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