-RADIATION; HIROSHIMA; DISEASES AB Thyroid cancer risk following exposure to ionizing radiation in childhood and adolescence is a topic of public concern. To characterize the long-term temporal trend and age-at-exposure variation in the radiation-induced risk of thyroid cancer, we analyzed thyroid cancer incidence data for the period from 1958 through 2005 among 105,401 members of the Life Span Study cohort of Japanese atomic-bomb survivors. During the follow-up period, 371 thyroid cancer cases (excluding those with microcarcinoma with a diameter <10 mm) were identified as a first primary among the eligible subjects. Using a linear dose-response model, the excess relative risk of thyroid cancer at 1 Gy of radiation exposure was estimated as 1.28 (95% confidence interval: 0.59-2.70) at age 60 after acute exposure at age 10. The risk decreased sharply with increasing age-at-exposure and there was little evidence of increased thyroid cancer rates for those exposed after age 20. About 36% of the thyroid cancer cases among those exposed before age 20 were estimated to be attributable to radiation exposure. While the magnitude of the excess risk has decreased with increasing attained age or time since exposure, the excess thyroid cancer risk associated with childhood exposure has persisted for >50 years after exposure. C1 [Furukawa, Kyoji; Funamoto, Sachiyo; Tokuoka, Shoji; Sugiyama, Hiromi; Soda, Midori; Ozasa, Kotaro] Radiat Effects Res Fdn, Hiroshima, Japan. [Furukawa, Kyoji; Funamoto, Sachiyo; Tokuoka, Shoji; Sugiyama, Hiromi; Soda, Midori; Ozasa, Kotaro] Radiat Effects Res Fdn, Nagasaki, Japan. [Preston, Dale] Hirosoft Int, Eureka, CA USA. [Yonehara, Shuji] Welf Assoc Onomichi Gen Hosp, Onomichi, Japan. [Ito, Masahiro] Natl Hosp Org Nagasaki Med Ctr, Nagasaki, Japan. [Mabuchi, Kiyohiko] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Furukawa, K (reprint author), 5-2 Hijiyama Pk,Minami Ku, Hiroshima 7320815, Japan. EM furukawa@rerf.or.jp FU US National Cancer Institute Intramural Research Program [N01CP31012 N]; RERF Research Protocols, Japanese Ministry of Health, Labour and Welfare (MHLW); U.S. Department of Energy (DOE) [DE-HS0000031] FX Grant sponsor: US National Cancer Institute Intramural Research Program; Grant number: N01CP31012 N; Grant sponsors: RERF Research Protocols 6-91 and 5-11, Japanese Ministry of Health, Labour and Welfare (MHLW) and the U.S. Department of Energy (DOE); Grant number: DE-HS0000031 NR 22 TC 33 Z9 37 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2013 VL 132 IS 5 BP 1222 EP 1226 DI 10.1002/ijc.27749 PG 5 WC Oncology SC Oncology GA 078AU UT WOS:000314071300025 PM 22847218 ER PT J AU Chang, CD Middeldorp, J Yu, KJ Juwana, H Hsu, WL Lou, PJ Wang, CP Chen, JY Liu, MY Pfeiffer, RM Chen, CJ Hildesheim, A AF Chang, Cindy Middeldorp, Jaap Yu, Kelly J. Juwana, Hedy Hsu, Wan-Lun Lou, Pei-Jen Wang, Cheng-Ping Chen, Jen-Yang Liu, Mei-Ying Pfeiffer, Ruth M. Chen, Chien-Jen Hildesheim, Allan TI Characterization of ELISA detection of broad-spectrum anti-Epstein-Barr virus antibodies associated with nasopharyngeal carcinoma SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE Epstein-Barr virus; EBNA1; VCA; IgA; nasopharyngeal carcinoma; screening ID RISK; FAMILIES; DIAGNOSIS; RESPONSES; INDIVIDUALS; COMBINATION; PROTEIN; TAIWAN; CHINA; DNASE AB EpsteinBarr virus (EBV) infection is associated with undifferentiated nasopharyngeal carcinomas (NPC). A distinct seroreactivity pattern to EBV is predictive of subsequent risk of sporadic and familial nasopharyngeal carcinomas. There are currently no accepted screening tools for guiding the clinical management of individuals at high-risk for nasopharyngeal carcinomas, particularly unaffected relatives from nasopharyngeal carcinoma multiplex families. Therefore, the reproducibility of a panel of largely synthetic peptide-based anti-EBV antibody ELISAs was evaluated and their ability to distinguish nasopharyngeal carcinoma cases from controls was explored. IgG and IgA antibodies against 6 different EBV antigens (10 assays, total) were tested on sera from 97 individuals representing the full spectrum of anti-EBV seroprevalence (i.e., healthy individuals with no known EBV seroreactivity, healthy individuals with known EBV seroreactivity, and nasopharyngeal carcinoma cases). Each specimen was tested in triplicate to assess within-batch and across-batch variation, and the triplicate testing was repeated on two separate days. Reproducibility was assessed by the coefficients of variation (CVs) and intraclass correlation coefficients (ICCs). All markers were detectable in 17% or more of samples. For all but one marker, the overall, within-batch, and across-batch CVs were below 15%, and the ICCs were above 70% for all but three markers. Sensitivity of these markers to detect prevalent nasopharyngeal carcinomas ranged from 22% to 100%, and among unaffected controls, most distinguished those with and without known seropositivity. In conclusion, a large number of EBV markers can be measured reliably in serum samples using peptide-based anti-EBV ELISAs. J. Med. Virol. 85:524529, 2013. Puiblished 2012. This is a US government work, and, as such, is in the public domain of The United States of America. C1 [Chang, Cindy; Yu, Kelly J.; Pfeiffer, Ruth M.; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD 20892 USA. [Middeldorp, Jaap; Juwana, Hedy] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Yu, Kelly J.] NCI, Canc Prevent Div, Dept Hlth & Human Serv, NIH, Rockville, MD 20892 USA. [Hsu, Wan-Lun; Chen, Chien-Jen] Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Taipei 10764, Taiwan. [Hsu, Wan-Lun; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Chen, Jen-Yang] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan Town, Miaoli County, Taiwan. [Liu, Mei-Ying] Natl Taipei Univ Nursing & Hlth Sci, Ctr Gen Educ, Taipei, Taiwan. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS 7066, Rockville, MD 20892 USA. EM hildesha@mail.nih.gov RI Chen, Chien-Jen/C-6976-2008; Hildesheim, Allan/B-9760-2015; Chen, Jen-Yang/D-2085-2010; OI Hildesheim, Allan/0000-0003-0257-2363; WANG, CHENG-PING/0000-0001-7872-1463; LOU, PEI-JEN/0000-0002-3383-8593; Middeldorp, Jaap/0000-0002-0765-4125 FU Intramural Research Program of the National Cancer Institute; National Institutes of Health FX Grant sponsor: Intramural Research Program of the National Cancer Institute; Grant sponsor: National Institutes of Health. NR 23 TC 3 Z9 4 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 EI 1096-9071 J9 J MED VIROL JI J. Med. Virol. PD MAR PY 2013 VL 85 IS 3 BP 524 EP 529 DI 10.1002/jmv.23498 PG 6 WC Virology SC Virology GA 076HH UT WOS:000313946600021 PM 23280934 ER PT J AU Freedman, BR Sheehan, FT AF Freedman, Benjamin R. Sheehan, Frances T. TI Predicting three-dimensional patellofemoral kinematics from static imaging-based alignment measures SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE patellofemoral joint; patellofemoral pain syndrome; magnetic resonance imaging; kinematics; Q-angle ID ANTERIOR KNEE PAIN; PATELLAR HEIGHT RATIOS; IN-VIVO; TIBIOFEMORAL KINEMATICS; QUADRICEPS CONTRACTION; COMPUTED-TOMOGRAPHY; WEIGHT-BEARING; FEMORAL SHAPE; JOINT; TRACKING AB Patellofemoral pain syndrome causes significant discomfort and disability among much of the general population. Despite recent breakthroughs in dynamic three-dimensional imaging technologies to assess pathological patellofemoral motion, such tools remain costly for clinical diagnostics applications. Thus, this study investigated whether three-dimensional patellofemoral kinematics could be predicted from routine two-dimensional static measures of patellofemoral joint alignment quantified from magnetic resonance imaging (MRI) data acquired in full knee extension. Twenty-six volunteers clinically diagnosed with patellofemoral pain (19 F/7 M, 25.9 +/- 11.1 years) and 26 control subjects (19 F/7 M, 25.3 +/- 7.7 years) were included in this IRB-approved study. Static three-dimensional sagittal T1-weighted gradient recall echo and dynamic MRI scans were acquired. For the dynamic image acquisition, subjects cyclically flexed and extended their knee (at 30?cycles/min) while a full cine-phase contrast MRI set (24 time frames of anatomic images and x-, y-, and z-velocity images) was acquired. From these data, static measures of patellofemoral alignment and three-dimensional patellofemoral kinematics were derived. Single and multiple regressions between static and kinematic variables were evaluated. Although shown reliable, the static MRI measures could only partially predict patellofemoral kinematics, with r2-values ranging from 16% to 77%. This makes it imperitave that the current precise, accurate, 3D, dynamic imaging techniques be translated into clinical tools. (C) 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 441447, 2013 C1 [Freedman, Benjamin R.; Sheehan, Frances T.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Sheehan, FT (reprint author), NIH, Dept Rehabil Med, CRC Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov RI sheehan, frances/B-6962-2009 FU NIH Clinical Center Intramural Research Program; National Institute of Biomedical Imaging and Bioengineering Intramural Program; Diagnostic Radiology Department at the NIH FX This research was supported by the NIH Clinical Center Intramural Research Program and the National Institute of Biomedical Imaging and Bioengineering Intramural Program. Special thanks is given to S. Sadeghi, A.J. Behnam, C. Zampieri-Gallagher, T.J. Brindle, CY Shieh, B. Damaska, and the Diagnostic Radiology Department at the NIH for their support and research time. NR 45 TC 11 Z9 13 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD MAR PY 2013 VL 31 IS 3 BP 441 EP 447 DI 10.1002/jor.22246 PG 7 WC Orthopedics SC Orthopedics GA 076TJ UT WOS:000313980600015 PM 23097251 ER PT J AU Muscal, JA Thompson, PA Horton, TM Ingle, AM Ahern, CH McGovern, RM Reid, JM Ames, MM Espinoza-Delgado, I Weigel, BJ Blaney, SM AF Muscal, Jodi A. Thompson, Patrick A. Horton, Terzah M. Ingle, Ashish M. Ahern, Charlotte H. McGovern, Renee M. Reid, Joel M. Ames, Matthew M. Espinoza-Delgado, Igor Weigel, Brenda J. Blaney, Susan M. TI A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: A Children's Oncology Group phase I consortium study (ADVL0916) SO PEDIATRIC BLOOD & CANCER LA English DT Article DE bortezomib; Children's Oncology Group; pediatric cancer; Phase I trial; solid tumors; vorinostat ID PROTEASOME INHIBITOR BORTEZOMIB; HISTONE DEACETYLASE INHIBITORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; PANCREATIC-CANCER CELLS; MULTIPLE-MYELOMA; HEMATOLOGIC MALIGNANCIES; ANTITUMOR-ACTIVITY; PEDIATRIC-PATIENTS; APOPTOSIS; COMBINATION AB Background A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors. Procedure Oral vorinostat was administered on days 15 and 812 of a 21-day cycle (starting dose 180 mg/m2/day with dose escalations to 230 and 300 mg/m2/day). Bortezomib (1.3 mg/m2 i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1. Results Twenty-three eligible patients [17 male, median age 12 years (range: 120)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m2/day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-kappa B activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients. Conclusion The recommended Phase 2 dose and schedule is vorinostat (230 mg/m2/day PO on days 15 and 812) in combination with bortezomib (1.3 mg/m2/day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors. Pediatr Blood Cancer 2013; 60: 390-395. (C) 2012 Wiley Periodicals, Inc. C1 [Muscal, Jodi A.; Thompson, Patrick A.; Horton, Terzah M.; Blaney, Susan M.] Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Muscal, Jodi A.; Thompson, Patrick A.; Horton, Terzah M.; Blaney, Susan M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Ingle, Ashish M.] Childrens Oncol Grp, Arcadia, CA USA. [Ahern, Charlotte H.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [McGovern, Renee M.; Reid, Joel M.; Ames, Matthew M.] Mayo Clin, Dept Oncol, Rochester, MN USA. [Espinoza-Delgado, Igor] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Weigel, Brenda J.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. RP Muscal, JA (reprint author), Texas Childrens Canc Ctr, 1102 Bates St,Suite 1220, Houston, TX 77030 USA. EM jamuscal@txch.org FU National Cancer Institute (NCI) Phase I/Pilot Consortium [U01 CA97452]; NCI Pediatric Clinical Oncology Research Training Program [5K12CA90433-09]; Kappa Alpha Theta Research Scholar Award; Carousel Faculty Research Scholar Award FX Grant sponsor: National Cancer Institute (NCI) Phase I/Pilot Consortium; Grant number: U01 CA97452; Grant sponsor: NCI Pediatric Clinical Oncology Research Training Program; Grant number: 5K12CA90433-09; Grant sponsor: Kappa Alpha Theta Research Scholar Award; Grant sponsor: Carousel Faculty Research Scholar Award. NR 43 TC 25 Z9 25 U1 0 U2 4 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2013 VL 60 IS 3 BP 390 EP 395 DI 10.1002/pbc.24271 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 073ET UT WOS:000313727000008 PM 22887890 ER PT J AU Kim, A Dombi, E Tepas, K Fox, E Martin, S Wolters, P Balis, FM Jayaprakash, N Turkbey, B Muradyan, N Choyke, PL Reddy, A Korf, B Widemann, BC AF Kim, AeRang Dombi, Eva Tepas, Kathleen Fox, Elizabeth Martin, Staci Wolters, Pamela Balis, Frank M. Jayaprakash, Nalini Turkbey, Baris Muradyan, Naira Choyke, Peter L. Reddy, Alyssa Korf, Bruce Widemann, Brigitte C. TI Phase I trial and pharmacokinetic study of sorafenib in children with neurofibromatosis type I and plexiform neurofibromas SO PEDIATRIC BLOOD & CANCER LA English DT Article DE neurofibromatosis type I; phase I; plexiform neurofibromas; sorafenib ID REFRACTORY SOLID TUMORS; FACTOR RECEPTOR INHIBITOR; DAYS ON/7 DAYS; SCHWANN-CELLS; RAF KINASE; HEPATOCELLULAR-CARCINOMA; GROWTH-PLATE; BAY-43-9006; SAFETY; NF1 AB Background Sorafenib targets multiple pathways thought to be crucial in growth of plexiform neurofibroma (PN) in children with neurofibromatosis type 1 (NF1). Sorafenib has been tolerated with manageable toxicities in adults and children with refractory cancer. We conducted a separate study in this population. Monitoring long-term toxicities such as effects on growth and obtaining additional pharmacokinetic data were of importance due to the young age and long duration of therapy seen in previous phase I trials in children with NF1. Procedure Children >= 3 and <= 18-year-old with NF1 and inoperable PN were eligible. Sorafenib was administered orally twice daily for consecutive 28-day cycles. Maximum tolerated dose (MTD) was determined from toxicities observed during the first three cycles. Results Nine children enrolled, median age 8 (612) years. At the starting 115 mg/m2/dose (n = 5), two experienced dose-limiting grade 3 pain in their PN. At the de-escalated 80 mg/m2/dose (n = 4), approximately 40% of the pediatric solid tumor MTD, two had dose-limiting toxicity (grade 3 rash and grade 4 mood alteration), exceeding the MTD. At 80 mg/m2/dose, the median AUC012 hours at steady-state was 39.5 mu g hours/ml. Toxicities appeared to correspond with decreases in quality of life (QOL). No tumor shrinkage was observed. Conclusions Children with NF1 and PN did not tolerate sorafenib at doses substantially lower than the MTD in children and adults with malignant solid tumors. Future trials with targeted agents for children with NF1 may require a more conservative starting dose and separate definitions of dose limiting toxicities (DLT) than children with cancer. Pediatr Blood Cancer 2013; 60: 396-401. (C) 2012 Wiley Periodicals, Inc. C1 [Kim, AeRang; Dombi, Eva; Tepas, Kathleen; Martin, Staci; Wolters, Pamela; Jayaprakash, Nalini; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, CCR, Bethesda, MD 20892 USA. [Kim, AeRang] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Fox, Elizabeth; Balis, Frank M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Muradyan, Naira] iCAD Inc, Nashua, NH USA. [Reddy, Alyssa] Univ Alabama Birmingham, Childrens Hosp, Birmingham, AL USA. [Korf, Bruce] Univ Alabama Birmingham, Birmingham, AL USA. RP Kim, A (reprint author), Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, 111 Michigan Ave NW, Washington, DC 20010 USA. EM aekim@childrensnational.org FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Children's Tumor Foundation Clinical Trial Award FX Grant sponsor: Intramural Research Program of the NIH; Grant sponsor: National Cancer Institute; Grant sponsor: Center for Cancer Research; Grant sponsor: Children's Tumor Foundation Clinical Trial Award. NR 48 TC 26 Z9 27 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2013 VL 60 IS 3 BP 396 EP 401 DI 10.1002/pbc.24281 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 073ET UT WOS:000313727000009 PM 22961690 ER PT J AU Brinkman, TM Zhang, N Ullrich, NJ Brouwers, P Green, DM Srivastava, DK Zeltzer, LK Stovall, M Robison, LL Krull, KR AF Brinkman, Tara M. Zhang, Nan Ullrich, Nicole J. Brouwers, Pim Green, Daniel M. Srivastava, Deo Kumar Zeltzer, Lonnie K. Stovall, Marilyn Robison, Leslie L. Krull, Kevin R. TI Psychoactive medication use and neurocognitive function in adult survivors of childhood cancer: A report from the childhood cancer survivor study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE neurocognition; psychoactive medication; survivorship ID ACUTE LYMPHOBLASTIC-LEUKEMIA; QUALITY-OF-LIFE; NEUROPSYCHOLOGICAL PERFORMANCE; VIGILANCE PERFORMANCE; REUPTAKE INHIBITION; HEALTHY-VOLUNTEERS; PEDIATRIC CANCER; ATTENTION; CHILDREN; DEFICITS AB Background Adult survivors of childhood cancer are at risk for long-term morbidities, which may be managed pharmacologically. Psychoactive medication treatment has been associated with adverse effects on specific neurocognitive processes in non-cancer populations, yet these associations have not been examined in adult survivors of childhood cancer. Procedure Outcomes were evaluated in 7,080 adult survivors from the Childhood Cancer Survivor Study (CCSS) using a validated self-report Neurocognitive Questionnaire. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for neurocognitive impairment using demographic and treatment factors and survivors' report of prescription medication use. Results Controlling for cranial radiation, pain, psychological distress, and stroke/seizure, use of antidepressant medications was associated with impaired task efficiency (OR = 1.80, 95% CI = 1.47-2.21), organization (OR = 1.83, 95% CI = 1.48-2.25), memory (OR = 1.53, 95% CI = 1.27-1.84), and emotional regulation (OR = 2.06, 95% CI = 1.70-2.51). Neuroleptics and stimulants were associated with impaired task efficiency (OR = 2.46, 95% CI = 1.29-4.69; OR = 2.82, 95% CI = 1.61-4.93, respectively) and memory (OR = 2.08, 95% CI = 1.13-3.82; OR = 2.69, 95% CI = 1.59-4.54, respectively). Anticonvulsants were associated with impaired task efficiency, memory, and emotional regulation, although survivors who use these medications may be at risk for neurocognitive impairment on the basis of seizure disorder and/or underlying tumor location (CNS). Conclusions These findings suggest that specific psychoactive medications and/or mental health conditions may be associated with neurocognitive function in adult survivors of childhood cancer. The extent to which these associations are causal or indicative of underlying neurological impairment for which the medications are prescribed remains to be ascertained. Pediatr Blood Cancer 2013; 60: 486-493. (C) 2012 Wiley Periodicals, Inc. C1 [Brinkman, Tara M.; Green, Daniel M.; Robison, Leslie L.; Krull, Kevin R.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Zhang, Nan; Srivastava, Deo Kumar] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Ullrich, Nicole J.] Childrens Hosp Boston, Dept Neurol, Boston, MA USA. [Brouwers, Pim] NIMH, Div AIDS Res, Rockville, MD 20857 USA. [Zeltzer, Lonnie K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. RP Brinkman, TM (reprint author), St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 262 Danny Thomas Pl,MS 735, Memphis, TN 38105 USA. EM tara.brinkman@stjude.org OI Zeltzer, Lonnie/0000-0001-9306-9450 FU National Cancer Institute [U24 CA 55727]; Cancer Center Support (CORE) [CA21765]; American Lebanese-Syrian Associated Charities (ALSAC) FX Grant sponsor: The National Cancer Institute; Grant number: U24 CA 55727; Grant sponsor: Cancer Center Support (CORE); Grant number: CA21765; Grant sponsor: The American Lebanese-Syrian Associated Charities (ALSAC). NR 49 TC 5 Z9 5 U1 0 U2 14 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2013 VL 60 IS 3 BP 486 EP 493 DI 10.1002/pbc.24255 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 073ET UT WOS:000313727000024 PM 22848025 ER PT J AU Zhang, LQ Sodt, AJ Venable, RM Pastor, RW Buck, M AF Zhang, Liqun Sodt, Alexander J. Venable, Richard M. Pastor, Richard W. Buck, Matthias TI Prediction, refinement, and persistency of transmembrane helix dimers in lipid bilayers using implicit and explicit solvent/lipid representations: Microsecond molecular dynamics simulations of ErbB1/B2 and EphA1 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE structure prediction; implicit solvent and lipid; Generalized Born model; replica exchange; receptor tyrosine kinases; solution NMR ID RECEPTOR TYROSINE KINASE; GLYCOPHORIN-A; PROTEIN STRUCTURES; MEMBRANE-PROTEINS; SPATIAL STRUCTURE; ALPHA-HELICES; FORCE-FIELD; FREE-ENERGY; DOMAIN; DIMERIZATION AB All-atom simulations are carried out on ErbB1/B2 and EphA1 transmembrane helix dimers in lipid bilayers starting from their solution/DMPC bicelle NMR structures. Over the course of microsecond trajectories, the structures remain in close proximity to the initial configuration and satisfy the majority of experimental tertiary contact restraints. These results further validate CHARMM protein/lipid force fields and simulation protocols on Anton. Separately, dimer conformations are generated using replica exchange in conjunction with an implicit solvent and lipid representation. The implicit model requires further improvement, and this study investigates whether lengthy all-atom molecular dynamics simulations can alleviate the shortcomings of the initial conditions. The simulations correct many of the deficiencies. For example, excessive helix twisting is eliminated over a period of hundreds of nanoseconds. The helix tilt, crossing angles, and dimer contacts approximate those of the NMR-derived structure, although the detailed contact surface remains off-set for one of two helices in both systems. Hence, even microsecond simulations are not long enough for extensive helix rotations. The alternate structures can be rationalized with reference to interaction motifs and may represent still sought after receptor states that are important in ErbB1/B2 and EphA1 signaling. Proteins 2013. (C) 2012 Wiley Periodicals, Inc. C1 [Buck, Matthias] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Sodt, Alexander J.; Venable, Richard M.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Buck, Matthias] Case Western Reserve Univ, Dept Neurosci, Cleveland, OH 44106 USA. [Buck, Matthias] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA. [Buck, Matthias] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. RP Buck, M (reprint author), Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM matthias.buck@case.edu RI Buck, Matthias/B-2106-2017 OI Buck, Matthias/0000-0002-2958-0403 FU ARRA [R01GM073071, R01GM092851, T32DK007470]; NIH, National Heart, Lung and Blood Institute; Teragrid [TG-MCB070074N]; NIH [MCB110023P, RC2GM0933307] FX Grant sponsor: ARRA Supplement to NIH; Grant numbers: R01GM073071 and R01GM092851 (to M.B. and L.Z.); as well as T32DK007470 (to L.Z.); Grant sponsor: Intramural Research Program of the NIH, National Heart, Lung and Blood Institute (to R.W.P., R.M.V., and A.J.S.); Grant sponsor: Teragrid; Grant number: TG-MCB070074N; Grant sponsor: NIH; Grant numbers: MCB110023P and RC2GM0933307 (to C.M.U.) NR 55 TC 11 Z9 11 U1 0 U2 55 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAR PY 2013 VL 81 IS 3 BP 365 EP 376 DI 10.1002/prot.24192 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 079OI UT WOS:000314179600001 PM 23042146 ER PT J AU Damjanovic, A Miller, BT Schleif, R AF Damjanovic, Ana Miller, Benjamin T. Schleif, Robert TI Understanding the basis of a class of paradoxical mutations in AraC through simulations SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE Langevin dynamics; molecular dynamics; hydrophobic cluster; in vivo measurements; AraC protein; gene regulation ID GUIDED LANGEVIN DYNAMICS; L-ARABINOSE SYSTEM; ESCHERICHIA-COLI; MOLECULAR-DYNAMICS; DIMERIZATION DOMAIN; POSITIVE CONTROL; SUGAR-BINDING; PROTEIN; OPERON; CONFORMATIONS AB Most mutations at position 15 in the N-terminal arm of the regulatory protein AraC leave the protein incapable of responding to arabinose and inducing the proteins required for arabinose catabolism. Mutations at other positions of the arm do not have this behavior. Simple energetic analysis of the interactions between the arm and bound arabinose do not explain the uninducibility of AraC with mutations at position 15. Extensive molecular dynamics (MD) simulations, carried out largely on the Open Science Grid, were done of the wild-type protein with and without bound arabinose and of all possible mutations at position 15, many of which were constructed and measured for this work. Good correlation was found for deviation of arm position during the simulations and inducibility as measured in vivo of the same mutant proteins. Analysis of the MD trajectories revealed that preservation of the shape of the arm is critical to inducibility. To maintain the correct shape of the arm, the strengths of three interactions observed to be strong in simulations of the wild-type AraC protein need to be preserved. These interactions are between arabinose and residue 15, arabinose and residues 89, and residue 13 and residue 15. The latter interaction is notable because residues L9, Y13, F15, W95, and Y97 form a hydrophobic cluster which needs to be preserved for retention of the correct shape. Proteins 2013. (C) 2012 Wiley Periodicals, Inc. C1 [Damjanovic, Ana] Johns Hopkins Univ, Dept Biophys, Baltimore, MD 21218 USA. [Damjanovic, Ana; Miller, Benjamin T.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Schleif, Robert] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Schleif, R (reprint author), Johns Hopkins Univ, Dept Biol, 3400 N Charles St, Baltimore, MD 21218 USA. EM schleif@jhu.edu OI Miller, Benjamin/0000-0003-1647-0122 FU NSF [1021031]; NIH; NHLBI; Open Science Grid; National Science Foundation; U.S. Department of Energy's Office of Science FX Grant sponsor: NSF; Grant number: 1021031 (R.S.); Grant sponsors: NIH, NHLBI, Open Science Grid; Grant sponsors: National Science Foundation and the U.S. Department of Energy's Office of Science NR 47 TC 2 Z9 2 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 J9 PROTEINS JI Proteins PD MAR PY 2013 VL 81 IS 3 BP 490 EP 498 DI 10.1002/prot.24207 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 079OI UT WOS:000314179600012 PM 23150197 ER PT J AU Minig, L Velez, JI Trimble, EL Biffi, R Maggioni, A Jeffery, DD AF Minig, Lucas Velez, Jorge Ivan Trimble, Edward L. Biffi, Roberto Maggioni, Angelo Jeffery, Diana D. TI Changes in short-term health-related quality of life in women undergoing gynecologic oncologic laparotomy: an associated factor analysis SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Quality of life; Gynecologic cancer; Laparotomy ID OVARIAN-CANCER; SURGERY; RELIABILITY; VALIDITY; OUTCOMES AB The primary purpose of this study is to evaluate health-related quality of life (HR-QOL) of gynecologic cancer patients undergoing laparotomy. Women who underwent laparotomy by gynecologic cancer completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaires (QLQaEuroC30 and QLQaEuroOV28) presurgery and at 1 month. Of the 181 women studied between January 2007 and March 2008, 116 women (64.1 %) had ovarian cancer, 27 (14.9 %) had cervical cancer, and 29 (16.0 %) had endometrial cancer. By 1 month post-surgery, there was a significant decrease in HR-QOL on the global, abdominal/gastrointestinal (GI) score, body image, chemotherapy side effects, and other single items of the OV28 questionnaire, as well as on physical, role and social functioning, fatigue, nausea and vomiting, pain, insomnia, constipation, appetite loss, and financial difficulties items on C30 questionnaires. Emotional functioning on C30 questionnaires was significantly improved 1 month after surgery. The majority of these items persisted 1 month after surgery only in patients with ovarian cancer. Abdominal/GI score on OV28 questionnaires as well as role and physical functioning on C30 questionnaires were significantly lower between baseline and postsurgical HR-QOL in women with other gynecologic malignancies. The results suggest a significant impact of HR-QOL among gynecologic cancer patients 1 month after laparotomy, particularly among those with ovarian cancer. C1 [Minig, Lucas; Maggioni, Angelo] European Inst Oncol, Dept Gynecol, Milan, Italy. [Minig, Lucas] Hosp Univ Madrid Sanchinarro, Gynecol Oncol Program, CIOCC, Madrid 28050, Spain. [Trimble, Edward L.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Velez, Jorge Ivan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Biffi, Roberto] European Inst Oncol, Abdominopelv Surg Dept, Milan, Italy. [Jeffery, Diana D.] Dept Def, Off Assistant Secretary Def Hlth Affairs, TRICARE Management Act Hlth Program Anal & Evalua, Falls Church, VA 22041 USA. RP Minig, L (reprint author), Hosp Univ Madrid Sanchinarro, Gynecol Oncol Program, CIOCC, Calle Ona 10, Madrid 28050, Spain. EM lucasminig@yahoo.com FU National Human Genome Research Institute, National Institutes of Health FX The authors thank Carmen Beltrami, RN; Emanuella D'Anna; and all the nursing staff of the Gynecologic Department, European Institute of Oncology, Milan, Italy for their active participation in the execution of this study. Finally, the authors recognize the great efforts made by Anna Attanasio (Anesthesiology Department, European Institute of Oncology, Milan, Italy) and Maira Bigioggero (data manager, Gynecologic Department, European Institute of Oncology, Milan, Italy) in retrieving the data. This research was supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 18 TC 6 Z9 6 U1 1 U2 7 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 MAR PY 2013 VL 21 IS 3 BP 715 EP 726 DI 10.1007/s00520-012-1571-z PG 12 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 081FD UT WOS:000314301900007 PM 22930239 ER PT J AU Hong, SP Fuciarelli, AF Johnson, JD Graves, SW Bates, DJ Waidyanatha, S Smith, CS AF Hong, S. Peter Fuciarelli, Alfred F. Johnson, Jerry D. Graves, Steven W. Bates, Derrick J. Waidyanatha, Suramya Smith, Cynthia S. TI Toxicokinetics of methyleugenol in F344 rats and B6C3F(1) mice SO XENOBIOTICA LA English DT Article DE Methyleugenol; toxicokinetics; bioavailability ID NATURALLY-OCCURRING ALKENYLBENZENES; UNSCHEDULED DNA-SYNTHESIS; SAFROLE; EUGENOL; GENOTOXICITY; DERIVATIVES; CHEMICALS; TOXICITY; OIL; MUTAGENICITY AB 1. Methyleugenol (MEG) has been used as a flavouring agent in food, as a fragrance in cosmetic products, and as an insect attractant. MEG was carcinogenic in both rats and mice following gavage administration. In this study we investigated plasma toxicokinetics of MEG in F344 rats and B6C3F(1) mice of both sexes following single gavage (37, 75, or 150 mg/kg) and intravenous (IV) (37 mg/kg) administration. 2. Following IV administration, MEG was rapidly distributed and cleared from the systemic circulation in both species and sexes. Absorption of MEG was rapid following gavage administration with secondary peaks in the plasma MEG concentration-versus-time profiles. C-max and AUC(T) increased and the clearance decreased greater than proportional to the dose in rats and mice of both sexes. In general, rats had higher internal exposure to MEG than mice. 3. The results for AUC(T) and clearance suggest that perhaps the metabolism of MEG is saturated at higher doses tested in this study. Absolute bioavailability following gavage administration of 37 mg/kg was low in both rats (similar to 4%) and mice (7-9%) of both sexes indicating extensive first-pass metabolism. There was no sex difference in plasma toxicokinetics of MEG following gavage administration both in rats and mice. C1 [Hong, S. Peter; Johnson, Jerry D.; Graves, Steven W.] Battelle Mem Inst, Columbus, OH 43201 USA. [Fuciarelli, Alfred F.] Valdosta State Univ, Valdosta, GA USA. [Bates, Derrick J.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Waidyanatha, Suramya; Smith, Cynthia S.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Hong, SP (reprint author), Battelle Mem Inst, 505 King Ave, Columbus, OH 43201 USA. EM hongs@battelle.org NR 44 TC 1 Z9 1 U1 1 U2 17 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD MAR PY 2013 VL 43 IS 3 BP 293 EP 302 DI 10.3109/00498254.2012.711496 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 083PC UT WOS:000314476000008 PM 22876784 ER PT J AU Dogan, RI Gil, Y Hirsh, H Krishnan, NC Lewis, M Mericli, C Rashidi, P Raskin, V Swarup, S Sun, W Taylor, JM Yeganova, L AF Dogan, Rezarta Islamaj Gil, Yolanda Hirsh, Haym Krishnan, Narayanan C. Lewis, Michael Mericli, Cetin Rashidi, Parisa Raskin, Victor Swarup, Samarth Sun, Wei Taylor, Julia M. Yeganova, Lana TI Reports on the 2012 AAAI Fall Symposium Series SO AI MAGAZINE LA English DT Article AB The Association for the Advancement of Artificial Intelligence was pleased to present the 2012 Fall Symposium Series, held Friday through Sunday, November 2-4, at the Westin Arlington Gateway in Arlington, Virginia. The titles of the eight symposia were as follows: AI for Gerontechnology (FS-12-01), Artificial Intelligence of Humor (FS-12-02), Discovery Informatics: The Role of AI Research in Innovating Scientific Processes (FS-12-03), Human Control of Bio-Inspired Swarms (FS-12-04), Information Retrieval and Knowledge Discovery in Biomedical Text (FS-12-05), Machine Aggregation of Human judgment (FS-12-06), Robots Learning Interactively from Human Teachers (FS-12-07), and Social Networks and Social Contagion (FS-12-08). The highlights of each symposium are presented in this report. C1 [Dogan, Rezarta Islamaj; Yeganova, Lana] Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Gil, Yolanda] Univ So Calif, Inst Informat Sci, Los Angeles, CA 90089 USA. [Hirsh, Haym] Rutgers State Univ, Dept Comp Sci, Piscataway, NJ 08855 USA. [Krishnan, Narayanan C.] Washington State Univ, Sch Elect Engn & Comp Sci, Pullman, WA 99164 USA. [Lewis, Michael] Univ Pittsburgh, Sch Informat Sci, Pittsburgh, PA 15260 USA. [Mericli, Cetin] Carnegie Mellon Univ, Dept Comp Sci, Pittsburgh, PA 15213 USA. [Rashidi, Parisa] Northwestern Univ, Feinberg Sch Med, Biomed Informat Div, Evanston, IL 60208 USA. [Raskin, Victor; Taylor, Julia M.] Purdue Univ, W Lafayette, IN 47907 USA. [Swarup, Samarth] Virginia Inst Technol, Virginia Bioinformat Inst, Blacksburg, VA USA. [Sun, Wei] George Mason Univ, Ctr Excellence Command Control Commun Comp & Inte, Fairfax, VA 22030 USA. RP Dogan, RI (reprint author), Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC ARTIFICIAL INTELL PI MENLO PK PA 445 BURGESS DRIVE, MENLO PK, CA 94025-3496 USA SN 0738-4602 J9 AI MAG JI AI Mag. PD SPR PY 2013 VL 34 IS 1 BP 93 EP 100 PG 8 WC Computer Science, Artificial Intelligence SC Computer Science GA AI5FV UT WOS:000336891700011 ER PT J AU Quick, VM McWilliams, R Byrd-Bredbenner, C AF Quick, Virginia M. McWilliams, Rita Byrd-Bredbenner, Carol TI Fatty, Fatty, Two-by-Four: Weight-Teasing History and Disturbed Eating in Young Adult Women SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID DISORDER EXAMINATION QUESTIONNAIRE; BODY-IMAGE; LONGITUDINAL FINDINGS; ANOREXIA-NERVOSA; ADOLESCENT GIRLS; RISK-FACTORS; PROJECT EAT; PREVALENCE; BEHAVIORS; PREDICTORS AB Objective. We investigated the long-term effect of weight teasing during childhood. Methods. Young adult women (n = 1533; aged 18-26 years) from 3 large universities participated in a survey (Fall 2009 to Spring 2010) that assessed disturbed eating behaviors; weight status at ages 6, 12, and 16 years; and weight-teasing history. Results. Nearly half of the participants were weight-teased as a child. Participants who experienced childhood weight teasing were significantly more likely to have disturbed eating behaviors now than non-weight-teased peers. As the variety of weight teasing insults recalled increased, so did disturbed eating behaviors and current body mass index. Those who recalled their weight at ages 6, 12, or 16 years as being heavier than average endured weight teasing significantly more frequently and felt greater distress than their lighter counterparts. Conclusions. Weight teasing may contribute to the development of disturbed eating and eating disorders in young women. Health care professionals, parents, teachers, and other childcare givers must help shift social norms to make weight teasing as unacceptable as other types of bullying. To protect the health of children, efforts to make weight teasing unacceptable are warranted. C1 [Quick, Virginia M.; Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. [McWilliams, Rita] Rutgers State Univ, Food Policy Inst, New Brunswick, NJ 08903 USA. RP Quick, VM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Bethesda, MD 20892 USA. EM gingermquick@gmail.com RI Byrd-Bredbenner, Carol/F-8064-2015; OI Byrd-Bredbenner, Carol/0000-0002-8010-3987; Quick, Virginia/0000-0002-4338-963X FU Kappa Omicron Nu Research Fellowship FX Funding for this study was provided by the Kappa Omicron Nu Research Fellowship. NR 51 TC 10 Z9 10 U1 6 U2 20 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2013 VL 103 IS 3 BP 508 EP 515 DI 10.2105/AJPH.2012.300898 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA0CL UT WOS:000330762600037 PM 23327257 ER PT J AU Beckjord, EB Rutten, LJF Blake, K Moser, RP Naveed, S Hesse, BW AF Beckjord, Ellen B. Rutten, Lila J. Finney Blake, Kelly Moser, Richard P. Naveed, Sana Hesse, Bradford W. TI TRENDS IN THE AMERICAN PUBLIC'S USE OF, BELIEFS ABOUT, AND ATTITUDES TOWARD INFORMATION TECHNOLOGY IN HEALTH CARE SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Beckjord, Ellen B.] Univ Pittsburgh, Pittsburgh, PA 15232 USA. [Blake, Kelly; Moser, Richard P.; Naveed, Sana; Hesse, Bradford W.] NCI, Bethesda, MD 20892 USA. [Rutten, Lila J. Finney] Mayo Clin, Rochester, MN USA. EM beckjorde@upmc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3027 BP S155 EP S155 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001183 ER PT J AU Chou, WYS Prestin, A Naveed, S AF Chou, Wen-ying Sylvia Prestin, Abby Naveed, Sana TI SOCIAL MEDIA FOR HEALTH: DATA FROM HINTS 4 SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Chou, Wen-ying Sylvia; Prestin, Abby; Naveed, Sana] NCI, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. EM chouws@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3028 BP S156 EP S156 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001184 ER PT J AU Czajkowski, SM AF Czajkowski, Susan M. TI OBESITY RELATED BEHAVIORAL INTERVENTION TRIALS ( ORBIT): TRANSLATING BASIC BEHAVIORAL & SOCIAL SCIENCES DISCOVERIES INTO INTERVENTIONS TO REDUCE OBESITY SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Czajkowski, Susan M.] NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. EM Czajkows@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2060 BP S70 EP S70 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000273 ER PT J AU Czajkowski, SM Grenard, JL Carcone, AI Spring, BJ AF Czajkowski, Susan M. Grenard, Jerry L. Carcone, April I. Spring, Bonnie J. TI USING DATA ON MECHANISMS OF BEHAVIOR CHANGE TO DEVELOP OBESITY INTERVENTIONS: FINDINGS FROM THE OBESITY-RELATED BEHAVIORAL INTERVENTION TRIALS (ORBIT) SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Czajkowski, Susan M.] NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Grenard, Jerry L.] Claremont Grad Univ, Sch Community & Global Hlth, Claremont, CA USA. [Carcone, April I.] Wayne State Univ, Dept Pediat Prevent Res, Detroit, MI USA. [Spring, Bonnie J.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. EM Czajkows@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2059 BP S70 EP S70 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000272 ER PT J AU Damschroder, L Spring, B Goodrich, DE Glasgow, RE AF Damschroder, Laura Spring, Bonnie Goodrich, David E. Glasgow, Russell E. TI TRANSLATION OF NON-TRADITIONAL LIFESTYLE BEHAVIOR CHANGE INTERVENTIONS INTO REAL-WORLD CLINICAL SETTINGS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Damschroder, Laura; Goodrich, David E.] Ann Arbor VA Ctr Clin Management Res, Diabet QUERI, Ann Arbor, MI 48113 USA. [Spring, Bonnie] Northwestern Univ, Psychiat & Behav Sci, Chicago, IL 60611 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM laura.-damschroder@va.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2022 BP S60 EP S60 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000235 ER PT J AU Dunton, GF Schembre, S Huh, J Riley, W AF Dunton, Genevieve F. Schembre, Susan Huh, Jimi Riley, William TI ADVANCEMENTS IN ECOLOGICAL MOMENTARY ASSESSMENT (EMA) METHODS FOR HEALTH BEHAVIOR RESEARCH SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Dunton, Genevieve F.; Huh, Jimi] Univ Southern Calif, Prevent Med, Los Angeles, CA 90033 USA. [Schembre, Susan] UT MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX USA. [Riley, William] NCI, Sci Res & Technol Branch, Rockville, MD USA. EM dunton@usc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3055 BP S164 EP S164 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001216 ER PT J AU Eggly, S Meert, K AF Eggly, Susan Meert, Kathleen TI FEASIBILITY AND ACCEPTABILITY OF PHYSICIAN-PARENT MEETINGS AFTER A CHILD'S DEATH IN A PEDIATRIC INTENSIVE CARE UNIT (PICU) SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Eggly, Susan] Wayne State Univ, Detroit, MI 48201 USA. [Meert, Kathleen] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Meert, Kathleen] NICHD, Collaborat Pediat Crit Care Res Network, Detroit, MI USA. EM egglys@karmanos.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA A-126 BP S32 EP S32 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000125 ER PT J AU Elwood, WN Jonas, S Lee, E Kulinowski, K Nek, R AF Elwood, William N. Jonas, Seth Lee, Elizabeth Kulinowski, Kristen Nek, Rashida TI BASIC RESEARCH, MULTIPLE IMPLICATIONS: AN ANALYSIS OF THE NATIONAL INSTITUTES OF HEALTH OPPNET PORTFOLIO SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Elwood, William N.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Jonas, Seth; Lee, Elizabeth; Kulinowski, Kristen; Nek, Rashida] Sci & Technol Policy Inst, Washington, DC USA. EM william.elwood@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA B-139 BP S130 EP S130 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001081 ER PT J AU Fisher, EB Thom, DH Safford, M Heisler, M Glasgow, RE AF Fisher, Edwin B. Thom, David H. Safford, Monika Heisler, Michele Glasgow, Russell E. TI OUTCOMES OF PEER SUPPORT PROGRAMS FOR DIABETES MANAGEMENT PEERS FOR PROGRESS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Fisher, Edwin B.] Univ North Carolina Chapel Hill, Hlth Behav, Chapel Hill, NC 27599 USA. [Fisher, Edwin B.] Amer Acad Family Phys Fdn, Peers Progress, Leawood, KS USA. [Thom, David H.] Univ Calif San Francisco, Dept Family & Community Med, San Francisco, CA 94143 USA. [Safford, Monika] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Heisler, Michele] Univ Michigan, Ann Arbor, MI 48109 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3030 BP S156 EP S156 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001186 ER PT J AU Fitzpatrick, SL Glasgow, RE Johnson, SB Jones, KR Vogel, M AF Fitzpatrick, Stephanie L. Glasgow, Russell E. Johnson, Suzanne Bennett Jones, Kenneth R. Vogel, Mark TI INTEGRATED CARE TEAM APPROACHES FOR TREATMENT OF OBESITY SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Fitzpatrick, Stephanie L.] Johns Hopkins Sch Med, Div Gen Internal Med, Welch Ctr, Baltimore, MD USA. [Glasgow, Russell E.] NCI, Implementat Sci Div Canc Control & Populat Sci, Rockville, MD USA. [Johnson, Suzanne Bennett] Amer Psychol Assoc, Washington, DC 20036 USA. [Jones, Kenneth R.] Natl Ctr Hlth Promot & Dis Prevent, VHA Off Patient Care Serv, Durham, NC USA. [Vogel, Mark] Michigan State Univ, Dept Family Med, E Lansing, MI 48824 USA. EM sfitzpa8@jhmi.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3038 BP S158 EP S158 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001194 ER PT J AU Fuemmeler, BF Nilsen, W AF Fuemmeler, Bernard F. Nilsen, Wendy TI MOBILE AND WEB-BASED SERIOUS GAMES FOR BEHAVIOR CHANGE IN CHILD AND ADOLESCENT POPULATIONS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Fuemmeler, Bernard F.] Duke Univ Hlth Syst, Commun & Family Med & Psychol & Neurosci, Durham, NC 27710 USA. [Nilsen, Wendy] NIH, Bethesda, MD 20892 USA. EM bernard.fuemmeler@duke.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2063 BP S71 EP S71 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000276 ER PT J AU Glasgow, RE Kessler, R Krist, A Rodriguez, H Heurtin-Roberts, S AF Glasgow, Russell E. Kessler, Rodger Krist, Alex Rodriguez, Hector Heurtin-Roberts, Suzanne TI INTEGRATED CARE TEAMS: DEFINITION, EXAMPLES AND NECESSARY TOOLS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Glasgow, Russell E.; Heurtin-Roberts, Suzanne] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Kessler, Rodger] Univ Vermont, Coll Med, Dept Family Med, Berlin, VT USA. [Krist, Alex] Virginia Commonwealth Univ, Dept Family Med, Richmond, VA USA. [Rodriguez, Hector] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3040 BP S159 EP S159 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001196 ER PT J AU Gorin, SS Haggstrom, D Fairfield, K Han, P Heurtin-Roberts, S Finke, B Burke, M Clauser, S AF Gorin, Sherri Sheinfeld Haggstrom, David Fairfield, Kathleen Han, Paul Heurtin-Roberts, Suzanne Finke, Bruce Burke, Matthew Clauser, Steve CA Work Grp Qccc Cci TI A SYSTEMATIC REVIEW OF CANCER CARE COORDINATION: APPROACH AND PRELIMINARY FINDINGS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Gorin, Sherri Sheinfeld] Columbia Univ, NCI, SAIC, New York, NY 10027 USA. [Haggstrom, David] VA HSR&D Ctr Excellence Implementing Evidence Bas, Indianapolis, IN USA. [Fairfield, Kathleen; Han, Paul] Maine Med Ctr, CORE, Scarborough, ME USA. [Clauser, Steve] NCI, ORB, ARP, DCCPS, Bethesda, MD 20892 USA. [Finke, Bruce] IHS, Elder Care Initiat, Indian Hlth Serv, Northampton, MA USA. [Heurtin-Roberts, Suzanne] NCI, Implementat Sci, DCCPS, Bethesda, MD 20892 USA. [Burke, Matthew] Franklin Sq, Residency Fac, Baltimore, MD USA. [Work Grp Qccc Cci] NCI, QCCC CCI Work Grp, ORB, ARP,DCCPS, Bethesda, MD 20892 USA. EM sherri.gorin@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2084 BP S76 EP S76 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000297 ER PT J AU Gorin, SS McDonald, K Han, P Haggstrom, D Clauser, S AF Gorin, Sherri Sheinfeld McDonald, Kathryn Han, Paul Haggstrom, David Clauser, Steve TI COORDINATING CANCER CARE: WHAT HAVE WE LEARNED FROM TWENTY YEARS OF EMPIRICAL STUDIES? SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Gorin, Sherri Sheinfeld] Columbia Univ, NCI, SAIC, New York, NY 10027 USA. [Clauser, Steve] NCI, ORB, ARP, DCCPS, Bethesda, MD 20892 USA. [Haggstrom, David] VA HSR&D Ctr Excellence Implementing Evidence Bas, Indianapolis, IN USA. [Han, Paul] Maine Med Ctr, Res Inst, Ctr Outcomes Res & Evaluat, Scarborough, ME USA. [McDonald, Kathryn] Stanford Univ, CHP PCOR, Stanford, CA 94305 USA. EM sherri.gorin@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2081 BP S75 EP S75 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000294 ER PT J AU Hartigan, DB Viswanath, K AF Hartigan, Danielle Blanch Viswanath, Kasisomayajula TI CANCER SURVIVORS' USE OF MULTIPLE INFORMATION SOURCES FOR CANCER-RELATED INFORMATION: THE MORE THE MERRIER? SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Hartigan, Danielle Blanch] NCI, Off Canc Survivorship, Rockville, MD 20892 USA. [Viswanath, Kasisomayajula] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Viswanath, Kasisomayajula] Harvard Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA USA. EM danielleblanch@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA B-017 BP S101 EP S101 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000396 ER PT J AU Hartigan, DB Viswanath, K AF Hartigan, Danielle Blanch Viswanath, Kasisomayajula TI SOCIOECONOMIC AND SOCIODEMOGRAPHIC PREDICTORS OF SOURCES OF CANCER-RELATED INFORMATION USED BY CANCER SURVIVORS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Hartigan, Danielle Blanch] NCI, Off Canc Survivorship, Rockville, MD 20892 USA. [Viswanath, Kasisomayajula] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Viswanath, Kasisomayajula] Harvard Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA USA. EM danielleblanch@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA B-016 BP S101 EP S101 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000395 ER PT J AU Hesse, BW Rutten, LJF Chou, WY Beckjord, EB Chirstensen, A AF Hesse, Bradford W. Rutten, Lila J. Finney Chou, Wen-ying (Sylvia) Beckjord, Ellen B. Chirstensen, Alan TI QUANTIFYING THE HEALTH INFORMATION REVOLUTION SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Hesse, Bradford W.; Chou, Wen-ying (Sylvia)] NCI, Behav Res Program, Rockville, MD 20852 USA. [Beckjord, Ellen B.] Univ Pittsburgh, Pittsburgh, PA USA. [Rutten, Lila J. Finney] Mayo Clin, Rochester, MN USA. [Chirstensen, Alan] Univ Iowa, Psychol, Iowa City, IA USA. EM hesseb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3026 BP S155 EP S155 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001182 ER PT J AU Hunt, Y AF Hunt, Yvonne TI THE SMOKEFREE APPROACH TO CESSATION: TOOLS, TECHNOLOGIES & STRATEGIES FOR ENGAGEMENT SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Hunt, Yvonne] NIH, Bethesda, MD 20892 USA. EM Yvonne.hunt@nih.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3070 BP S168 EP S168 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001231 ER PT J AU Kaufman, A AF Kaufman, Annette TI APPROACHES TO STUDYING AND UNDERSTANDING TOBACCO RISK PERCEPTIONS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufman, Annette] NCI, Rockville, MD USA. EM kaufmana@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3083 BP S171 EP S171 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001244 ER PT J AU Kaufman, A Cameron, LD Peters, E Rothman, A Klein, W AF Kaufman, Annette Cameron, Linda D. Peters, Ellen Rothman, Alex Klein, William CA CTP TI SOCIAL POLICY PANEL ON CIGARETTE GRAPHIC WARNING LABELS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufman, Annette; Klein, William] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Cameron, Linda D.] Univ Calif Merced, Psychol, Merced, CA USA. [Peters, Ellen] Ohio State Univ, Psychol, Columbus, OH 43210 USA. [Rothman, Alex] Univ Minnosota, Psychol, Minneapolis, MN USA. [CTP] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. EM kaufmana@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2054 BP S68 EP S68 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000267 ER PT J AU Keefe, B Prestin, A Blake, K Beckjord, E AF Keefe, Brian Prestin, Abby Blake, Kelly Beckjord, Ellen TI UTILIZING SOCIAL MEDIA TO ENGAGE A COMMUNITY OF HEALTH DATA USERS: A CASE STUDY USING HINTS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Keefe, Brian; Prestin, Abby; Blake, Kelly] NCI, Rockville, MD 20852 USA. [Beckjord, Ellen] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. EM bpkeefe@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA D-130 BP S288 EP S288 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928002107 ER PT J AU Kirkpatrick, S Subar, AF Mittl, B Zimmerman, T Thompson, FE Bingley, C Willis, G Potischman, N AF Kirkpatrick, Sharon Subar, Amy F. Mittl, Beth Zimmerman, Thea Thompson, Fran E. Bingley, Christopher Willis, Gordon Potischman, Nancy TI USING THE WEB TO ENHANCE DIETARY ASSESSMENT: THE AUTOMATED SELF-ADMINISTERED 24-HOUR DIETARY RECALL (ASA24) SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kirkpatrick, Sharon; Subar, Amy F.; Thompson, Fran E.; Willis, Gordon; Potischman, Nancy] NCI, Bethesda, MD 20892 USA. [Mittl, Beth; Zimmerman, Thea; Bingley, Christopher] Westat Corp, Bethesda, MD USA. EM kirkpatricksi@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA C-095 BP S213 EP S213 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001408 ER PT J AU Koblitz, AR Kaufman, A Park, E Klein, W Ferrer, R AF Koblitz, Amber R. Kaufman, Annette Park, Elyse Klein, William Ferrer, Rebecca TI LUNG CANCER-RELATED RISK PERCEPTIONS IN THE NATIONAL LUNG SCREENING TRIAL: RELIABILITY AND PREDICTION ACROSS TIME SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Koblitz, Amber R.; Kaufman, Annette; Klein, William; Ferrer, Rebecca] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Park, Elyse] Massachusetts Gen Hosp, Dept Psychiat, Ctr Canc, Boston, MA 02114 USA. EM amber.koblitz@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3084 BP S171 EP S171 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001245 ER PT J AU Kobrin, S Tanaka, M Han, P Sepucha, K Naveed, S Moser, R AF Kobrin, Sarah Tanaka, Miho Han, Paul Sepucha, Karen Naveed, Sana Moser, Richard TI SHARED DECISION MAKING MEASURES: PROMOTING HARMONIZED DATA USING THE NATIONAL CANCER INSTITUTE'S GRID-ENABLED MEASURES (GEM) PORTAL SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kobrin, Sarah; Tanaka, Miho; Naveed, Sana; Moser, Richard] NCI, Rockville, MD 20852 USA. [Han, Paul] Maine Med Ctr, Scarborough, ME USA. [Sepucha, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM miho.tanaka@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3047 BP S161 EP S161 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001203 ER PT J AU McNeely, JM Gamaldo, AA Shah, MT Waldstein, SR Evans, MK Zonderman, AB AF McNeely, Jessica M. Gamaldo, Alyssa A. Shah, Mauli T. Waldstein, Shari R. Evans, Michele K. Zonderman, Alan B. TI INFLUENCES OF POVERTY AND EDUCATION ON SELF-REPORTED SLEEP IN URBAN DWELLING RESIDENTS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [McNeely, Jessica M.; Shah, Mauli T.; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Psychol, Baltimore, MD 21228 USA. [McNeely, Jessica M.; Gamaldo, Alyssa A.; Shah, Mauli T.; Evans, Michele K.; Zonderman, Alan B.] NIA, Baltimore, MD 21224 USA. [Waldstein, Shari R.] Univ Maryland, Sch Med, Dept Med, Div Gerontol, Baltimore, MD 21201 USA. EM mcneelyj@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA D-191 BP S302 EP S302 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928002163 ER PT J AU Moser, RP Naveed, S Liu, B Yu, MD Rutten, LF Blake, K Riley, W AF Moser, Richard P. Naveed, Sana Liu, Benmei Yu, Mandi Rutten, Lila F. Blake, Kelly Riley, William TI APPLYING INTEGRATIVE DATA ANALYTIC METHODS TO POPULATION-LEVEL CROSS-SECTIONAL SURVEY DATA SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Moser, Richard P.; Naveed, Sana; Liu, Benmei; Yu, Mandi; Blake, Kelly; Riley, William] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rutten, Lila F.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. EM moserr@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 1003 BP S1 EP S1 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000004 ER PT J AU Nansel, TR Lipsky, LM Iannotti, RJ AF Nansel, Tonja R. Lipsky, Leah M. Iannotti, Ronald J. TI A LONGITUDINAL EXAMINATION OF GENERAL AND DIABETES-SPECIFIC PARENTING IN RELATION TO DIABETES OUTCOMES AND QUALITY OF LIFE SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Nansel, Tonja R.; Lipsky, Leah M.; Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA B-050 BP S109 EP S109 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000427 ER PT J AU Nguyen, AB Clark, TT AF Nguyen, Anh B. Clark, Trenette T. TI THE MODERATING ROLE OF ACCULTURATION ON COLLECTIVIST ATTITUDES AND CANCER SCREENING VARIABLES AMONG VIETNAMESE WOMEN SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Nguyen, Anh B.] NCI, Bethesda, MD 20892 USA. [Clark, Trenette T.] Univ N Carolina, Chapel Hill, NC USA. EM bao2no1@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA A-001 BP S4 EP S4 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000011 ER PT J AU Nigg, C Clark, D AF Nigg, Claudio Clark, David TI INNOVATIVE APPROACHES TO ORAL HEALTH IN CHILDREN SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Nigg, Claudio] Univ Hawaii, Publ Hlth Sci, Honolulu, HI 96822 USA. [Clark, David] Natl Inst Dent & Craniofacial Res, Behav & Social Sci Res Branch, NIH, Bethesda, MD USA. EM cnigg@hawaii.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3091 BP S173 EP S173 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001252 ER PT J AU Nilsen, W Evans, WD Jordan, J Hunt, Y AF Nilsen, Wendy Evans, W. Douglas Jordan, Jeff Hunt, Yvonne TI MARKETING HEALTH SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Nilsen, Wendy; Hunt, Yvonne] NIH, Bethesda, MD 20892 USA. [Jordan, Jeff] Rescue Social Change, San Diego, CA USA. [Evans, W. Douglas] George Washington Univ, Washington, DC USA. EM nilsenwj@od.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3067 BP S167 EP S167 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001228 ER PT J AU Nilsen, W AF Nilsen, Wendy TI NIH ADHERENCE RESEARCH NETWORK: A ROUNDTABLE DISCUSSION ON HOW TO ADVANCE THE SCIENCE AND PRACTICE OF ADHERENCE SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Nilsen, Wendy] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. EM nilsenwj@od.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3053 BP S162 EP S162 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001209 ER PT J AU Nilsen, W Czajkowski, S Stirratt, M Fitzsimmons, S Patrick, H Simoni, J Keefe, F Kiernan, M AF Nilsen, Wendy Czajkowski, Susan Stirratt, Michael Fitzsimmons, Stacey Patrick, Heather Simoni, Jane Keefe, Francis Kiernan, Michaela TI NIH GRANT WRITING SEMINAR FOR EARLY CAREER RESEARCHERS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Nilsen, Wendy; Czajkowski, Susan; Stirratt, Michael; Fitzsimmons, Stacey; Patrick, Heather] NIH, Bethesda, MD 20892 USA. [Kiernan, Michaela] Stanford Univ, Stanford, CA 94305 USA. [Keefe, Francis] Duke Univ, Chapel Hill, NC USA. [Simoni, Jane] Univ Washington, Seattle, WA 98195 USA. EM nilsenwj@od.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 1002 BP S1 EP S1 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000003 ER PT J AU Palmer, NR Weaver, KE Andrykowski, M Parry, C AF Palmer, Nynikka R. Weaver, Kathryn E. Andrykowski, Michael Parry, Carly TI UNDERSTUDIED AND UNDERSERVED: CANCER SURVIVORS LIVING IN RURAL AREAS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Palmer, Nynikka R.; Weaver, Kathryn E.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Andrykowski, Michael] Univ Kentucky, Coll Med, Dept Behav Sci, Lexington, KY 40536 USA. [Parry, Carly] NCI, Off Canc Survivorship, Behav Res Program, Bethesda, MD 20892 USA. EM npalmer@wakehealth.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3075 BP S169 EP S169 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001236 ER PT J AU Phillips, SM McAuley, E AF Phillips, Siobhan M. McAuley, Edward TI PHYSICAL ACTIVITYAND WEIGHT CHANGES PRE- AND POST-BREAST CANCER DIAGNOSIS: IMPACT ON HEALTH OUTCOMES SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Phillips, Siobhan M.; McAuley, Edward] Univ Illinois, Kinesiol & Community Hlth, Urbana, IL 61801 USA. [Phillips, Siobhan M.] NCI, Off Canc Survivorship, Bethesda, MD 20852 USA. EM siobhan.white@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA B-022 BP S102 EP S102 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000401 ER PT J AU Phillips, SM McAuley, E AF Phillips, Siobhan M. McAuley, Edward TI PHYSICAL ACTIVITY AND QUALITY OF LIFE IN A BREAST CANCER SURVIVORS: A PANEL ANALYSIS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Phillips, Siobhan M.; McAuley, Edward] Univ Illinois, Kinesiol & Community Hlth, Urbana, IL 61801 USA. [Phillips, Siobhan M.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. EM siobhan.white@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA A-175 BP S44 EP S44 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000172 ER PT J AU Prestin, A Chou, WYS AF Prestin, Abby Chou, Wen-ying Sylvia TI EXPLORING PUBLIC DISCOURSE ABOUT OBESITY ACROSS SOCIAL MEDIA PLATFORMS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Prestin, Abby; Chou, Wen-ying Sylvia] NCI, Hlth Commun & Informat Res Branch, Bethesda, MD 20852 USA. EM abigail.prestin@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA D-117 BP S285 EP S285 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928002095 ER PT J AU Rabin, BA Glasgow, RE AF Rabin, Borsika A. Glasgow, Russell E. TI GENERALIZABILITY AND DISSEMINATION OF EHEALTH INTERVENTIONS (EHIS) SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Rabin, Borsika A.] Kaiser Permanente Colorado, Denver, CO 80231 USA. [Glasgow, Russell E.] NCI, Bethesda, MD 20892 USA. EM borsika.a.rabin@gmail.com FU NCI [1P20 CA137219] FX This study was funded through NCI 1P20 CA137219. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2093 BP S78 EP S78 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000306 ER PT J AU Ramirez, AS Galica, K Chou, WYS Blake, K Hesse, B AF Ramirez, A. Susana Galica, Kasia Chou, Wen-Ying Sylvia Blake, Kelly Hesse, Bradford TI CANCER COMMUNICATION FUNDING TRENDS, 2000-2012 SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Ramirez, A. Susana; Galica, Kasia; Chou, Wen-Ying Sylvia; Blake, Kelly; Hesse, Bradford] NCI, Behav Res Program, North Bethesda, MD 20892 USA. EM ramirezas@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA D-017 BP S262 EP S262 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928002002 ER PT J AU Riley, W Michie, S West, R Strecher, V Rothman, A AF Riley, William Michie, Susan West, Robert Strecher, Victor Rothman, Alexander TI APPLICATION OF HEALTH BEHAVIOR THEORY TO TECHNOLOGY-DELIVERED INTERVENTIONS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Riley, William] NCI, Sci Res & Technol Branch, Rockville, MD 20852 USA. [Michie, Susan] UCL, Dept Clin Educ & Hlth Psychol, London, England. [West, Robert] UCL, Dept Epidemiol & Publ Hlth, London, England. [Strecher, Victor] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Rothman, Alexander] Univ Minnesota, Dept Psychol, Minneapolis, MN USA. EM wiriley@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2099 BP S80 EP S80 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000312 ER PT J AU Robinson, C Pickworth, W Heishman, S Waters, A AF Robinson, Cendrine Pickworth, Wallace Heishman, Stephen Waters, Andrew TI AFRICAN AMERICAN SMOKERS REPORT GREATER ATTENTIONAL BIAS TO SMOKING CUES THAN WHITE SMOKERS: IMPLICATIONS FOR SMOKING CESSATION SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Robinson, Cendrine; Waters, Andrew] Uniformed Serv Univ Hlth Sci, Washington, DC 20002 USA. [Pickworth, Wallace] Battelle Ctr Publ Hlth Res & Evaluat, Baltimore, MD USA. [Heishman, Stephen] NIDA, Intramural Res Program, Baltimore, MD USA. EM crobinson@usuhs.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA D-200 BP S304 EP S304 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928002172 ER PT J AU Rutten, LJ Arora, N Beckjord, EB Moser, RP Hesse, BW AF Rutten, Lila J. Arora, Neeraj Beckjord, Ellen Burke Moser, Richard P. Hesse, Bradford W. TI USE OF ELECTRONIC HEALTH RECORDS AND RATINGS OF CARE QUALITY SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Rutten, Lila J.; Hesse, Bradford W.] Mayo Clin, Populat Hlth, Ctr Sci Hlth Care Delivery, Dept Hlth Sci Res,Div Epidemiol, Rochester, MN 55905 USA. [Arora, Neeraj; Moser, Richard P.] NCI, Bethesda, MD 20892 USA. [Beckjord, Ellen Burke] Univ Pittsburgh, Pittsburgh, PA USA. EM Rutten.Lila@mayo.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3029 BP S156 EP S156 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001185 ER PT J AU Salsman, JM Sanford, SD Smith, AW AF Salsman, John M. Sanford, Stacy D. Smith, Ashley W. TI UNDERSTANDING YOUNG ADULT CANCER PATIENTS AND SURVIVORS: SYMPTOM MANAGEMENT, HEALTH-RELATED QUALITY OF LIFE, AND HEALTH BEHAVIORS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Salsman, John M.; Sanford, Stacy D.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Smith, Ashley W.] NCI, Bethesda, MD 20892 USA. EM j-salsman@northwestern.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2014 BP S58 EP S58 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000227 ER PT J AU Shaikh, AR Mullen, S Ritterband, LM Fair, A Shen, B AF Shaikh, Abdul R. Mullen, Sean Ritterband, Lee M. Fair, Alex Shen, Bern TI TRANSLATIONAL PIPELINES FOR EVIDENCE-BASED DIGITAL HEALTH SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Shaikh, Abdul R.] NCI, Bethesda, MD 20892 USA. [Ritterband, Lee M.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Fair, Alex] MedStartr, New York, NY USA. [Shen, Bern] HealthCrowd, San Francisco, CA USA. [Mullen, Sean] Univ Illinois, Urbana, IL USA. EM shaikhab@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3054 BP S162 EP S162 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001210 ER PT J AU Smith, AW Bellizzi, KM Zebrack, B Kent, EE Lynch, C Chen, V Neale, AV Keegan, TM AF Smith, Ashley W. Bellizzi, K. M. Zebrack, B. Kent, E. E. Lynch, C. Chen, V. Neale, A. V. Keegan, T. M. TI HEALTH-RELATED QUALITY OF LIFE OF ADOLESCENT AND YOUNG ADULT CANCER PATIENTS IN THE UNITED STATES SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Smith, Ashley W.; Kent, E. E.] NCI, Bethesda, MD 20892 USA. [Bellizzi, K. M.] Univ Connecticut, Storrs, CT USA. [Zebrack, B.] Univ Michigan, Ann Arbor, MI 48109 USA. [Lynch, C.] Univ Iowa, Iowa City, IA USA. [Chen, V.] Louisiana State Univ, New Orleans, LA USA. [Neale, A. V.] Wayne State Univ, Detroit, MI USA. [Keegan, T. M.] Canc Prevent Inst Calif, Fremont, CA USA. EM smithas@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 2016 BP S59 EP S59 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928000229 ER PT J AU Tagai, EK Holt, CL Atkinson, N Bowie, J Scheirer, MA Santos, SLZ Haider, M Slade, J Wang, MQ Whitehead, T AF Tagai, Erin K. Holt, Cheryl L. Atkinson, Nancy Bowie, Janice Scheirer, Mary Ann Santos, Sherie Lou Z. Haider, Muhiuddin Slade, Jimmie Wang, Min Qi Whitehead, Tony TI INSTRUMENT DEVELOPMENT TO ASSESS ORGANIZATIONAL FACTORS IN FAITH-BASED SETTINGS PARTNERING IN HEALTH INTERVENTIONS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Tagai, Erin K.; Holt, Cheryl L.; Santos, Sherie Lou Z.; Haider, Muhiuddin; Wang, Min Qi; Whitehead, Tony] Univ Maryland, College Pk, MD 20742 USA. [Scheirer, Mary Ann] Scheirer Consulting, Princeton, NJ USA. [Slade, Jimmie] Community Minist Prince Georges Cty, Upper Marlboro, MD USA. [Bowie, Janice] Johns Hopkins Univ, Hlth Behav & Soc, Baltimore, MD USA. [Atkinson, Nancy] NCI, Off Market Res & Evaluat, Rockville, MD USA. EM ekelly7@umd.edu FU National Cancer Institute [1 R01 CA147313] FX This research is funded by the National Cancer Institute (#1 R01 CA147313). NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA B-093 BP S119 EP S119 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001039 ER PT J AU Tanaka, M Juon, HS Xue, QL Bowie, J Nelson, K AF Tanaka, Miho Juon, Hee-Soon Xue, Qian-Li Bowie, Janice Nelson, Kenrad TI A BEHAVIORAL PATHWAY ANALYSIS FOR HEPATITIS B SCREENING AMONG ASIAN AMERICANS SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Tanaka, Miho] NCI, Rockville, MD 20852 USA. [Juon, Hee-Soon; Bowie, Janice; Nelson, Kenrad] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Xue, Qian-Li] Johns Hopkins Sch Med, Baltimore, MD USA. EM miho.tanaka@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA D-025 BP S264 EP S264 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928002010 ER PT J AU Tanaka, M Kobrin, S Portnoy, D Moser, R AF Tanaka, Miho Kobrin, Sarah Portnoy, David Moser, Richard TI SHARED DECISION MAKING (SDM) PREVALENCE FOR MAMMOGRAPHY SCREENING AMONG WOMEN AGED 40 TO 49 YEARS: THE 2011-12 HEALTH INFORMATION NATIONAL TRENDS SURVEY(HINTS4) SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Tanaka, Miho; Kobrin, Sarah; Moser, Richard] NCI, Rockville, MD 20852 USA. [Portnoy, David] US FDA, Rockville, MD 20857 USA. EM miho.tanaka@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA D-026 BP S264 EP S264 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928002011 ER PT J AU Waters, EA Janssen, E Kaufman, AR Peterson, LM Musanell, NL Guadagno, RE Stock, ML AF Waters, Erika A. Janssen, Eva Kaufman, Annette R. Peterson, Laurel M. Musanell, Nicole L. Guadagno, Rosanna E. Stock, Michelle L. TI BELIEFS ABOUT NICOTINE ADDICTION AND PERCEPTIONS OF DELAYED HARM OF CIGARETTE SMOKING: IMPLICATIONS FOR FEELINGS OF RISK AND INTENTIONS TO QUIT SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Waters, Erika A.] Washington Univ, St Louis, MO 63110 USA. [Janssen, Eva] Maastricht Univ, Maastricht, Netherlands. [Kaufman, Annette R.] NCI, Rockville, MD USA. [Peterson, Laurel M.; Stock, Michelle L.] George Washington Univ, Washington, DC USA. [Musanell, Nicole L.; Guadagno, Rosanna E.] Univ Alabama, Tuscaloosa, AL USA. EM waterse@wudosis.wustl.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA 3085 BP S172 EP S172 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001246 ER PT J AU Yeo, S Logan, J Thompson, W Thomas, M AF Yeo, SeonAe Logan, Jeongok Thompson, Wanda Thomas, Monecia TI DURATION OF EXERCISE, WORK, AND SEDENTARY ACTIVITIES OF LOW-INCOME PREGNANT SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Yeo, SeonAe; Thompson, Wanda] Univ North Carolina Chapel Hill, Chapel Hill, NC 27599 USA. [Logan, Jeongok] NINR, Bethesda, MD 20892 USA. [Thomas, Monecia] Yadkin Cty Hlth Dept, Yadkinville, NC USA. EM syeo@email.unc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD MAR PY 2013 VL 45 SU 2 MA C-164 BP S229 EP S229 PG 1 WC Psychology, Multidisciplinary SC Psychology GA V47BT UT WOS:000209928001472 ER PT J AU Shah, SJ Heitner, JF Sweitzer, NK Anand, IS Kim, HY Harty, B Boineau, R Clausell, N Desai, AS Diaz, R Fleg, JL Gordeev, I Lewis, EF Markov, V O'Meara, E Kobulia, B Shaburishvili, T Solomon, SD Pitt, B Pfeffer, MA Li, R AF Shah, Sanjiv J. Heitner, John F. Sweitzer, Nancy K. Anand, Inder S. Kim, Hae-Young Harty, Brian Boineau, Robin Clausell, Nadine Desai, Akshay S. Diaz, Rafael Fleg, Jerome L. Gordeev, Ivan Lewis, Eldrin F. Markov, Valetin O'Meara, Eileen Kobulia, Bondo Shaburishvili, Tamaz Solomon, Scott D. Pitt, Bertram Pfeffer, Marc A. Li, Rebecca TI Baseline Characteristics of Patients in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial SO CIRCULATION-HEART FAILURE LA English DT Article DE aldosterone; diastolic heart failure; mineralocorticoid receptor; randomized controlled trial; spironolactone ID QUALITY-OF-LIFE; VENTRICULAR EJECTION FRACTION; SYSTOLIC FUNCTION; DIASTOLIC FUNCTION; HYPERTENSIVE PATIENTS; SPIRONOLACTONE; MORTALITY; HEALTH; QUESTIONNAIRE; IRBESARTAN AB Background-Treatment of Preserved Cardiac Function with an Aldosterone Antagonist (TOPCAT) is an ongoing randomized controlled trial of spironolactone versus placebo for heart failure with preserved ejection fraction (HFpEF). We sought to describe the baseline clinical characteristics of subjects enrolled in TOPCAT relative to other contemporary observational studies and randomized clinical trials of HFpEF. Methods and Results-Between August 2006 and January 2012, 3445 patients with symptomatic HFpEF from 270 sites in 6 countries were enrolled in TOPCAT. At the baseline study visit, all subjects provided a detailed medical history and underwent physical examination, electrocardiography, quality of life, and laboratory assessment. Key parameters were compared with other large, contemporary HFpEF studies. The mean age was 68.6+/-9.6 years with a slight female predominance (52%); mean body mass index was 32 kg/m(2); and comorbidities were common. History of hypertension (91% prevalence in TOPCAT) exceeded all other major HFpEF clinical trials. However, baseline blood pressure was well controlled (129/76 mm Hg; systolic blood pressure 7-16 mm Hg lower than other similar trials). Other common comorbidities included coronary artery disease (57%), atrial fibrillation (35%), chronic kidney disease (38%) and diabetes mellitus (32%). Self-reported activity levels were low, quality of life scores were comparable with those reported for patients with end-stage renal disease, and the prevalence of moderate or greater depression was 27%. Conclusions-TOPCAT subjects share many common characteristics with contemporary HFpEF cohorts. Low activity level, significantly decreased quality of life, and depression were common at baseline in TOPCAT, underscoring the continued unmet need for evidence-based treatment strategies in HFpEF. C1 [Shah, Sanjiv J.] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA. [Heitner, John F.] New York Methodist Hosp, Div Cardiol, Brooklyn, NY USA. [Sweitzer, Nancy K.] Univ Wisconsin, Dept Med, Div Cardiol, Madison, WI USA. [Anand, Inder S.] VA Med Ctr, Minneapolis, MN USA. [Anand, Inder S.] Univ Minnesota, Minneapolis, MN USA. [Kim, Hae-Young; Harty, Brian; Li, Rebecca] New England Res Inst, Watertown, MA 02172 USA. [Boineau, Robin; Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Clausell, Nadine] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Desai, Akshay S.; Lewis, Eldrin F.; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Diaz, Rafael] Estudios Clin Latinoamer, Rosario, Santa Fe, Argentina. [Gordeev, Ivan] State Healthcare Inst Moscow, Moscow, Russia. [Markov, Valetin] Res Cardiol Inst Tomsk Sci Ctr, Tomsk, Russia. [O'Meara, Eileen] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Kobulia, Bondo] Inst Cardiol, Tbilisi, Rep of Georgia. [Shaburishvili, Tamaz] Diagnost Serv Clin, Tbilisi, Rep of Georgia. [Pitt, Bertram] Univ Michigan, Ann Arbor, MI 48109 USA. RP Shah, SJ (reprint author), Northwestern Univ, Heart Failure Preserved Eject Fract Program, Div Cardiol, Dept Med,Feinberg Sch Med, 676 N St Clair St,Suite 600, Chicago, IL 60611 USA. EM sanjiv.shah@northwestern.edu RI Clausell, Nadine /C-7813-2016 OI Clausell, Nadine /0000-0003-4207-3809 FU National Institutes of Health, National Heart, Lung, and Blood Institute [N01 HC45207] FX The study was supported by a grant from the National Institutes of Health, National Heart, Lung, and Blood Institute (N01 HC45207). NR 41 TC 49 Z9 50 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAR PY 2013 VL 6 IS 2 BP 184 EP 192 DI 10.1161/CIRCHEARTFAILURE.112.972794 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA8YP UT WOS:000331381200011 PM 23258572 ER PT J AU Ho, JE Lyass, A Lee, DS Vasan, RS Kannel, WB Larson, MG Levy, D AF Ho, Jennifer E. Lyass, Asya Lee, Douglas S. Vasan, Ramachandran S. Kannel, William B. Larson, Martin G. Levy, Daniel TI Predictors of New-Onset Heart Failure Differences in Preserved Versus Reduced Ejection Fraction SO CIRCULATION-HEART FAILURE LA English DT Article DE ejection fraction; epidemiology; heart failure; risk factors ID VENTRICULAR SYSTOLIC FUNCTION; CLINICAL CHARACTERISTICS; RISK; EPIDEMIOLOGY; FRAMINGHAM; POPULATION; COMMUNITY; DIAGNOSIS; DISEASE; HEALTH AB Background-About one half of patients with heart failure (HF) have preserved ejection fraction (HFPEF) rather than reduced ejection fraction (HFREF). The differences in risk factors predisposing to the 2 subtypes of HF are poorly understood. We sought to identify clinical predictors of new-onset HF and to explore differences in HFPEF versus HFREF. Methods and Results-We studied new-onset HF cases between 1981 and 2008 in Framingham Heart Study participants, classified into HFPEF and HFREF (ejection fraction >45% versus <= 45%). We used Cox multivariable regression to examine predictors of 8-year risk of incident HF and competing-risks analysis to identify predictors that differed between HFPEF and HFREF. Among 6340 participants (60+/-12 years) with 97 808 person-years of follow-up, 512 developed incident HF. Of 457 participants with left ventricular ejection fraction evaluation at the time of HF diagnosis, 196 (43%) were classified as HFPEF and 261 (56%) as HFREF. Fourteen predictors of overall HF were identified. Older age, diabetes mellitus, and a history of valvular disease predicted both types of HF (P=0.0025 for all). Higher body mass index, smoking, and atrial fibrillation predicted HFPEF only, whereas male sex, higher total cholesterol, higher heart rate, hypertension, cardiovascular disease, left ventricular hypertrophy, and left bundle-branch block predicted risk of HFREF. Conclusions-Although multiple risk factors preceded overall HF, distinct clusters of risk factors determine risk for new-onset HFPEF versus HFREF. This knowledge may enable the design of clinical trials of targeted prevention and the introduction of therapeutic strategies for prevention of HF and its 2 major subtypes. C1 [Ho, Jennifer E.; Lyass, Asya; Vasan, Ramachandran S.; Kannel, William B.; Larson, Martin G.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ho, Jennifer E.; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Ho, Jennifer E.] Boston Univ, Med Ctr, Dept Med, Cardiovasc Med Sect, Boston, MA USA. [Lyass, Asya; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Lee, Douglas S.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Lee, Douglas S.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. RP Levy, D (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nhlbi.nih.gov RI Lee, Douglas/J-4315-2014; OI Larson, Martin/0000-0002-9631-1254; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association Clinical Research Program award; Canadian Institutes of Health Research FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Drs Ho and Levy, contract No. N01-HC-25195). Dr Ho is supported by an American Heart Association Clinical Research Program award. Dr Lee is supported by a clinician-scientist award from the Canadian Institutes of Health Research. NR 39 TC 54 Z9 56 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAR PY 2013 VL 6 IS 2 BP 279 EP + DI 10.1161/CIRCHEARTFAILURE.112.972828 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA8YP UT WOS:000331381200023 PM 23271790 ER PT J AU Taiwo, B Barcena, L Tressler, R AF Taiwo, Babafemi Barcena, Luis Tressler, Randall TI Understanding and Controlling Chronic Immune Activation in the HIV-Infected Patients Suppressed on Combination Antiretroviral Therapy SO CURRENT HIV/AIDS REPORTS LA English DT Article DE Immune activation; HIV; Microbial translocation; Combination antiretroviral therapy (cART); Co-infections; HIV pathogenesis and treatment; Chronic immune activation ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL-ACTIVATION; RANDOMIZED CONTROLLED-TRIAL; MULTICENTER AIDS COHORT; RALTEGRAVIR INTENSIFICATION; MICROBIAL TRANSLOCATION; RHEUMATOID-ARTHRITIS; VIRAL LOAD; DECOMPENSATED CIRRHOSIS; PROVIRAL DNA AB Combination antiretroviral therapy (cART) has resulted in tremendous gains in survival among HIV-infected patients, but as a group those who achieve undetectable viral loads on cARTexperience a greater degree of immune activation and inflammation than the general population. HIV-infected patients continue to experience premature immune senescence with earlier and more frequent non-AIDS events compared to HIV-uninfected individuals. Chronic immune activation during suppressive cART derives from a variety of sourcesmediated by cytokines, chemokines, coagulation, microbial translocation, immune regulators and Teffector cell activation abnormalities, among others. Current investigational strategies to control immune activation target potential causes of persistently heightened immune activation during cART such as microbial translocation, co-infections, and comorbidities or mediators along a common final pathway. Although several interventions have shown promise in vitro or in preliminary clinical trials, no intervention has sufficient evidence for routine use, making control of immune activation during cART an unmet need. C1 [Taiwo, Babafemi; Barcena, Luis] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Tressler, Randall] Henry Jackson Fdn Adv Mil Med, Div AIDS NIAID NIH, Bethesda, MD 20892 USA. RP Taiwo, B (reprint author), Northwestern Univ, Feinberg Sch Med, Div Infect Dis, 645 North Michigan Ave,Suite 900, Chicago, IL 60611 USA. EM b-taiwo@northwestern.edu; Luis-Barcena@fsm.northwestern.edu; randall.tressler@nih.gov FU National Institute of Allergy and Infectious Disease, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Disease, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C NR 100 TC 15 Z9 15 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD MAR PY 2013 VL 10 IS 1 BP 21 EP 32 DI 10.1007/s11904-012-0147-3 PG 12 WC Infectious Diseases SC Infectious Diseases GA AJ7SV UT WOS:000337898300004 PM 23225316 ER PT J AU Quick, VM Byrd-Bredbenner, C AF Quick, Virginia M. Byrd-Bredbenner, Carol TI Eating Disorders Examination Questionnaire (EDE-Q): norms for US college students SO EATING AND WEIGHT DISORDERS-STUDIES ON ANOREXIA BULIMIA AND OBESITY LA English DT Article DE EDE-Q; College students; Eating disorders; Norms; Disordered eating ID SELF-REPORT QUESTIONNAIRE; ANOREXIA-NERVOSA; INTERVIEW; ADOLESCENTS AB Purpose To present normative data for the Eating Disorders Examination Questionnaire, 6th edition (EDE-Q) from a large (n = 2,448), diverse (56 % White) sample of college students. Methods Participants completed the EDE-Q online. Mean scores and percentile ranks for global and subscale (restraint and eating, weight, and shape concerns) scores and binge eating and inappropriate compensatory behavior (dietary restraint, self-induced vomiting, medicine misuse, excessive exercise) frequencies were computed. Results Women had higher global and subscale scores and tended to engage in inappropriate compensatory behaviors more often than men. Women with clinically significant restraint, and eating, shape, and weight concerns scores equaled 5.4, 2.0, 18.6, and 13.0 %, respectively, and, for men, equaled 3.0, 0.3, 6.0, and 2.0 %. Compared with less diverse samples, women in this study had significantly higher shape concern and lower restraint and eating concern scores and men had lower shape and weight concern scores. Conclusions Normative data from this diverse sample can help healthcare professionals and researchers better interpret EDE-Q scores. C1 [Quick, Virginia M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. RP Quick, VM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. EM gingermquick@gmail.com; bredbenner@aesop.rutgers.edu RI Byrd-Bredbenner, Carol/F-8064-2015; OI Byrd-Bredbenner, Carol/0000-0002-8010-3987; Quick, Virginia/0000-0002-4338-963X FU Kappa Omicron Nu Research Fellowship FX This study was funded by Kappa Omicron Nu Research Fellowship. NR 32 TC 8 Z9 9 U1 3 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1124-4909 EI 1590-1262 J9 EAT WEIGHT DISORD-ST JI Eat. Weight Disord.-Stud. Anorex. PD MAR PY 2013 VL 18 IS 1 BP 29 EP 35 DI 10.1007/s40519-013-0015-1 PG 7 WC Psychiatry SC Psychiatry GA AA0PL UT WOS:000330797600005 PM 23757248 ER PT J AU Jurek, B Slattery, DA Liu, Y Neumann, ID Aguilera, G van den Burg, EH AF Jurek, B. Slattery, D. A. Liu, Y. Neumann, I. D. Aguilera, G. van den Burg, E. H. TI Oxytocin controls CRF gene expression through TORC3: implications for stress-related disorders SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Jurek, B.; Slattery, D. A.; Neumann, I. D.; van den Burg, E. H.] Univ Regensburg, Dept Neurobiol & Anim Physiol, D-93053 Regensburg, Germany. [Liu, Y.; Aguilera, G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrine Physiol, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2013 VL 23 SU 1 MA P.1.006 BP S7 EP S8 PG 3 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40HQ UT WOS:000209470100009 ER PT J AU Pati, D Pietrzak, MP Harvey, TE Armstrong, WB Clarke, R Weissman, NJ Rapp, PE Smith, MS Fairbanks, RJ Collins, JMG AF Pati, Debajyoti Pietrzak, Michael P. Harvey, Thomas E., Jr. Armstrong, Walter B. Clarke, Robert Weissman, Neil J. Rapp, Paul E. Smith, Mark S. Fairbanks, Rollin J. Collins, Jeffrey M. G. TI Advancing Translational Research through Facility Design in Non-AMC Hospitals SO HERD-HEALTH ENVIRONMENTS RESEARCH & DESIGN JOURNAL LA English DT Article DE Hospital; interdisciplinary; leadership; planning; work environment AB OBJECTIVE: This article aims to explore the future of translational research and its physical design implications for community hospitals and hospitals not attached to large centralized research platforms. BACKGROUND: With a shift in medical services delivery focus to community wellness, continuum of care, and comparative effectiveness research, healthcare research will witness increasing pressure to include community-based practitioners. METHODS: The roundtable discussion group, comprising 14 invited experts from 10 institutions representing the fields of biomedical research, research administration, facility planning and design, facility management, finance, and environmental design research, examined the issue in a structured manner. The discussion was conducted at the Washington Hospital Center, MedStar Health, Washington, D.C. CONCLUSIONS: Institutions outside the AMCs will be increasingly targeted for future research. Three factors are crucial for successful research in non-AMC hospitals: operational culture, financial culture, and information culture. An operating culture geared towards creation, preservation, and protection of spaces needed for research; creative management of spaces for financial accountability; and a flexible information infrastructure at the system level that enables complete link of key programmatic areas to academic IT research infrastructure are critical to success of research endeavors. C1 [Pati, Debajyoti] Texas Tech Univ, Dept Design, Lubbock, TX 79409 USA. [Harvey, Thomas E., Jr.] HKS Inc, Atlanta, GA USA. [Armstrong, Walter B.] NIH, Facil Planner, Off Res Facil, Bethesda, MD USA. [Clarke, Robert] Georgetown Univ, Washington, DC 20057 USA. [Rapp, Paul E.] Uniformed Serv Univ Hlth Sci, Traumat Injury Res Program, Bethesda, MD USA. RP Pati, D (reprint author), Texas Tech Univ, Dept Design, Lubbock, TX 79409 USA. EM d.pati@ttu.edu RI Clarke, Robert/A-6485-2008 OI Clarke, Robert/0000-0002-9278-0854 FU NIBIB NIH HHS [K08 EB009090] NR 10 TC 0 Z9 0 U1 0 U2 1 PU VENDOME GROUP LLC PI NEW YORK PA 6 EAST 32 ST, 8 FLOOR, NEW YORK, NY 10016 USA SN 1937-5867 EI 2167-5112 J9 HERD-HEALTH ENV RES JI Herd-Health Env. Res. Des. J. PD SPR PY 2013 VL 6 IS 3 BP 126 EP 137 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AN9LY UT WOS:000340929500010 PM 23817911 ER PT J AU McDonald, CL Benson, J Cornetta, K Diggins, M Johnston, JC Sepelak, S Wang, GS Wilson, JM Wright, JF Skarlatos, SI AF McDonald, Cheryl L. Benson, Janet Cornetta, Kenneth Diggins, Margaret Johnston, Julie C. Sepelak, Susan Wang, Gensheng Wilson, James M. Wright, J. Fraser Skarlatos, Sonia I. TI Advancing Translational Research Through the NHLBI Gene Therapy Resource Program (GTRP) SO HUMAN GENE THERAPY CLINICAL DEVELOPMENT LA English DT Review ID NIH AB Translational research is a lengthy, complex, and necessary endeavor in order to bring basic science discoveries to clinical fruition. The NIH offers several programs to support translational research including an important resource established specifically for gene therapy researchers-the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program (GTRP). This paper reviews the core components of the GTRP and describes how the GTRP provides researchers with resources that are critical to advancing investigational gene therapy products into clinical testing. C1 [McDonald, Cheryl L.; Skarlatos, Sonia I.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Benson, Janet; Wang, Gensheng] Lovelace Biomed & Environm Res Inst, Albuquerque, NM 87108 USA. [Cornetta, Kenneth] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Diggins, Margaret; Sepelak, Susan] Social & Sci Syst, Silver Spring, MD 20910 USA. [Johnston, Julie C.; Wilson, James M.] Univ Penn, Dept Pathol & Lab Med, Gene Therapy Program, Philadelphia, PA 19104 USA. [Wright, J. Fraser] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA USA. [Wright, J. Fraser] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP McDonald, CL (reprint author), NHLBI, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8114, Bethesda, MD 20892 USA. EM mcdonalc@nhlbi.nih.gov FU NHLBI [HHSN2682012000041, HHSN2682012000051, HHSN2622012000031, HHSN268200041C]; NHLBI (Clinical Coordinating Center) [HHSN2682012000021] FX The authors recognize and thank the other members of the GTRP Core teams and the NHLBI Gene Therapy Group: Ms. Jenee Bevett, Mr. Eric Daniels, Ms. Nora Rivera, and Drs. Ray Ebert, Pankaj Qasba, Rita Sarkar, and Susan Schlegel. Sources of funding: Each GTRP Core component is supported under a contract with the NHLBI as follows: AAV Core (HHSN2682012000041); Clinical Coordinating Center (HHSN2682012000021); Lentivirus Core (HHSN2682012000051); Pharmacology/Toxicology Core (HHSN2622012000031); Preclinical Core (HHSN268200041C). NR 9 TC 3 Z9 3 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2324-8637 EI 2324-8645 J9 HUM GENE THER CL DEV JI Hum. Gene Ther. Clin. Dev. PD MAR PY 2013 VL 24 IS 1 BP 5 EP 10 DI 10.1089/humc.2013.036 PG 6 WC Biotechnology & Applied Microbiology; Critical Care Medicine; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; General & Internal Medicine; Research & Experimental Medicine GA AD0QT UT WOS:000332939900002 PM 23692378 ER PT J AU Sorkness, CA Wildfire, JJ Calatroni, A Mitchell, HE Busse, WW O'Connor, GT Pongracic, JA Ross, K Gill, MA Kattan, M Morgan, WJ Teach, SJ Gergen, PJ Liu, AH Szefler, SJ AF Sorkness, Christine A. Wildfire, Jeremy J. Calatroni, Agustin Mitchell, Herman E. Busse, William W. O'Connor, George T. Pongracic, Jacqueline A. Ross, Kristie Gill, Michelle A. Kattan, Meyer Morgan, Wayne J. Teach, Stephen J. Gergen, Peter J. Liu, Andrew H. Szefler, Stanley J. TI Reassessment of Omalizumab-Dosing Strategies and Pharmacodynamics in Inner-City Children and Adolescents SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Asthma exacerbations; Biomarkers; Dosing regimens; Inhaled corticosteroids; Omalizumab; Pharmacodynamics; Response predictors AB BACKGROUND: Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment. OBJECTIVES: Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers. METHODS: Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks. RESULTS: Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy. CONCLUSIONS: A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE > 1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection. (C) 2013 American Academy of Allergy, Asthma & Immunology C1 [Sorkness, Christine A.; Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Wildfire, Jeremy J.; Calatroni, Agustin; Mitchell, Herman E.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [O'Connor, George T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Pongracic, Jacqueline A.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Ross, Kristie] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Gill, Michelle A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Kattan, Meyer] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Morgan, Wayne J.] Univ Arizona, Coll Med, Tucson, AZ USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gergen, Peter J.] NIAID, Bethesda, MD 20892 USA. [Liu, Andrew H.; Szefler, Stanley J.] Natl Jewish Hlth, Denver, CO USA. [Liu, Andrew H.; Szefler, Stanley J.] Univ Colorado, Sch Med, Denver, CO USA. RP Sorkness, CA (reprint author), Univ Wisconsin, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA. EM sorkness@wisc.edu OI O'Connor, George/0000-0002-6476-3926 FU National Institute of Allergy and Infectious Diseases, the National Institutes of Health [NO1-AI-25496, NO1-AI-25482]; National Center for Research Resources, National Institutes of Health [M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, 5M01RR020359-04, UL1RR031988, 1UL1RR025780, UL1 RR024982]; Novartis Pharmaceuticals FX This project was funded in whole or in part by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health (contracts NO1-AI-25496 and NO1-AI-25482); the National Center for Research Resources, National Institutes of Health (grants M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, 5M01RR020359-04, UL1RR031988, 1UL1RR025780, and UL1 RR024982); Novartis Pharmaceuticals, under a clinical trial agreement with the University of Wisconsin-Madison, Dey Pharma (which provided EpiPens), and SC Johnson (which provided household pest control). NR 18 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD MAR PY 2013 VL 1 IS 2 BP 163 EP 171 DI 10.1016/j.jaip.2013.01.011 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA V38WU UT WOS:000209374300008 PM 24565455 ER PT J AU Arany, P AF Arany, Praveen TI PHOTOBIOMODULATION: MOLECULAR MECHANISMS AND MODELS FOR CLINICAL EFFICACY SO LASERS IN SURGERY AND MEDICINE LA English DT Meeting Abstract C1 [Arany, Praveen] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD MAR PY 2013 VL 45 SU 25 MA 191 BP 60 EP 60 PG 1 WC Dermatology; Surgery SC Dermatology; Surgery GA V38YX UT WOS:000209379800171 ER PT J AU Folio, L Solomon, J Biassou, N Fischer, T Dworzak, J Raymont, V Sinaii, N Wassermann, EM Grafman, J AF Folio, Les Solomon, Jeffrey Biassou, Nadia Fischer, Tatjana Dworzak, Jenny Raymont, Vanessa Sinaii, Ninet Wassermann, Eric M. Grafman, Jordan TI Semi-Automated Trajectory Analysis of Deep Ballistic Penetrating Brain Injury SO MILITARY MEDICINE LA English DT Article ID BULLET; MRI; CT AB Background: Penetrating head injuries (PHIs) are common in combat operations and most have visible wound paths on computed tomography (CT). Objective: We assess agreement between an automated trajectory analysis-based assessment of brain injury and manual tracings of encephalomalacia on CT. Methods: We analyzed 80 head CTs with ballistic PHI from the Institutional Review Board approved Vietnam head injury registry. Anatomic reports were generated from spatial coordinates of projectile entrance and terminal fragment location. These were compared to manual tracings of the regions of encephalomalacia. Dice's similarity coefficients, kappa, sensitivities, and specificities were calculated to assess agreement. Times required for case analysis were also compared. Results: Results show high specificity of anatomic regions identified on CT with semiautomated anatomical estimates and manual tracings of tissue damage. Radiologist's and medical students' anatomic region reports were similar (Kappa 0.8, t-test p < 0.001). Region of probable injury modeling of involved brain structures was sensitive (0.7) and specific (0.9) compared with manually traced structures. Semiautomated analysis was 9-fold faster than manual tracings. Conclusion: Our region of probable injury spatial model approximates anatomical regions of encephalomalacia from ballistic PHI with time-saving over manual methods. Results show potential for automated anatomical reporting as an adjunct to current practice of radiologist/neurosurgical review of brain injury by penetrating projectiles. C1 [Folio, Les; Biassou, Nadia] NIH, Dept Radiol, Bethesda, MD 20892 USA. [Solomon, Jeffrey] Expert Image Anal LLC, Potomac, MD 20854 USA. [Fischer, Tatjana] Tech Univ Munich, D-8033 Munich, Germany. [Dworzak, Jenny] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. [Raymont, Vanessa] Univ London Imperial Coll Sci Technol & Med, Dept Med, London W1G 9QD, England. [Sinaii, Ninet] NIH, Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. [Wassermann, Eric M.] NINDS, NIH, Bethesda, MD 20814 USA. [Grafman, Jordan] Rehabil Inst Chicago, Brain Injury Res Lab, Chicago, IL 60611 USA. RP Folio, L (reprint author), NIH, Dept Radiol, 10 Ctr Dr MSC 1440, Bethesda, MD 20892 USA. OI Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS [Z99 NS999999] NR 21 TC 2 Z9 2 U1 0 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD MAR PY 2013 VL 178 IS 3 BP 338 EP 345 DI 10.7205/MILMED-D-12-00353 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AN7TX UT WOS:000340805000017 PM 23707123 ER PT J AU Liu, SL Hassink, M Selvaraj, R Yap, LP Park, R Wang, H Chen, XY Fox, JM Li, ZB Conti, PS AF Liu, Shuanglong Hassink, Matthew Selvaraj, Ramajeyam Yap, Li-Peng Park, Ryan Wang, Hui Chen, Xiaoyuan Fox, Joseph M. Li, Zibo Conti, Peter S. TI Efficient F-18 Labeling of Cysteine-Containing Peptides and Proteins Using Tetrazine-Trans-Cyclooctene Ligation SO MOLECULAR IMAGING LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; POSITRON-EMISSION-TOMOGRAPHY; REACTIVE F-18-LABELING AGENT; FACTOR RECEPTOR EXPRESSION; RGD PEPTIDE; TUMOR ANGIOGENESIS; CANCER-PATIENTS; PET; INTEGRIN; TRACER AB F-18 positron emission tomography (PET) has a number of attributes that make it clinically attractive, including nearly 100% positron efficiency, very high specific radioactivity, and a short half-life of approximate to 110 minutes. However, the short half-life of F-18 and the poor nucleophilicity of fluoride introduce challenges for the incorporation of F-18 into complex molecules. Recently, the tetrazine-trans-cyclooctene ligation was introduced as a novel F-18 labeling method that proceeds with fast reaction rates without catalysis. Herein we report an efficient method for F-18 labeling of free cysteines of peptides and proteins based on sequential ligation with a bifunctional tetrazinyl-maleimide and an F-18-labeled trans-cyclooctene. The newly developed method was tested for site-specific labeling of both c(RGDyC) peptide and vascular endothelial growth factor (VEGF)-SH protein. Starting with 4 mCi of F-18-trans-cyclooctene and only 10 mu g of tetrazine-RGD (80-100 mu M) or 15 mg of tetrazine-VEGF (6.0 mu M), F-18-labeled RGD peptide and VEGF protein could be obtained within 5 minutes in 95% yield and 75% yield, respectively. The obtained tracers were then evaluated in mice. In conclusion, a highly efficient method has been developed for site-specific F-18 labeling of cysteine-containing peptides and proteins. The special characteristics of the tetrazine-trans-cyclooctene ligation provide unprecedented opportunities to synthesize F-18-labeled probes with high specific activity for PET applications. C1 [Li, Zibo] Univ So Calif, Mol Imaging Ctr, Keck Sch Med, Dept Radiol, Los Angeles, CA 90033 USA. [Fox, Joseph M.] Univ Delaware, Dept Chem & Biochem, Brown Labs, Newark, DE 19803 USA. Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Li, ZB (reprint author), Univ So Calif, Mol Imaging Ctr, Keck Sch Med, Dept Radiol, Los Angeles, CA 90033 USA. EM jmfox@udel.edu; ziboli@usc.edu FU National Institutes of Health from the Centers of Biomedical Research Excellence Program of the National Center for Research Resources [P20 RR017716]; National Cancer Institute [P30CA014089]; Department of Energy [DE-SC0002353]; University of Southern California Department of Radiology; National Science Foundation CRIF:MU [CHE 0840401, CHE-0541775] FX Financial disclosure of authors: This work was supported by National Institutes of Health grant number P20 RR017716 from the Centers of Biomedical Research Excellence Program of the National Center for Research Resources, grant number P30CA014089 from the National Cancer Institute, and research grant DE-SC0002353 from the Department of Energy and by the University of Southern California Department of Radiology. Spectra were obtained with instrumentation supported by National Science Foundation CRIF:MU grants CHE 0840401 and CHE-0541775. NR 36 TC 23 Z9 23 U1 2 U2 25 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 EI 1536-0121 J9 MOL IMAGING JI Mol. Imaging PD MAR-APR PY 2013 VL 12 IS 2 BP 121 EP 128 DI 10.2310/7290.2012.00013 PG 8 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA AI2XI UT WOS:000336722000006 PM 23415400 ER PT J AU Kim, T Afonin, KA Viard, M Koyfman, AY Sparks, S Heldman, E Grinberg, S Linder, C Blumenthal, RP Shapiro, BA AF Kim, Taejin Afonin, Kirill A. Viard, Mathias Koyfman, Alexey Y. Sparks, Selene Heldman, Eliahu Grinberg, Sarina Linder, Charles Blumenthal, Robert P. Shapiro, Bruce A. TI In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE bolaamphiphiles; cryo-EM; molecular dynamics simulations; FRET; poly-cationic micelles; RNA-based therapeutics; siRNA delivery; specific gene silencing ID RNA INTERFERENCE; VERNONIA OIL; EMERGING FIELD; NANOPARTICLES; VESICLES; DESIGN; NANOTECHNOLOGY; SYSTEMS; HUMANS; DNA AB However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biological membranes due to their negative charge. These obstacles can be overcome by using siRNAs complexed with bolaamphiphiles, consisting of two positively charged head groups that flank an internal hydrophobic chain. Bolaamphiphiles have relatively low toxicities, long persistence in the blood stream, and most importantly, in aqueous conditions can form poly-cationic micelles thus, becoming amenable to association with siRNAs. Herein, two different bolaamphiphiles with acetylcholine head groups attached to an alkyl chain in two distinct configurations are compared for their abilities to complex with siRNAs and deliver them into cells inducing gene silencing. Our explicit solvent molecular dynamics (MD) simulations showed that bolaamphiphiles associate with siRNAs due to electrostatic, hydrogen bonding, and hydrophobic interactions. These in silico studies are supported by various in vitro and in cell culture experimental techniques as well as by some in vivo studies. Results demonstrate that depending on the application, the extent of siRNA chemical protection, delivery efficiency, and further intracellular release can be varied by simply changing the type of bolaamphiphile used. C1 [Kim, Taejin; Afonin, Kirill A.; Viard, Mathias; Sparks, Selene; Blumenthal, Robert P.; Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 20872 USA. [Viard, Mathias; Heldman, Eliahu] SAIC Frederick Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Koyfman, Alexey Y.] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Natl Ctr Macromol Imaging, Houston, TX 77030 USA. [Heldman, Eliahu; Grinberg, Sarina; Linder, Charles] Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 20872 USA. EM shapirbr@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; National Institutes of Health [P41GM103832, RC2GM092599]; Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia (CPRIT) [RP101489] FX This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD and the National Cancer Institute's Advanced Biomedical Computing Center (ABCC) of the Frederick National Laboratory for Cancer Research, Frederick, MD. The authors thank Nimit Patel, Lisa Riffle, and Joseph Kalen in the Small Animal Imaging Program at the Frederick National Laboratory for Cancer Research for their guidance and support in animal imaging. They also thank Matthew Dougherty for help in preparing the movies and EckartBindewald for technical assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. 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. 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. This research was supported in part by the National Institutes of Health P41GM103832 and RC2GM092599 and the Postdoctoral Training Fellowship from the Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia to A.Y.K. (CPRIT grant no. RP101489). NR 36 TC 16 Z9 17 U1 1 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD MAR PY 2013 VL 2 AR e80 DI 10.1038/mtna.2013.5 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC3ZV UT WOS:000332461200005 PM 23511334 ER PT J AU Gaudet, MM Kuchenbaecker, KB Vijai, J Klein, RJ Kirchhoff, T McGuffog, L Barrowdale, D Dunning, AM Lee, A Dennis, J Healey, S Dicks, E Soucy, P Sinilnikova, O Pankratz, VS Wang, XS Eldridge, RC Tessier, DC Vincent, D Bacot, F Hogervorst, FBL Peock, S Stoppa-Lyonnet, D Peterlongo, P Schmutzler, RK Nathanson, KL Piedmonte, M Singer, CF Thomassen, M Hansen, TVO Neuhausen, SL Blanco, I Greene, MH Garber, J Weitzel, JN Andrulis, IL Goldgar, DE D'Andrea, E Caldes, T Nevanlinna, H Osorio, A van Rensburg, EJ Arason, A Rennert, G van den Ouweland, AMW van der Hout, AH Kets, CM Aalfs, CM Wijnen, JT Ausems, MGEM Frost, D Ellis, S Fineberg, E Platte, R Evans, DG Jacobs, C Adlard, J Tischkowitz, M Porteous, ME Damiola, F Golmard, L Barjhoux, L Longy, M Belotti, M Ferrer, SF Mazoyer, S Spurdle, AB Manoukian, S Barile, M Genuardi, M Arnold, N Meindl, A Sutter, C Wappenschmidt, B Domchek, SM Pfeiler, G Friedman, E Jensen, UB Robson, M Shah, S Lazaro, C Mai, PL Benitez, J Southey, MC Schmidt, MK Fasching, PA Peto, J Humphreys, MK Wang, Q Michailidou, K Sawyer, EJ Burwinkel, B Guenel, P Bojesen, SE Milne, RL Brenner, H Lochmann, M Aittomaki, K Dork, T Margolin, S Mannermaa, A Lambrechts, D Chang-Claude, J Radice, P Giles, GG Haiman, CA Winqvist, R Devillee, P Garcia-Closas, M Schoof, N Hooning, MJ Cox, A Pharoah, PDP Jakubowska, A Orr, N Gonzalez-Neira, A Pita, G Alonso, MR Hall, P Couch, FJ Simard, J Altshuler, D Easton, DF Chenevix-Trench, G Antoniou, AC Offit, K AF Gaudet, Mia M. Kuchenbaecker, Karoline B. Vijai, Joseph Klein, Robert J. Kirchhoff, Tomas McGuffog, Lesley Barrowdale, Daniel Dunning, Alison M. Lee, Andrew Dennis, Joe Healey, Sue Dicks, Ed Soucy, Penny Sinilnikova, Olgam. Pankratz, Vernon S. Wang, Xianshu Eldridge, Ronald C. Tessier, Daniel C. Vincent, Daniel Bacot, Francois Hogervorst, Frans B. L. Peock, Susan Stoppa-Lyonnet, Dominique Peterlongo, Paolo Schmutzler, Rita K. Nathanson, Katherine L. Piedmonte, Marion Singer, Christian F. Thomassen, Mads Hansen, Thomas V. O. Neuhausen, Susan L. Blanco, Ignacio Greene, Mark H. Garber, Judith Weitzel, Jeffrey N. Andrulis, Irene L. Goldgar, David E. D'Andrea, Emma Caldes, Trinidad Nevanlinna, Heli Osorio, Ana van Rensburg, Elizabeth J. Arason, Adalgeir Rennert, Gad van den Ouweland, Ans M. W. van der Hout, Annemarie H. Kets, Carolien M. Aalfs, Cora M. Wijnen, Juul T. Ausems, Margreet G. E. M. Frost, Debra Ellis, Steve Fineberg, Elena Platte, Radka Evans, D. Gareth Jacobs, Chris Adlard, Julian Tischkowitz, Marc Porteous, Mary E. Damiola, Francesca Golmard, Lisa Barjhoux, Laure Longy, Michel Belotti, Muriel Ferrer, Sandra Fert Mazoyer, Sylvie Spurdle, Amanda B. Manoukian, Siranoush Barile, Monica Genuardi, Maurizio Arnold, Norbert Meindl, Alfons Sutter, Christian Wappenschmidt, Barbara Domchek, Susan M. Pfeiler, Georg Friedman, Eitan Jensen, Uffe Birk Robson, Mark Shah, Sohela Lazaro, Conxi Mai, Phuong L. Benitez, Javier Southey, Melissa C. Schmidt, Marjanka K. Fasching, Peter A. Peto, Julian Humphreys, Manjeet K. Wang, Qin Michailidou, Kyriaki Sawyer, Elinor J. Burwinkel, Barbara Guenel, Pascal Bojesen, Stig E. Milne, Roger L. Brenner, Hermann Lochmann, Magdalena Aittomaki, Kristiina Doerk, Thilo Margolin, Sara Mannermaa, Arto Lambrechts, Diether Chang-Claude, Jenny Radice, Paolo Giles, Graham G. Haiman, Christopher A. Winqvist, Robert Devillee, Peter Garcia-Closas, Montserrat Schoof, Nils Hooning, Maartje J. Cox, Angela Pharoah, Paul D. P. Jakubowska, Anna Orr, Nick Gonzalez-Neira, Anna Pita, Guillermo Rosario Alonso, M. Hall, Per Couch, Fergus J. Simard, Jacques Altshuler, David Easton, Douglas F. Chenevix-Trench, Georgia Antoniou, Antonis C. Offit, Kenneth CA KConFab Investigators Ontario Canc Genetics Network HEBON EMBRACE GEMO Study Collaborators GENICA Network TI Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk SO PLOS GENETICS LA English DT Article ID BRCA2 MUTATION CARRIERS; TRANSCRIPTION FACTOR AP-2; GENOME-WIDE ASSOCIATION; COMMON VARIANTS; SUSCEPTIBILITY ALLELES; OVARIAN-CANCER; ZNF365; POPULATION; CONSORTIUM; SUBTYPES AB Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 x 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer. C1 [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Dicks, Ed; Peock, Susan; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Humphreys, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Pharoah, Paul D. P.; Easton, Douglas F.; Antoniou, Antonis C.; EMBRACE] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Vijai, Joseph; Robson, Mark; Shah, Sohela; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. [Klein, Robert J.] Mem Sloan Kettering Canc Ctr, Program Canc Biol & Genet, New York, NY 10021 USA. [Kirchhoff, Tomas] NYU, Dept Environm Med, Div Epidemiol, Sch Med, New York, NY 10016 USA. [Dunning, Alison M.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Healey, Sue; Spurdle, Amanda B.; Chenevix-Trench, Georgia] Queensland Inst Med Res, Genet & Populat Hlth Div, Brisbane, Qld 4006, Australia. [Soucy, Penny; Simard, Jacques] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Soucy, Penny; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Sinilnikova, Olgam.] Hosp Civils Lyon, Unite Mixte Genet Constitut Canc Frequents, Ctr Leon Berard, Lyon, France. [Pankratz, Vernon S.; Damiola, Francesca; Barjhoux, Laure; Mazoyer, Sylvie] Univ Lyon 1, INSERM U1052, CNRS UMR5286, Ctr Rech Cancerol Lyon, F-69365 Lyon, France. [Wang, Xianshu; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci, Rochester, MN USA. [Eldridge, Ronald C.; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Tessier, Daniel C.] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Vincent, Daniel; Bacot, Francois] Ctr Innovat Genome Quebec, Montreal, PQ, Canada. 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[Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Gynecol Oncol Grp, Stat & Data Ctr, Buffalo, NY 14263 USA. [Singer, Christian F.; Pfeiler, Georg] Med Univ Vienna, Dept Obstet & Gyncol, Vienna, Austria. [Singer, Christian F.; Pfeiler, Georg] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Andrulis, Irene L.; Ontario Canc Genetics Network] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Ctr Genom Med, Rigshosp, Copenhagen, Denmark. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA. [Blanco, Ignacio] IDIBELL Catalan Inst Oncol, Genet Counseling Unit, Hereditary Canc Program, Barcelona, Spain. [Greene, Mark H.; Mai, Phuong L.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Garber, Judith] Dana Farber Partners CancerCare, Dept Med Oncol, Boston, MA USA. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, City Hope Clin Canc Genet Community Res Network, Duarte, CA USA. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A1, Canada. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [D'Andrea, Emma] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy. [D'Andrea, Emma] Ist Oncolog Veneto IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Caldes, Trinidad] Hosp Clin San Carlos, Mol Oncol Lab, IdISSC, Madrid, Spain. [Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Osorio, Ana; Benitez, Javier; Milne, Roger L.] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Osorio, Ana; Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa. [Arason, Adalgeir] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Arason, Adalgeir] Univ Iceland, BMC, Fac Med, Reykjavik, Iceland. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, Haifa, Israel. [van den Ouweland, Ans M. W.] Erasmus Univ, Dept Clin Genet, Family Canc Clin, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [van der Hout, Annemarie H.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Kets, Carolien M.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Aalfs, Cora M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Wijnen, Juul T.; Devillee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Wijnen, Juul T.] Leiden Univ, Dept Clin Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Ausems, Margreet G. E. M.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [HEBON] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Jacobs, Chris] Guys & St Thomas NHS Fdn Trust, London, England. [Adlard, Julian] Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Tischkowitz, Marc] Univ Cambridge, Dept Med Genet, Cambridge, England. [Porteous, Mary E.] Western Gen Hosp, South East Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. [Longy, Michel] Univ Bordeaux, Canc Genet Unit, INSERM U916, Inst Bergonie, Bordeaux, France. [Ferrer, Sandra Fert] Hotel Dieu Ctr Hosp, Lab Genet Chromosom, Chambery, France. [Manoukian, Siranoush] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Barile, Monica] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Genuardi, Maurizio] Univ Florence, Fiorgen Fdn Pharmacogenom, Florence, Italy. [Genuardi, Maurizio] Univ Florence, Unit Med Genet, Dept Clin Physiopathol, Florence, Italy. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Kiel, Germany. [Meindl, Alfons; Lochmann, Magdalena] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-80290 Munich, Germany. [Sutter, Christian] Heidelberg Univ, Heidelberg, Germany. [Friedman, Eitan] Chaim Sheba Med Ctr, Tel Aviv, Israel. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Lazaro, Conxi] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain. [Southey, Melissa C.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Fasching, Peter A.] Univ Hosp Erlangen, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Peto, Julian] London Sch Hyg & Trop Med, London WC1, England. [Sawyer, Elinor J.] Guys St Thomas NHS Fdn Trust Partnership Kings Co, Div Canc Studies, NIHR Comprehens Biomed Res Ctr, London, England. [Burwinkel, Barbara] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Guenel, Pascal] INSERM, CESP Ctr Res Epidemiol & Populat Health, Environm Epidemiol Canc U1018, Villejuif, France. [Guenel, Pascal] Univ Paris 11, UMR S 1018, Villejuif, France. [Bojesen, Stig E.] Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Dept Clin Biochem, Herlev Hosp, Copenhagen Univ Hosp, Copenhagen, Denmark. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. Univ Tubingen, Tubingen, Germany. Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany. German Social Accid Insurance IPA, Inst Prevent & Occupat Med, Bochum, Germany. Univ Saarland, Inst & Outpatient Clin Occupat Med, Med Ctr, Homburg, Germany. Univ Saarland, Fac Med, Homburg, Germany. Univ Bonn, Inst Pathol, Fac Med, Bonn, Germany. [GENICA Network] Johanniter Krankenhaus, Dept Internal Med, Evangel Kliniken Bonn gGmbH, Bonn, Germany. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Doerk, Thilo] Hannover Med Sch, Dept Obstet & Gynecol, Hannover, Germany. [Margolin, Sara] Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden. [Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Bioctr Kuopio, Sch Med,Canc Ctr Eastern Finland, Kuopio, Finland. [Mannermaa, Arto] Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, SF-70210 Kuopio, Finland. [Lambrechts, Diether] Katholieke Univ Leuven VIB, Vesalius Res Ctr, Louvain, Belgium. [Lambrechts, Diether] Katholieke Univ Leuven, Lab Translat Genet, Dept Oncol, Louvain, Belgium. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Winqvist, Robert] Univ Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol, Dept Clin Genet, Oulu, Finland. [Winqvist, Robert] Univ Oulu, Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland. [Devillee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Div Breast Canc Res, Sutton, Surrey, England. [Garcia-Closas, Montserrat; Orr, Nick; Hall, Per] Inst Canc Res, Div Breast Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Schoof, Nils] Karolinska Inst, Stockholm, Sweden. [Hooning, Maartje J.] Erasmus Univ, Dept Med Oncol, Med Ctr, Rotterdam, Netherlands. [Cox, Angela] Univ Sheffield, CRUK YCR Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Jakubowska, Anna] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Gonzalez-Neira, Anna; Pita, Guillermo; Rosario Alonso, M.] Spanish Natl Canc Res Ctr CNIO, Human Genotyping CEGEN Unit, Human Canc Genet Program, Madrid, Spain. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol & Med, Boston, MA 02114 USA. [Altshuler, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Gaudet, MM (reprint author), Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. EM offitk@mskcc.org RI Klein, Robert/K-1888-2013; Dork, Thilo/J-8620-2012; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Spurdle, Amanda/A-4978-2011; Jakubowska, Anna/O-8050-2014; Altshuler, David/A-4476-2009; Verdrengh, Evelien/H-4571-2012; Blanco, Ignacio/D-2565-2013; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Osorio, Ana/I-4324-2014; Joseph, Vijai/J-9158-2013; Radice, Paolo/O-3119-2013; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Arnold, Norbert/E-3012-2010; Andrulis, Irene/E-7267-2013 OI Dennis, Joe/0000-0003-4591-1214; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Kirchhoff, Tomas/0000-0002-9055-2364; Jacobs, Chris/0000-0002-9557-9080; Giles, Graham/0000-0003-4946-9099; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Evans, Gareth/0000-0002-8482-5784; Klein, Robert/0000-0003-3539-5391; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Barton, David E/0000-0002-2031-9719; Robson, Mark/0000-0002-3109-1692; Nathanson, Katherine/0000-0002-6740-0901; Spurdle, Amanda/0000-0003-1337-7897; Barrowdale, Daniel/0000-0003-1661-3939; Altshuler, David/0000-0002-7250-4107; Blanco, Ignacio/0000-0002-7414-7481; Garcia-Closas, Montserrat /0000-0003-1033-2650; Osorio, Ana/0000-0001-8124-3984; Joseph, Vijai/0000-0002-7933-151X; Arnold, Norbert/0000-0003-4523-8808; FU University of Eastern Finland; Cancer Fund of North Savo; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria; Cancer Councils of New South Wales, Tasmania; Cancer Councils of New South Wales, South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of Tasmania; NHMRC [199600]; NHMRC; Cancer Australia [628333]; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]; Stichting tegen Kanker [232-2008, 196-2010]; FWO; KULPFV/10/016-SymBioSysII; Deutsche Krebshilfe e.V. [70-2892-BR I]; Hamburg Cancer Society; German Cancer Research Center; Federal Ministry of Education and Research (BMBF) [01KH0402]; NIH [CA128978, CA63464, CA54281, CA098758, CA132839]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; Breast Cancer Research Foundation; Komen Foundation for the Cure; Fondazione Italiana per la Ricerca sul Cancro; Italian Association for Cancer Research (AIRC) [IG 8713]; Italian Ministry of Health ("Progetto Tumori Femminili"); Italian citizens; Fondazione IRCCS Istituto Nazionale Tumori; VicHealth and Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Jewish General Hospital; Niehaus Clinical Cancer Genetics Initiative; Andrew Sabin Family Foundation; Lymphoma Foundation; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Intramural Research Program of the US National Cancer Institute, NIH; Westat, Rockville, MD [NO2-CP-11019-50, N02-CP-65504]; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF); Russian Federation for Basic Research [11-04-00227, 12-04-00928, 12-04-01490]; Federal Agency for Science and Innovations, Russia [02.740.11.0780]; Finnish Cancer Foundation; Academy of Finland; University of Oulu; Oulu University Hospital; Dutch Cancer Society [RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Ohio State University Comprehensive Cancer Center; Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation; National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); U.S. National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research [S295, S299, S305PA]; Malaysian Ministry of Science, Technology and Innovation; Ministry of Higher Education [UM.C/HIR/MOHE/06]; Cancer Research UK [[C490/A10124][C8197/A10123]; Swedish Cancer Society; U.S. National Cancer Institute (NIH/NCI); Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance,; Jonsson Comprehensive Cancer Center Foundation; UCSF Cancer Risk Program; Helen Diller Family Comprehensive Cancer Center; Breakthrough Breast Cancer; Institute of Cancer Research (ICR); NHS; CRUK; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Rooney Family Foundation; Susan G. Komen Foundation for the Cure; Facdonald Family Foundation; Victorian Cancer Agency; Cancer Australia; American Cancer Society [SIOP-06-258-01-COUN]; Ligue National Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; [C8197/A10865]; [PBZ_KBN_122/P05/2004] FX Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. Kathleen Cuningham Consortium for Research into Familial Breast Cancer: kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. G Chenevix-Trench and AB Spurdle are NHMRC Senior Research Fellows. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], the Cancer Council of Tasmania and Cancer Foundation of Western Australia, and the NHMRC [199600]. G Chenevix-Trench is supported by the NHMRC. The Clinical Follow Up Study (funded 2001-2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) Korean Hereditary Breast Cancer Study: KOHBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). Leuven Multidisciplinary Breast Centre: LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). D Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. Mammary Carcinoma Risk Factor Investigation: The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center, and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. Mayo Clinic: MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341), and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. Milan Breast Cancer Study Group: MBCSG was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumors"), Italian Association for Cancer Research (AIRC, IG 8713), Italian Ministry of Health ("Progetto Tumori Femminili"), and by Italian citizens who allocated the 561000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000"). Melbourne Collaborative Cohort Study: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. McGill University: The McGill Study was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Multi-Ethnic Cohort: The MEC was supported by NIH grants CA63464, CA54281, CA098758, and CA132839. Memorial Sloan-Kettering Cancer Center: The MSKCC was supported by Breast Cancer Research Foundation, Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Family Foundation, and Lymphoma Foundation. Montreal Gene-Environment Breast Cancer Study: The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program grant CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade grant PSR-SIIRI-701.; J Simard is Chairholder of the Canada Research Chair in Oncogenetics. National Cancer Institute: The research of MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. National Israeli Cancer Control Center: NICCC is supported by Clalit Health Services in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), New York. N. N. Petrov Institute of Oncology: The NNPIO study has been supported by the Russian Federation for Basic Research (grants 11-04-00227, 12-04-00928, and 12-04-01490) and the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780). Oulu Breast Cancer Study: The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital. Leiden University Medical Centre Breast Cancer Study: The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The Ohio State University Comprehensive Cancer Center: OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. The U. S. National Cancer Institute Polish Breast Cancer Study: The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Karolinska Mammography Project for Risk Prediction of Breast Cancer - prevalent cases: The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. Rotterdam Breast Cancer Study: The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). Singapore and Sweden Breast Cancer Study: The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the U.S. National Institute of Health (NIH), and the Susan G. Komen Breast Cancer Foundation. Sheffield Breast Cancer Study: The SBCS was supported by Yorkshire Cancer Research S295, S299, and S305PA. South East Asian Breast Cancer Association Study: SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. The Malaysian Breast Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation; Ministry of Higher Education (UM.C/HIR/MOHE/06);and charitable funding from Cancer Research Initiatives Foundation. Study of Epidemiology and Risk Factors in Cancer Heredity: SEARCH is funded by programmegrants from Cancer Research UK [C490/A10124][C8197/A10123]. AM Dunning was funded by [C8197/A10865]. Sheba Medical Centre: The SMC study was partially funded through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium. Swedish Breast Cancer Study: SWE-BRCA collaborators are supported by the Swedish Cancer Society. IHCC-Szczecin Breast Cancer Study: The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The University of Chicago Center for Clinical Cancer Genetics and Global Health: UCHICAGO is supported by grants from the U.S.; National Cancer Institute (NIH/NCI) and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. University of California Los Angeles: The UCLA study was supported by the Jonsson Comprehensive Cancer Center Foundation and the Breast Cancer Research Foundation. University of California San Francisco: The UCSF study was supported by the UCSF Cancer Risk Program and the Helen Diller Family Comprehensive Cancer Center. United Kingdom Breakthrough Generations Study: The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. United Kingdom Familial Ovarian Cancer Registries: UKFOCR was supported by a project grant from CRUK to PDP Pharoah. University of Pennsylvania: The UPENN study was supported by the National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855), Breast Cancer Research Foundation, Rooney Family Foundation, Susan G. Komen Foundation for the Cure, and the Facdonald Family Foundation. Victorian Familial Cancer Trials Group: The VFCTG study was supported by the Victorian Cancer Agency, Cancer Australia, and National Breast Cancer Foundation. Women's Cancer Program: The WCP at the Samuel Oschin Comprehensive Cancer Institute is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study: The study was supported by the Ligue National Contre le Cancer, the Association "Le cancer du sein, parlons-en!" Award, and the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 51 Z9 51 U1 3 U2 14 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 MAR PY 2013 VL 9 IS 3 AR e1003173 DI 10.1371/journal.pgen.1003173 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 116EY UT WOS:000316866700001 PM 23544012 ER PT J AU Gilbert, ES Sokolnikov, ME Preston, DL Schonfeld, SJ Schadilov, AE Vasilenko, EK Koshurnikova, NA AF Gilbert, E. S. Sokolnikov, M. E. Preston, D. L. Schonfeld, S. J. Schadilov, A. E. Vasilenko, E. K. Koshurnikova, N. A. TI Lung Cancer Risks from Plutonium: An Updated Analysis of Data from the Mayak Worker Cohort SO RADIATION RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; NUCLEAR-COMPLEX; MORTALITY RISK; RADIATION; EXPOSURE; SMOKING; DOSIMETRY; MINERS; PLANT AB Workers at the Mayak nuclear facility in the Russian Federation offer a unique opportunity to evaluate health risks from exposure to inhaled plutonium. Risks of mortality from lung cancer, the most serious carcinogenic effect of plutonium, were evaluated in 14,621 Mayak workers who were hired in the period from 1948-1982, followed for at least 5 years, and either monitored for plutonium or never worked with plutonium. Over the follow-up period from 1953-2008, there were 486 deaths from lung cancer, 446 of them in men. In analyses that were adjusted for external radiation dose and smoking, the plutonium excess relative risk (ERR) per Gy declined with attained age and was higher for females than for males. The ERR per Gy for males at age 60 was 7.4 (95% CI: 5.0-11) while that for females was 24 (95% CI: 11-56). When analyses were restricted to plutonium doses <0.2 Gy, the ERR per Gy for males at age 60 was similar: 7.0 (95% CI: 2.5-13). Of the 486 lung cancer deaths, 105 (22%) were attributed to plutonium exposure and 29 (6%) to external exposure. Analyses of the 12,708 workers with information on smoking indicated that the relationship of plutonium exposure and smoking was likely sub-multiplicative (P = 0.011) and strongly indicated that it was super-additive (P < 0.001). Although extensive efforts have been made to improve plutonium dose estimates in this cohort, they are nevertheless subject to large uncertainties. Large bioassay measurement errors alone are likely to have resulted in serious underestimation of risks, whereas other sources of uncertainty may have biased results in ways that are difficult to predict. (C) 2013 by Radiation Research Society C1 [Gilbert, E. S.; Schonfeld, S. J.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Sokolnikov, M. E.; Schadilov, A. E.; Vasilenko, E. K.; Koshurnikova, N. A.] Southern Urals Biophys Inst, Ozyorsk, Chelyabinsk Reg, Russia. [Preston, D. L.] HiroSoft Int Corp, Eureka, CA USA. RP Gilbert, ES (reprint author), Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MS 7238, Rockville, MD 20852 USA. EM gilberte@mail.nih.gov FU U.S. Department of Energy (DOE) under the JCCRER; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Japanese Ministry of Health, Labour and Welfare (MHLW); U.S. Department of Energy through the National Academy of Sciences FX We wish to acknowledge the role of the late Elaine Ron in establishing the collaborative research between the U.S. and Russia that made this article possible. We also wish to thank Alexander Efimov, Vadim Vostrotin and Alan Birchall for their work in finalizing the plutonium doses used in our analyses. Support for this study has been provided by the U.S. Department of Energy (DOE) under the auspices of the JCCRER and by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. This report makes use of data obtained from RERF in Hiroshima, Japan. RERF is a private, non-profit foundation funded equally by the Japanese Ministry of Health, Labour and Welfare (MHLW) and the U.S. Department of Energy through the National Academy of Sciences. The data include information obtained from the Hiroshima City, Hiroshima Prefecture, Nagasaki City and Nagasaki Prefecture Tumor Registries and the Hiroshima and Nagasaki Tissue Registries. The conclusions in this report are those of the authors and do not necessarily reflect the scientific judgment of RERF or its funding agencies. NR 20 TC 26 Z9 29 U1 0 U2 5 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD MAR PY 2013 VL 179 IS 3 BP 332 EP 342 DI 10.1667/RR3054.1 PG 11 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AA3HO UT WOS:000330983700008 PM 23391147 ER PT J AU Hsu, WL Preston, DL Soda, M Sugiyama, H Funamoto, S Kodama, K Kimura, A Kamada, N Dohy, H Tomonaga, M Iwanaga, M Miyazaki, Y Cullings, HM Suyama, A Ozasa, K Shore, RE Mabuchi, K AF Hsu, Wan-Ling Preston, Dale L. Soda, Midori Sugiyama, Hiromi Funamoto, Sachiyo Kodama, Kazunori Kimura, Akiro Kamada, Nanao Dohy, Hiroo Tomonaga, Masao Iwanaga, Masako Miyazaki, Yasushi Cullings, Harry M. Suyama, Akihiko Ozasa, Kotaro Shore, Roy E. Mabuchi, Kiyohiko TI The Incidence of Leukemia, Lymphoma and Multiple Myeloma among Atomic Bomb Survivors: 1950-2001 SO RADIATION RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CANCER-MORTALITY RISK; IONIZING-RADIATION; WORKERS; CLASSIFICATION; HIROSHIMA; NAGASAKI; AMERICAN; REGISTRY; COHORT AB A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This article presents analyses of radiation effects on leukemia, lymphoma and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor-and leukemia-registry based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose-response relationship and, to the extent the data allowed, to investigate variation in the excess risks with gender, attained age, exposure age and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a nonlinear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this nonlinearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence that the radiation-associated excess leukemia risks, especially for acute myeloid leukemia, had persisted throughout the follow-up period out to 55 years after the bombings. As in earlier analyses, there was a weak suggestion of a radiation dose response for non-Hodgkin lymphoma among men, with no indication of such an effect among women. There was no evidence of radiation-associated excess risks for either Hodgkin lymphoma or multiple myeloma. (C) 2013 by Radiation Research Society C1 [Hsu, Wan-Ling; Soda, Midori; Sugiyama, Hiromi; Funamoto, Sachiyo; Kodama, Kazunori; Cullings, Harry M.; Suyama, Akihiko; Ozasa, Kotaro; Shore, Roy E.] Radiat Effects Res Fdn, Hiroshima 7320815, Japan. [Hsu, Wan-Ling; Soda, Midori; Sugiyama, Hiromi; Funamoto, Sachiyo; Kodama, Kazunori; Cullings, Harry M.; Suyama, Akihiko; Ozasa, Kotaro; Shore, Roy E.] Radiat Effects Res Fdn, Nagasaki, Japan. [Preston, Dale L.] Hirosoft Int, Eureka, CA USA. [Kimura, Akiro] Hiroshima Univ, Dept Hematol & Oncol, Hiroshima, Japan. [Kamada, Nanao] Hiroshima A Bomb Survivors Relief Fdn, Hiroshima, Japan. [Dohy, Hiroo] Hiroshima Red Cross Hosp, Hiroshima, Japan. [Dohy, Hiroo] Atom Bomb Survivors Hosp, Hiroshima, Japan. [Tomonaga, Masao] Japanese Red Cross Nagasaki Genbaku Hosp, Nagasaki, Japan. [Iwanaga, Masako] Teikyo Univ, Grad Sch Publ Hlth, Tokyo 173, Japan. [Miyazaki, Yasushi] Nagasaki Univ, Dept Hematol, Nagasaki 852, Japan. [Mabuchi, Kiyohiko] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Preston, DL (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Koen, Hiroshima 7320815, Japan. EM preston@hirosoft.net FU Japanese Ministry of Health, Labour and Welfare; U.S. Department of Energy; DOE [DE-HS0000031]; U.S. National Cancer Institute [N02-CP-2009-00005]; Intramural Research Program of the NIH Division of Cancer Epidemiology and Genetics FX The Radiation Effects Research Foundation is a private, non-profit foundation funded by the Japanese Ministry of Health, Labour and Welfare and the U.S. Department of Energy, the latter in part through DOE award DE-HS0000031 to the National Academy of Sciences, which supported WLH, HMC and RES. This research was also supported by the U.S. National Cancer Institute contract N02-CP-2009-00005 and in part by the Intramural Research Program of the NIH Division of Cancer Epidemiology and Genetics. The views of the authors do not necessarily reflect those of the two governments. We are especially grateful to the diligent work of tracing and abstracting hospital records by the staff of the Hiroshima and Nagasaki tumor registries and of the hematologists and others who were engaged in the operation of the Leukemia Registry. NR 48 TC 74 Z9 84 U1 0 U2 10 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD MAR PY 2013 VL 179 IS 3 BP 361 EP 382 DI 10.1667/RR2892.1 PG 22 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AA3HO UT WOS:000330983700011 PM 23398354 ER PT J AU Ehrenthal, DB Haynes, SG Martin, KE Hitch, JA Addo, SF O'Neill, E Pina, IL Taubenheim, AM Sloan, NL AF Ehrenthal, Deborah B. Haynes, Suzanne G. Martin, Kristen E. Hitch, Jeanne A. Addo, Sonya Feinberg O'Neill, Elizabeth Pina, Ileana L. Taubenheim, Ann M. Sloan, Nancy L. TI Evaluation of the Heart Truth Professional Education Campaign on Provider Knowledge of Women and Heart Disease SO WOMENS HEALTH ISSUES LA English DT Article ID MANAGED CARE PLANS; CARDIOVASCULAR-DISEASE; GENDER DISPARITIES; MEDICAL-EDUCATION; ASSOCIATION; PREVENTION; MORTALITY; SEX AB Background: The Heart Truth Professional Education Campaign was developed to facilitate education of health care providers in evidence-based strategies to prevent cardiovascular disease (CVD) in women. Methods: As part of the 3-year campaign, lectures based on the American Heart Association's evidence-based guidelines for CVD prevention in women were presented by local speakers to healthcare providers and students in three high-risk states: Delaware, Ohio, and New York. Participants' responses to pretest and posttest questions about CVD in women are presented. We performed t-test and multivariable linear regression to assess the influence of provider characteristics on baseline knowledge and knowledge change after the lecture. Results: Between 2008 and 2011, 2,995 healthcare providers, students, and other participants completed the baseline assessment. Knowledge scores at baseline were highest for physicians, with obstetrician/gynecologists scoring lowest (63%) and cardiologists highest (76%). Nurses had intermediate total knowledge (56%) and students had the lowest total knowledge (49%) at baseline. Pre- and post-lecture assessments were completed by 1,893 (63%) of attendees. Scores were significantly higher after the educational lecture (p <= .001), with greater increase for those with lower baseline scores. Baseline knowledge of the use of statins, hormone therapy, and antioxidants, as well as approaches to smoking cessation and treatment of hypertension, differed by provider type. Conclusion: Tailoring of lectures for non-physician audiences may be beneficial given differences in baseline knowledge. More emphasis is needed on statin use for all providers and on smoking cessation and treatment of hypertension for nurses, students, and other healthcare professionals. Copyright (C) 2013 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Ehrenthal, Deborah B.; Addo, Sonya Feinberg; O'Neill, Elizabeth; Sloan, Nancy L.] Christiana Care Hlth Syst, Newark, DE 19718 USA. [Ehrenthal, Deborah B.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Haynes, Suzanne G.] US Dept HHS, Off Womens Hlth, Washington, DC 20201 USA. [Martin, Kristen E.] SUNY Buffalo, Jacobs Neurol Inst, Res Ctr Stroke & Heart Dis, Buffalo, NY 14260 USA. [Hitch, Jeanne A.] Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Cleveland, OH 44106 USA. [Pina, Ileana L.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Taubenheim, Ann M.] NHLBI, Off Commun, NIH, Bethesda, MD 20892 USA. RP Ehrenthal, DB (reprint author), Christiana Care Hlth Syst, Hlth Serv Res Women & Children, 4755 Ogletown Stanton Rd, Newark, DE 19718 USA. EM dehrenthal@christianacare.org NR 15 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD MAR-APR PY 2013 VL 23 IS 2 BP E87 EP E93 DI 10.1016/j.whi.2013.01.001 PG 7 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA AO1WD UT WOS:000341105300004 PM 23481694 ER PT J AU Lam, KH Hsu, HS Li, Y Lee, CY Lin, A Zhou, QF Kim, ES Shung, KK AF Lam, Kwok Ho Hsu, Hsiu-Sheng Li, Ying Lee, Changyang Lin, Anderson Zhou, Qifa Kim, Eun Sok Shung, Kirk Koping TI Ultrahigh frequency lensless ultrasonic transducers for acoustic tweezers application SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE ultrasonic transducer; acoustic tweezers; particle manipulation ID SINGLE; FABRICATION; FORCE; DESIGN; SPHERE; BEAM AB Similar to optical tweezers, a tightly focused ultrasound microbeam is needed to manipulate microparticles in acoustic tweezers. The development of highly sensitive ultrahigh frequency ultrasonic transducers is crucial for trapping particles or cells with a size of a few microns. As an extra lens would cause excessive attenuation at ultrahigh frequencies, two types of 200-MHz lensless transducer design were developed as an ultrasound microbeam device for acoustic tweezers application. Lithium niobate single crystal press-focused (PF) transducer and zinc oxide self-focused transducer were designed, fabricated and characterized. Tightly focused acoustic beams produced by these transducers were shown to be capable of manipulating single microspheres as small as 5 mu m two-dimensionally within a range of hundreds of micrometers in distilled water. The size of the trapped microspheres is the smallest ever reported in the literature of acoustic PF devices. These results suggest that these lensless ultrahigh frequency ultrasonic transducers are capable of manipulating particles at the cellular level and that acoustic tweezers may be a useful tool to manipulate a single cell or molecule for a wide range of biomedical applications. Biotechnol. Bioeng. 2013; 110: 881886. (c) 2012 Wiley Periodicals, Inc. C1 [Lam, Kwok Ho; Hsu, Hsiu-Sheng; Li, Ying; Lee, Changyang; Zhou, Qifa; Shung, Kirk Koping] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Lam, Kwok Ho; Hsu, Hsiu-Sheng; Li, Ying; Lee, Changyang; Zhou, Qifa; Shung, Kirk Koping] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Hsu, Hsiu-Sheng] Univ So Calif, Mork Family Dept Chem Engn & Mat Sci, Los Angeles, CA 90089 USA. [Lin, Anderson; Kim, Eun Sok] Univ So Calif, Dept Elect Engn Electrophys, Los Angeles, CA 90089 USA. RP Lam, KH (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM kokokhlam@gmail.com RI Lam, K.H./B-7765-2014; OI Lam, K.H./0000-0003-1456-9049; Lee, Changyang/0000-0002-3746-7304 FU NIH [R01-EB12058, P41-EB2182] FX Contract grant sponsor: NIH; Contract grant number: R01-EB12058; P41-EB2182 NR 26 TC 33 Z9 33 U1 3 U2 69 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD MAR PY 2013 VL 110 IS 3 BP 881 EP 886 DI 10.1002/bit.24735 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 074IP UT WOS:000313806400021 PM 23042219 ER PT J AU Poma, HR Rajal, VB Fernandez, MDB Barril, PA Giordano, MO Masachessi, G Martinez, LC Isa, MB Freire, MC Riviello, GL Cisterna, D Nates, SV Mbayed, VA AF Ramiro Poma, Hugo Beatriz Rajal, Veronica Blanco Fernandez, Maria Dolores Angelica Barril, Patricia Oscar Giordano, Miguel Masachessi, Gisela Cecilia Martinez, Laura Beatriz Isa, Maria Cecilia Freire, Maria Lopez Riviello, Gabriela Cisterna, Daniel Viviana Nates, Silvia Andrea Mbayed, Viviana TI Evaluation of concentration efficiency of the Pseudomonas aeruginosa phage PP7 in various water matrixes by different methods SO ENVIRONMENTAL MONITORING AND ASSESSMENT LA English DT Article DE Virus concentration; Surface water; PP7; Absorption/elution; Polyethylene glycol; Ultrafiltration; qRT-PCR ID HOLLOW-FIBER ULTRAFILTRATION; FELINE CALICIVIRUS; MURINE NOROVIRUS; ENVIRONMENTAL WATERS; POLYETHYLENE-GLYCOLS; VIRUS CONCENTRATION; ENTERIC VIRUSES; ELUTION METHOD; SURFACE-WATER; FILTRATION AB Enteric viruses monitoring in surface waters requires the concentration of viruses before detection assays. The aim of this study was to evaluate different methods in terms of recovery efficiencies of bacteriophage PP7 of Pseudomonas aeruginosa, measured by real-time PCR, using it as a viral control process in water analysis. Different nucleic acid extraction methods (silica-guanidinium thiocyanate, a commercial kit (Qiagen Viral RNA Kit) and phenol-chloroform with alcohol precipitation) exhibited very low recovery efficiencies (0.08-4.18 %), being the most efficient the commercial kit used for subsequent experiments. To evaluate the efficiency of three concentration methods, PBS (as model for clean water) and water samples from rivers were seeded to reach high (HC, 10(6) pfu ml(-1)) and low concentrations (LC, 10(4) pfu ml(-1)) of PP7. Tangential ultrafiltration proved to be more efficient (50.36 +/- 12.91, 17.21 +/- 9.22 and 12.58 +/- 2.35 % for HC in PBS and two river samples, respectively) than adsorption-elution with negatively charged membranes (1.00 +/- 1.34, 2.79 +/- 2.62 and 0.05 +/- 0.08 % for HC in PBS and two river samples, respectively) and polyethylene glycol precipitation (15.95 +/- 7.43, 4.01 +/- 1.12 and 3.91 +/- 0.54 %, for HC in PBS and two river samples, respectively), being 3.2-50.4 times more efficient than the others for PBS and 2.7-252 times for river samples. Efficiencies also depended on the initial virus concentration and aqueous matrixes composition. In consequence, the incorporation of an internal standard like PP7 along the process is useful as a control of the water concentration procedure, the nucleic acid extraction, the presence of inhibitors and the variability of the recovery among replicas, and for the calculation of the sample limit of detection. Thus, the use of a process control, as presented here, is crucial for the accurate quantification of viral contamination. C1 [Ramiro Poma, Hugo; Beatriz Rajal, Veronica] Univ Nacl Salta, INIQUI CONICET, RA-4400 Salta, Argentina. [Beatriz Rajal, Veronica] Univ Calif Davis, Fogarty Int Ctr, Davis, CA 95616 USA. [Blanco Fernandez, Maria Dolores; Andrea Mbayed, Viviana] Univ Buenos Aires, Fac Farm & Bioquim, Catedra Virol, RA-1113 Buenos Aires, DF, Argentina. [Angelica Barril, Patricia; Oscar Giordano, Miguel; Masachessi, Gisela; Cecilia Martinez, Laura; Beatriz Isa, Maria; Viviana Nates, Silvia] Univ Nacl Cordoba, Inst Virol Dr JM Vanella, RA-5000 Cordoba, Argentina. [Lopez Riviello, Gabriela] Prefectura Naval Argentina, Dept Cient Pericial, RA-1107 Buenos Aires, DF, Argentina. [Cecilia Freire, Maria; Cisterna, Daniel] INEI ANLIS Dr Carlos G Malbran, Inst Nacl Enfermedades Infecciosas, RA-1281 Buenos Aires, DF, Argentina. RP Rajal, VB (reprint author), Univ Nacl Salta, INIQUI CONICET, Av Bolivia 5150, RA-4400 Salta, Argentina. EM vbrajal@gmail.com FU Agencia Nacional de Promocion de Ciencia y Tecnica in Argentina (ANPCyT) [PICT-Red 276/06]; NIH [D43 TW005718]; Fogarty International Center; National Institute of Environmental Health Sciences, USA; CONICET; ANPCyT FX This research was part of the project PICT-Red 276/06 funded by the Agencia Nacional de Promocion de Ciencia y Tecnica in Argentina (ANPCyT). This project was partially supported by NIH Grant D43 TW005718 funded by the Fogarty International Center and the National Institute of Environmental Health Sciences, USA. Hugo Ramiro Poma, Patricia Angelica Barril and Gisela Masachessi received fellowships from CONICET and Maria Dolores Blanco Fernandez from ANPCyT. NR 46 TC 6 Z9 7 U1 2 U2 32 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6369 J9 ENVIRON MONIT ASSESS JI Environ. Monit. Assess. PD MAR PY 2013 VL 185 IS 3 BP 2565 EP 2576 DI 10.1007/s10661-012-2731-9 PG 12 WC Environmental Sciences SC Environmental Sciences & Ecology GA 077NB UT WOS:000314033300042 PM 22763654 ER PT J AU Lorieau, JL Louis, JM Bax, A AF Lorieau, Justin L. Louis, John M. Bax, Ad TI Impact of Influenza Hemagglutinin Fusion Peptide Length and Viral Subtype on Its Structure and Dynamics SO BIOPOLYMERS LA English DT Article DE NMR; chemical shift; dynamics; boomerang; hairpin ID MEMBRANE-FUSION; CONFORMATIONAL-CHANGE; VIRUS HEMAGGLUTININ; LIPID-BILAYERS; PROTEIN; NMR; DOMAIN; RELAXATION; MECHANISM; TOPOLOGY AB A peptide comprising no fewer than the first 20 residues of the influenza hemagglutinin HA2 subunit suffices to induce lipid mixing between the membranes of different unilamellar vesicles. This 20-residue peptide was previously reported to adopt an open "boomerang" structure that differs significantly from the closed helical-hairpin structure of a fusion peptide consisting of the first 23 residues of the HA2 sequence. This study investigates the structural and dynamic features of fusion peptides of different length and subtype. Lacking key interactions that stabilize the closed, helical-hairpin structure, the 20-residue peptide is in a dynamic equilibrium between closed and open states, adopting a ca. 11% population of the former when solubilized by DPC micelles. Peptides shorter than 20 residues would have even fewer interactions to stabilize a helical hairpin fold, resulting in a vanishing hairpin population. Considering the conserved nature of hairpin-stabilizing interactions across all serotypes, and the minimum of 20 residues needed for fusion, we postulate that the closed state plays an essential role in the fusion process. However, opening of this hairpin structure may be essential to the formation of a membrane pore at the final stage of the fusion process. Published 2012 Wiley Periodicals, Inc.* Biopolymers 99: 189-195, 2013. C1 [Lorieau, Justin L.; Louis, John M.; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Office of the Director, NIH FX Contract grant sponsors: Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH NR 39 TC 13 Z9 14 U1 1 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD MAR PY 2013 VL 99 IS 3 SI SI BP 189 EP 195 DI 10.1002/bip.22102 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 074SJ UT WOS:000313833300004 PM 23015412 ER PT J AU Sajjad, M Ahmadi, M Guinel, MJF Lin, Y Feng, P AF Sajjad, Muhammad Ahmadi, Majid Guinel, Maxime J-F Lin, Yi Feng, Peter TI Large scale synthesis of single-crystal and polycrystalline boron nitride nanosheets SO JOURNAL OF MATERIALS SCIENCE LA English DT Article ID CHEMICAL-VAPOR-DEPOSITION; THIN-FILM; PHOTOLUMINESCENCE; NANORIBBONS; NANOTUBES; BN AB Boron nitride nanosheets (BNNSs) have an identical crystal structure and similar lattice parameter to those of graphene sheets. However, growing quality BNNSs consisting of only several atomic layers remains a challenge. Here, we report on the synthesis of BNNSs at a temperature of 350 A degrees C using a CO2 pulsed laser plasma deposition (CO2-PLD) technique by irradiating a pyrolytic hexagonal boron nitride (h-BN) target. The deposition was performed either in vacuum at a pressure of 0.2 Pa, for which we obtained polycrystalline BN, or in hydrogen (H-2) atmosphere at a pressure of 26 Pa for which we obtained single-crystal BNNSs. The presence of H-2 seems to minimize the side effects of sputtering and the material shows higher purity and better crystallinity. High resolution transmission electron microscopy (HRTEM) showed the sheets to be mostly defect-free and to have the characteristic honeycomb structure of six-membered B-3-N-3 hexagon. HRTEM, electron diffraction, X-ray diffraction, Raman scattering, and Fourier transform infrared spectroscopy clearly identified h-BN. C1 [Sajjad, Muhammad; Ahmadi, Majid; Guinel, Maxime J-F; Feng, Peter] Univ Puerto Rico, Coll Nat Sci, Dept Phys, San Juan, PR 00936 USA. [Guinel, Maxime J-F] Univ Puerto Rico, Dept Chem, Coll Nat Sci, San Juan, PR 00936 USA. [Lin, Yi] NIA, Hampton, VA 23666 USA. RP Feng, P (reprint author), Univ Puerto Rico, Coll Nat Sci, Dept Phys, POB 70377, San Juan, PR 00936 USA. EM p.feng@upr.edu FU UPR; NSF; NASA FX The electron microscopy was performed at the Nanoscopy Facility, a user facility at the University of Puerto Rico (UPR), sponsored UPR, NSF, and NASA. NR 34 TC 10 Z9 11 U1 7 U2 226 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-2461 EI 1573-4803 J9 J MATER SCI JI J. Mater. Sci. PD MAR PY 2013 VL 48 IS 6 BP 2543 EP 2549 DI 10.1007/s10853-012-7044-4 PG 7 WC Materials Science, Multidisciplinary SC Materials Science GA 063YL UT WOS:000313038000029 ER PT J AU Pereira, IT Coletta, CE Perez, EV Kim, DH Gallagher, M Goldberg, IG Rapp, PR AF Pereira, Ines Tomas Coletta, Christopher E. Perez, Evelyn V. Kim, David H. Gallagher, Michela Goldberg, Ilya G. Rapp, Peter R. TI CREB-binding protein levels in the rat hippocampus fail to predict chronological or cognitive aging SO NEUROBIOLOGY OF AGING LA English DT Article DE Epigenetics; Memory; Image analysis; Quantitative microscopy ID RUBINSTEIN-TAYBI-SYNDROME; LONG-TERM-MEMORY; SPATIAL-LEARNING IMPAIRMENT; AGED RATS; HISTONE ACETYLATION; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; COACTIVATOR CBP; MOUSE MODEL; EXPRESSION AB Normal cognitive aging is associated with deficits in memory processes dependent on the hippocampus, along with large-scale changes in the hippocampal expression of many genes. Histone acetylation can broadly influence gene expression and has been recently linked to learning and memory. We hypothesized that CREB-binding protein (CBP), a key histone acetyltransferase, may contribute to memory decline in normal aging. Here, we quantified CBP protein levels in the hippocampus of young, aged unimpaired, and aged impaired rats, classified on the basis of spatial memory capacity documented in the Morris water maze. First, CBP-immunofluorescence was quantified across the principal cell layers of the hippocampus using both low and high resolution laser scanning imaging approaches. Second, digital images of CBP immunostaining were analyzed by a multipurpose classifier algorithm with validated sensitivity across many types of input materials. Finally, CBP protein levels in the principal subfields of the hippocampus were quantified by quantitative Western blotting. CBP levels were equivalent as a function of age and cognitive status in all analyses. The sensitivity of the techniques used was substantial, sufficient to reveal differences across the principal cell fields of the hippocampus, and to correctly classify images from young and aged animals independent of CBP immunoreactivity. The results are discussed in the context of recent evidence suggesting that CBP decreases may be most relevant in conditions of aging that, unlike normal cognitive aging, involve significant neuron loss. Published by Elsevier Inc. C1 [Pereira, Ines Tomas] Mt Sinai Sch Med, Neurosci Grad Program, New York, NY USA. [Pereira, Ines Tomas; Perez, Evelyn V.; Kim, David H.; Rapp, Peter R.] NIA, Neurocognit Aging Sect, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Coletta, Christopher E.; Goldberg, Ilya G.] NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Gallagher, Michela] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA. RP Rapp, PR (reprint author), NIA, Neurocognit Aging Sect, Lab Expt Gerontol, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM rappp@mail.nih.gov RI Goldberg, Ilya/H-5307-2011; OI Goldberg, Ilya/0000-0001-8514-6110; Tomas Pereira, Ines/0000-0003-2388-8164 FU Intramural Research Program of the National Institute on Aging; NIH [AG09973]; Fundacao para a Ciencia e a Tecnologia [SFRH/BD/27758/2006] FX The authors thank Robert McMahan, Dr. James Castellano, and Dr. Bonnie Fletcher for technical support, and the members of the Neurocognitive Aging Section of the Laboratory of Experimental Gerontology for helpful discussions. This research was supported by the Intramural Research Program of the National Institute on Aging; by NIH grant AG09973; and by Fundacao para a Ciencia e a Tecnologia grant SFRH/BD/27758/2006. NR 55 TC 7 Z9 7 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2013 VL 34 IS 3 BP 832 EP 844 DI 10.1016/j.neurobiolaging.2012.07.010 PG 13 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 065AF UT WOS:000313117900016 ER PT J AU Griffioen, KJ Rothman, SM Ladenheim, B Wan, RQ Vranis, N Hutchison, E Okun, E Cadet, JL Mattson, MP AF Griffioen, Kathleen J. Rothman, Sarah M. Ladenheim, Bruce Wan, Ruiqian Vranis, Neil Hutchison, Emmette Okun, Eitan Cadet, Jean Lud Mattson, Mark P. TI Dietary energy intake modifies brainstem autonomic dysfunction caused by mutant alpha-synuclein SO NEUROBIOLOGY OF AGING LA English DT Article DE alpha-synuclein; Acetylcholine; ANS; BDNF; Brainstem; Parasympathetic; Parkinson's disease ID HIGH-FAT DIET; PARKINSONS-DISEASE; CALORIC RESTRICTION; BEHAVIORAL DEFICITS; NEUROTROPHIC FACTOR; LOCUS-COERULEUS; HEART-RATE; MICE; NEURONS; SYSTEM AB Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of alpha-synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of alpha-synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of alpha-synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of alpha-synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals. Published by Elsevier Inc. C1 [Griffioen, Kathleen J.; Rothman, Sarah M.; Wan, Ruiqian; Vranis, Neil; Hutchison, Emmette; Okun, Eitan; Mattson, Mark P.] NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. [Ladenheim, Bruce; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Branch, Intramural Res Program, Baltimore, MD USA. [Okun, Eitan] Bar Ilan Univ, Fac Life Sci, Ramat Gan, Israel. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. NR 39 TC 12 Z9 12 U1 1 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2013 VL 34 IS 3 BP 928 EP 935 DI 10.1016/j.neurobiolaging.2012.07.008 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 065AF UT WOS:000313117900023 PM 22883907 ER PT J AU Ma, WX Coon, S Zhao, L Fariss, RN Wong, WT AF Ma, Wenxin Coon, Steven Zhao, Lian Fariss, Robert N. Wong, Wai T. TI A2E accumulation influences retinal microglial activation and complement regulation SO NEUROBIOLOGY OF AGING LA English DT Article DE Microglia; Retina; Lipofuscin; A2E; Aging; Age-related macular degeneration; Complement; Activation; Neuroprotection; Photoreceptors; Chemokine ID PIGMENTED EPITHELIAL-CELLS; SUBRETINAL DRUSENOID DEPOSITS; LIGHT-INDUCED DAMAGE; MACULAR DEGENERATION; MOUSE RETINA; FACTOR-H; LIPOFUSCIN FLUOROPHORE; GENE-EXPRESSION; RPE LIPOFUSCIN; UNITED-STATES AB Age-related macular degeneration is an outer retinal disease that involves aging and immune dysfunction. In the aging retina, microglia aggregate in the outer retina and acquire intracellular autofluorescent lipofuscin deposits. In this study, we investigated whether accumulation of A2E, a key bisretinoid constituent of ocular lipofuscin, alters the physiology of retinal microglia in pathologically relevant ways. Our findings show that sublethal accumulations of intracellular A2E in cultured retinal microglia increased microglial activation and decreased microglial neuroprotection of photoreceptors. Increased A2E accumulation also lowered microglial expression of chemokine receptors and suppressed microglial chemotaxis, suggesting that lipofuscin accumulation may potentiate subretinal microglial accumulation. Significantly, A2E accumulation altered microglial complement regulation by increasing complement factor B and decreasing complement factor H expression, favoring increased complement activation and deposition in the outer retina. Taken together, our findings highlight the role of microglia in the local control of complement activation in the retina and present the age-related accumulation of ocular lipofuscin in subretinal microglia as a cellular mechanism capable of driving outer retinal immune dysregulation in age-related macular degeneration pathogenesis. Published by Elsevier Inc. C1 [Ma, Wenxin; Zhao, Lian; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Coon, Steven] NICHHD, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Biol Imaging Core, 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 NEI Intramural by the National Eye Institute Intramural Research Program; American Health Assistance Foundation (AHAF) FX We are grateful to Dr. Maria M. Campos for her assistance with histopathology of aged and AMD eyes. This study was supported by the NEI Intramural by the National Eye Institute Intramural Research Program and a grant from the American Health Assistance Foundation (AHAF). Acknowledgement is made to the donors of ADR, a program of the American Health Assistance Foundation, for support of this research. NR 79 TC 38 Z9 41 U1 3 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2013 VL 34 IS 3 BP 943 EP 960 DI 10.1016/j.neurobiolaging.2012.06.010 PG 18 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 065AF UT WOS:000313117900025 PM 22819137 ER PT J AU Duverger, O Isaac, J Zah, A Hwang, J Berdal, A Lian, JB Morasso, MI AF Duverger, Olivier Isaac, Juliane Zah, Angela Hwang, Joonsung Berdal, Ariane Lian, Jane B. Morasso, Maria I. TI In vivo impact of Dlx3 conditional inactivation in neural crest-derived craniofacial bones SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID HOMEODOMAIN PROTEINS; TARGETED DISRUPTION; MURINE DENTITION; CALCITONIN-GENE; HOMEOBOX GENES; TDO SYNDROME; MICE; DIFFERENTIATION; EXPRESSION; SKELETAL AB Mutations in DLX3 in humans lead to defects in craniofacial and appendicular bones, yet the in vivo activities related to Dlx3 function during normal skeletal development have not been fully elucidated. Here we used a conditional knockout approach to analyze the effects of neural crest deletion of Dlx3 on craniofacial bones development. At birth, mutant mice exhibit a normal overall positioning of the skull bones, but a change in the shape of the calvaria was observed. Molecular analysis of the genes affected in the frontal bones and mandibles from these mice identified several bone markers known to affect bone development, with a strong prediction for increased bone formation and mineralization in vivo. Interestingly, while a subset of these genes were similarly affected in frontal bones and mandibles (Sost, Mepe, Bglap, Alp, Ibsp, Agt), several genes, including Lect1 and Calca, were specifically affected in frontal bones. Consistent with these molecular alterations, cells isolated from the frontal bone of mutant mice exhibited increased differentiation and mineralization capacities ex vivo, supporting cell autonomous defects in neural crest cells. However, adult mutant animals exhibited decreased bone mineral density in both mandibles and calvaria, as well as a significant increase in bone porosity. Together, these observations suggest that mature osteoblasts in the adult respond to signals that regulate adult bone mass and remodeling. This study provides new downstream targets for Dlx3 in craniofacial bone, and gives additional evidence of the complex regulation of bone formation and homeostasis in the adult skeleton. J. Cell. Physiol. 228: 654664, 2013. (C) 2012 Wiley Periodicals, Inc. C1 [Duverger, Olivier; Isaac, Juliane; Zah, Angela; Hwang, Joonsung; Morasso, Maria I.] NIAMS, Dev Skin Biol Sect, NIH, Bethesda, MD 20892 USA. [Berdal, Ariane] Univ Paris 05, INSERM, UMRS 872, Team 5, Paris, France. [Berdal, Ariane] Univ Paris 06, INSERM, UMRS 872, Team 5, Paris, France. [Lian, Jane B.] Univ Massachusetts, Sch Med, Dept Cell Biol, Amherst, MA 01003 USA. [Lian, Jane B.] Univ Massachusetts, Sch Med, Dept Orthoped Surg, Amherst, MA 01003 USA. RP Morasso, MI (reprint author), NIAMS, Dev Skin Biol Sect, NIH, 50 South Dr,Room 1523, Bethesda, MD 20892 USA. EM morasso@nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; National Institute of Health [R37, DE012528]; NIH [R37 DE012528] FX Contract grant sponsor: Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.; Contract grant sponsor: National Institute of Health;; Contract grant numbers: R37, DE012528.; This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. J.B.L is supported by NIH grant R37 DE012528. For the use of instruments, we thank Dr. Pamela G. Robey (X-ray). For microarray analysis, we thank George Poy and Weiping Chen. We thank the Mouse Imaging Facility of the NIH. We thank Dr. Jonathan Gordon for helpful direction and technical advice for the culture of primary osteblasts from mouse calvaria. NR 48 TC 10 Z9 10 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD MAR PY 2013 VL 228 IS 3 BP 654 EP 664 DI 10.1002/jcp.24175 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 048LL UT WOS:000311912900019 PM 22886599 ER PT J AU Cao, Y Bender, IK Konstantinidis, AK Shin, SC Jewell, CM Cidlowski, JA Schleimer, RP Lu, NZ AF Cao, Yun Bender, Ingrid K. Konstantinidis, Athanasios K. Shin, Soon Cheon Jewell, Christine M. Cidlowski, John A. Schleimer, Robert P. Lu, Nick Z. TI Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans SO BLOOD LA English DT Article ID SELECTIVE REGULATION; DIFFERENTIATION; DEXAMETHASONE; CORTICOSTEROIDS; ANTIGEN; MOUSE; PIMECROLIMUS; ACTIVATION; MECHANISMS; EXPRESSION AB Although glucocorticoids are a profoundly important class of anti-inflammatory and immunosuppressive agents, their actions in dendritic cells (DCs) are not well understood. We found that dexamethasone, a potent glucocorticoid, selectively induced apoptosis in mature, but not in immature, DCs in healthy mice, in mice with experimental airway inflammation, and in vitro in bone marrow-derived DCs. Distinct glucocorticoid receptor (GR) translational isoforms expressed in immature and mature DCs probably contribute to the DC maturational stage-specific glucocorticoid sensitivity. The GR-D isoforms were the predominant isoforms in immature DCs, whereas the proapoptotic GR-A isoform was the main isoform in mature DCs. Ectopic expression of the GR-A isoform in immature DCs increased glucocorticoid sensitivity and RU486, a selective GR antagonist, inhibited the glucocorticoid sensitivity of mature DCs. Furthermore, the distinct expression pattern of GR isoforms in immature and mature murine DCs was also observed in human monocyte-derived DCs. These studies suggest that glucocorticoids may spare immature DCs and suppress mature DCs and inflammation via differential expression of GR translational isoforms. C1 [Cao, Yun; Bender, Ingrid K.; Konstantinidis, Athanasios K.; Shin, Soon Cheon; Schleimer, Robert P.; Lu, Nick Z.] Northwestern Univ, Div Allergy Immunol, Dept Med, Chicago, IL 60611 USA. [Jewell, Christine M.; Cidlowski, John A.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, NZ (reprint author), Northwestern Univ, Div Allergy Immunol, Dept Med, Feinberg Sch Med, McGaw Rm M301,240 E Huron, Chicago, IL 60611 USA. EM nickzlu@northwestern.edu FU National Institutes of Health [NIH 1R01HL094558-01A1, NIH 3R01HL094558-01A1S1, NIH 2R37HL068546-26] FX This work was supported by National Institutes of Health grants NIH 1R01HL094558-01A1 (N.Z.L.) NIH 3R01HL094558-01A1S1 (N.Z.L.), and NIH 2R37HL068546-26 (R.P.S). NR 41 TC 18 Z9 18 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 28 PY 2013 VL 121 IS 9 BP 1553 EP 1562 DI 10.1182/blood-2012-05-432336 PG 10 WC Hematology SC Hematology GA 182NM UT WOS:000321750300017 PM 23297131 ER PT J AU Afonso, PV McCann, CP Kapnick, SM Parent, CA AF Afonso, Philippe V. McCann, Colin P. Kapnick, Senta M. Parent, Carole A. TI Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices SO BLOOD LA English DT Article ID EXTRACELLULAR-MATRIX; 3-DIMENSIONAL COLLAGEN; SYNOVIAL FIBROBLASTS; LEUKOCYTE MIGRATION; CELL-MIGRATION; EXPRESSION; INFLAMMATION; PEPTIDE; DDR1; CHEMOATTRACTANT AB Neutrophils express a variety of collagen receptors at their surface, yet their functional significance remains unclear. Although integrins are essential for neutrophil adhesion and migration on 2-dimensional (2D) surfaces, neutrophils can compensate for the absence of integrins in 3-dimensional (3D) lattices. In contrast, we demonstrate that the inhibition of the tyrosine-kinase collagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migration on 2D surfaces but is an important regulator of neutrophil chemotaxis in 3D collagen matrices. In this context, we show that DDR2 activation specifically regulates the directional migration of neutrophils in chemoattractant gradients. We further demonstrate that DDR2 regulates directionality through its ability to increase secretion of metalloproteinases and local generation of collagen-derived chemotactic peptide gradients. Our findings highlight the importance of collagen-derived extracellular signaling during neutrophil chemotaxis in 3D matrices. C1 [Afonso, Philippe V.; McCann, Colin P.; Kapnick, Senta M.; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [McCann, Colin P.] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Kapnick, Senta M.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Parent, CA (reprint author), NIH, LCMB, CCR, 37 Convent Dr,Bldg 37,Rm 2066, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov RI Afonso, Philippe/D-2234-2014 OI Afonso, Philippe/0000-0002-4828-3797 FU Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. NR 40 TC 16 Z9 17 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 28 PY 2013 VL 121 IS 9 BP 1644 EP 1650 DI 10.1182/blood-2012-08-451575 PG 7 WC Hematology SC Hematology GA 182NM UT WOS:000321750300026 PM 23233663 ER PT J AU Solomon, SB Wang, D Sun, JF Kanias, T Feng, J Helms, CC Solomon, MA Alimchandani, M Quezado, M Gladwin, MT Kim-Shapiro, DB Klein, HG Natanson, C AF Solomon, Steven B. Wang, Dong Sun, Junfeng Kanias, Tamir Feng, Jing Helms, Christine C. Solomon, Michael A. Alimchandani, Meghna Quezado, Martha Gladwin, Mark T. Kim-Shapiro, Daniel B. Klein, Harvey G. Natanson, Charles TI Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia SO BLOOD LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; CELL-FREE HEMOGLOBIN; STORAGE LESION; RED; HEMOLYSIS; SURVIVAL; MODEL; BIOAVAILABILITY; VIABILITY; SURGERY AB Two-year-old purpose-bred beagles (n = 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7- or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P = .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P <= .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for similar to 10 hours afterward (all P <= .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P = .03) noted at the infection site postmortem. Plasma cell-free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P <= .03). The low haptoglobin (r = 0.61; P = .003) and high NO consumption levels at 24 hours (r = -0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P = .03) and not associated with survival (P = NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion. C1 [Solomon, Steven B.; Wang, Dong; Sun, Junfeng; Feng, Jing; Solomon, Michael A.; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kanias, Tamir; Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Helms, Christine C.; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Helms, Christine C.; Kim-Shapiro, Daniel B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Alimchandani, Meghna; Quezado, Martha] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Gladwin, Mark T.] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Klein, Harvey G.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Natanson, C (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Rm 2C145, Bethesda, MD 20892 USA. EM cnatanson@cc.nih.gov RI Kanias, Tamir/K-2384-2016 OI Kanias, Tamir/0000-0001-6558-0913 FU Intramural NIH funds; NIH [HL058091, HL098032]; US government FX Intramural NIH funds and NIH external grants HL058091 and HL098032 were used to support this study. The work by the authors was done as part of US government-funded research; however, the opinions expressed are not necessarily those of the National Institutes of Health. NR 38 TC 70 Z9 70 U1 1 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 28 PY 2013 VL 121 IS 9 BP 1663 EP 1672 DI 10.1182/blood-2012-10-462945 PG 10 WC Hematology SC Hematology GA 182NM UT WOS:000321750300028 PM 23255558 ER PT J AU McGill, LA Ismail, T Nielles-Vallespin, S Ferreira, P Scott, AD Roughton, M Kilner, PJ Ho, SY McCarthy, KP Gatehouse, PD de Silva, R Speier, P Feiweier, T Mekkaoui, C Sosnovik, DE Prasad, SK Firmin, DN Pennell, DJ AF McGill, Laura-Ann Ismail, Tevfik Nielles-Vallespin, Sonia Ferreira, Pedro Scott, Andrew D. Roughton, Michael Kilner, Philip J. Ho, S. Yen McCarthy, Karen P. Gatehouse, Peter D. de Silva, Ranil Speier, Peter Feiweier, Thorsten Mekkaoui, Choukkri Sosnovik, David E. Prasad, Sanjay K. Firmin, David N. Pennell, Dudley J. TI reproducibility of in-vivo diffusion tensor cardiovascular magnetic resonance in hypertrophic cardiomyopathy (vol 14, pg 86, 2012) SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Correction C1 [McGill, Laura-Ann; Ismail, Tevfik; Nielles-Vallespin, Sonia; Ferreira, Pedro; Scott, Andrew D.; Roughton, Michael; Kilner, Philip J.; Ho, S. Yen; McCarthy, Karen P.; Gatehouse, Peter D.; de Silva, Ranil; Prasad, Sanjay K.; Firmin, David N.; Pennell, Dudley J.] Royal Brompton Hosp, Cardiovasc Magnet Resonance Unit, London SW3 6LY, England. [McGill, Laura-Ann; Nielles-Vallespin, Sonia; Ferreira, Pedro; Scott, Andrew D.; Kilner, Philip J.; Ho, S. Yen; McCarthy, Karen P.; de Silva, Ranil; Prasad, Sanjay K.; Firmin, David N.; Pennell, Dudley J.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Nielles-Vallespin, Sonia] NHLBI, NIH, DHHS, Bethesda, MD 20892 USA. [Speier, Peter; Feiweier, Thorsten] Siemens AG Med Solut, MR R&D, Erlangen, Germany. [Mekkaoui, Choukkri; Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Firmin, DN (reprint author), Royal Brompton Hosp, Cardiovasc Magnet Resonance Unit, London SW3 6LY, England. EM d.firmin@imperial.ac.uk NR 1 TC 2 Z9 2 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD FEB 28 PY 2013 VL 15 AR 22 DI 10.1186/1532-429X-15-22 PG 1 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 128AI UT WOS:000317739900001 ER PT J AU Smith, AW Cronin, KA Bowles, H Willis, G Jacobs, DR Ballard-Barbash, R Troiano, RP AF Smith, Ashley Wilder Cronin, Kathleen A. Bowles, Heather Willis, Gordon Jacobs, David R., Jr. Ballard-Barbash, Rachel Troiano, Richard P. TI Reproducibility of physical activity recall over fifteen years: longitudinal evidence from the CARDIA study SO BMC PUBLIC HEALTH LA English DT Article ID ACTIVITY QUESTIONNAIRE; RELIABILITY; HEALTH; WOMEN; VALIDITY; RISK AB Background: To examine the benefits of physical activity (PA) on diseases with a long developmental period, it is important to determine reliability of long-term PA recall. Methods: We investigated 15-year reproducibility of PA recall. Participants were 3605 White and African-American adults in the Coronary Artery Risk Development in Young Adults study, aged 33-45 at the time of recall assessment. Categorical questions assessed PA before and during high school (HS) and overall PA level at Baseline, with the same timeframes recalled 15 years later. Moderate-and vigorous-intensity scores were calculated from reported months of participation in specific activities. Results: HS PA recall had higher reproducibility than overall PA recall (weighted kappa = 0.43 vs. 0.21). Correlations between 15-year recall and Baseline reports of PA were r = 0.29 for moderate-intensity scores, and r = 0.50 for vigorous-intensity. Recall of vigorous activities had higher reproducibility than moderate-intensity activities. Regardless of number of months originally reported for specific activities, most participants recalled either no activity or activity during all 12 months. Conclusion: PA recall from the distant past is moderately reproducible, but poor at the individual level, among young and middle aged adults. C1 [Smith, Ashley Wilder; Bowles, Heather; Willis, Gordon; Ballard-Barbash, Rachel; Troiano, Richard P.] NCI, Appl Res Progam, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Cronin, Kathleen A.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Jacobs, David R., Jr.] Univ Oslo, Sch Med, Dept Nutr, Oslo, Norway. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, Appl Res Program, Bethesda, MD 20892 USA. RP Smith, AW (reprint author), NCI, Appl Res Progam, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM smithas@mail.nih.gov OI Troiano, Richard/0000-0002-6807-989X FU National Cancer Institute [Y2-PC-0010-DC]; National Heart, Lung and Blood Institute, CARDIA [N01-HC-48047 - N01-HC-48050, N01-HC-95095] FX This work was supported by the National Cancer Institute, contract number: Y2-PC-0010-DC and by the National Heart, Lung and Blood Institute, CARDIA contract numbers: N01-HC-48047 - N01-HC-48050 and N01-HC-95095. The authors thank Dr. Laurence Freedman for statistical advice and Lisa Kahle for programming support. NR 23 TC 5 Z9 5 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD FEB 28 PY 2013 VL 13 AR 180 DI 10.1186/1471-2458-13-180 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 119TW UT WOS:000317121600001 PM 23448132 ER PT J AU Cui, X Yeliseev, A Liu, RY AF Cui, Xu Yeliseev, Alexei Liu, Renyu TI Ligand interaction, binding site and G protein activation of the mu opioid receptor SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Mu opioid receptor; G protein activation; Structure; Function; Docking; Binding site ID UNITED-STATES; ABUSE; DOCKING; ANTAGONIST; NALTREXONE; DEPENDENCE; SUBUNITS; CAVITIES; AUTODOCK; AGONISTS AB With the recently solved crystal structure of the murine mu opioid receptor, the elucidation of the structure function relationships of the human mu receptor becomes feasible. In this study, we analyzed the available structural information along with ligand binding and G protein activation of human mu receptor. Affinity determinations were performed in a HEK293 cell line stably transfected with the human mu opioid receptor for 6 different agonists (morphine, DMAGO, and herkinom) and antagonists (naloxone, beta-Funaltrexamine, and Norbinaltorphimine). G protein activation was investigated in membrane preparations containing human mu receptors treated with the agonist, partial agonist, or antagonist compounds. 4DKL.pdb was utilized for structural analysis and docking calculations for 28 mu receptor ligands. The predicted affinities from docking were compared with those experimentally determined. While all known ligands bind to the receptor through the same binding site that is large enough to accommodate molecules of various sizes, interaction with D147 (D149 in human mu receptor) is essential for binding. No distinguishable interaction pattern in the binding site for agonist, partial agonist, or antagonist to predict pharmacological activities was found. The failure to reconcile the predicted affinities from docking with experimental values indicates that the receptor might undergo significant conformational changes from one state to the other states upon different ligand binding. A simplified model to understand the complicated system is proposed and further study on these multiple conformations using high resolution structural approaches is suggested. (C) 2013 Elsevier B.V. All rights reserved. C1 [Cui, Xu] Capital Med Univ, Beijing Tongren Hosp, Dept Anesthesiol, Beijing, Peoples R China. [Cui, Xu; Liu, Renyu] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Yeliseev, Alexei] NIAAA, NIH, Bethesda, MD USA. RP Liu, RY (reprint author), Univ Penn, Sch Med, Dept Anesthesiol & Crit Care, 336 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM liur@uphs.upenn.edu FU NIH [K08-GM-093115-01]; Intramural Research Program of the NIAAA, NIH; department of anesthesiology and Critical Care at University of Pennsylvania; Foundation for Anesthesia Education and Research; Department of Anesthesiology at Beijing Tongren Hospital; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C (NIMH PDSP)]; GROFF FX This research was supported by NIH K08-GM-093115-01 (PI:RL) and the Intramural Research Program of the NIAAA, NIH (PI, AY). This research is also supported by the departmental funding from the department of anesthesiology and Critical Care at University of Pennsylvania (PI RL), funding from the Foundation for Anesthesia Education and Research (PI, RL), GROFF (PI, RL).; The authors thank the support from the Department of Anesthesiology and Critical Care at the University of Pennsylvania and the Department of Anesthesiology at Beijing Tongren Hospital affiliated to Capital Medical University, Beijing China. The authors thank useful discussion with Professor Jeffery G Saven at the Department of Chemistry at the University of Pennsylvania; thank the outstanding technical support and manuscript editing from Mr. Felipe Matsunaga, BS at the Department of Anesthesiology and Critical Care at the University of Pennsylvania. The authors acknowledges the support from the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP), which is directed by Bryan L Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. NR 36 TC 9 Z9 10 U1 6 U2 31 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 28 PY 2013 VL 702 IS 1-3 BP 309 EP 315 DI 10.1016/j.ejphar.2013.01.060 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 120EH UT WOS:000317153100040 PM 23415745 ER PT J AU Jin, DY Shi, YB Wu, TC AF Jin, Dong-Yan Shi, Yun-Bo Wu, T-C TI In memoriam: Kuan-Teh Jeang, MD PhD (1958-2013) SO CELL AND BIOSCIENCE LA English DT Biographical-Item C1 [Jin, Dong-Yan] Univ Hong Kong, Dept Biochem, Pokfulam, Hong Kong, Peoples R China. [Shi, Yun-Bo] NIH, Bethesda, MD 20892 USA. [Wu, T-C] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Jin, DY (reprint author), Univ Hong Kong, Dept Biochem, Pokfulam, Hong Kong, Peoples R China. EM dyjin@hku.hk NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD FEB 28 PY 2013 VL 3 AR 13 DI 10.1186/2045-3701-3-13 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109CS UT WOS:000316343600001 PM 23448135 ER PT J AU Liu, P Giam, CZ Zheng, ZM AF Liu, Paul Giam, Chou-Zen Zheng, Zhi-Ming TI Dr. Kuan-Teh Jeang (1958-2013): an outstanding scientist, a caring mentor, a role model and leader of the Asian American scientist community - an eulogy delivered by Paul Liu at NIH on February 8, 2013, with additional modifications SO CELL AND BIOSCIENCE LA English DT Editorial Material C1 [Liu, Paul] NHGRI, NIH, Bethesda, MD 20892 USA. [Giam, Chou-Zen] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Zheng, Zhi-Ming] NCI, NIH, Bethesda, MD 20892 USA. RP Liu, P (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD FEB 28 PY 2013 VL 3 AR 14 DI 10.1186/2045-3701-3-14 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 114HU UT WOS:000316732500001 PM 23448159 ER PT J AU Koonin, EV Mulkidjanian, AY AF Koonin, Eugene V. Mulkidjanian, Armen Y. TI Evolution of Cell Division: From Shear Mechanics to Complex Molecular Machineries SO CELL LA English DT Editorial Material AB Cell division depends on sophisticated molecular machinery. However, wall-less forms of bacteria use a much simpler mechanism that mimics spontaneous division of synthetic lipid vesicles. Mercier et al. (2013) show that this "mechanical" division can be activated by increased lipid synthesis. Conceivably, the first cells divided via this route. C1 [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. [Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, Sch Bioengn & Bioinformat, Moscow 119992, Russia. [Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119992, Russia. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Mulkidjanian, Armen/J-8086-2013 OI Mulkidjanian, Armen/0000-0001-5844-3064 NR 10 TC 7 Z9 7 U1 4 U2 42 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 28 PY 2013 VL 152 IS 5 BP 942 EP 944 DI 10.1016/j.cell.2013.02.008 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 100OK UT WOS:000315710300004 PM 23452845 ER PT J AU Lauberth, SM Nakayama, T Wu, XL Ferris, AL Tang, ZY Hughes, SH Roeder, RG AF Lauberth, Shannon M. Nakayama, Takahiro Wu, Xiaolin Ferris, Andrea L. Tang, Zhanyun Hughes, Stephen H. Roeder, Robert G. TI H3K4me3 Interactions with TAF3 Regulate Preinitiation Complex Assembly and Selective Gene Activation SO CELL LA English DT Article ID RNA-POLYMERASE-II; CHROMATIN IN-VITRO; HISTONE MODIFICATIONS; CORE PROMOTER; DEPENDENT TRANSCRIPTION; BINDING MODULES; DNA-DAMAGE; P53; APOPTOSIS; TRIMETHYLATION AB Histone modifications regulate chromatin-dependent processes, yet the mechanisms by which they contribute to specific outcomes remain unclear. H3K4me3 is a prominent histone mark that is associated with active genes and promotes transcription through interactions with effector proteins that include initiation factor TFIID. We demonstrate that H3K4me3-TAF3 interactions direct global TFIID recruitment to active genes, some of which are p53 targets. Further analyses show that (1) H3K4me3 enhances p53-dependent transcription by stimulating preinitiation complex (PIC) formation; (2) H3K4me3, through TAF3 interactions, can act either independently or cooperatively with the TATA box to direct PIC formation and transcription; and (3) H3K4me3-TAF3/TFIID interactions regulate gene-selective functions of p53 in response to genotoxic stress. Our findings indicate a mechanism by which H3K4me3 directs PIC assembly for the rapid induction of specific p53 target genes. C1 [Lauberth, Shannon M.; Nakayama, Takahiro; Tang, Zhanyun; Roeder, Robert G.] Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10065 USA. [Wu, Xiaolin] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Ferris, Andrea L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Roeder, RG (reprint author), Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10065 USA. EM roeder@rockefeller.edu FU NRSA [CA 09673]; NIH, Center for Cancer Research, National Cancer Institute; NIH [CA129325, DK071900]; Leukemia and Lymphoma Society [7132-08] FX We are grateful to Tomoyoshi Nakadai and Zhu Xie for technical assistance and Sohail Malik, Beth Moorefield, Christina Hughes, and Michael Rauchman for insightful discussions of the project. This work was supported by NRSA Training Grant CA 09673 to S. L., the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute to S. H. H., and by grants from the NIH (CA129325 and DK071900) and the Leukemia and Lymphoma Society (7132-08) to R.G.R. NR 43 TC 104 Z9 107 U1 2 U2 43 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 28 PY 2013 VL 152 IS 5 BP 1021 EP 1036 DI 10.1016/j.cell.2013.01.052 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 100OK UT WOS:000315710300011 PM 23452851 ER PT J AU Meffert, H Blanken, L Blair, KS White, SF Blair, JR AF Meffert, Harma Blanken, Laura Blair, Karina S. White, Stuart F. Blair, James R. TI The influence of valence and decision difficulty on self-referential processing SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE fMRI; self-referential processing; decision making; emotion; affect ID ANTERIOR CINGULATE CORTEX; MEDIAL PREFRONTAL CORTEX; TASK-DIFFICULTY; COGNITIVE CONTROL; FRONTAL-CORTEX; FMRI; BRAIN; WORDS; RATINGS; SYSTEMS AB Self-referential processing is defined as the process by which a person becomes aware that specific contents are related to his or her own self. Cortical midline structures (CMS), such as dorsal and medial prefrontal cortex, and regions such as inferior frontal cortex, insula, and temporal pole have been implicated in self-referential processing. However, the specific contribution of each of these areas is still largely unknown. More particularly, not many studies have examined the influence of valence and decision making difficulty on regions involved in self-referential processing. In this study, participants evaluated how well personality traits, differing in valence and decision difficulty, described themselves or the current US President. In line with predictions, ventral, rostral, and dorsal parts of medial prefrontal cortex showed greater activity when participants judged traits about themselves relative to judging traits about the current US President. However, none of these regions showed significant modulation by trait valence. Increasing trait decision difficulty was associated with increased activity within dorsal medial prefrontal cortex and bilateral anterior insula. However, there was very minimal overlap (6/119 voxels, i.e., 5%) of the regions of dorsal medial prefrontal cortex implicated in self-referential processing and those implicated in trait decision difficulty. The results are interpreted within current accounts of self-referential processing. C1 [Meffert, Harma; White, Stuart F.; Blair, James R.] NIH, Sect Affective & Cognitive Neurosci, Bethesda, MD 20892 USA. [Blanken, Laura] Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands. [Blair, Karina S.] NIMH, NIH, Bethesda, MD 20892 USA. RP Meffert, H (reprint author), NIMH, Sect Affect & Cognitive Neurosci, NIH, 15K North Dr, Bethesda, MD 20892 USA. EM harma.meffert@nih.gov OI Meffert, Harma/0000-0002-7298-7276 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860-08] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health under grant number 1-ZIA-MH002860-08. NR 58 TC 4 Z9 4 U1 3 U2 15 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD FEB 28 PY 2013 VL 7 AR 46 DI 10.3389/fnhum.2013.00046 PG 14 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 101NU UT WOS:000315782500001 PM 23450237 ER PT J AU Reed, GW Choi, H Lee, SY Lee, M Kim, Y Park, H Lee, J Zhan, X Kang, H Hwang, S Carroll, M Cai, Y Cho, SN Barry, CE Via, LE Kornfeld, H AF Reed, George W. Choi, Hongjo Lee, So Young Lee, Myungsun Kim, Youngran Park, Hyemi Lee, Jongseok Zhan, Xin Kang, Hyeungseok Hwang, SooHee Carroll, Matthew Cai, Ying Cho, Sang-Nae Barry, Clifton E., III Via, Laura E. Kornfeld, Hardy TI Impact of Diabetes and Smoking on Mortality in Tuberculosis SO PLOS ONE LA English DT Article ID PULMONARY TUBERCULOSIS; TREATMENT OUTCOMES; SUSCEPTIBILITY; INFECTION; RISK AB Background: Diabetes mellitus is a risk factor for tuberculosis (TB) disease. There is evidence that diabetes also influences TB severity and treatment outcomes but information is incomplete and some published results have been inconsistent. Methods: A longitudinal cohort study was conducted at the National Masan Tuberculosis Hospital in the Republic of Korea. Subjects presenting with a first episode of TB or for retreatment of TB were followed from enrollment through completion of treatment. Demographic, clinical, and microbiological variables were recorded, along with assessment of outcomes. Results were compared in TB patients with and without diabetes or smoking history. Data were adjusted for gender, age, cohort, educational level and alcohol consumption. Results: The combined cohorts comprised 657 subjects. Diabetes was present in 25% and was associated with greater radiographic severity and with recurrent or relapsed TB. Diabetes and cigarette smoking independently increased the risk of death in the first 12 months after enrollment. Estimating the combined impact of diabetes and smoking yielded a hazard ratio of 5.78. Only 20% of diabetic subjects were non-smokers; 54% smoked >= 1 pack daily. In this cohort, the impact of diabetes on mortality was greater in patients younger than 50 years, compared to older patients. Conclusions: In this cohort of Korean patients, diabetes exacerbated the severity of TB disease. Diabetic subjects who smoked >= 1 pack of cigarettes daily were at particularly high risk of death from TB. Strategies to improve TB outcomes could productively focus resources for patient education and TB prevention on the vulnerable population of younger diabetics, particularly those who also smoke. C1 [Reed, George W.] Univ Massachusetts, Sch Med, Dept Prevent & Behav Med, Worcester, MA USA. [Choi, Hongjo; Lee, So Young; Lee, Myungsun; Kim, Youngran; Park, Hyemi; Lee, Jongseok; Cho, Sang-Nae] Int TB Res Ctr, Chang Won, South Korea. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Zhan, Xin] Univ Massachusetts, Sch Med, Informat Serv Dept, Worcester, MA USA. [Kang, Hyeungseok; Hwang, SooHee] Natl Masan TB Hosp, Chang Won, South Korea. [Carroll, Matthew; Cai, Ying; Barry, Clifton E., III; Via, Laura E.] NIAID, TB Res Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Kornfeld, Hardy] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. RP Kornfeld, H (reprint author), Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. EM hardy.kornfeld@umassmed.edu RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521 FU University of Massachusetts Medical School Office of Global Health; Intramural Research Division of the National Institute of Allergy and Infectious Diseases (National Institutes of Health); Korean Ministry of Health and Welfare FX This study was funded in part by the University of Massachusetts Medical School Office of Global Health, the Intramural Research Division of the National Institute of Allergy and Infectious Diseases (National Institutes of Health), and the Korean Ministry of Health and Welfare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 25 TC 31 Z9 31 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 28 PY 2013 VL 8 IS 2 AR e58044 DI 10.1371/journal.pone.0058044 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098DA UT WOS:000315524900230 PM 23469139 ER PT J AU Song, C Chen, GK Millikan, RC Ambrosone, CB John, EM Bernstein, L Zheng, W Hu, JJ Ziegler, RG Nyante, S Bandera, EV Ingles, SA Press, MF Deming, SL Rodriguez-Gil, JL Chanock, SJ Wan, P Sheng, X Pooler, LC Van Den Berg, DJ Le Marchand, L Kolonel, LN Henderson, BE Haiman, CA Stram, DO AF Song, Chi Chen, Gary K. Millikan, Robert C. Ambrosone, Christine B. John, Esther M. Bernstein, Leslie Zheng, Wei Hu, Jennifer J. Ziegler, Regina G. Nyante, Sarah Bandera, Elisa V. Ingles, Sue A. Press, Michael F. Deming, Sandra L. Rodriguez-Gil, Jorge L. Chanock, Stephen J. Wan, Peggy Sheng, Xin Pooler, Loreall C. Van Den Berg, David J. Le Marchand, Loic Kolonel, Laurence N. Henderson, Brian E. Haiman, Chris A. Stram, Daniel O. TI A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women SO PLOS ONE LA English DT Article ID LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY LOCI; P-VALUES; UNRELATED INDIVIDUALS; INFERRED HAPLOTYPES; MAXIMUM-LIKELIHOOD; TRUNCATED PRODUCT; SCORE TESTS; ASSOCIATION; POPULATION AB Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density. C1 [Song, Chi; Chen, Gary K.; Ingles, Sue A.; Wan, Peggy; Sheng, Xin; Pooler, Loreall C.; Van Den Berg, David J.; Henderson, Brian E.; Haiman, Chris A.; Stram, Daniel O.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Song, Chi; Chen, Gary K.; Ingles, Sue A.; Press, Michael F.; Wan, Peggy; Sheng, Xin; Pooler, Loreall C.; Van Den Berg, David J.; Henderson, Brian E.; Haiman, Chris A.; Stram, Daniel O.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Chen, Gary K.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Millikan, Robert C.; Nyante, Sarah] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Canc Inst, Stanford, CA USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Zheng, Wei; Deming, Sandra L.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Zheng, Wei; Deming, Sandra L.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Ziegler, Regina G.; Chanock, Stephen J.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ USA. [Press, Michael F.] Univ So Calif, Dept Pathol, Keck Sch Med, Los Angeles, CA 90089 USA. [Van Den Berg, David J.] Univ So Calif, Epigenome Ctr, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. RP Stram, DO (reprint author), Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. EM stram@usc.edu RI Bandera, Elisa/M-4169-2014 OI Bandera, Elisa/0000-0002-8789-2755 FU Department of Defense Breast Cancer Research Program Era of Hope Scholar Award; Norris Foundation; California Breast Cancer Research Program [15UB-8402]; MEC (National Institutes of Health) [R01-CA63464, R37-CA54281]; CARE (National Institute for Child Health and Development) [NO1-HD-3-3175, K05 CA136967]; WCHS (U.S. Army Medical Research and Material Command (USAMRMC) [DAMD-17-01-0-0334]; National Institutes of Health [R01-CA100598]; Breast Cancer Research Foundation; SFBCS (National Institutes of Health) [R01-CA77305]; SFBCS (United States Army Medical Research Program) [DAMD17-96-6071]; NC-BCFR (National Institutes of Health) [U01-CA69417]; CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer) [P50-CA58223]; Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, National Institutes of Health [P30-ES10126]; PLCO (Intramural Research Program, National Cancer Institute, National Institutes of Health); NBHS (National Institutes of Health) [R01-CA100374]; WFBC (National Institutes of Health) [R01-CA73629]; National Cancer Institute, National Institutes of Health [RFA-CA-06-503]; National Heart, Lung, and Blood Institute, NIH, U. S. 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] FX This work was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH and the Norris Foundation and by the California Breast Cancer Research Program (15UB-8402). Each of the participating studies was supported by the following grants: MEC (National Institutes of Health grants R01-CA63464 and R37-CA54281); CARE (National Institute for Child Health and Development grant NO1-HD-3-3175, K05 CA136967), WCHS (U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the National Institutes of Health grant R01-CA100598, and the Breast Cancer Research Foundation, SFBCS (National Institutes of Health grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071), NC-BCFR (National Institutes of Health grant U01-CA69417), CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, National Institutes of Health, grant number P30-ES10126), PLCO (Intramural Research Program, National Cancer Institute, National Institutes of Health), NBHS (National Institutes of Health grantR01-CA100374), WFBC (National Institutes of Health grant R01-CA73629). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government or the BCFR. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U. S. 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 7 Z9 8 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 28 PY 2013 VL 8 IS 2 AR e57298 DI 10.1371/journal.pone.0057298 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 098DA UT WOS:000315524900070 PM 23468962 ER EF