FN Thomson Reuters Web of Science™ VR 1.0 PT J AU McLean, MH Neurath, MF Durum, SK AF McLean, Mairi H. Neurath, Markus F. Durum, Scott K. TI Targeting Interleukins for the Treatment of Inflammatory Bowel Disease-What Lies Beyond Anti-TNF Therapy? SO INFLAMMATORY BOWEL DISEASES LA English DT Review DE inflammatory bowel disease; cytokines; interleukins ID ACTIVE ULCERATIVE-COLITIS; REGULATORY T-CELLS; CHRONIC INTESTINAL INFLAMMATION; JANUS KINASE INHIBITOR; CROHNS-DISEASE; EPITHELIAL-CELLS; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; RECEPTOR ANTAGONIST; SERUM CONCENTRATION AB Inflammatory bowel disease accounts for significant patient morbidity in the Western world. Several immunosuppressive therapies are available but are associated with potential significant adverse effects. In addition, there remains a cohort of patients with refractory or relapsing disease. Therefore, the search for novel therapeutic agents continues. In this review, we evaluate the role of a number of designated cytokines that are candidates in the pathogenesis of inflammatory bowel disease and discuss how their manipulation has been explored as a therapeutic strategy for this disease. The interleukins (ILs) chosen for discussion reflect those that currently show most promise as future therapeutic targets, as well as discussing the role of some of the most recently identified ILs, such as IL-27, IL-33, IL-35, and IL-22, in this context. C1 [McLean, Mairi H.; Durum, Scott K.] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Neurath, Markus F.] Univ Erlangen Nurnberg, Dept Internal Med, D-91054 Erlangen, Germany. RP McLean, MH (reprint author), NCI, Mol Immunoregulat Lab, Bldg 560,1050 Boyles St, Frederick, MD 21702 USA. EM mairi.mclean@nih.gov FU National Institutes of Health, National Cancer Institute; Crohn's and Colitis Foundation of America FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Fellowship funded by Crohn's and Colitis Foundation of America (M.H.M.). NR 131 TC 10 Z9 10 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2014 VL 20 IS 2 BP 389 EP 397 DI 10.1097/01.MIB.0000437616.37000.41 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AH0DT UT WOS:000335790000025 PM 24356385 ER PT J AU Yin, JW Lin, JD Luo, XD Chen, YY Li, Z Ma, GD Li, KS AF Yin, Jingwen Lin, Juda Luo, Xudong Chen, Yanyan Li, Zheng Ma, Guoda Li, Keshen TI miR-137: A New Player in Schizophrenia SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE miR-137; schizophrenia; neurodevelopment; target gene; signaling pathway ID EMBRYONIC STEM-CELLS; DORSOLATERAL PREFRONTAL CORTEX; MICRORNA BIOGENESIS; GENE CACNA1C; CROSS-TALK; BRAIN; SUSCEPTIBILITY; VARIANT; DIFFERENTIATION; DISORDER AB Schizophrenia is a complex genetic disease and characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are critical to neurodevelopment and adult neuronal processes by modulating the activity of multiple genes within biological networks. MiR-137 as a brain-enriched microRNA, plays important roles in regulating embryonic neural stem cells (NSCs) fate determination, neuronal proliferation and differentiation, and synaptic maturation. Its dysregulation causes changes in the gene expression regulation network of the nervous system, thus inducing mental disorders. Recently, miR-137 has been confirmed as a gene related to schizophrenia susceptibility. In the following review, we summarize the expression pattern, epigenetic regulation and functions of miR-137. A more complete picture of the miR-137, which is dysregulated in psychiatric illness, may improve our understanding of the molecular mechanisms underlying schizophrenia. C1 [Yin, Jingwen; Chen, Yanyan; Ma, Guoda; Li, Keshen] Guangdong Med Coll, Inst Neurol, Zhanjiang 524001, Peoples R China. [Yin, Jingwen; Lin, Juda; Luo, Xudong] Guangdong Med Coll, Dept Psychiat, Affiliated Hosp, Zhanjiang 524001, Peoples R China. [Li, Zheng] NIMH, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Ma, GD (reprint author), Guangdong Med Coll, Inst Neurol, Zhanjiang 524001, Peoples R China. EM amysays@live.com; linjuda@126.com; lxd708@163.com; xiaohonghuacyy@163.com; lizheng2@mail.nih.gov; sihan1107@126.com; likeshen1971@126.com RI Li, Zheng/I-8016-2014 OI Li, Zheng/0000-0002-2978-2531 FU US-China Biomedical Collaborative Research Program [81261120404]; National Nature Science Foundation of China [31171219, 81271213, 81070878, 81271214]; Science and Technology Innovation Fund of Guangdong Medical College [STIF 201101] FX This work was supported by funding from the US-China Biomedical Collaborative Research Program (grant number 81261120404), the National Nature Science Foundation of China (grant numbers 31171219, 81271213, 81070878 and 81271214), and the Science and Technology Innovation Fund of Guangdong Medical College (No. STIF 201101). NR 42 TC 22 Z9 22 U1 2 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD FEB PY 2014 VL 15 IS 2 BP 3262 EP 3271 DI 10.3390/ijms15023262 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA AG9YP UT WOS:000335776400095 PM 24566148 ER PT J AU Rosenzweig, SD AF Rosenzweig, Sergio D. TI News from the CIS Executive Committee SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Editorial Material C1 NIH, Rockville, MD 20892 USA. RP Rosenzweig, SD (reprint author), NIH, Rockville, MD 20892 USA. EM srosenzweig@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD FEB PY 2014 VL 34 IS 2 BP 129 EP 129 DI 10.1007/s10875-013-9984-0 PG 1 WC Immunology SC Immunology GA AH3SK UT WOS:000336045400002 PM 24402622 ER PT J AU Sowerwine, KJ Shaw, PA Gu, W Ling, JC Collins, MT Darnell, DN Anderson, VL Davis, J Hsu, A Welch, P Puck, JM Holland, SM Freeman, AF AF Sowerwine, Kathryn J. Shaw, Pamela A. Gu, Wenjuan Ling, Jennifer C. Collins, Michael T. Darnell, Dirk N. Anderson, Victoria L. Davis, Joie Hsu, Amy Welch, Pamela Puck, Jennifer M. Holland, Steven M. Freeman, Alexandra F. TI Bone Density and Fractures in Autosomal Dominant Hyper IgE Syndrome SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Autosomal dominant hyper IgE syndrome (AD-HIES); job's syndrome; signal transducer and activator of transcription 3 (STAT3); osteoporosis; retained primary teeth ID MUTATIONS AB Purpose Autosomal Dominant Hyper IgE Recurrent Infection Syndrome (AD-HIES) is caused by mutations in STAT3 and characterized by eczema, recurrent bacterial infections, and skeletal and connective tissue abnormalities. To further understand the minimal trauma fractures of AD-HIES, we examined bone mineral density (BMD) and laboratory markers of bone turnover. Methods Patients with AD-HIES enrolled in a prospective natural history study were examined with dual x-ray absorptiometry (DEXA) scans and laboratory studies of bone metabolism. The number of fractures was recorded as well as clinical features of AD-HIES including scoliosis and retained primary teeth. Patients on medications with skeletal effects, including bisphosphonates, were examined separately. Results Twenty-three AD-HIES children (6-18 years) and 33 AD-HIES adults (21-50 years) not receiving bone-active drugs were studied. Fourteen of the 23 children (61 %) had histories of minimal trauma fractures, as did 26 of the 33 adults (79 %). Osteopenia or osteoporosis was found in 79% of children and adults. Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. Markers of bone metabolism did not correlate with minimal trauma fractures or BMD. Patients on bone-active medications had improved BMD, but still sustained fractures. Conclusions Minimal trauma fractures and decreased BMD are common in AD-HIES. Low radial BMD is associated with fractures, but hip and spine BMD are not. Treatment with bisphosphonates increased BMD but its role in fracture prevention remains undefined. C1 [Sowerwine, Kathryn J.; Darnell, Dirk N.; Anderson, Victoria L.; Davis, Joie; Hsu, Amy; Holland, Steven M.; Freeman, Alexandra F.] NIAID, Labs Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Gu, Wenjuan; Welch, Pamela] Clin Res Directorate CMRP SAIC Frederick, Biostat Res Branch, Natl Lab Canc Res, Frederick, MD 21703 USA. [Ling, Jennifer C.] Univ Washington, Dept Allergy & Infect Dis, Seattle, WA USA. [Collins, Michael T.] NIDCR, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. RP Freeman, AF (reprint author), NIAID, Labs Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov FU Division of Intramural Research; NIAID; NIH; National Cancer Institute; National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This research was supported by the Division of Intramural Research, NIAID, NIH. The views expressed in this article are those of the authors and do not reflect the official policy of the U. S. Government. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This research was supported [in part] by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 6 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD FEB PY 2014 VL 34 IS 2 BP 260 EP 264 DI 10.1007/s10875-013-9982-2 PG 5 WC Immunology SC Immunology GA AH3SK UT WOS:000336045400019 PM 24402620 ER PT J AU Li, CM Li, RW Ashley, CG Smiley, JM Cohen, JH Dee, DL AF Li, Chuan-Ming Li, Ruowei Ashley, Cindy G. Smiley, Janice M. Cohen, Jennifer H. Dee, Deborah L. TI Associations of Hospital Staff Training and Policies with Early Breastfeeding Practices SO JOURNAL OF HUMAN LACTATION LA English DT Article DE hospitals; policy; Alabama; Maternity Practices in Infant Nutrition and Care; maternity care; breastfeeding; Baby-Friendly Hospital Initiative ID UNITED-STATES; RISK; ATTITUDES; IMPACT; PROFESSIONALS; METAANALYSIS; PROMOTION; INCREASE; DISEASE; INFANCY AB Background: In 2009, the Centers for Disease Control and Prevention implemented the Maternity Practices in Infant Nutrition and Care (mPINC) survey in all US birth facilities to assess breastfeeding-related maternity practices. Maternity practices and hospital policies are known to influence breastfeeding, and Alabama breastfeeding rates are very low. Objective: Our objective was to assess whether staff training and structural-organizational aspects of care, such as policies, were associated with infants' breastfeeding behaviors 24 to 48 hours postpartum. Methods: We linked 2009 mPINC data from 48 Alabama hospitals with birth certificate and newborn screening databases. We used data collected 24 to 48 hours postpartum to classify 41 536 healthy, term, singleton infants as breastfed (any breast milk) or completely formula fed and examined associations with hospitals' mPINC scores in comparison with the state mean. We conducted multilevel analyses to assess infants' likelihood of being breastfed if their birth hospital scores were lower versus at least equal to the Alabama mean, accounting for hospital clustering, demographics, payment method, and prenatal care. Results: The odds of breastfeeding were greater in hospitals with a higher-than-state-mean score on the following: new employees' breastfeeding education, nurses' receipt of breastfeeding education in the past year, prenatal breastfeeding classes offered, having a lactation coordinator, and having a written breastfeeding policy. The number of recommended elements included in hospitals' written breastfeeding policies was positively associated with newborn breastfeeding rates. Conclusion: Educating hospital staff to improve breastfeeding-related knowledge, attitudes, and skills; implementing a written hospital breastfeeding policy; and ensuring continuity of prenatal and postnatal breastfeeding education and support may improve newborn breastfeeding rates. C1 [Li, Chuan-Ming; Ashley, Cindy G.; Smiley, Janice M.] Alabama Dept Publ Hlth, Bur Family Hlth Serv, Montgomery, AL 36102 USA. [Li, Ruowei] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Atlanta, GA USA. [Cohen, Jennifer H.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Dee, Deborah L.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. RP Li, CM (reprint author), Natl Inst Deafness & Other Commun Disorders, Div Sci Programs, NIH, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM chuan-ming.li@nih.gov NR 39 TC 3 Z9 3 U1 2 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-3344 EI 1552-5732 J9 J HUM LACT JI J. Hum. Lact. PD FEB PY 2014 VL 30 IS 1 BP 88 EP 96 DI 10.1177/0890334413484551 PG 9 WC Nursing; Obstetrics & Gynecology; Pediatrics SC Nursing; Obstetrics & Gynecology; Pediatrics GA AH1OP UT WOS:000335890900013 PM 23603574 ER PT J AU Piel, FB Tatem, AJ Huang, ZJ Gupta, S Williams, TN Weatherall, DJ AF Piel, Frederic B. Tatem, Andrew J. Huang, Zhuojie Gupta, Sunetra Williams, Thomas N. Weatherall, David J. TI Global migration and the changing distribution of sickle haemoglobin: a quantitative study of temporal trends between 1960 and 2000 SO LANCET GLOBAL HEALTH LA English DT Article ID CELL-DISEASE; HEALTH BURDEN; S GENE; POPULATION; THALASSEMIA; IMMIGRATION; VARIANTS; EUROPE; EPIDEMIOLOGY; CHALLENGES AB Background Changes in the geographical distribution of genetic disorders are often thought to happen slowly, especially when compared with infectious diseases. Whereas mutations, genetic drift, and natural selection take place over many generations, epidemics can spread through large populations within a few days or weeks. Nevertheless, population movements can interfere with these processes, and few studies have been done of their effect on genetic disorders. We aimed to investigate the effect of global migration on the distribution of the sickle-cell gene-the most common and clinically significant haemoglobin structural variant. Methods For each country, we extracted data from the World Bank's Global Bilateral Migration Database about international human migrations between 1960 and 2000. We combined this information with evidence-based estimates of national HbS allele frequencies, generated within a Bayesian geostatistical framework, to analyse temporal changes in the net numbers of migrants, and classified countries with an index summarising these temporal trends. Findings The number of international migrants increased from 92.6 million in 1960, to 165.2 million in 2000. The estimated global number of migrants with HbS increased from about 1.6 million in 1960, to 3.6 million in 2000. This increase was largely due to an increase in the number of migrants from countries with HbS allele frequencies higher than 10%, from 3.1 million in 1960, to 14.2 million in 2000. Additionally, the mean number of countries of origin for each destination country increased from 70 (SE 46) in 1960, to 98 (48) in 2000, showing an increasing diversity in the network of international migrations between countries. Our index of change map shows a patchy distribution of the magnitude of temporal changes, with the highest positive and negative values scattered across all continents. Interpretation Global human population movements have had a substantial effect on the distribution of the HbS gene. Population movements can create a long-term burden on health-care systems. Our findings, which emphasise countries in which migration fluxes are changing the most, should increase awareness about the global burden of haemoglobinopathies and encourage policy makers to implement specific public health interventions, such as screening programmes and genetic counselling. C1 [Piel, Frederic B.; Gupta, Sunetra] Univ Oxford, Dept Zool, Evolutionary Ecol Infect Dis Grp, Oxford OX1 3PS, England. [Piel, Frederic B.; Williams, Thomas N.] Global Sickle Cell Dis Network, Toronto, ON, Canada. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Huang, Zhuojie] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Huang, Zhuojie] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Williams, Thomas N.] Kilifi Dist Hosp, Ctr Geog Med Res Coast, Wellcome Trust Programme, Kenya Med Res Inst, Kilifi, Kenya. [Williams, Thomas N.] Univ London Imperial Coll Sci Technol & Med, St Marys Hosp, Dept Med, London, England. [Weatherall, David J.] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. RP Piel, FB (reprint author), Univ Oxford, Dept Zool, Evolutionary Ecol Infect Dis Grp, Tinbergen Bldg, Oxford OX1 3PS, England. EM fred.piel@zoo.ox.ac.uk OI Piel, Frederic B./0000-0001-8131-7728 FU Wellcome Trust; European Research Council; Bill & Melinda Gates Foundation; National Institute of Allergy and Infectious Diseases-National Institutes of Health; Research and Policy for Infectious Disease Dynamics program, Fogarty International Center FX Wellcome Trust, European Research Council, Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases-National Institutes of Health, the Research and Policy for Infectious Disease Dynamics program, Fogarty International Center. NR 64 TC 18 Z9 18 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD FEB PY 2014 VL 2 IS 2 BP E80 EP E89 DI 10.1016/S2214-109X(13)70150-5 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AH8YO UT WOS:000336424300014 PM 24748392 ER PT J AU Guha, S Natarajan, O Murbach, CG Dinh, J Wilson, EC Cao, M Zou, SG Dong, YQ AF Guha, Sujay Natarajan, Ojas Murbach, Cole G. Dinh, Jessica Wilson, Ethan C. Cao, Min Zou, Sige Dong, Yuqing TI Supplement Timing of Cranberry Extract Plays a Key Role in Promoting Caenorhabditis elegans Healthspan SO NUTRIENTS LA English DT Review DE aging intervention; timing; nutraceuticals; cranberry polyphenols; healthspan; Caenorhabditis elegans ID LIFE-SPAN; LONGEVITY; GENETICS; DISEASES AB Consumption of nutraceuticals is a major and potent dietary intervention for delaying aging. As the timing of administration is critical for the efficacy of bioactive compounds in medicine, the effectiveness of nutraceuticals may also be dramatically affected by the timing of supplementation. Cranberry exact (CBE), rich in polyphenols, is consumed as a nutraceutical, and possesses anti-aging properties. Here, we examined the influence of timing on the beneficial effects of CBE supplementation in C. elegans. The prolongevity effect of CBE in different aged worms, young adults, middle-age adults, and aged adults, was determined. Early-start intervention with CBE prolonged the remaining lifespan of worms of different ages more robustly than late-start intervention. The effectiveness of CBE on stress responses and physiological behaviors in different aged worms was also investigated. The early-start intervention prominently promoted motility and resistance to heat shocks and V. cholera infection, especially in aged worms. Together, these findings suggest that the timing of CBE supplementation critically influences its beneficial effects on C. elegans lifespan and healthspan. It is of interest to further investigate whether the similar results would occur in humans. C1 [Guha, Sujay; Natarajan, Ojas; Murbach, Cole G.; Dinh, Jessica; Wilson, Ethan C.; Cao, Min; Dong, Yuqing] Clemson Univ, Dept Biol Sci, Clemson, SC 29634 USA. [Cao, Min] Clemson Univ, Inst Engaged Aging, Clemson, SC 29634 USA. [Zou, Sige] NIA, Funct Genom Unit, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Dong, YQ (reprint author), Clemson Univ, Dept Biol Sci, Clemson, SC 29634 USA. EM sguha@g.clemson.edu; onatara@clemson.edu; cmurbac@g.clemson.edu; jdinh@g.clemson.edu; pelamisplaturus@gmail.com; mcao@clemson.edu; zous@grc.nia.nih.gov; ydong@clemson.edu FU Clemson University (Clemson, SC, USA); National Institute on Aging, NIH (Baltimore, MD, USA) FX The authors are grateful to members of the Dong laboratory for helpful discussions. We especially thank Dan Souza (Decas Botanical Synergies, Sagamore, MA, USA) for providing cranberry extract and Jun (Jay) Zhu (University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA) for providing the V. cholerae strain. This work was supported by the Creative Inquiry fund at Clemson University (Clemson, SC, USA) to Y.D. and M. C. and the Intramural Research Program at the National Institute on Aging, NIH (Baltimore, MD, USA) to S.Z. NR 22 TC 6 Z9 6 U1 0 U2 7 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD FEB PY 2014 VL 6 IS 2 BP 911 EP 921 DI 10.3390/nu6020911 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AG9NJ UT WOS:000335745900029 PM 24566444 ER PT J AU Ramulu, PY Hochberg, C Maul, EA Chan, ES Ferrucci, L Friedman, DS AF Ramulu, Pradeep Y. Hochberg, Chad Maul, Eugenio A. Chan, Emilie S. Ferrucci, Luigi Friedman, David S. TI Glaucomatous Visual Field Loss Associated with Less Travel from Home SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE glaucoma; visual field; life space; global positioning system; quality of life ID SALISBURY EYE EVALUATION; OLDER-ADULTS; LIFE-SPACE; PHYSICAL-ACTIVITY; MOBILITY PERFORMANCE; VISION LOSS; IMPAIRMENT; AGE; MORTALITY; DISEASE AB Purpose To determine the association between glaucoma and travel away from home. Methods Fifty-nine glaucoma suspect controls with normal vision and 80 glaucoma subjects with bilateral visual field (VF) loss wore a cellular tracking device during 1 week of normal activity. Location data were used to evaluate the number of daily excursions away from home as well as daily time spent away from home. Results Control and glaucoma subjects were similar in age, race, sex, employment, driving support, cognitive ability, mood, and comorbid illness (p > 0.1 for all). Better-eye VF mean deviation (MD) averaged 0.0 decibels (dB) in controls and -11.1 dB in glaucoma subjects. In multivariable models, glaucoma was associated with fewer daily excursions ( = -0.20; 95% confidence interval [95% CI], -0.38 to -0.02) and a greater likelihood of not leaving home on a given day (odds ratio [OR], 1.82; 95% CI, 1.05 to 3.06). Each 5-dB decrement in the better-eye VF MD was associated with fewer daily excursions ( = -0.06; 95% CI, -0.11 to -0.01) and a greater chance of not leaving home on a given day (OR, 1.24; 95% CI, 1.04 to 1.47). Time spent away from home did not significantly differ between the glaucoma subjects and suspects (p = 0.18). However, each 5-dB decrement in the better-eye MD was associated with 6% less time away (95% CI, -12 to -1%). Conclusions Individuals with glaucoma, particularly those with greater VF loss, are more home bound and travel away from home less than individuals with normal vision. Because being confined to the home environment may have detrimental effects on fitness and health, individuals with glaucoma should be considered for interventions such as orientation and mobility training to encourage safe travel away from home. C1 [Ramulu, Pradeep Y.; Hochberg, Chad; Maul, Eugenio A.; Chan, Emilie S.; Friedman, David S.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. RP Ramulu, PY (reprint author), 600 North Wolfe St Maumenee B-110, Baltimore, MD 21287 USA. EM pramulu1@jhmi.edu FU Dennis W. Jahnigen Memorial Award, National Institutes of Health [EY018595]; Research to Prevent Blindness FX This work was supported by the Dennis W. Jahnigen Memorial Award, National Institutes of Health grant number EY018595, and Research to Prevent Blindness. The funding organizations had no role in the design or conduct of the study. NR 35 TC 9 Z9 9 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD FEB PY 2014 VL 91 IS 2 BP 187 EP 193 DI 10.1097/OPX.0000000000000139 PG 7 WC Ophthalmology SC Ophthalmology GA AH6SP UT WOS:000336261300012 PM 24374635 ER PT J AU Schulte, JM Bellamy, AR Hook, EW Bernstein, DI Levin, MJ Leone, PA Sokol-Anderson, ML Ewell, MG Wolff, PA Heineman, TC Belshe, RB AF Schulte, Joann M. Bellamy, Abbie R. Hook, Edward W., III Bernstein, David I. Levin, Myron J. Leone, Peter A. Sokol-Anderson, Marcia L. Ewell, Marian G. Wolff, Peter A. Heineman, Thomas C. Belshe, Robert B. TI HSV-1 and HSV-2 Seroprevalence in the United States among Asymptomatic Women Unaware of Any Herpes Simplex Virus Infection (Herpevac Trial for Women) SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE herpes simplex; seroprevalence ID GENITAL HERPES; CHANGING EPIDEMIOLOGY; HAD SEX; TYPE-1; TRANSMISSION; POPULATION; ANTIBODIES AB Objectives Recent evidence suggests that the epidemiology of herpes simplex viruses (HSVs) is changing because fewer HSV-1 infections are acquired in childhood and increased sexual transmission of HSV-1 is reported. The objective of the study was to assess the seroprevalence of type-specific antibodies to HSV-1 and HSV-2 in the United States. Methods We used the Western blot antibody screening data from a large phase III vaccine efficacy trial (Herpevac Trial for Women) to assess the seroprevalence of type-specific antibodies to HSV-1 and HSV-2 in the United States. Results The antibody status of 29,022 women (>31,000 women interviewed and then had their blood drawn for the HSV testing [29,022 women]) between the ages of 18 and 30 years in the United States revealed that increasing age was associated with increasing seroprevalence to HSV. Overall, in asymptomatic women unaware of any HSV infection, HSV-1/-2 status was positive/negative in 45%, negative/positive in 5%, positive/positive in 7%, negative/negative in 38%, and indeterminate in 5%. HSV-1 infections were more common in Hispanic and non-Hispanic black women and in the US northeast and in individuals living in urban areas. HSV-2 was more common in non-Hispanic black women, the US south, and in urban areas. Conclusions Seronegative status for both HSV-1 and HSV-2 was the second most common finding after positive antibody to HSV-1 but negative antibody to HSV-2. Despite recent changes in genital herpes epidemiology, most women acquired HSV-1 but not HSV-2 infections before 18 years of age. Among participants screened for study participation and who were unaware of any HSV infection, progressively higher prevalence of the HSV-1 or HSV-2 antibody was observed in older subjects. Many women who test positive for HSV-1 and/or HSV-2 are unaware of their status. C1 NIAID, NIH, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. Univ Colorado Denver, Aurora, CO USA. Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA. St Louis Univ, Div Infect Dis Allergy & Immunol, St Louis, MO 63103 USA. GlaxoSmithKline, King Of Prussia, PA USA. RP Schulte, JM (reprint author), Ctr Dis Control & Prevent, Global AIDS Program, MS E04,1600 Clifton Rd NE, Atlanta, GA 30333 USA. EM jzs1@cdc.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [N01-AI-45250]; GlaxoSmithKline; EMMES Corporation; BD Diagnostics; Cempra; Roche Molecular Systems; Hologic; Gen-Probe FX This study was funded by Contract #N01-AI-45250 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by GlaxoSmithKline.; A.R.B. has received a consultancy fee from EMMES Corporation. E. W. H. has been a consultant to Cempra, Hologic, and Scienta Advisors; has received grants from BD Diagnostics, Cempra, Roche Molecular Systems, Hologic, and Gen-Probe; has served on the speakers' bureaus of BD Diagnostics and Cepheid; has received royalties from McGraw-Hill Companies; has received compensation for development of educational presentations from Quest Diagnostics and Omnia Education; and has received compensation from MedHelp.org. D. I. B. has received royalties from GlaxoSmithKline for an unrelated vaccine, has been a member of the speakers' bureau for GlaxoSmithKline, has received compensation from the National Institutes of Health (NIH) related to the present study, has been a consultant to N&N Scientific, and has received compensation from GlaxoSmithKline for the Rotarix patent and the sale of Rotarix; his institution has been compensated for the same patent and sale. M.J.L. has received research funds for a separate GlaxoSmithKline study and has been a consultant to GlaxoSmithKline on vaccine policy. P. A. L. has been a consultant to Merck and has served on the speakers' bureau of Abbott Diagnostics. T. C. H. is an employee of GlaxoSmithKline. R. B. B. has served on a data and safety monitoring board for GlaxoSmithKline on an unrelated vaccine, has received compensation from the NIH for the present study, has consulted to Genocea, and has served on the speakers' bureau of Medimmune. The other authors have no financial relationships to disclose and no conflicts of interest to report. NR 27 TC 8 Z9 8 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD FEB PY 2014 VL 107 IS 2 BP 79 EP 84 DI 10.1097/SMJ.0000000000000062 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA AH6TV UT WOS:000336264600005 PM 24926671 ER PT J AU Prescott, J DeBuysscher, BL Brown, KS Feldmann, H AF Prescott, Joseph DeBuysscher, Blair L. Brown, Kyle S. Feldmann, Heinz TI Long-Term Single-Dose Efficacy of a Vesicular Stomatitis Virus-Based Andes Virus Vaccine in Syrian Hamsters SO VIRUSES-BASEL LA English DT Article DE Andes virus; vaccine; durability; antibody response; hantavirus ID HANTAVIRUS PULMONARY SYNDROME; TO-PERSON TRANSMISSION; INFECTION; ARGENTINA; MODEL AB Andes virus (ANDV) is highly pathogenic in humans and is the primary etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. Case-fatality rates are as high as 50% and there are no approved vaccines or specific therapies for infection. Our laboratory has recently developed a replication-competent recombinant vesicular stomatitis virus (VSV)-based vaccine that expressed the glycoproteins of Andes virus in place of the native VSV glycoprotein (G). This vaccine is highly efficacious in the Syrian hamster model of HCPS when given 28 days before challenge with ANDV, or when given around the time of challenge (peri-exposure), and even protects when administered post-exposure. Herein, we sought to test the durability of the immune response to a single dose of this vaccine in Syrian hamsters. This vaccine was efficacious in hamsters challenged intranasally with ANDV 6 months after vaccination (p = 0.025), but animals were not significantly protected following 1 year of vaccination (p = 0.090). The decrease in protection correlated with a reduction of measurable neutralizing antibody responses, and suggests that a more robust vaccination schedule might be required to provide long-term immunity. C1 [Prescott, Joseph; DeBuysscher, Blair L.; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [DeBuysscher, Blair L.] Univ Montana, Div Biol Sci, Missoula, MT 59840 USA. [Brown, Kyle S.] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK S7N 5A2, Canada. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. EM prescottjb@niaid.nih.gov; debuysscherb@niaid.nih.gov; kyle.brown@usask.ca; feldmannh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health FX We would like to thank Elaine Haddock for her technical assistance in performing experiments, and Anita Mora for graphical support in preparing the figures. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health. NR 15 TC 3 Z9 3 U1 0 U2 1 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2014 VL 6 IS 2 BP 516 EP 523 DI 10.3390/v6020516 PG 8 WC Virology SC Virology GA AG9OH UT WOS:000335748500020 PM 24492621 ER PT J AU Morissette, R Schoenhoff, F Xu, Z Shilane, DA Griswold, BF Chen, WY Yang, JD Zhu, J Fert-Bober, J Sloper, L Lehman, J Commins, N Van Eyk, JE McDonnell, NB AF Morissette, Rachel Schoenhoff, Florian Xu, Zhi Shilane, David A. Griswold, Benjamin F. Chen, Wuyan Yang, Jiandong Zhu, Jie Fert-Bober, Justyna Sloper, Leslie Lehman, Jason Commins, Natalie Van Eyk, Jennifer E. McDonnell, Nazli B. TI Transforming Growth Factor-beta and Inflammation in Vascular (Type IV) Ehlers-Danlos Syndrome SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article ID III PROCOLLAGEN; MARFAN-SYNDROME; AORTIC-ANEURYSMS; MOUSE MODEL; ADHESION MOLECULES; ARTERIAL ANEURYSMS; COL3A1 ALLELE; MUTATIONS; GENE; DISSECTIONS C1 [Morissette, Rachel; Xu, Zhi; Griswold, Benjamin F.; Chen, Wuyan; Yang, Jiandong; Sloper, Leslie; Lehman, Jason; Commins, Natalie; McDonnell, Nazli B.] NIA, Lab Clin Invest, Baltimore, MD 21225 USA. [Schoenhoff, Florian; Zhu, Jie; Fert-Bober, Justyna; Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Med, Johns Hopkins Bayview Prote Ctr, Baltimore, MD USA. [Schoenhoff, Florian] Univ Hosp Bern, Dept Cardiovasc Surg, CH-3010 Bern, Switzerland. [Shilane, David A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP McDonnell, NB (reprint author), NIA, NIH, Clin Unit, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM nazli.mcdonnell@gmail.com FU Intramural Research Program of the National Institutes of Health, National Institute on Aging [1U54RR023561-01A1, 5RC1HL100021-02] FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Grants 1U54RR023561-01A1 and 5RC1HL100021-02 were used for plasma biomarker studies at Johns Hopkins. NR 47 TC 12 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2014 VL 7 IS 1 BP 80 EP 88 PG 9 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA AA9IC UT WOS:000331406000012 PM 24399159 ER PT J AU Lederman, RJ Rogers, T Faranesh, AZ AF Lederman, Robert J. Rogers, Toby Faranesh, Anthony Z. TI Letter by Lederman et al Regarding Article, "MRI-Induced Stent Dislodgment Soon After Left Main Coronary Artery Stenting" SO CIRCULATION-CARDIOVASCULAR INTERVENTIONS LA English DT Letter C1 [Lederman, Robert J.; Rogers, Toby; Faranesh, Anthony Z.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HL999999]; NHLBI NIH HHS [Z01 HL005062] NR 4 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7640 EI 1941-7632 J9 CIRC-CARDIOVASC INTE JI Circ.-Cardiovasc. Interv. PD FEB PY 2014 VL 7 IS 1 BP 128 EP 128 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA8PY UT WOS:000331358600019 PM 24550534 ER PT J AU Matsuura, K Watanabe, T Tanaka, Y AF Matsuura, Kentaro Watanabe, Tsunamasa Tanaka, Yasuhito TI Role of IL28B for chronic hepatitis C treatment toward personalized medicine SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Review DE direct-acting antiviral (DAA); genome-wide association study (GWAS); hepatitis C virus (HCV); interleukin 28B (IL28B) ID GENOME-WIDE ASSOCIATION; AMINO-ACID SUBSTITUTION; GENOTYPE 1 INFECTION; SINGLE-NUCLEOTIDE POLYMORPHISMS; RIBAVIRIN COMBINATION THERAPY; VIRUS-COINFECTED PATIENTS; ACUTE HCV INFECTION; GENETIC-VARIATION; PEGYLATED INTERFERON; SPONTANEOUS CLEARANCE AB Genome-wide association studies recently revealed that certain interleukin-28B (IL28B) polymorphisms are strongly associated with responses to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients chronically infected with hepatitis C virus (HCV) genotype 1, as well as with spontaneous clearance of HCV. Subsequent reports revealed that IL28B genotypes also affect treatment efficacy in chronic infection with other HCV genotypes. Furthermore, there have been several reports that implicate IL28B genotypes in inflammatory status, progression of fibrosis and adverse clinical outcomes in chronic hepatitis C (CHC). Therapy of CHC recently entered a new era with the deployment of direct-acting antivirals. These include nonstructural 3/4A protease inhibitors which have shown promise in combination with PEG-IFN/RBV in several clinical trials. IFN-free therapy is expected to be useful especially in IFN-resistant patients and may become the standard of care in the future. Several clinical trials have revealed an association between IL28B genotype and treatment efficacy in triple therapy or IFN-free regimens. On the other hand the mechanism of the effect of IL28B on HCV infection has not yet been elucidated. Recently, it was shown that the polymorphism of IFN-lambda 4 (IFNL4) is in high linkage disequilibrium with that of near IL28B, and more strongly associated with spontaneous or treatment-induced HCV clearance than IL28B genotypes, especially in individuals of African ancestry. This finding provides new insights into the genetic regulation of HCV clearance and its clinical management. IL28B genotyping will be also useful for personalized CHC treatment in the forthcoming era of direct-acting antivirals. C1 [Matsuura, Kentaro; Watanabe, Tsunamasa; Tanaka, Yasuhito] Nagoya City Univ Grad Sch Med Sci, Dept Virol, Liver Unit, Nagoya, Aichi 4678601, Japan. [Matsuura, Kentaro] Nagoya City Univ Grad Sch Med Sci, Dept Gastroenterol & Metab, Nagoya, Aichi 4678601, Japan. [Matsuura, Kentaro] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Tanaka, Y (reprint author), Nagoya City Univ Grad Sch Med Sci, Dept Virol, Liver Unit, Nagoya, Aichi 4678601, Japan. EM ytanaka@med.nagoya-cu.ac.jp FU Ministry of Health, Labour and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology FX This work was supported in part by a grant-in-aid from the Ministry of Health, Labour and Welfare of Japan, and a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology. NR 92 TC 22 Z9 23 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0815-9319 EI 1440-1746 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD FEB PY 2014 VL 29 IS 2 BP 241 EP 249 DI 10.1111/jgh.12475 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AH6PG UT WOS:000336252400007 PM 24325405 ER PT J AU Boghossian, NS Hansen, NI Bell, EF Stoll, BJ Murray, JC Carey, JC Adams-Chapman, I Shankaran, S Walsh, MC Laptook, AR Faix, RG Newman, NS Hale, EC Das, A Wilson, LD Hensman, AM Grisby, C Collins, MV Vasil, DM Finkle, J Maffett, D Ball, MB Lacy, CB Bara, R Higgins, RD AF Boghossian, Nansi S. Hansen, Nellie I. Bell, Edward F. Stoll, Barbara J. Murray, Jeffrey C. Carey, John C. Adams-Chapman, Ira Shankaran, Seetha Walsh, Michele C. Laptook, Abbot R. Faix, Roger G. Newman, Nancy S. Hale, Ellen C. Das, Abhik Wilson, Leslie D. Hensman, Angelita M. Grisby, Cathy Collins, Monica V. Vasil, Diana M. Finkle, Joanne Maffett, Deanna Ball, M. Bethany Lacy, Conra B. Bara, Rebecca Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 SO PEDIATRICS LA English DT Article DE trisomy 13; trisomy 18; trisomy 21; very low birth weight; preterm; infants ID NATURAL-HISTORY; UNITED-STATES; CARDIAC-SURGERY; MANAGEMENT; CHILDREN; CARE; EXPERIENCE; SURVIVAL; NETWORK AB OBJECTIVE: Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects. METHODS: Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994-2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18. RESULTS: Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis. CONCLUSIONS: In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early. Pediatrics 2014; 133: 226-235 C1 [Boghossian, Nansi S.; Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Hansen, Nellie I.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Stoll, Barbara J.; Adams-Chapman, Ira; Hale, Ellen C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.; Adams-Chapman, Ira; Hale, Ellen C.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Murray, Jeffrey C.; Carey, John C.; Faix, Roger G.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Shankaran, Seetha; Bara, Rebecca] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Walsh, Michele C.; Newman, Nancy S.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Walsh, Michele C.; Newman, Nancy S.] Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Laptook, Abbot R.; Hensman, Angelita M.] Brown Univ, Dept Pediat, Providence, RI 02912 USA. [Laptook, Abbot R.; Hensman, Angelita M.] Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Wilson, Leslie D.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Grisby, Cathy] Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Cincinnati, OH 45229 USA. [Collins, Monica V.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Vasil, Diana M.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Finkle, Joanne] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Maffett, Deanna] Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. [Ball, M. Bethany] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Ball, M. Bethany] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Lacy, Conra B.] Univ New Mexico, Dept Pediat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Bell, EF (reprint author), Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM edward-bell@uiowa.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NICHD; National Institutes of Health (NIH); NICHD [U10 HD27904, U10 HD21364, M01 RR80, U10 HD27853, M01 RR8084, U10 HD40492, M01 RR30, M01 RR39, U10 HD27851, U10 HD27856, M01 RR750, U10 HD36790, U10 HD27880, M01 RR70, U10 HD34216, M01 RR32]; National Institute of Child Health and Human Development (NICHD) [U10 HD53089, M01 RR997, U10 HD40521, M01 RR44, UL1 RR024160, M01 RR633, U10 HD40689, U10 HD21373, U10 HD21385] 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's Generic Database Study. Drs Boghossian and Higgins are employed by the NICHD. The institutions of the other authors received grant funding from NICHD in support of this study (grants U10 HD27904, U10 HD21364, M01 RR80, U10 HD27853, M01 RR8084, U10 HD40492, M01 RR30, M01 RR39, U10 HD27851, U10 HD27856, M01 RR750, U10 HD36790, U10 HD27880, M01 RR70, U10 HD34216, M01 RR32, U10 HD53089, M01 RR997, U10 HD40521, M01 RR44, UL1 RR024160, M01 RR633, U10 HD40689, U10 HD21373, U10 HD21385). Funded by the National Institutes of Health (NIH). NR 28 TC 10 Z9 11 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD FEB PY 2014 VL 133 IS 2 BP 226 EP 235 DI 10.1542/peds.2013-1702 PG 10 WC Pediatrics SC Pediatrics GA AD7AR UT WOS:000333413600008 PM 24446439 ER PT J AU Kim, HK Green, JE AF Kim, Hark Kyun Green, Jeffrey E. TI Predictive biomarker candidates for the response of gastric cancer to targeted and cytotoxic agents SO PHARMACOGENOMICS LA English DT Review DE biomarker; chemotherapy; gastric cancer; predictive marker; targeted therapy ID EPIDERMAL-GROWTH-FACTOR; FGFR2 GENE AMPLIFICATION; METASTATIC BREAST-CANCER; MESSENGER-RNA LEVELS; PHASE-II TRIAL; FACTOR RECEPTOR; GASTROESOPHAGEAL JUNCTION; SIGNALING PATHWAYS; RIBOSOMAL-PROTEIN; 1ST-LINE THERAPY AB Gastric cancer is the second most common cause of cancer death worldwide. Recent development of targeted agents provides clinicians with additional systemic treatment options to conventional cytotoxic agents. Predictive markers are undoubtedly important for guiding the appropriate use of targeted and cytotoxic agents. Currently, however, HER2 is the only predictive biomarker validated for gastric cancer. In this review, candidate predictive markers for response to other targeted agents and cytotoxic chemotherapeutic agents are discussed. C1 [Kim, Hark Kyun] Natl Canc Ctr, Ctr Gastr Canc, Goyang 410769, South Korea. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kim, HK (reprint author), Natl Canc Ctr, Ctr Gastr Canc, Goyang 410769, South Korea. EM hkim@ncc.re.kr FU Proteogenomic Research Program; Ministry of Science, ICT and Future Planning of Korea [2013K000429]; National Institute of Health Intramural Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA FX This work was supported by the Proteogenomic Research Program and 2013K000429 through the Ministry of Science, ICT and Future Planning of Korea, and by the National Institute of Health Intramural Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. 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 75 TC 4 Z9 4 U1 0 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD FEB PY 2014 VL 15 IS 3 BP 375 EP 384 DI 10.2217/pgs.13.250 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AB0AP UT WOS:000331454500020 PM 24533716 ER PT J AU Belfer, I Youngblood, V Darbari, DS Wang, ZY Diaw, L Freeman, L Desai, K Dizon, M Allen, D Cunnington, C Channon, KM Milton, J Hartley, SW Nolan, V Kato, GJ Steinberg, MH Goldman, D Taylor, JG AF Belfer, Inna Youngblood, Victoria Darbari, Deepika S. Wang, Zhengyuan Diaw, Lena Freeman, Lita Desai, Krupa Dizon, Michael Allen, Darlene Cunnington, Colin Channon, Keith M. Milton, Jacqueline Hartley, Stephen W. Nolan, Vikki Kato, Gregory J. Steinberg, Martin H. Goldman, David Taylor, James G. TI A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID NITRIC-OXIDE; GTP CYCLOHYDROLASE; FETAL-HEMOGLOBIN; RISK-FACTORS; IN-VIVO; DISEASE; GENE; SENSITIVITY; MICE; POLYMORPHISMS AB GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n=228; odds ratio [OR] 2.26; P=0.009) and replication (n=513; OR 2.23; P=0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P=0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21-5.94; P=0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry. Am. J. Hematol. 89:187-193, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Belfer, Inna] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Youngblood, Victoria; Darbari, Deepika S.; Wang, Zhengyuan; Diaw, Lena; Desai, Krupa; Dizon, Michael; Taylor, James G.] NHLBI, Genom Med Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Darbari, Deepika S.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Pediat Hematol, Washington, DC 20010 USA. [Freeman, Lita; Allen, Darlene; Kato, Gregory J.] NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Cunnington, Colin; Channon, Keith M.] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Milton, Jacqueline; Hartley, Stephen W.; Steinberg, Martin H.] Boston Univ, Sch Med, Ctr Excellence Sickle Cell Dis, Boston, MA 02118 USA. [Milton, Jacqueline; Hartley, Stephen W.; Steinberg, Martin H.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Nolan, Vikki] Univ Memphis, Sch Publ Hlth, Memphis, TN 38152 USA. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. RP Taylor, JG (reprint author), NHLBI, Genom Med Sect, Hematol Branch, NIH, Bldg 10,CRC Room 5-5140,MSC 1476, Bethesda, MD 20892 USA. EM jamesta@mail.nih.gov RI Kato, Gregory/I-7615-2014; Goldman, David/F-9772-2010; OI Kato, Gregory/0000-0003-4465-3217; Goldman, David/0000-0002-1724-5405; Taylor, James/0000-0002-4421-1809 FU Intramural Research Programs of NHLBI [1 ZIA HL006012, 1 ZIA HL006160]; National Heart, Lung and Blood Institute (NHLBI) [HL R01 87681, HL 068970, T32 HL007501] FX Contract grant sponsor: Intramural Research Programs of NHLBI; Contract grant numbers: 1 ZIA HL006012; 1 ZIA HL006160.; Contract grant sponsor: National Heart, Lung and Blood Institute (NHLBI); Contract grant number: HL R01 87681, HL 068970, T32 HL007501.. NR 48 TC 9 Z9 9 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD FEB PY 2014 VL 89 IS 2 BP 187 EP 193 DI 10.1002/ajh.23613 PG 7 WC Hematology SC Hematology GA AA8GS UT WOS:000331334200012 PM 24136375 ER PT J AU Verma, M Rogers, S Divi, RL Schully, SD Nelson, S Su, J Ross, SA Pilch, S Winn, DM Khoury, MJ AF Verma, Mukesh Rogers, Scott Divi, Rao L. Schully, Sheri D. Nelson, Stefanie Su, Joseph Ross, Sharon A. Pilch, Susan Winn, Deborah M. Khoury, Muin J. TI Epigenetic Research in Cancer Epidemiology: Trends, Opportunities, and Challenges SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID SQUAMOUS-CELL CARCINOMA; CERVICAL INTRAEPITHELIAL NEOPLASIA; MOLECULARLY DEFINED SUBTYPES; EPITHELIAL OVARIAN-CANCER; DNA METHYLATION LEVELS; NEW-YORK SITE; COLORECTAL-CANCER; BREAST-CANCER; PROMOTER METHYLATION; FAMILY REGISTRY AB Epigenetics is emerging as an important field in cancer epidemiology that promises to provide insights into gene regulation and facilitate cancer control throughout the cancer care continuum. Increasingly, investigators are incorporating epigenetic analysis into the studies of etiology and outcomes. To understand current progress and trends in the inclusion of epigenetics in cancer epidemiology, we evaluated the published literature and the National Cancer Institute (NCI)-supported research grant awards in this field to identify trends in epigenetics research. We present a summary of the epidemiologic studies in NCI's grant portfolio (from January 2005 through December 2012) and in the scientific literature published during the same period, irrespective of support from the NCI. Blood cells and tumor tissue were the most commonly used biospecimens in these studies, although buccal cells, cervical cells, sputum, and stool samples were also used. DNA methylation profiling was the focus of the majority of studies, but several studies also measured microRNA profiles. We illustrate here the current status of epidemiologic studies that are evaluating epigenetic changes in large populations. The incorporation of epigenomic assessments in cancer epidemiology studies has and is likely to continue to provide important insights into the field of cancer research. C1 [Verma, Mukesh; Rogers, Scott; Divi, Rao L.; Schully, Sheri D.; Nelson, Stefanie; Su, Joseph; Winn, Deborah M.; Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Ross, Sharon A.] NCI, Canc Prevent Div, Rockville, MD 20852 USA. [Pilch, Susan] NIH, Off Director, Informat Resources & Serv Branch, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Verma, M (reprint author), NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd, Rockville, MD 20852 USA. EM vermam@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 89 TC 11 Z9 12 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2014 VL 23 IS 2 BP 223 EP 233 DI 10.1158/1055-9965.EPI-13-0573 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AG0ZG UT WOS:000335143900001 PM 24326628 ER PT J AU Shiels, MS Koritzinsky, EH Clarke, CA Suneja, G Morton, LM Engels, EA AF Shiels, Meredith S. Koritzinsky, Erik H. Clarke, Christina A. Suneja, Gita Morton, Lindsay M. Engels, Eric A. TI Prevalence of HIV Infection among U. S. Hodgkin Lymphoma Cases SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ANTIRETROVIRAL THERAPY; CANCER; DISEASE; IMMUNODEFICIENCY; POPULATION; CLASSIFICATION AB Background: Hodgkin lymphoma is uncommon in the U. S. general population; however, Hodgkin lymphoma risk is elevated in people with human immunodeficiency virus (HIV) infection. Thus, despite the low HIV prevalence in the United States, the HIV epidemic may have contributed substantially to the general population burden of Hodgkin lymphoma. Methods: We used data from 14 U. S. cancer registries in the Surveillance, Epidemiology, and End Results Program that recorded HIV status of Hodgkin lymphoma cases at diagnosis during 2000 to 2010. We computed the HIV prevalence in Hodgkin lymphoma cases by demographic and tumor characteristics, the proportion of deaths among Hodgkin lymphoma cases because of HIV, and 5-year mortality by HIV status. Results: Of 22,355 Hodgkin lymphoma cases, 848 (3.79%) were HIV infected at diagnosis. HIV prevalence in Hodgkin lymphoma cases was greater among males than females (6.0% vs. 1.2%). Among males, HIV prevalence was greatest among 40-to 59-year-olds (14.2%), non-Hispanic blacks (16.9%), Hispanics (9.9%), and among cases of lymphocyte-depleted (15.1%), and mixed cellularity Hodgkin lymphoma (10.5%). Eight percent of male and 1.5% of female Hodgkin lymphoma cases died from HIV. Five-year mortality was two-fold higher in HIV-infected Hodgkin lymphoma cases (36.9% vs. 17.5%). Conclusion: In the United States, a substantial proportion of lymphocyte-depleted and mixed cellularity Hodgkin lymphoma cases and Hodgkin lymphoma cases among non-Hispanic black, Hispanic, and middle-aged men are HIV infected. In addition, HIV is an important cause of death among Hodgkin lymphoma cases. Impact: Clinicians should be aware of the high prevalence of HIV in certain subgroups of patients with Hodgkin lymphoma and routine HIV testing should be recommended for all patients presenting with Hodgkin lymphoma. C1 [Shiels, Meredith S.; Koritzinsky, Erik H.; Morton, Lindsay M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Suneja, Gita] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Shiels, MS (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 6E-218 MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 27 TC 14 Z9 14 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 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2014 VL 23 IS 2 BP 274 EP 281 DI 10.1158/1055-9965.EPI-13-0865 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AG0ZG UT WOS:000335143900004 PM 24326629 ER PT J AU McShane, CM Murray, LJ Landgren, O O'Rorke, MA Korde, N Kunzmann, AT Ismail, MR Anderson, LA AF McShane, Charlene M. Murray, Liam J. Landgren, Ola O'Rorke, Michael A. Korde, Neha Kunzmann, Andrew T. Ismail, Mohammad Roshidi Anderson, Lesley A. TI Prior Autoimmune Disease and Risk of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma: A Systematic Review SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID POPULATION-BASED COHORT; CHRONIC ANTIGENIC-STIMULATION; INFLAMMATORY-BOWEL-DISEASE; PRIMARY SJOGRENS-SYNDROME; TERM-FOLLOW-UP; CANCER-RISK; RHEUMATOID-ARTHRITIS; PERNICIOUS-ANEMIA; LUPUS-ERYTHEMATOSUS; LONG-TERM AB Background: Several observational studies have investigated autoimmune disease and subsequent risk of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. Findings have been largely inconsistent and hindered by the rarity and heterogeneity of the autoimmune disorders investigated. A systematic review of the literature was undertaken to evaluate the strength of the evidence linking prior autoimmune disease and risk of MGUS/multiple myeloma. Methods: A broad search strategy using key terms for MGUS, multiple myeloma, and 50 autoimmune diseases was used to search four electronic databases (PubMed, Medline, Embase, and Web of Science) from inception through November 2011. Results: A total of 52 studies met the inclusion criteria, of which 32 were suitably comparable to perform a meta-analysis. "Any autoimmune disorder" was associated with an increased risk of both MGUS [n 760 patients; pooled relative risk (RR) 1.42; 95% confidence interval (CI), 1.14-1.75] and multiple myeloma (n > 2,530 patients; RR 1.13, 95% CI, 1.04-1.22). This risk was disease dependent with only pernicious anemia showing an increased risk of both MGUS (RR 1.67; 95% CI, 1.21-2.31) and multiple myeloma (RR 1.50; 95% CI, 1.25-1.80). Conclusions: Our findings, based on the largest number of autoimmune disorders and patients with MGUS/multiple myeloma reported to date, suggest that autoimmune diseases and/or their treatment may be important in the etiology of MGUS/multiple myeloma. The strong associations observed for pernicious anemia suggest that anemia seen in plasma cell dyscrasias may be of autoimmune origin. Impact: Underlying mechanisms of autoimmune diseases, general immune dysfunction, and/or treatment of autoimmune diseases may be important in the pathogenesis of MGUS/multiple myeloma. C1 [McShane, Charlene M.; Murray, Liam J.; O'Rorke, Michael A.; Kunzmann, Andrew T.; Ismail, Mohammad Roshidi; Anderson, Lesley A.] Queens Univ Belfast, Ctr Publ Hlth, Canc Epidemiol & Hlth Serv Res Grp, Belfast, Antrim, North Ireland. [Landgren, Ola; Korde, Neha] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Ismail, Mohammad Roshidi] Univ Malaya, Fac Med, Dept Social & Prevent Med, Ctr Populat Hlth, Kuala Lumpur, Malaysia. RP Anderson, LA (reprint author), Inst Clin Sci, Ctr Publ Hlth, Canc Epidemiol & Hlth Serv Res Grp, Block B,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM l.anderson@qub.ac.uk OI Anderson, Lesley/0000-0002-1000-3649 FU Medical Research Council [MR/K023241/1] NR 86 TC 9 Z9 9 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2014 VL 23 IS 2 BP 332 EP 342 DI 10.1158/1055-9965.EPI-13-0695 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AG0ZG UT WOS:000335143900011 PM 24451437 ER PT J AU Anizan, S Huestis, MA AF Anizan, Sebastien Huestis, Marilyn A. TI The Potential Role of Oral Fluid in Antidoping Testing SO CLINICAL CHEMISTRY LA English DT Review ID CHROMATOGRAPHY-MASS-SPECTROMETRY; ATHLETE BIOLOGICAL PASSPORT; CONTROLLED SMOKED CANNABIS; DOPING CONTROL ANALYSIS; GROWTH-FACTOR-I; HUMAN URINE; ENDOGENOUS STEROIDS; SALIVARY TESTOSTERONE; SERUM TESTOSTERONE; DETECTION TIMES AB BACKGROUND: Currently, urine and blood are the only matrices authorized for antidoping testing by the World Anti-Doping Agency (WADA). Although the usefulness of urine and blood is proven, issues remain for monitoring some drug classes and for drugs prohibited only in competition. The alternative matrix oral fluid (OF) may offer solutions to some of these issues. OF collection is easy, noninvasive, and sex neutral and is directly observed, limiting potential adulteration, a major problem for urine testing. OF is used to monitor drug intake in workplace, clinical toxicology, criminal justice, and driving under the influence of drugs programs and potentially could complement urine and blood for antidoping testing in sports. CONTENT: This review outlines the present state of knowledge and the advantages and limitations of OF testing for each of the WADA drug classes and the research needed to advance OF testing as a viable alternative for antidoping testing. SUMMARY: Doping agents are either prohibited at all times or prohibited in competition only. Few OF data from controlled drug administration studies are available for substances banned at all times, whereas for some agents prohibited only in competition, sufficient data may be available to suggest appropriate analytes and cutoffs (analytical threshold concentrations) to identify recent drug use. Additional research is needed to characterize the disposition of many banned substances into OF; OF collection methods and doping agent stability in OF also require investigation to allow the accurate interpretation of OF tests for antidoping monitoring. (C) 2013 American Association for Clinical Chemistry C1 [Anizan, Sebastien; Huestis, Marilyn A.] Natl Inst Drug, Intramural Res Program, NIH, Baltimore, MD USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, IRP, Biomed Res Ctr, 251 Bayview Blvd,Rm 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse; NIH FX Intramural Research Program of the National Institute on Drug Abuse, NIH. NR 73 TC 14 Z9 14 U1 1 U2 26 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2014 VL 60 IS 2 BP 307 EP 322 DI 10.1373/clinchem.2013.209676 PG 16 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AG1AD UT WOS:000335146300008 PM 24153253 ER PT J AU Desrosiers, NA Lee, D Concheiro-Guisan, M Scheidweiler, KB Gorelick, DA Huestis, MA AF Desrosiers, Nathalie A. Lee, Dayong Concheiro-Guisan, Marta Scheidweiler, Karl B. Gorelick, David A. Huestis, Marilyn A. TI Urinary Cannabinoid Disposition in Occasional and Frequent Smokers: Is THC-Glucuronide in Sequential Urine Samples a Marker of Recent Use in Frequent Smokers? SO CLINICAL CHEMISTRY LA English DT Article ID ALKALINE-HYDROLYSIS; TEMPORAL INDICATION; ORAL FLUID; METABOLISM; 11-NOR-9-CARBOXY-DELTA(9)-TETRAHYDROCANNABINOL; DELTA(9)-TETRAHYDROCANNABINOL; DELTA-9-TETRAHYDROCANNABINOL; PHARMACOKINETICS; EXCRETION; MARIJUANA AB BACKGROUND: There is extended urinary excretion of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH- THC), and 11-nor-9-carboxy-THC (THCCOOH) in abstinent frequent cannabis smokers. We characterized THC, 11-OH-THC, THCCOOH, cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide disposition in urine of frequent and occasional cannabis smokers, and we propose a model to predict recent cannabis smoking. METHODS: Frequent and occasional smokers resided on a closed research unit and smoked one 6.8% THC cannabis cigarette ad libitum. Urinary cannabinoids were quantified in each void by liquid chromatographytandem mass spectrometry within 24 h of collection. RESULTS: No urine samples had measureable THC, 11-OH- THC, cannabidiol, or cannabinol. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were measurable in all frequent smokers' urine and 60%, 100%, and 100% of occasional smokers' urine samples, respectively. Pre- and postdose maximal concentrations (non-and creatinine normalized) and probability of being positive were significantly higher in frequent smokers' samples. THC-glucuronide concentrations peaked 0.6-7.4 h after smoking; THCCOOH and THCCOOH-glucuronide concentrations were highly variable. At the newly adopted THCCOOH175-mu g/L World Anti-Doping Agency decision limit, only 50% of frequent smokers were positive 0-6 h postdose; no occasional smokers' samples were positive. An absolute % difference of >= 50% between 2 consecutive THC-glucuronide-positive samples with a creatinine-normalized concentration of >= 2 mu g/g in the first sample predicted cannabis smoking with efficiencies of 93.1% in frequent and 76.9% in occasional smokers within 6 h of first sample collection. CONCLUSIONS: These controlled urinary cannabinoid data provide a possible means of identifying recent cannabis intake in cannabis smokers' urine within a short collection time frame after smoking. (C) 2013 American Association for Clinical Chemistry C1 [Desrosiers, Nathalie A.; Lee, Dayong; Concheiro-Guisan, Marta; Scheidweiler, Karl B.; Gorelick, David A.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, Baltimore, MD 21224 USA. [Desrosiers, Nathalie A.; Lee, Dayong] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200 Rm 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, NIH; Intramural Research Program, National Institute on Drug Abuse, NIH FX Intramural Research Program of the National Institute on Drug Abuse, NIH. NR 33 TC 8 Z9 8 U1 2 U2 9 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2014 VL 60 IS 2 BP 361 EP 372 DI 10.1373/clinchem.2013.214106 PG 12 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AG1AD UT WOS:000335146300013 PM 24185550 ER PT J AU Gounden, V Soldin, SJ AF Gounden, Verena Soldin, Steven J. TI Clinical Use of Reference Intervals Derived from Some CALIPER Studies Questioned SO CLINICAL CHEMISTRY LA English DT Letter ID PEDIATRIC REFERENCE INTERVALS; BIOCHEMICAL MARKERS C1 [Gounden, Verena; Soldin, Steven J.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Soldin, Steven J.] Georgetown Univ, Dept Med, Washington, DC USA. RP Soldin, SJ (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10,Rm 2C-249, Bethesda, MD 20892 USA. EM soldinsj@cc.nih.gov NR 5 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2014 VL 60 IS 2 BP 416 EP 417 DI 10.1373/clinchem.2013.214684 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AG1AD UT WOS:000335146300020 PM 24363369 ER PT J AU Etemadi, A Abnet, CC Kamangar, F Islami, F Khademi, H Pourshams, A Poustchi, H Bagheri, M Sohrabpour, AA Aliasgar, A Khoshnia, M Wacholder, S Matthews, CC Pharoah, PD Brennan, P Boffetta, P Malekzadeh, R Dawsey, SM AF Etemadi, Arash Abnet, Christian C. Kamangar, Farin Islami, Farhad Khademi, Hooman Pourshams, Akram Poustchi, Hossein Bagheri, Mohammad Sohrabpour, Amir Ali Aliasgar, Ali Khoshnia, Masoud Wacholder, Sholom Matthews, Charles C. Pharoah, Paul D. Brennan, Paul Boffetta, Paolo Malekzadeh, Reza Dawsey, Sanford M. TI Impact of body size and physical activity during adolescence and adult life on overall and cause-specific mortality in a large cohort study from Iran SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Obesity; Physical activity; Adolescence; Mortality; Cancer; Cardiovascular disease ID CARDIOVASCULAR-DISEASE RISK; CORONARY-HEART-DISEASE; MASS INDEX; CHILDHOOD OBESITY; FOLLOW-UP; SOCIOECONOMIC-STATUS; ESOPHAGEAL CANCER; PROGENITOR CELLS; GOLESTAN COHORT; OVERWEIGHT AB We conducted this study to examine life-course body size and physical activity in relation to total and cause-specific mortality, which has not previously been studied in the low and middle-income countries in Asia. The Golestan Cohort Study is a population-based cohort in northeastern Iran in which 50,045 people above the age of 40 have been followed since 2004. Participants were shown a validated pictogram to assess body size at ages 15, 30, and the time of recruitment. Information on occupational physical activity at these ages was also collected. Subjects were followed up annually, and cause of death was determined. Cox regression models were adjusted for age at cohort start, smoking, socioeconomic status, ethnicity, place of residence, education, and opium use. Models for body size were also adjusted for physical activity at the same age, and vice versa. During a total of 252,740 person-years of follow-up (mean follow-up duration 5.1 +/- 1.3 years) through December 2011, 2,529 of the cohort participants died. Larger body sizes at ages 15 or 30 in both sexes were associated with increased overall mortality. Cancer mortality was more strongly associated with adolescent obesity, and cardiovascular mortality with early adulthood body size. Weight gain between these ages was associated with cardiovascular mortality. Obese adolescents who lost weight still had increased mortality from all medical causes in both sexes. Physical activity during adolescence and early adulthood had no association with mortality, but at cohort baseline higher levels of activity were associated with reduced mortality. Mortality in this Middle-Eastern population was associated with obesity both during adolescence and early adult life. C1 [Etemadi, Arash; Kamangar, Farin; Islami, Farhad; Khademi, Hooman; Pourshams, Akram; Poustchi, Hossein; Bagheri, Mohammad; Sohrabpour, Amir Ali; Aliasgar, Ali; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. [Etemadi, Arash; Abnet, Christian C.; Wacholder, Sholom; Matthews, Charles C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Khademi, Hooman; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Khoshnia, Masoud] Gorgan Univ Med Sci, Gorgan, Iran. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Etemadi, A (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM arash.etemadi@nih.gov RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; Khoshnia, Masoud/P-5665-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Khoshnia, Masoud/0000-0001-7352-8058; Malekzadeh, Reza/0000-0003-1043-3814 FU intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute; Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; International Agency for Research on Cancer FX This work was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute; the Digestive Disease Research Center of Tehran University of Medical Sciences [Grant No. 82-603]; and by the International Agency for Research on Cancer. NR 48 TC 9 Z9 9 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 EI 1573-7284 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD FEB PY 2014 VL 29 IS 2 BP 95 EP 109 DI 10.1007/s10654-014-9883-6 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AG2FF UT WOS:000335230800003 PM 24557643 ER PT J AU Goodman, M LaKind, JS Fagliano, JA Lash, TL Wiemels, JL Winn, DM Patel, C Van Eenwyk, J Kohler, BA Schisterman, EF Albert, P Mattison, DR AF Goodman, Michael LaKind, Judy S. Fagliano, Jerald A. Lash, Timothy L. Wiemels, Joseph L. Winn, Deborah M. Patel, Chirag Van Eenwyk, Juliet Kohler, Betsy A. Schisterman, Enrique F. Albert, Paul Mattison, Donald R. TI Cancer Cluster Investigations: Review of the Past and Proposals for the Future SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Review DE cancer; cluster investigations; cancer biomarkers; case grouping; leukemia; exposome; infection ID ACUTE LYMPHOBLASTIC-LEUKEMIA; INVESTIGATIONS TELL US; LAST 20 YEARS; AMYOTROPHIC-LATERAL-SCLEROSIS; ACUTE MYELOID-LEUKEMIA; FOR-DISEASE-CONTROL; CHILDHOOD LEUKEMIA; BREAST-CANCER; MULTIPLE-SCLEROSIS; RARE DISEASES AB Residential clusters of non-communicable diseases are a source of enduring public concern, and at times, controversy. Many clusters reported to public health agencies by concerned citizens are accompanied by expectations that investigations will uncover a cause of disease. While goals, methods and conclusions of cluster studies are debated in the scientific literature and popular press, investigations of reported residential clusters rarely provide definitive answers about disease etiology. Further, it is inherently difficult to study a cluster for diseases with complex etiology and long latency (e. g., most cancers). Regardless, cluster investigations remain an important function of local, state and federal public health agencies. Challenges limiting the ability of cluster investigations to uncover causes for disease include the need to consider long latency, low statistical power of most analyses, uncertain definitions of cluster boundaries and population of interest, and in-and out-migration. A multi-disciplinary Workshop was held to discuss innovative and/or under-explored approaches to investigate cancer clusters. Several potentially fruitful paths forward are described, including modern methods of reconstructing residential history, improved approaches to analyzing spatial data, improved utilization of electronic data sources, advances using biomarkers of carcinogenesis, novel concepts for grouping cases, investigations of infectious etiology of cancer, and "omics" approaches. C1 [Goodman, Michael; Lash, Timothy L.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [LaKind, Judy S.] LaKind Associates LLC, Catonsville, MD 21228 USA. [LaKind, Judy S.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [LaKind, Judy S.] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pediat, Hershey, PA 17033 USA. [Fagliano, Jerald A.] New Jersey Dept Hlth, Div Epidemiol Environm & Occupat Hlth, Trenton, NJ 08625 USA. [Wiemels, Joseph L.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, Div Canc Epidemiol, San Francisco, CA 94158 USA. [Winn, Deborah M.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Patel, Chirag] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Van Eenwyk, Juliet] Washington State Dept Hlth, Olympia, WA 98504 USA. [Kohler, Betsy A.] North Amer Assoc Cent Canc Registries Inc, Springfield, IL 62704 USA. [Schisterman, Enrique F.; Albert, Paul] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Mattison, Donald R.] Risk Sci Int, Ottawa, ON K1N 7G2, Canada. [Mattison, Donald R.] Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON K1N 7G2, Canada. RP LaKind, JS (reprint author), LaKind Associates LLC, 106 Oakdale Ave, Catonsville, MD 21228 USA. EM mgoodm2@emory.edu; lakindassoc@comcast.net; Jerald.Fagliano@doh.state.nj.us; timothy.lee.lash@emory.edu; Joe.Wiemels@ucsf.edu; WINNDE@MAIL.NIH.GOV; cjp@stanford.edu; juliet.vaneenwyk@doh.wa.gov; bkohler@naaccr.org; schistee@mail.nih.gov; albertp@mail.nih.gov; mattisond@risksciences.com RI Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; Schisterman, Enrique/0000-0003-3757-641X FU Research Foundation for Health and Environmental Effects (RFHEE); NIEHS/EPA [P01ES018172]; NCI [R01CA155461]; NIEHS [R01ES09137]; NHLBI [T32HL007034]; National Cancer Institute [N01 PC35135] FX This workshop was supported by a grant from the Research Foundation for Health and Environmental Effects (RFHEE). RFHEE was not involved in the design, collection, management, analysis, or interpretation of the information in the manuscript; or in the preparation or approval of the manuscript. Workshop participants or their affiliated organizations received an honorarium (except Jerald Fagliano, Deborah Winn, Juliet Van Eenwyk, Enrique Schisterman, Paul Albert) and travel support (except Jerald Fagliano, Deborah Winn, Enrique Schisterman, Paul Albert, Betsy Kohler). Judy LaKind received support for Workshop development; Judy LaKind and Michael Goodman consult to governmental and private sectors. Joseph Wiemels is supported by the following grants: NIEHS/EPA P01ES018172, NCI R01CA155461, NIEHS R01ES09137. Chirag Patel is supported by the following grant: NHLBI T32HL007034. Michael Goodman receives salary support from the National Cancer Institute's contract N01 PC35135. Donald Mattison is an employee of Risk Sciences International and the McLaughlin Centre for Population Health and consults to government and private sectors, and conducts research with government, private sectors and independently. No other competing interests are declared. NR 122 TC 2 Z9 2 U1 2 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD FEB PY 2014 VL 11 IS 2 BP 1479 EP 1499 DI 10.3390/ijerph110201479 PG 21 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AF0WZ UT WOS:000334436600017 PM 24477211 ER PT J AU Apolo, AB Parnes, HL Madan, RA Gulley, JL Wright, JJ Hoffman-Censits, JH Dawson, NA Trepel, JB Khadar, K Schlom, J Merino, M Raffeld, M Steinberg, SM Choyke, PL Lindenberg, ML Folio, L Agarwal, PK Figg, WD Bottaro, DP Dahut, WL AF Apolo, Andrea Borghese Parnes, Howard L. Madan, Ravi Amrit Gulley, James L. Wright, John Joseph Hoffman-Censits, Jean H. Dawson, Nancy Ann Trepel, Jane B. Khadar, Kattie Schlom, Jeffrey Merino, Maria Raffeld, Mark Steinberg, Seth M. Choyke, Peter L. Lindenberg, Maria Liza Folio, Les Agarwal, Piyush K. Figg, William Douglas Bottaro, Donald P. Dahut, William L. TI A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Mol Diagnost Core Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. 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TI Using MRI/ultrasound fusion biopsy to detect clinically significant prostate cancer in the African American population SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 57 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100060 ER PT J AU Hakimi, AA Ostrovnaya, I Jacobsen, A Coleman, JA Russo, P Mano, R Sankin, A Motzer, RJ Purdue, M Pomerantz, M Freedman, ML Choueiri, TK Hsieh, J Klein, RJ AF Hakimi, A. 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Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. RI Jacobsen, Anders/K-1081-2013 OI Jacobsen, Anders/0000-0001-6847-4980 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 395 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100395 ER PT J AU Karzai, FH Shah, AA Ojemuyiwa, MA Madan, RA Apolo, AB Dawson, NA Arlen, PM Theoret, MR Wright, JJ Chen, C Trepel, JB Couvillon, A Chun, G Harold, N Steinberg, SM Price, DK Gulley, JL Figg, WD Dahut, WL AF Karzai, Fatima H. Shah, Avani Atul Ojemuyiwa, Michelle A. Madan, Ravi Amrit Apolo, Andrea Borghese Dawson, Nancy Ann Arlen, Philip M. Theoret, Marc Robert Wright, John Joseph Chen, Clara Trepel, Jane B. Couvillon, Anna Chun, Guinevere Harold, Nancy Steinberg, Seth M. Price, Douglas K. Gulley, James L. Figg, William Douglas Dahut, William L. TI A phase I study of the multikinase inhibitor cabozantinib (C) plus docetaxel (D) and prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. NCI, Ctr Clin, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. NCI, Biostatist & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 108 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100111 ER PT J AU Madan, RA Tsang, KY Jochems, C Marte, JL Tucker, JA Hodge, JW Singh, H Surolia, I Coyne, GHO Liewehr, DJ Steinberg, SM Heery, CR Schlom, J Gulley, JL AF Madan, Ravi Amrit Tsang, Kwong Yok Jochems, Caroline Marte, Jennifer L. Tucker, Jo A. Hodge, James W. Singh, Harpreet Surolia, Ira Coyne, Geraldine Helen O'Sullivan Liewehr, David J. Steinberg, Seth M. Heery, Christopher Ryan Schlom, Jeffrey Gulley, James L. TI Immune impact induced by PSA-tricom, a therapeutic vaccine for prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 245 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100248 ER PT J AU Metwalli, AR Turkbey, B McKinney, Y Weaver, J Yaqub-Ogun, N Merino, M Lindenberg, ML Linehan, WM Choyke, PL AF Metwalli, Adam R. Turkbey, Baris McKinney, Yolanda Weaver, Juanita Yaqub-Ogun, Nana Merino, Maria Lindenberg, Maria Liza Linehan, W. Marston Choyke, Peter L. TI Results of a phase II trial of novel carbonic anhydrase IX radiotracer 18F-VM4-037 in renal cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA LBA400 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100005 ER PT J AU Ojemuyiwa, MA Karzai, FH Shah, AA Theoret, MR Harold, N Chun, G Couvillon, A Apolo, AB Price, DK Madan, RA Figg, WD Gulley, JL Dahut, WL AF Ojemuyiwa, Michelle A. Karzai, Fatima H. Shah, Avani Atul Theoret, Marc Robert Harold, Nancy Chun, Guinevere Couvillon, Anna Apolo, Andrea Borghese Price, Douglas K. Madan, Ravi Amrit Figg, William Douglas Gulley, James L. Dahut, William L. TI A safety study of trebananib (AMG 386) and abiraterone in metastatic castration-resistant prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Ctr Clin, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 218 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100221 ER PT J AU Okoro, C Rais-Bahrami, S George, A Walton-Diaz, A Siddiqui, M Shakir, N Rothwax, J Raskolnikov, D Stamatakis, L Su, D Turkbey, B Choyke, PL Wood, BJ Merino, M Pinto, PA AF Okoro, Chinonyerem Rais-Bahrami, Soroush George, Arvin Walton-Diaz, Annerleim Siddiqui, Minhaj Shakir, Nabeel Rothwax, Jason Raskolnikov, Dima Stamatakis, Lambros Su, Daniel Turkbey, Baris Choyke, Peter L. Wood, Bradford J. Merino, Maria Pinto, Peter A. TI The performance of targeted magnetic resonance imaging/ultrasound fusion biopsy versus random 12-core biopsy for prediction of total prostate cancer tumor volume SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 34 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100037 ER PT J AU Pichun, MEB Acquavella, N Edgerly, M Bates, SE Balasubramaniam, S Fojo, AT AF Pichun, Mauricio Emmanuel Burotto Acquavella, Nicolas Edgerly, Maureen Bates, Susan Elaine Balasubramaniam, Sanjeeve Fojo, Antonio Tito TI Phase II clinical trial of bevacizumab plus ixabepilone in renal cell carcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 427 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100425 ER PT J AU Rais-Bahrami, S Siddiqui, M Vourganti, S Turkbey, B Rastinehad, A Stamatakis, L Truong, H Walton-Diaz, A Hoang, AN Nix, J Merino, M Wood, BJ Simon, R Choyke, PL Pinto, PA AF Rais-Bahrami, Soroush Siddiqui, Minhaj Vourganti, Srinivas Turkbey, Baris Rastinehad, Ardeshir Stamatakis, Lambros Truong, Hong Walton-Diaz, Annerleim Hoang, Anthony N. Nix, Jeffrey Merino, Maria Wood, Bradford J. Simon, Richard Choyke, Peter L. Pinto, Peter A. TI Diagnostic value of biparametric MRI as an adjunct to PSA-based detection of prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 193 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100196 ER PT J AU Raskolnikov, D Rais-Bahrami, S George, A Turkbey, B Okoro, C Rothwax, J Shakir, N Walton-Diaz, A Siddiqui, M Su, D Stamatakis, L Wood, BJ Choyke, PL Pinto, PA AF Raskolnikov, Dima Rais-Bahrami, Soroush George, Arvin Turkbey, Baris Okoro, Chinonyerem Rothwax, Jason Shakir, Nabeel Walton-Diaz, Annerleim Siddiqui, Minhaj Su, Daniel Stamatakis, Lambros Wood, Bradford J. Choyke, Peter L. Pinto, Peter A. TI Utility of multiparametric MRI at 3 tesla and MRI/ultrasound fusion-guided biopsy in detecting seminal vesicle invasion by prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 128 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100131 ER PT J AU Seliger, B Leisz, S Schulz, K Erb, S Wang, E Marincola, F Stehle, F AF Seliger, Barbara Leisz, Sandra Schulz, Kristin Erb, Susanne Wang, Ena Marincola, Francesco Stehle, Franziska TI Discrimination between Von Hippel-Lindau gene and hypoxia-regulated alterations in the metabolism and protein expression in renal cell carcinoma using ome-based strategies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 Univ Halle Wittenberg, Dept Med Immunol, D-06108 Halle, Germany. Univ Halle Wittenberg, Inst Med Immunol, Halle, Saale, Germany. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Sidra Med & Res Ctr, Doha, Qatar. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 447 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100445 ER PT J AU Shah, AA Kang, ZG Madan, RA Marte, JL Gulley, JL Dahut, WL Cao, L AF Shah, Avani Atul Kang, Zhigang Madan, Ravi Amrit Marte, Jennifer L. Gulley, James L. Dahut, William L. Cao, Liang TI AR(v567es) as detected in circulating tumor cells: An innovative methodology for the detection of a prognostic and therapeutic biomarker SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 112 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100115 ER PT J AU Shakir, N Walton-Diaz, A Rais-Bahrami, S Turkbey, B Rothwax, J Hong, CW Stamatakis, L George, A Okoro, C Raskolnikov, D Siddiqui, M Su, D Simon, R Wood, BJ Choyke, PL Pinto, PA AF Shakir, Nabeel Walton-Diaz, Annerleim Rais-Bahrami, Soroush Turkbey, Baris Rothwax, Jason Hong, Cheng William Stamatakis, Lambros George, Arvin Okoro, Chinonyerem Raskolnikov, Dima Siddiqui, Minhaj Su, Daniel Simon, Richard Wood, Bradford J. Choyke, Peter L. Pinto, Peter A. TI Multiparametric prostate MRI and MRI/ultrasound fusion biopsy as tools to follow prostate cancer progression for men on active surveillance SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 63 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100066 ER PT J AU Shuch, B Stamatakis, L Chen, C Gautam, R Merino, M Choyke, PL Linehan, WM Srinivasan, R AF Shuch, Brian Stamatakis, Lambros Chen, Clara Gautam, Rabindra Merino, Maria Choyke, Peter L. Linehan, W. Marston Srinivasan, Ramaprasad TI Utility of 2-(F-18) fluoro-2 deoxy-D-glucose PET/CT in advanced papillary renal cell carcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 Yale Univ, Dept Urol, New Haven, CT USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 419 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100417 ER PT J AU Siddiqui, MM Rais-Bahrami, S Truong, H Stamatakis, L Walton-Diaz, A George, A Rothwax, J Su, D Shakir, N Wood, BJ Merino, M Turkbey, B Choyke, PL Simon, R Pinto, PA AF Siddiqui, Mohummad Minhaj Rais-Bahrami, Soroush Truong, Hong Stamatakis, Lambros Walton-Diaz, Annerleim George, Arvin Rothwax, Jason Su, Daniel Shakir, Nabeel Wood, Bradford J. Merino, Maria Turkbey, Baris Choyke, Peter L. Simon, Richard Pinto, Peter A. TI Prediction of prostate cancer Gleason score using a MRI-based nomogram. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 255 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100258 ER PT J AU Solomon, DA Kim, JS Bondaruk, J Shariat, SF Wang, ZF Elkahloun, A Gerard, J Zhuang, DZ Zhang, SZ Robinson, BD Rubin, MA Volkmer, B Hautmann, R Kuefer, R Netto, GJ Theodorescu, D Czerniak, B Miettinen, M Waldman, T AF Solomon, David A. Kim, Jung-Sik Bondaruk, Jolanta Shariat, Shahrokh F. Wang, Zeng-Feng Elkahloun, Abdel Gerard, Julia Zhuang, DaZhong Zhang, Shizhen Robinson, Brian D. Rubin, Mark A. Volkmer, Bjoern Hautmann, Richard Kuefer, Rainer Netto, George J. Theodorescu, Dan Czerniak, Bogdan Miettinen, Markku Waldman, Todd TI Frequent truncating mutations of the cohesin complex gene STAG2 in urothelial carcinoma of the bladder. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Georgetown Univ, Sch Med, Lombardi Canc Ctr, Washington, DC USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Med Univ Vienna, Vienna, Austria. NCI, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Weill Cornell Med Coll, New York, NY USA. Hosp Kassel, Kassel, Germany. Univ Hosp Ulm, Ulm, Germany. Hosp Eichert, Goppingen, Germany. Johns Hopkins Univ, Baltimore, MD USA. Univ Colorado, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 290 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100291 ER PT J AU Su, D Okoro, C George, A Linehan, WM Metwalli, AR AF Su, Daniel Okoro, Chinonyerem George, Arvin Linehan, W. Marston Metwalli, Adam R. TI Bilateral multifocal papillary type I renal cell carcinoma: Clinical characteristics and association with chronic renal insufficiency. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 [Su, Daniel; Okoro, Chinonyerem; George, Arvin; Linehan, W. Marston; Metwalli, Adam R.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 482 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100480 ER PT J AU Su, D George, A Siddiqui, M Rais-Bahrami, S Stamatakis, L Hong, CW Rothwax, J Okoro, C Raskolnikov, D Shakir, N Walton-Diaz, A Simon, R Turkbey, B Wood, BJ Choyke, PL Pinto, PA AF Su, Daniel George, Arvin Siddiqui, Minhaj Rais-Bahrami, Soroush Stamatakis, Lambros Hong, Cheng William Rothwax, Jason Okoro, Chinonyerem Raskolnikov, Dima Shakir, Nabeel Walton-Diaz, Annerleim Simon, Richard Turkbey, Baris Wood, Bradford J. Choyke, Peter L. Pinto, Peter A. TI Comparing magnetic resonance imaging/ultrasound-fusion biopsy and systemic 12-core transrectal ultrasound biopsy for whole gland pathology. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 84 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100087 ER PT J AU Tsao, CK Agarwal, N Apolo, AB Lee, KM Godbold, JH Oh, WK Galsky, MD AF Tsao, Che-Kai Agarwal, Neeraj Apolo, Andrea Borghese Lee, Karen M. Godbold, James H. Oh, William K. Galsky, Matt D. TI Phase Ib/II trial of gemcitabine, cisplatin, plus lenalidomide as first-line therapy for patients with metastatic urothelial carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 321 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100322 ER PT J AU Tully, CM Apolo, AB Zabor, EC Regazzi, AM Ostrovnaya, I Rosenberg, JE Bajorin, DF AF Tully, Christopher Michael Apolo, Andrea Borghese Zabor, Emily C. Regazzi, Ashley Marie Ostrovnaya, Irina Rosenberg, Jonathan E. Bajorin, Dean F. TI The high incidence of vascular thromboembolic events (VTE) in advanced urothelial cancer (UC) patients (pts) treated with carboplatin (Cb): Analysis of treatment with gemcitabine (G)/cb (GCb), gcb/bevacizumab (GCbBev), or gemcitabine/cisplatin (GCis) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 316 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100317 ER PT J AU Weinberg, BA Lindenberg, ML Kurdziel, KA Steinberg, SM Liewehr, DJ Khadar, K McKinney, Y Choyke, PL Apolo, AB AF Weinberg, Benjamin Adam Lindenberg, Maria Liza Kurdziel, Karen A. Steinberg, Seth M. Liewehr, David J. Khadar, Kattie McKinney, Yolanda Choyke, Peter L. Apolo, Andrea Borghese TI Assessment of bone metastases in patients (pts) with urothelial carcinoma using F-18-sodium fluoride PET/CT (F-18-NaF) versus F-18-fluorodeoxyglucose PET/CT (F-18-FDG). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 30-FEB 01, 2014 CL San Francisco, CA C1 Georgetown Univ Hosp, Washington, DC 20007 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 SU S MA 329 PG 1 WC Oncology SC Oncology GA AG3LF UT WOS:000335318100330 ER PT J AU Ozbabacan, SEA Gursoy, A Nussinov, R Keskin, O AF Ozbabacan, Saliha Ece Acuner Gursoy, Attila Nussinov, Ruth Keskin, Ozlem TI The Structural Pathway of Interleukin 1 (IL-1) Initiated Signaling Reveals Mechanisms of Oncogenic Mutations and SNPs in Inflammation and Cancer SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; SOMATIC MUTATIONS; MOLECULAR DOCKING; BRAIN-TUMORS; DATA-BANK; RECEPTOR; KINASE; SCALE; EXPRESSION; INTERFACES AB Interleukin-1 (IL-1) is a large cytokine family closely related to innate immunity and inflammation. IL-1 proteins are key players in signaling pathways such as apoptosis, TLR, MAPK, NLR and NF-kappa B. The IL-1 pathway is also associated with cancer, and chronic inflammation increases the risk of tumor development via oncogenic mutations. Here we illustrate that the structures of interfaces between proteins in this pathway bearing the mutations may reveal how. Proteins are frequently regulated via their interactions, which can turn them ON or OFF. We show that oncogenic mutations are significantly at or adjoining interface regions, and can abolish (or enhance) the protein-protein interaction, making the protein constitutively active (or inactive, if it is a repressor). We combine known structures of protein-protein complexes and those that we have predicted for the IL-1 pathway, and integrate them with literature information. In the reconstructed pathway there are 104 interactions between proteins whose three dimensional structures are experimentally identified; only 15 have experimentally-determined structures of the interacting complexes. By predicting the protein-protein complexes throughout the pathway via the PRISM algorithm, the structural coverage increases from 15% to 71%. In silico mutagenesis and comparison of the predicted binding energies reveal the mechanisms of how oncogenic and single nucleotide polymorphism (SNP) mutations can abrogate the interactions or increase the binding affinity of the mutant to the native partner. Computational mapping of mutations on the interface of the predicted complexes may constitute a powerful strategy to explain the mechanisms of activation/inhibition. It can also help explain how an oncogenic mutation or SNP works. Author Summary Structural pathways are important because they provide insight into signaling mechanisms; help understand the mechanism of disease-related mutations; and help in drug discovery. While extremely useful, common pathway diagrams lacking structural data are unable to provide mechanistic insight to explain oncogenic mutations or SNPs. Here we focus on the construction of the IL-1 structural pathway and map oncogenic mutations and SNPs to complexes in this pathway. Our results indicate that computational modeling of protein-protein interactions on a large scale can provide accurate, structural atom-level detail of signaling pathways in the human cell and help delineate the mechanism through which a mutation leads to disease. We show that the mutations either thwart the interactions, activating the proteins even in their absence or stabilize them, leading to the same uncontrolled outcome. Computational mapping of mutations on the interface of the predicted complexes may constitute an effective strategy to explain the mechanisms of mutations- constitutive activation or deactivation. C1 [Ozbabacan, Saliha Ece Acuner; Gursoy, Attila; Keskin, Ozlem] Koc Univ, Ctr Computat Biol & Bioinformat, Sariyer, Turkey. [Ozbabacan, Saliha Ece Acuner; Gursoy, Attila; Keskin, Ozlem] Koc Univ, Coll Engn, Sariyer, Turkey. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Ozbabacan, SEA (reprint author), Koc Univ, Ctr Computat Biol & Bioinformat, Sariyer, Turkey. EM agursoy@ku.edu.tr; okeskin@ku.edu.tr RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Scientific and Technological Research Council of Turkey Fellowship [113E164] FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. This work was supported by the Scientific and Technological Research Council of Turkey Fellowship to Saliha Ece Acuner Ozbabacan (Grant No: 113E164). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 1 Z9 1 U1 1 U2 10 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pcbi.1003470 PG 14 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AB8CC UT WOS:000332016700031 ER PT J AU Shreif, Z Periwal, V AF Shreif, Zeina Periwal, Vipul TI A Network Characteristic That Correlates Environmental and Genetic Robustness SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID BACTERIAL CHEMOTAXIS; BIOCHEMICAL NETWORKS; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; MUTATIONAL ROBUSTNESS; BIOLOGICAL NETWORKS; SIGNAL-TRANSDUCTION; PERFECT ADAPTATION; SYNTHETIC BIOLOGY; EVOLUTION AB As scientific advances in perturbing biological systems and technological advances in data acquisition allow the large-scale quantitative analysis of biological function, the robustness of organisms to both transient environmental stresses and inter-generational genetic changes is a fundamental impediment to the identifiability of mathematical models of these functions. An approach to overcoming this impediment is to reduce the space of possible models to take into account both types of robustness. However, the relationship between the two is still controversial. This work uncovers a network characteristic, transient responsiveness, for a specific function that correlates environmental imperturbability and genetic robustness. We test this characteristic extensively for dynamic networks of ordinary differential equations ranging up to 30 interacting nodes and find that there is a power-law relating environmental imperturbability and genetic robustness that tends to linearity as the number of nodes increases. Using our methods, we refine the classification of known 3-node motifs in terms of their environmental and genetic robustness. We demonstrate our approach by applying it to the chemotaxis signaling network. In particular, we investigate plausible models for the role of CheV protein in biochemical adaptation via a phosphorylation pathway, testing modifications that could improve the robustness of the system to environmental and/or genetic perturbation. Author Summary Advances in the ways that living systems can be perturbed in order to study how they function and sharp reductions in the cost of computer resources have allowed the collection of large amounts of data. The aim of biological system modeling is to analyze this data in order to pin down the precise interactions of molecules that underlie the observed functions. This is made difficult due to two features of biological systems: (1) Living things do not show an appreciable loss of function across large ranges of environmental factors. (2) Their function is inherited from parent to child more or less unchanged in spite of random mutations in genetic sequences. We find that these two features are more correlated in a specific subset of networks and show how to use this observation to find networks in which these two features appear together. Working within this smaller space of networks may make it easier to find suitable underlying models from data. C1 [Shreif, Zeina; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Shreif, Z (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov FU NIH, NIDDK FX The research was supported by the Intramural Research Program of the NIH, NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 1 Z9 1 U1 0 U2 8 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pcbi.1003474 PG 23 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AB8CC UT WOS:000332016700028 ER PT J AU Tsai, CJ Nussinov, R AF Tsai, Chung-Jung Nussinov, Ruth TI A Unified View of "How Allostery Works" SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID AMINO-ACID BIOSYNTHESIS; MYCOBACTERIUM-TUBERCULOSIS; SYNERGISTIC ALLOSTERY; RECEPTOR ACTIVATION; ENERGY LANDSCAPES; SIGNALING PROTEIN; DYNAMIC-ANALYSIS; DRUG DISCOVERY; 2-STATE MODEL; HEMOGLOBIN AB The question of how allostery works was posed almost 50 years ago. Since then it has been the focus of much effort. This is for two reasons: first, the intellectual curiosity of basic science and the desire to understand fundamental phenomena, and second, its vast practical importance. Allostery is at play in all processes in the living cell, and increasingly in drug discovery. Many models have been successfully formulated, and are able to describe allostery even in the absence of a detailed structural mechanism. However, conceptual schemes designed to qualitatively explain allosteric mechanisms usually lack a quantitative mathematical model, and are unable to link its thermodynamic and structural foundations. This hampers insight into oncogenic mutations in cancer progression and biased agonists' actions. Here, we describe how allostery works from three different standpoints: thermodynamics, free energy landscape of population shift, and structure; all with exactly the same allosteric descriptors. This results in a unified view which not only clarifies the elusive allosteric mechanism but also provides structural grasp of agonist-mediated signaling pathways, and guides allosteric drug discovery. Of note, the unified view reasons that allosteric coupling (or communication) does not determine the allosteric efficacy; however, a communication channel is what makes potential binding sites allosteric. C1 [Tsai, Chung-Jung; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab,Ctr Canc Res, 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 Tsai, CJ (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab,Ctr Canc Res, Frederick, MD 21701 USA. EM tsaic@mail.nih.gov; nussinor@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in the preparation of the manuscript. NR 62 TC 76 Z9 76 U1 5 U2 45 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pcbi.1003394 PG 12 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AB8CC UT WOS:000332016700029 ER PT J AU Agler, C Nielsen, DM Urkasemsin, G Singleton, A Tonomura, N Sigurdsson, S Tang, RQ Linder, K Arepalli, S Hernandez, D Lindblad-Toh, K van de Leemput, J Motsinger-Reif, A O'Brien, DP Bell, J Harris, T Steinberg, S Olby, NJ AF Agler, Caryline Nielsen, Dahlia M. Urkasemsin, Ganokon Singleton, Andrew Tonomura, Noriko Sigurdsson, Snaevar Tang, Ruqi Linder, Keith Arepalli, Sampath Hernandez, Dena Lindblad-Toh, Kerstin van de Leemput, Joyce Motsinger-Reif, Alison O'Brien, Dennis P. Bell, Jerold Harris, Tonya Steinberg, Steven Olby, Natasha J. TI Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24 SO PLOS GENETICS LA English DT Article ID CEREBELLAR CORTICAL DEGENERATION; DOMESTIC DOG; SPINOCEREBELLAR ATAXIA; GRANULOPRIVAL DEGENERATION; CONSTITUTIVE AUTOPHAGY; LINKAGE DISEQUILIBRIUM; LABRADOR RETRIEVER; SCOTTISH TERRIERS; INHERITED ATAXIA; SMALL GTPASES AB Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia. Author Summary Neurodegenerative diseases are one of the most important causes of decline in an aging population. An important subset of these diseases are known as the hereditary ataxias, familial neurodegenerative diseases that affect the cerebellum causing progressive gait disturbance in both humans and dogs. We identified a mutation in RAB24, a gene associated with autophagy, in Old English Sheepdogs and Gordon Setters with hereditary ataxia. Autophagy is a process by which cell proteins and organelles are removed and recycled and its critical role in maintenance of the continued health of cells is becoming clear. We evaluated the brains of affected dogs and identified accumulations of autophagosomes within the cerebellum, suggesting a defect in the autophagy pathway. Our results suggest that a defect in the autophagy pathway results in neuronal death in a naturally occurring disease in dogs. The autophagy pathway should be investigated in human hereditary ataxia and may represent a therapeutic target in neurodegenerative diseases. C1 [Agler, Caryline; Urkasemsin, Ganokon; Harris, Tonya; Olby, Natasha J.] N Carolina State Univ, Coll Vet Med, Dept Clin Sci, Raleigh, NC 27695 USA. [Nielsen, Dahlia M.; Motsinger-Reif, Alison] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Singleton, Andrew; Arepalli, Sampath; Hernandez, Dena; van de Leemput, Joyce] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Tonomura, Noriko; Sigurdsson, Snaevar; Tang, Ruqi; Lindblad-Toh, Kerstin] Broad Inst MIT & Harvard, Cambridge, MA USA. [Tonomura, Noriko; Bell, Jerold] Tufts Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA. [Linder, Keith] N Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC USA. [Lindblad-Toh, Kerstin] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden. [Motsinger-Reif, Alison; Olby, Natasha J.] N Carolina State Univ, Ctr Comparat Med & Translat Res, Raleigh, NC 27695 USA. [O'Brien, Dennis P.] Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Columbia, MO 65211 USA. [Steinberg, Steven] VCA Vet Referral Associates, Gaithersbrug, MD USA. RP Agler, C (reprint author), N Carolina State Univ, Coll Vet Med, Dept Clin Sci, Raleigh, NC 27695 USA. EM Natasha_olby@ncsu.edu RI Singleton, Andrew/C-3010-2009 FU American Kennel Club Canine Health Foundation [CHF 0407, 0925]; Old English Sheepdog Club of America; TarTan Gordon Setter Club; OFA CHIC DNA Repository; EURYI from the European Science Foundation FX This work was supported by grants CHF 0407 and 0925, from the American Kennel Club Canine Health Foundation (www.akcchf.org). It was also supported by the Old English Sheepdog Club of America, the TarTan Gordon Setter Club and the OFA CHIC DNA Repository. KLT was funded by a EURYI from the European Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 7 Z9 7 U1 3 U2 20 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pgen.1003991 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AB8DY UT WOS:000332021500014 ER PT J AU Baek, JH Chattoraj, DK AF Baek, Jong Hwan Chattoraj, Dhruba K. TI Chromosome I Controls Chromosome II Replication in Vibrio cholerae SO PLOS GENETICS LA English DT Article ID ESCHERICHIA-COLI; INITIATOR PROTEIN; DNAA PROTEIN; PLASMID REPLICATION; CELL-CYCLE; BINDING-SITES; ORIGIN; LOCUS; RCTB; SEQUENCE AB Control of chromosome replication involves a common set of regulators in eukaryotes, whereas bacteria with divided genomes use chromosome-specific regulators. How bacterial chromosomes might communicate for replication is not known. In Vibrio cholerae, which has two chromosomes (chrI and chrII), replication initiation is controlled by DnaA in chrI and by RctB in chrII. DnaA has binding sites at the chrI origin of replication as well as outside the origin. RctB likewise binds at the chrII origin and, as shown here, to external sites. The binding to the external sites in chrII inhibits chrII replication. A new kind of site was found in chrI that enhances chrII replication. Consistent with its enhancing activity, the chrI site increased RctB binding to those chrII origin sites that stimulate replication and decreased binding to other sites that inhibit replication. The differential effect on binding suggests that the new site remodels RctB. The chaperone-like activity of the site is supported by the finding that it could relieve the dependence of chrII replication on chaperone proteins DnaJ and DnaK. The presence of a site in chrI that specifically controls chrII replication suggests a mechanism for communication between the two chromosomes for replication. Author Summary Genome maintenance in dividing cells requires that the chromosomes replicate reliably once per cell cycle, and that this replication be timed to allow for proper segregation of the daughter chromosomes before cell division. In organisms with divided genomes, eukaryotes and a significant class of bacteria, the chromosomes must avoid interference with one another. They exhibit disciplined chromosome choreography, involving several regulators and control circuits that, even in the simplest organisms, are poorly understood. Here we examine the regulatory processes involved in maintaining the two chromosomes of the well-studied and medically important pathogen Vibrio cholerae. We provide evidence that a site in chromosome I can control the frequency and timing of replication of chromosome II. The mechanism involves a DNA-mediated remodeling of the chromosome II-specific initiator of replication by the chromosome I site. The site enhances the activity of the protein by differentially affecting its affinity for inhibitory and stimulatory sites on chromosome II. Our results provide the groundwork for determining whether coordination of replication might be a conserved feature that maintains chromosomes in proliferating cells of higher organisms. C1 [Baek, Jong Hwan; Chattoraj, Dhruba K.] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Baek, JH (reprint author), NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM chattoraj@nih.gov FU Intramural Research Program of the Center for Cancer Research; NCI; NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 13 Z9 14 U1 0 U2 1 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pgen.1004184 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AB8DY UT WOS:000332021500057 ER PT J AU Borad, MJ Champion, MD Egan, JB Liang, WS Fonseca, R Bryce, AH McCullough, AE Barrett, MT Hunt, K Patel, MD Young, SW Collins, JM Silva, AC Condjella, RM Block, M McWilliams, RR Lazaridis, KN Klee, EW Bible, KC Harris, P Oliver, GR Bhavsar, JD Nair, AA Middha, S Asmann, Y Kocher, JP Schahl, K Kipp, BR Fritcher, EGB Baker, A Aldrich, J Kurdoglu, A Izatt, T Christoforides, A Cherni, I Nasser, S Reiman, R Phillips, L McDonald, J Adkins, J Mastrian, SD Placek, P Watanabe, AT LoBello, J Han, HY Von Hoff, D Craig, DW Stewart, AK Carpten, JD AF Borad, Mitesh J. Champion, Mia D. Egan, Jan B. Liang, Winnie S. Fonseca, Rafael Bryce, Alan H. McCullough, Ann E. Barrett, Michael T. Hunt, Katherine Patel, Maitray D. Young, Scott W. Collins, Joseph M. Silva, Alvin C. Condjella, Rachel M. Block, Matthew McWilliams, Robert R. Lazaridis, Konstantinos N. Klee, Eric W. Bible, Keith C. Harris, Pamela Oliver, Gavin R. Bhavsar, Jaysheel D. Nair, Asha A. Middha, Sumit Asmann, Yan Kocher, Jean-Pierre Schahl, Kimberly Kipp, Benjamin R. Fritcher, Emily G. Barr Baker, Angela Aldrich, Jessica Kurdoglu, Ahmet Izatt, Tyler Christoforides, Alexis Cherni, Irene Nasser, Sara Reiman, Rebecca Phillips, Lori McDonald, Jackie Adkins, Jonathan Mastrian, Stephen D. Placek, Pamela Watanabe, Aprill T. LoBello, Janine Han, Haiyong Von Hoff, Daniel Craig, David W. Stewart, A. Keith Carpten, John D. TI Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma SO PLOS GENETICS LA English DT Article ID GROWTH-FACTOR RECEPTOR; PRIMARY SCLEROSING CHOLANGITIS; TUMOR-SUPPRESSOR GENE; BILIARY-TRACT CANCER; FLUKE-ASSOCIATED CHOLANGIOCARCINOMA; NEGATIVE BREAST-CANCER; C-VIRUS-INFECTION; K-RAS MUTATIONS; RISK-FACTORS; HEPATITIS-C AB Author Summary Cholangiocarcinoma is a cancer that affects the bile ducts. Unfortunately, many patients diagnosed with cholangiocarcinoma have disease that cannot be treated with surgery or has spread to other parts of the body, thus severely limiting treatment options. New advances in drug treatment have enabled treatment of these cancers with "targeted therapy" that exploits an error in the normal functioning of a tumor cell, compared to other cells in the body, thus allowing only tumor cells to be killed by the drug. We sought to identify changes in the genetic material of cholangiocarcinoma patient tumors in order to identify potential errors in cellular functioning by utilizing cutting edge genetic sequencing technology. We identified three patient tumors possessing an FGFR2 gene that was aberrantly fused to another gene. Two of these patients were able to receive targeted therapy for FGFR2 with resulting tumor shrinkage. A fourth tumor contained an error in a gene that controls a very important cellular mechanism in cancer, termed epidermal growth factor pathway (EGFR). This patient received therapy targeting this mechanism and also demonstrated response to treatment. Thus, we have been able to utilize cutting edge technology with targeted drug treatment to personalize medical treatment for cancer in cholangiocarcinoma patients. Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50 approximate to 350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50 approximate to 8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations. C1 [Borad, Mitesh J.; Fonseca, Rafael; Bryce, Alan H.; Hunt, Katherine; Stewart, A. Keith] Mayo Clin, Div Hematol Oncol, Scottsdale, AZ 85259 USA. [Borad, Mitesh J.; Fonseca, Rafael; Bryce, Alan H.; Barrett, Michael T.; Condjella, Rachel M.; Von Hoff, Daniel; Stewart, A. Keith] Mayo Clin, Ctr Canc, Scottsdale, AZ USA. [Borad, Mitesh J.; Champion, Mia D.; Egan, Jan B.; Fonseca, Rafael; Bryce, Alan H.; Block, Matthew; McWilliams, Robert R.; Lazaridis, Konstantinos N.; Klee, Eric W.; Oliver, Gavin R.; Bhavsar, Jaysheel D.; Nair, Asha A.; Middha, Sumit; Asmann, Yan; Kocher, Jean-Pierre; Schahl, Kimberly; Stewart, A. Keith] Mayo Clin, Ctr Individualized Med, Rochester, MN USA. [Champion, Mia D.; Klee, Eric W.; Oliver, Gavin R.; Bhavsar, Jaysheel D.; Nair, Asha A.; Middha, Sumit; Asmann, Yan; Kocher, Jean-Pierre] Mayo Clin, Dept Biomed Stat & Informat, Scottsdale, AZ USA. [Liang, Winnie S.; Barrett, Michael T.; Baker, Angela; Aldrich, Jessica; Kurdoglu, Ahmet; Izatt, Tyler; Christoforides, Alexis; Cherni, Irene; Nasser, Sara; Reiman, Rebecca; Phillips, Lori; McDonald, Jackie; Adkins, Jonathan; Mastrian, Stephen D.; Placek, Pamela; Watanabe, Aprill T.; LoBello, Janine; Han, Haiyong; Von Hoff, Daniel; Craig, David W.; Carpten, John D.] Translat Genom Res Inst, Phoenix, AZ USA. [McCullough, Ann E.] Mayo Clin, Dept Pathol, Scottsdale, AZ USA. [Patel, Maitray D.; Young, Scott W.; Collins, Joseph M.; Silva, Alvin C.] Mayo Clin, Dept Radiol, Scottsdale, AZ USA. [Block, Matthew; McWilliams, Robert R.; Bible, Keith C.] Mayo Clin, Ctr Canc, Rochester, MN USA. [Harris, Pamela] NCI, Invest Drug Branch, Rockville, MD USA. [Kipp, Benjamin R.; Fritcher, Emily G. Barr] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. RP Borad, MJ (reprint author), Mayo Clin, Div Hematol Oncol, Scottsdale, AZ 85259 USA. EM borad.mitesh@mayo.edu; jcarpten@tgen.org OI Young, Scott/0000-0001-6691-0742; Middha, Sumit/0000-0003-4135-6268; Bryce, Alan H./0000-0002-0206-3895 FU NIH [K12 CA90628]; Center for Individualized Medicine FX This study was supported by the NIH Grant Number K12 CA90628 and the Center for Individualized Medicine. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 113 TC 20 Z9 20 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pgen.1004135 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA AB8DY UT WOS:000332021500062 ER PT J AU Link, J Leubner, M Schmitt, J Gob, E Benavente, R Jeang, KT Xu, RE Alsheimer, M AF Link, Jana Leubner, Monika Schmitt, Johannes Goeb, Eva Benavente, Ricardo Jeang, Kuan-Teh Xu, Rener Alsheimer, Manfred TI Analysis of Meiosis in SUN1 Deficient Mice Reveals a Distinct Role of SUN2 in Mammalian Meiotic LINC Complex Formation and Function SO PLOS GENETICS LA English DT Article ID NUCLEAR-ENVELOPE; PROTEINS; KASH; TELOMERES; CYTOSKELETON; RECOMBINATION; CHROMOSOMES; MOUSE; COMPONENTS; PROPHASE AB LINC complexes are evolutionarily conserved nuclear envelope bridges, composed of SUN (Sad-1/UNC-84) and KASH (Klarsicht/ANC-1/Syne/homology) domain proteins. They are crucial for nuclear positioning and nuclear shape determination, and also mediate nuclear envelope (NE) attachment of meiotic telomeres, essential for driving homolog synapsis and recombination. In mice, SUN1 and SUN2 are the only SUN domain proteins expressed during meiosis, sharing their localization with meiosis-specific KASH5. Recent studies have shown that loss of SUN1 severely interferes with meiotic processes. Absence of SUN1 provokes defective telomere attachment and causes infertility. Here, we report that meiotic telomere attachment is not entirely lost in mice deficient for SUN1, but numerous telomeres are still attached to the NE through SUN2/KASH5-LINC complexes. In Sun1(-/-) meiocytes attached telomeres retained the capacity to form bouquet-like clusters. Furthermore, we could detect significant numbers of late meiotic recombination events in Sun1(-/-) mice. Together, this indicates that even in the absence of SUN1 telomere attachment and their movement within the nuclear envelope per se can be functional. Author Summary Correct genome haploidization during meiosis requires tightly regulated chromosome movements that follow a highly conserved choreography during prophase I. Errors in these movements cause subsequent meiotic defects, which typically lead to infertility. At the beginning of meiotic prophase, chromosome ends are tethered to the nuclear envelope (NE). This attachment of telomeres appears to be mediated by well-conserved membrane spanning protein complexes within the NE (LINC complexes). In mouse meiosis, the two main LINC components SUN1 and SUN2 were independently described to localize at the sites of telomere attachment. While SUN1 has been demonstrated to be critical for meiotic telomere attachment, the precise role of SUN2 in this context, however, has been discussed controversially in the field. Our current study was targeted to determine the factual capacity of SUN2 in telomere attachment and chromosome movements in SUN1 deficient mice. Remarkably, although telomere attachment is impaired in the absence of SUN1, we could find a yet undescribed SUN1-independent telomere attachment, which presumably is mediated by SUN2 and KASH5. This SUN2 mediated telomere attachment is stable throughout prophase I and functional in moving telomeres within the NE. Thus, our results clearly indicate that SUN1 and SUN2, at least partially, fulfill redundant meiotic functions. C1 [Link, Jana; Leubner, Monika; Schmitt, Johannes; Goeb, Eva; Benavente, Ricardo; Alsheimer, Manfred] Univ Wurzburg, Dept Cell & Dev Biol, Bioctr, D-97070 Wurzburg, Germany. [Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Xu, Rener] Fudan Univ, Inst Dev Biol & Mol Med, Shanghai 200433, Peoples R China. [Xu, Rener] Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China. RP Link, J (reprint author), Univ Wurzburg, Dept Cell & Dev Biol, Bioctr, D-97070 Wurzburg, Germany. EM alsheimer@biozentrum.uni-wuerzburg.de FU German Research Foundation (DFG) [Al 1090/2-1, SPP1384]; Graduate School GK1048 of the University of Wurzburg; German Research Foundation (DFG); University of Wurzburg FX This study was supported by the German Research Foundation (DFG, http://www.dfg.de), grant Al 1090/2-1 (Priority Program SPP1384 "Mechanisms of genome haploidization") to MA, and the Graduate School GK1048 of the University of Wurzburg (http://www.gk-1048.uni-wuerzburg.de). It received further funding by the German Research Foundation (DFG) and the University of Wurzburg in the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 12 Z9 12 U1 0 U2 1 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pgen.1004099 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AB8DY UT WOS:000332021500048 ER PT J AU Medici, M Porcu, E Pistis, G Teumer, A Brown, SJ Jensen, RA Rawal, R Roef, GL Plantinga, TS Vermeulen, SH Lahti, J Simmonds, MJ Husemoen, LLN Freathy, RM Shields, BM Pietzner, D Nagy, R Broer, L Chaker, L Korevaar, TIM Plia, MG Sala, C Volker, U Richards, JB Sweep, FC Gieger, C Corre, T Kajantie, E Thuesen, B Taes, YE Visser, WE Hattersley, AT Kratzsch, J Hamilton, A Li, W Homuth, G Lobina, M Mariotti, S Soranzo, N Cocca, M Nauck, M Spielhagen, C Ross, A Arnold, A van de Bunt, M Liyanarachchi, S Heier, M Grabe, HJ Masciullo, C Galesloot, TE Lim, EM Reischl, E Leedman, PJ Lai, S Delitala, A Bremner, AP Philips, DIW Beilby, JP Mulas, A Vocale, M Abecasis, G Forsen, T James, A Widen, E Hui, J Prokisch, H Rietzschel, EE Palotie, A Feddema, P Fletcher, SJ Schramm, K Rotter, JI Kluttig, A Radke, D Traglia, M Surdulescu, GL He, HL Franklyn, JA Tiller, D Vaidya, B de Meyer, T Jorgensen, T Eriksson, JG O'Leary, PC Wichmann, E Hermus, AR Psaty, BM Ittermann, T Hofman, A Bosi, E Schlessinger, D Wallaschofski, H Pirastu, N Aulchenko, YS de la Chapelle, A Netea-Maier, RT Gough, SCL Meyer zu Schwabedissen, H Frayling, TM Kaufman, JM Linneberg, A Raikkonen, K Smit, JWA Kiemeney, LA Rivadeneira, F Uitterlinden, AG Walsh, JP Meisinger, C Den Heijer, M Visser, TJ Spector, TD Wilson, SG Voelzke, H Cappola, A Toniolo, D Sanna, S Naitza, S Peeters, RP AF Medici, Marco Porcu, Eleonora Pistis, Giorgio Teumer, Alexander Brown, Suzanne J. Jensen, Richard A. Rawal, Rajesh Roef, Greet L. Plantinga, Theo S. Vermeulen, Sita H. Lahti, Jari Simmonds, Matthew J. Husemoen, Lise Lotte N. Freathy, Rachel M. Shields, Beverley M. Pietzner, Diana Nagy, Rebecca Broer, Linda Chaker, Layal Korevaar, Tim I. M. Plia, Maria Grazia Sala, Cinzia Voelker, Uwe Richards, J. Brent Sweep, Fred C. Gieger, Christian Corre, Tanguy Kajantie, Eero Thuesen, Betina Taes, Youri E. Visser, W. Edward Hattersley, Andrew T. Kratzsch, Juergen Hamilton, Alexander Li, Wei Homuth, Georg Lobina, Monia Mariotti, Stefano Soranzo, Nicole Cocca, Massimiliano Nauck, Matthias Spielhagen, Christin Ross, Alec Arnold, Alice van de Bunt, Martijn Liyanarachchi, Sandya Heier, Margit Grabe, Hans Joergen Masciullo, Corrado Galesloot, Tessel E. Lim, Ee M. Reischl, Eva Leedman, Peter J. Lai, Sandra Delitala, Alessandro Bremner, Alexandra P. Philips, David I. W. Beilby, John P. Mulas, Antonella Vocale, Matteo Abecasis, Goncalo Forsen, Tom James, Alan Widen, Elisabeth Hui, Jennie Prokisch, Holger Rietzschel, Ernst E. Palotie, Aarno Feddema, Peter Fletcher, Stephen J. Schramm, Katharina Rotter, Jerome I. Kluttig, Alexander Radke, Doerte Traglia, Michela Surdulescu, Gabriela L. He, Huiling Franklyn, Jayne A. Tiller, Daniel Vaidya, Bijay de Meyer, Tim Jorgensen, Torben Eriksson, Johan G. O'Leary, Peter C. Wichmann, Eric Hermus, Ad R. Psaty, Bruce M. Ittermann, Till Hofman, Albert Bosi, Emanuele Schlessinger, David Wallaschofski, Henri Pirastu, Nicola Aulchenko, Yurii S. de la Chapelle, Albert Netea-Maier, Romana T. Gough, Stephen C. L. Meyer zu Schwabedissen, Henriette Frayling, Timothy M. Kaufman, Jean-Marc Linneberg, Allan Raeikkoenen, Katri Smit, Johannes W. A. Kiemeney, Lambertus A. Rivadeneira, Fernando Uitterlinden, Andre G. Walsh, John P. Meisinger, Christa Den Heijer, Martin Visser, Theo J. Spector, Timothy D. Wilson, Scott G. Voelzke, Henry Cappola, Anne Toniolo, Daniela Sanna, Serena Naitza, Silvia Peeters, Robin P. TI Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; IODIDE ORGANIFICATION DEFECTS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GRAVES-DISEASE; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; FEMALE RELATIVES; COMMON VARIANTS; WHICKHAM SURVEY; HEART-FAILURE AB Author Summary Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction. Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5x10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1x10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9x10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5x10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2x10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2x10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9x10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction. C1 [Medici, Marco; Chaker, Layal; Korevaar, Tim I. M.; Visser, W. Edward; Rivadeneira, Fernando; Uitterlinden, Andre G.; Visser, Theo J.; Peeters, Robin P.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Porcu, Eleonora; Plia, Maria Grazia; Lobina, Monia; Lai, Sandra; Mulas, Antonella; Sanna, Serena; Naitza, Silvia] Cittadella Univ Monserrato, Ist Ric Genet & Biomed IRGB, CNR, Cagliari, Italy. [Porcu, Eleonora; Mariotti, Stefano; Delitala, Alessandro] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Pistis, Giorgio; Sala, Cinzia; Corre, Tanguy; Cocca, Massimiliano; Masciullo, Corrado; Traglia, Michela; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Teumer, Alexander; Voelker, Uwe; Homuth, Georg] Univ Med & Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Brown, Suzanne J.; Walsh, John P.; Wilson, Scott G.] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia. [Jensen, Richard A.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Rawal, Rajesh; Gieger, Christian] Helmholtz Zentrum Munich, Inst Genet Epidemiol, Munich, Germany. [Roef, Greet L.; Taes, Youri E.; Kaufman, Jean-Marc] Univ Ghent, Univ Hosp Ghent, Dept Endocrinol & Internal Med, B-9000 Ghent, Belgium. [Plantinga, Theo S.; Hermus, Ad R.; Netea-Maier, Romana T.; Smit, Johannes W. A.] Radboud Univ Nijmegen Med Ctr, Div Endocrinol, Nijmegen, Netherlands. [Vermeulen, Sita H.; Sweep, Fred C.; Ross, Alec; Galesloot, Tessel E.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen Med Ctr, Dept Hlth Evidence, Nijmegen, Netherlands. [Lahti, Jari; Raeikkoenen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Simmonds, Matthew J.; Hamilton, Alexander; van de Bunt, Martijn; Gough, Stephen C. L.] UK Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Husemoen, Lise Lotte N.; Thuesen, Betina; Jorgensen, Torben; Linneberg, Allan] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Capital Region Denmark, Glostrup, Denmark. [Freathy, Rachel M.; Frayling, Timothy M.] Univ Exeter, Genet Complex Traits, Univ Exeter Med Sch, Exeter, Devon, England. [Shields, Beverley M.; Hattersley, Andrew T.] Univ Exeter, Univ Exeter Med Sch, Peninsula NIHR Clin Res Facil, Exeter, Devon, England. [Pietzner, Diana; Kluttig, Alexander; Tiller, Daniel] Univ Halle Wittenberg, Inst Med Epidemiol Biostat & Informat, D-06108 Halle, Germany. [Nagy, Rebecca; Li, Wei; Liyanarachchi, Sandya; He, Huiling; de la Chapelle, Albert] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Broer, Linda; Hofman, Albert; Aulchenko, Yurii S.; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Richards, J. Brent] McGill Univ, Dept Med, Lady Davis Inst, Montreal, PQ, Canada. [Richards, J. Brent] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Kajantie, Eero; Eriksson, Johan G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Kajantie, Eero] Helsinki Univ Cent Hosp, Hosp Children & Adolescents, Helsinki, Finland. [Kratzsch, Juergen; Wallaschofski, Henri] Univ Hosp Leipzig, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany. [Soranzo, Nicole] Wellcome Trust Sanger Inst, Hixton, England. [Nauck, Matthias; Spielhagen, Christin] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Arnold, Alice] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Heier, Margit; Meisinger, Christa] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, Neuherberg, Germany. [Grabe, Hans Joergen] Univ Med Greifswald, HELIOS Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Lim, Ee M.; Beilby, John P.; Hui, Jennie; Fletcher, Stephen J.] Pathwest Lab Med WA, Nedlands, WA, Australia. [Reischl, Eva] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Leedman, Peter J.; James, Alan; Walsh, John P.; Wilson, Scott G.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Leedman, Peter J.] Western Australian Inst Med Res, UWA Ctr Med Res, Perth, WA, Australia. [Bremner, Alexandra P.] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia. [Philips, David I. W.] Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton SO9 4XY, Hants, England. [Beilby, John P.; O'Leary, Peter C.] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA, Australia. [Vocale, Matteo] CRS4, High Performance Comp & Network, Pula, Italy. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Forsen, Tom] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Forsen, Tom] Vaasa Hlth Care Ctr, Diabet Unit, Vaasa, Finland. [James, Alan] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia. [Widen, Elisabeth; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Prokisch, Holger; Schramm, Katharina] Helmholtz Zentrum Munich, Inst Human Genet, Munich, Germany. [Prokisch, Holger] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Rietzschel, Ernst E.] Univ Hosp Ghent, Dept Cardiol & Internal Med, Ghent, Belgium. [Palotie, Aarno] Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Feddema, Peter] Diagnost Stago, Doncaster, Vic, Australia. [Rotter, Jerome I.] Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Radke, Doerte; Ittermann, Till; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Surdulescu, Gabriela L.; Spector, Timothy D.; Wilson, Scott G.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Franklyn, Jayne A.] Univ Birmingham, Sch Clin & Expt Med, Coll Med & Dent Sci, Birmingham, W Midlands, England. [Vaidya, Bijay] Royal Devon & Exeter NHS Fdn Trust, Diabet Endocrinol & Vasc Hlth Ctr, Exeter, Devon, England. [de Meyer, Tim] Univ Ghent, BIOBIX Lab Bioinformat & Computat Genom, Dept Math Modelling Stat & Bioinformat, Fac Biosci Engn, B-9000 Ghent, Belgium. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [O'Leary, Peter C.] Curtin Univ Technol, Curtin Hlth Innovat Res Inst, Bentley, WA 6102, Australia. [Wichmann, Eric] Helmholtz Zentrum Munich, Inst Epidemiol 1, Munich, Germany. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Bosi, Emanuele] Ist Sci San Raffaele, Dept Internal Med, Diabet & Endocrinol Unit, I-20132 Milan, Italy. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Pirastu, Nicola] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Trieste, Italy. [Pirastu, Nicola] Univ Trieste, Trieste, Italy. [Meyer zu Schwabedissen, Henriette] Univ Basel, Dept Pharmaceut Sci, Basel, Switzerland. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Netherlands Genom Initiat, Netherlands Consortium Healthy Aging, Leiden, Netherlands. [Den Heijer, Martin] Vrije Univ Amsterdam Med Ctr, Dept Internal Med, Amsterdam, Netherlands. [Cappola, Anne] Univ Penn, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Toniolo, Daniela] Inst Mol Genet CNR, Pavia, Italy. [Jensen, Richard A.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Jensen, Richard A.; Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Roef, Greet L.; Taes, Youri E.; Kaufman, Jean-Marc] Univ Ghent, Fac Med, B-9000 Ghent, Belgium. [Simmonds, Matthew J.; Hamilton, Alexander; van de Bunt, Martijn; Gough, Stephen C. L.] UK Churchill Hosp, NIHR Oxford Biomed Res Ctr, Oxford, England. [Richards, J. Brent] McGill Univ, Lady Davis Inst, Dept Human Genet, Montreal, PQ, Canada. [Richards, J. Brent] McGill Univ, Lady Davis Inst, Dept Epidemiol, Montreal, PQ, Canada. [Richards, J. Brent] McGill Univ, Lady Davis Inst, Dept Biostat, Montreal, PQ, Canada. [Kajantie, Eero] Univ Helsinki, Helsinki, Finland. [Rietzschel, Ernst E.] Univ Ghent, Fac Med, B-9000 Ghent, Belgium. [Palotie, Aarno] Univ Cent Hosp, Helsinki, Finland. [Bosi, Emanuele] Univ Vita Salute San Raffaele, Milan, Italy. RP Medici, M (reprint author), Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. EM m.medici@erasmusmc.nl RI Galesloot, Tessel/P-6667-2015; Ross, H.A./L-4613-2015; Vermeulen, H.H.M./L-4716-2015; Aulchenko, Yurii/M-8270-2013; Delitala, Alessandro/L-3194-2016; Naitza, Silvia/D-5620-2017; Meisinger, Christine/B-5358-2014; Rivadeneira, Fernando/O-5385-2015; Smit, J.W.A./H-8091-2014; Sweep, C.G.J./H-8096-2014; Leedman, Peter/O-4044-2014; Plantinga, Theo/A-6895-2015; Peeters, Robin/P-3603-2014; Visser, W. Edward/C-4062-2015; Kiemeney, Lambertus/D-3357-2009; den Heijer, Martin/J-8036-2015; Hermus, A.R.M.M./H-8043-2014; Netea, Mihai/N-5155-2014; Netea-Maier, R.T./L-4543-2015 OI Raikkonen, Katri/0000-0003-3124-3470; Linneberg, Allan/0000-0002-0994-0184; Cocca, Massimiliano/0000-0002-1127-7596; sanna, serena/0000-0002-3768-1749; van de Bunt, Martijn/0000-0002-6744-6125; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Meisinger, Christa/0000-0002-9026-6544; Jorgensen, Torben/0000-0001-9453-2830; Eriksson, Johan/0000-0002-2516-2060; Hattersley, Andrew/0000-0001-5620-473X; Lahti, Jari/0000-0002-4310-5297; Aulchenko, Yurii/0000-0002-7899-1575; Delitala, Alessandro/0000-0003-1729-8969; Freathy, Rachel/0000-0003-4152-2238; Walsh, John/0000-0002-1766-2612; Pirastu, Nicola/0000-0002-5363-3886; Mulas, Antonella/0000-0002-6856-1483; Lobina, Monia/0000-0003-3620-3160; Simmonds, Matt/0000-0003-3154-3510; Rivadeneira, Fernando/0000-0001-9435-9441; Visser, W. Edward/0000-0002-5248-863X; Kiemeney, Lambertus/0000-0002-2368-1326; den Heijer, Martin/0000-0003-3620-5617; FU Fonds voor Wetenschappelijk Onderzoek-Vlaanderen FWO [G. 0427.03, G. 0838.10N]; Healthway, Western Australia; National Health and Medical Research Council of Australia; Great Wine Estates Auctions; NHLBI [HHSN268201200036C, N01HC85239, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National Center for Research Resources [UL1RR033176]; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease [DK063491]; Cedars-Sinai Board of Governors' Chair in Medical Genetics; Deutsche Forschungsgemeinschaft as part of the Collaborative Research Center 598; Wilhelm-Roux Programme of the Martin-Luther-University Halle-Wittenberg; Ministry of Education and Cultural Affairs of Saxony-Anhalt; Federal Employment Office; South West NHS Research and Development; Exeter NHS Research and Development; Darlington Trust; Peninsula NIHR Clinical Research Facility at the University of Exeter; Endocrine Research Fund; Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust) [085541/Z/08/Z]; The Velux Foundation; Danish Medical Research Council; Danish Agency for Science, Technology and Innovation; Aase and Ejner Danielsens Foundation; ALK-Abello A/S (Horsholm, Denmark); Timber Merchant Vilhelm Bangs Foundation; MEKOS Laboratories (Denmark); Health Insurance Foundation; Research Centre for Prevention and Health; Capital Region of Denmark; Academy of Finland; Finnish Diabetes Research Society; Finnish Society for Cardiovascular Research; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Wellcome Trust [WT089062]; KORA; Helmholtz Center Munich; German Research Center for Environmental Health; German Federal Ministry of Education and Research; State of Bavaria; German Federal Ministry of Education and Research (BMBF); Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; Sanofi-Aventis; European Commission [POLYGENE: LSHC-CT-2005018827]; Radboud University Nijmegen Medical Centre; National Computing Facilities Foundation (NCF); NWO; National Cancer Institute, USA [P30 CA16058, P01 CA124570]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/ Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam; National Institute on Aging (NIA), National Institutes of Health (NIH); NIA [NO1-AG-1-2109, 263-MA-410953]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network Greifswald Approach to Individualized Medicine (GANI_MED); Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; German Research Foundation [DFG Vo 955/10-2, SPP 1629: THYROID TRANS ACT WA 1328/5-1]; Federal Ministry of Nutrition, Agriculture and Consumer's Safety [BMELV 07 HS 003]; German Research Foundation; Federal State of Mecklenburg, West Pomerania; Chronic Disease Research Foundation; European Community [HEALTH-F4-2007-201413]; Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; Canadian Institutes of Health Research; Canadian Foundation for Innovation; Fonds de la Recherche en Sante Quebec; Ministere du Developpement Economique, de l'Innovation et de l'Exportation Quebec; Lady Davis Institute of the Jewish General Hospital; Australian National Health and Medical Research Council [1010494, 1031422]; Sir Charles Gairdner Hospital Research Fund; Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy; Ministry of Health; Ricerca Finalizzata; [HG002651] FX The Asklepios Study was supported by a Fonds voor Wetenschappelijk Onderzoek-Vlaanderen FWO research grant G. 0427.03 and G. 0838.10N (Asklepios Study). The 1994-5 Busselton Health Survey was funded by Healthway, Western Australia. The Busselton Health Studies are supported by the National Health and Medical Research Council of Australia and the Great Wine Estates Auctions. The CHS research reported in this article was supported by NHLBI contracts HHSN268201200036C, N01HC85239, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Additional funding was provided by the Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR). The CARLA Study was founded by a grant from the Deutsche Forschungsgemeinschaft as part of the Collaborative Research Center 598 "Heart failure in the elderly-cellular mechanisms and therapy'' at the Medical Faculty of the Martin-Luther-University Halle-Wittenberg, by a grant of the Wilhelm-Roux Programme of the Martin-Luther-University Halle-Wittenberg; by the Ministry of Education and Cultural Affairs of Saxony-Anhalt, and by the Federal Employment Office. The Exeter Family Study of Childhood Health (EFSOCH) was supported by South West NHS Research and Development, Exeter NHS Research and Development, the Darlington Trust, and the Peninsula NIHR Clinical Research Facility at the University of Exeter. Genotyping of EFSOCH DNA samples was supported by the Endocrine Research Fund. ATH and BMS are employed as core members of the Peninsula NIHR Clinical Research Facility. RMF is funded by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant: 085541/Z/08/Z). The Health2006 Study is funded by grants from The Velux Foundation; The Danish Medical Research Council, Danish Agency for Science, Technology and Innovation; The Aase and Ejner Danielsens Foundation; ALK-Abello A/S (Horsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories (Denmark), the Health Insurance Foundation, and Research Centre for Prevention and Health, the Capital Region of Denmark. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Finnish Society for Cardiovascular Research, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). This work was supported by KORA, which is a research platform initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research and by the State of Bavaria.; The work of KORA is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus). The present research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Thyroid examinations in KORA-F4 were supported by Sanofi-Aventis in the framework of the Papillon Initiative. Collection and genotyping of the NBS samples was funded in part by the European Commission (POLYGENE: LSHC-CT-2005018827) and a research investment grant of the Radboud University Nijmegen Medical Centre. This work was sponsored by the National Computing Facilities Foundation (NCF) for the use of supercomputer facilities, with financial support from the NWO. The Thyroid Cancer Program (P. I. Matthew Ringel) at the Ohio State University is supported by grants P30 CA16058 and P01 CA124570 from the National Cancer Institute, USA. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/ Netherlands Organisation for Scientific Research (NWO) project no. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The SardiNIA study is supported by the Intramural Research Program of the National Institute on Aging (NIA), National Institutes of Health (NIH). The SardiNIA ("Progenia'') team was supported by Contract NO1-AG-1-2109 from the NIA; the efforts of SS were supported in part by contract 263-MA-410953 from the NIA to the University of Michigan and by research grant HG002651. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ` Greifswald Approach to Individualized Medicine (GANI_ MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-2; SPP 1629: THYROID TRANS ACT WA 1328/ 5-1) and the Federal Ministry of Nutrition, Agriculture and Consumer's Safety (BMELV 07 HS 003). SHIP-Trend is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Thyroid-related examinations have been funded by the Federal Ministry of Nutrition, Agriculture and Consumer's Safety (BMELV 07 HS 003) and the German Research Foundation (DFG Vo 955/ 10-1; SPP 1629: THYROID TRANS ACT WA 1328/ 5-1).; Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg, West Pomerania. Whole-body MR imaging was supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. TwinsUK received funding from the Wellcome Trust; the Chronic Disease Research Foundation; the European Community's Seventh Framework Program grant agreement (FP7/2007-2013); ENGAGE project grant agreement (HEALTH-F4-2007-201413); the Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London; the Canadian Institutes of Health Research, Canadian Foundation for Innovation, Fonds de la Recherche en Sante Quebec, Ministere du Developpement Economique, de l'Innovation et de l'Exportation Quebec and the Lady Davis Institute of the Jewish General Hospital; the Australian National Health and Medical Research Council (Project Grants 1010494, 1031422) and the Sir Charles Gairdner Hospital Research Fund. Val Borbera was supported by funds from Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy and Ministry of Health, Ricerca Finalizzata 2008. The UK Graves' disease cohort was funded by the Wellcome Trust grant 068181. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 29 Z9 29 U1 3 U2 10 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pgen.1004123 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AB8DY UT WOS:000332021500001 ER PT J AU Rouzine, IM Coffin, JM Weinberger, LS AF Rouzine, Igor M. Coffin, John M. Weinberger, Leor S. TI Fifteen Years Later: Hard and Soft Selection Sweeps Confirm a Large Population Number for HIV In Vivo SO PLOS GENETICS LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS; INFECTION; ADAPTATION; MUTATIONS; EVOLUTION; DYNAMICS; THERAPY; RECOMBINATION; INDIVIDUALS; GENEALOGIES C1 [Rouzine, Igor M.; Weinberger, Leor S.] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, Gladstone Inst, San Francisco, CA 94143 USA. [Coffin, John M.] Tufts Univ, Sackler Sch Biomed Sci, Boston, MA 02111 USA. [Coffin, John M.] NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Rouzine, IM (reprint author), Univ Calif San Francisco, Gladstone Inst Virol & Immunol, Gladstone Inst, San Francisco, CA 94143 USA. EM igor.rouzine@gladstone.ucsf.edu NR 32 TC 2 Z9 2 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pgen.1004179 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA AB8DY UT WOS:000332021500040 ER PT J AU Saunders, EJ Dadaev, T Leongamornlert, DA Jugurnauth-Little, S Tymrakiewicz, M Wiklund, F Al Olama, AA Benlloch, S Neal, DE Hamdy, FC Donovan, JL Giles, GG Severi, G Gronberg, H Aly, M Haiman, CA Schumacher, F Henderson, BE Lindstrom, S Kraft, P Hunter, DJ Gapstur, S Chanock, S Berndt, SI Albanes, D Andriole, G Schleutker, J Weischer, M Nordestgaard, BG Canzian, F Campa, D Riboli, E Key, TJ Travis, RC Ingles, SA John, EM Hayes, RB Pharoah, P Khaw, KT Stanford, JL Ostrander, EA Signorello, LB Thibodeau, SN Schaid, D Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Brenner, H Park, JY Kaneva, R Batra, J Clements, JA Teixeira, MR Xu, JF Mikropoulos, C Goh, C Govindasami, K Guy, M Wilkinson, RA Sawyer, EJ Morgan, A Easton, DF Muir, K Eeles, RA Kote-Jarai, Z AF Saunders, Edward J. Dadaev, Tokhir Leongamornlert, Daniel A. Jugurnauth-Little, Sarah Tymrakiewicz, Malgorzata Wiklund, Fredrik Al Olama, Ali Amin Benlloch, Sara Neal, David E. Hamdy, Freddie C. Donovan, Jenny L. Giles, Graham G. Severi, Gianluca Gronberg, Henrik Aly, Markus Haiman, Christopher A. Schumacher, Fredrick Henderson, Brian E. Lindstrom, Sara Kraft, Peter Hunter, David J. Gapstur, Susan Chanock, Stephen Berndt, Sonja I. Albanes, Demetrius Andriole, Gerald Schleutker, Johanna Weischer, Maren Nordestgaard, Borge G. Canzian, Federico Campa, Daniele Riboli, Elio Key, Tim J. Travis, Ruth C. Ingles, Sue A. John, Esther M. Hayes, Richard B. Pharoah, Paul Khaw, Kay-Tee Stanford, Janet L. Ostrander, Elaine A. Signorello, Lisa B. Thibodeau, Stephen N. Schaid, Daniel Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Brenner, Hermann Park, Jong Y. Kaneva, Radka Batra, Jyotsna Clements, Judith A. Teixeira, Manuel R. Xu, Jianfeng Mikropoulos, Christos Goh, Chee Govindasami, Koveela Guy, Michelle Wilkinson, Rosemary A. Sawyer, Emma J. Morgan, Angela Easton, Douglas F. Muir, Ken Eeles, Rosalind A. Kote-Jarai, Zsofia CA COGS-CRUK GWAS-ELLIPSE Initiative UK Genetic Prostate Canc Study UK ProtecT Study Collaborators PRACTICAL Consortium TI Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer SO PLOS GENETICS LA English DT Article ID GENOME-WIDE SCAN; SUSCEPTIBILITY GENES; INTERNATIONAL CONSORTIUM; G84E MUTATION; RISK; CARCINOMA; GENETICS; LOCI; METAANALYSIS; LINKAGE AB Author Summary Genome-wide association studies (GWAS) have identified numerous low penetrance disease susceptibility variants, yet few causal alleles have been unambiguously identified. The underlying causal variants are expected to be predominantly common; however synthetic associations with rare, higher penetrance variants have been hypothesised though not yet observed. Here, we report detection of a novel common, low penetrance prostate cancer association at the HOXB locus at ch17q and show that this signal can actually be attributed to a previously identified rare, moderate penetrance coding variant (G84E) in HOXB13. This study therefore provides the first experimental evidence for the existence of synthetic associations in cancer and shows that where GWAS signals arise through this phenomenon, risk predictions derived using the tag SNP would substantially underestimate the relative risk conferred and overestimate the number of carriers of the causal variant. Synthetic associations at GWAS signals could therefore account for a proportion of the missing heritability of complex diseases. The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62x10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility. C1 [Saunders, Edward J.; Dadaev, Tokhir; Leongamornlert, Daniel A.; Jugurnauth-Little, Sarah; Tymrakiewicz, Malgorzata; Mikropoulos, Christos; Goh, Chee; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A.; Sawyer, Emma J.; Morgan, Angela; Eeles, Rosalind A.; Kote-Jarai, Zsofia] Inst Canc Res, Sutton, Surrey, England. [Wiklund, Fredrik; Gronberg, Henrik; Aly, Markus] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Al Olama, Ali Amin; Benlloch, Sara; Pharoah, Paul; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Strangeways Lab, Cambridge, England. [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Cambridge CB2 2QQ, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Ingles, Sue A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Lindstrom, Sara; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Gapstur, Susan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Chanock, Stephen; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, NIH, EPS 3044, Bethesda, MD 20892 USA. [Andriole, Gerald] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Schleutker, Johanna] Univ Turku, Dept Medic Biochem & Genet, Turku, Finland. [Weischer, Maren; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Campa, Daniele] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Key, Tim J.; Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Nuffield Dept Populat Hlth, Oxford, England. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Hayes, Richard B.] NYU Canc Inst, Div Epidemiol, Dept Populat Hlth, NYU Langone Med Ctr, New York, NY USA. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Thibodeau, Stephen N.; Schaid, Daniel] Mayo Clin, Rochester, MN USA. [Maier, Christiane] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Div Urol Surg, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Park, Jong Y.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Kaneva, Radka] Med Univ Sofia, Mol Med Ctr, Sofia, Bulgaria. [Batra, Jyotsna; Clements, Judith A.] Queensland Univ Technol, Australian Prostate Canc Res Ctr Qld, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, P-4100 Oporto, Portugal. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Muir, Ken] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Neal, David E.] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Cambridge, England. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford OX3 9DU, England. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Schleutker, Johanna] Univ Tampere, Inst Biomed Technol & BioMediTech, FIN-33101 Tampere, Finland. [Schleutker, Johanna] FimLab Labs, Tampere, Finland. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Signorello, Lisa B.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med,Vanderbilt Epidemiol Ctr,Dept Epidemiol, Nashville, TN 37212 USA. [Maier, Christiane] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Cannon-Albright, Lisa] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT USA. [Kaneva, Radka] Med Univ Sofia, Dept Med Chem & Biochem, Sofia, Bulgaria. [Clements, Judith A.] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4001, Australia. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. RP Saunders, EJ (reprint author), Inst Canc Res, Sutton, Surrey, England. EM zsofia.kote-jarai@icr.ac.uk RI Albanes, Demetrius/B-9749-2015; Teixeira, Manuel/E-4885-2011; Batra, Jyotsna/B-4130-2011; Campa, Daniele/K-1617-2016; Brenner, Hermann/B-4627-2017; OI albright, lisa/0000-0003-2602-3668; Giles, Graham/0000-0003-4946-9099; Teixeira, Manuel/0000-0002-4896-5982; Campa, Daniele/0000-0003-3220-9944; Brenner, Hermann/0000-0002-6129-1572; Dadaev, Tokhir/0000-0002-8268-0438; Eeles, Rosalind/0000-0002-3698-6241; Neal, David/0000-0002-6033-5086; Leongamornlert, Daniel/0000-0002-3486-3168; Clements, Judith/0000-0001-6026-1964; Ostrander, Elaine/0000-0001-6075-9738; Hayes, Richard/0000-0002-0918-661X FU EU-FP7 COGS grant; Cancer Research UK [C5047/A15007, C8197/A10123, C8197/A10865] FX This work was supported by EU-FP7 COGS grant. Cancer Research UK grants C5047/A15007 supported the team at ICR, C8197/A10123 and C8197/A10865 supported the genotyping team in Cambridge. For more funding details for individual groups within the PRACTICAL consortium please see Supplementary file S2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 6 Z9 6 U1 3 U2 19 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 FEB PY 2014 VL 10 IS 2 DI 10.1371/journal.pgen.1004129 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA AB8DY UT WOS:000332021500003 PM 24550738 ER PT J AU Kleiner, DE Berk, PD Hsu, JY Courcoulas, AP Flum, D Khandelwal, S Pender, J Pomp, A Roerig, J Machado, LL Wolfe, BM Belle, SH AF Kleiner, David E. Berk, Paul D. Hsu, Jesse Y. Courcoulas, Anita P. Flum, David Khandelwal, Saurabh Pender, John Pomp, Alfons Roerig, James Machado, Laura L. Wolfe, Bruce M. Belle, Steven H. CA LABS Consortium TI Hepatic Pathology among Patients without Known Liver Disease Undergoing Bariatric Surgery: Observations and a Perspective from the Longitudinal Assessment of Bariatric Surgery (LABS) Study SO SEMINARS IN LIVER DISEASE LA English DT Review DE liver biopsy; steatohepatitis; bariatric surgery; NAFLD; cirrhosis ID DIRECT-ACTING ANTIVIRALS; ALANINE AMINOTRANSFERASE LEVELS; NONALCOHOLIC STEATOHEPATITIS; UNITED-STATES; CLINICAL-RESEARCH; SCORING SYSTEM; US ADULTS; OBESITY; PREVALENCE; TRANSPLANTATION AB Liver biopsy is not routine during bariatric surgery. Alanine aminotransferase (ALT) is widely used to screen for liver disease. We assessed the relationship between ALT and pathology in biopsies from Longitudinal Assessment of Bariatric Surgery (LABS) patients with normal preoperative ALTs. Biopsies from the LABS-1 and LABS-2 studies were scored using the NASH CRN and Ishak systems. Diagnosis and histology were examined in relation to alanine aminotransferase (ALT) values. Six-hundred ninety-three suitable biopsies were evaluated. Biopsied patients had a median age of 45 years; 78.6% were female and 35.1% diabetic; median body mass index was 46 kg/m(2). Six-hundred thirty-five biopsied patients had preoperative ALTs. Median ALT was 25 IU/L (interquartile range [IQR] 19-36 IU/L); 26.6% had an ALT > 35 IU/L and 29.9% exceeded the more restrictive Prati criteria for normal. Using the Prati criteria, 7.9% of participants with normal ALT had steatohepatitis and 5.3% had >= stage 2 fibrosis. Logistic regression models were used to predict the probabilities of having bridging fibrosis/cirrhosis or a diagnosis of borderline/definite steatohepatitis in the unbiopsied LABS-2 sample. The proportion of biopsied participants with these findings was very similar to the modeled results from the unbiopsied cohorts. We estimated that 86.0% of participants with advanced fibrosis and 88.1% of participants with borderline/definite steatohepatitis were not biopsied and went undiagnosed. As ALT did not reliably exclude significant obesity-related liver disease in bariatric surgery patients, consideration should be given to routine liver biopsy during bariatric surgery and medical follow-up of significant hepatic pathology. C1 [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Berk, Paul D.] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. [Hsu, Jesse Y.; Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Courcoulas, Anita P.] Univ Pittsburgh, Dept Surg, Med Ctr, Pittsburgh, PA USA. [Flum, David; Khandelwal, Saurabh] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Pender, John] E Carolina Univ, Dept Surg, Greenville, NC USA. [Pomp, Alfons] Weill Cornell Med Coll, Dept Surg, New York, NY USA. [Roerig, James] Univ N Dakota, Neuropsychiat Res Inst, Fargo, ND USA. [Machado, Laura L.] Sacramento Bariatr Med Associates, Sacramento, CA USA. [Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Div Gen Surg, Oregon Weight Loss Surg, Portland, OR 97201 USA. RP Kleiner, DE (reprint author), NCI, Pathol Lab, Bldg 10,Room 2B50,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. EM kleinerd@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [DCC-U01 DK066557]; CTRCM01RR-00037; CTRC [UL1-RR024153]; Intramural Research Program of the National Cancer Institute, NIH; [U01-DK66667]; [UL1-RR024996]; [U01-DK66568]; [U01-DK66526]; [U01-DK66585]; [U01-DK66555] FX LABS was funded by a cooperative agreement (Grant DCC-U01 DK066557) by the National Institute of Diabetes and Digestive and Kidney Diseases; Grant U01-DK66667 to Columbia-Presbyterian Hospital, New York, NY in collaboration with Grant UL1-RR024996 to Cornell University Medical Center, Clinical and Translational Research Center (CTRC), Ithaca, NY; Grant U01-DK66568 to the University of Washington, Seattle, WA in collaboration with Grant M01RR-00037 from CTRC; Grant U01-DK66471 to the Neuropsychiatric Research Institute, Fargo, ND; Grant U01-DK66526 to East Carolina University, Greenville, NC; Grant U01-DK66585 to the University of Pittsburgh Medical Center, Pittsburgh, PA in collaboration with Grant UL1-RR024153 from CTRC; and Grant U01-DK66555 to Oregon Health and Science University, Portland, OR. This liver biopsy research project was supported in part by the Intramural Research Program of the National Cancer Institute, NIH. NR 42 TC 15 Z9 15 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 EI 1098-8971 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD FEB PY 2014 VL 34 IS 1 BP 98 EP 107 DI 10.1055/s-0034-1371083 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AG4RZ UT WOS:000335409200012 PM 24782263 ER PT J AU Golan, T Bentin, S DeGutis, JM Robertson, LC Harel, A AF Golan, Tal Bentin, Shlomo DeGutis, Joseph M. Robertson, Lynn C. Harel, Assaf TI Association and dissociation between detection and discrimination of objects of expertise: Evidence from visual search SO ATTENTION PERCEPTION & PSYCHOPHYSICS LA English DT Article DE Visual search; Face perception; Perceptual categorization; Developmental prosopagnosia; Perceptual expertise ID FACE RECOGNITION ABILITY; HIGH-LEVEL POP; DEVELOPMENTAL PROSOPAGNOSIA; PERCEPTUAL EXPERTISE; ELECTROPHYSIOLOGICAL EVIDENCE; CONGENITAL PROSOPAGNOSIA; ATTENTIONAL BLINK; FLICKER PARADIGM; BASIC LEVEL; CATEGORIZATION AB Expertise in face recognition is characterized by high proficiency in distinguishing between individual faces. However, faces also enjoy an advantage at the early stage of basic-level detection, as demonstrated by efficient visual search for faces among nonface objects. In the present study, we asked (1) whether the face advantage in detection is a unique signature of face expertise, or whether it generalizes to other objects of expertise, and (2) whether expertise in face detection is intrinsically linked to expertise in face individuation. We compared how groups with varying degrees of object and face expertise (typical adults, developmental prosopagnosics [DP], and car experts) search for objects within and outside their domains of expertise (faces, cars, airplanes, and butterflies) among a variable set of object distractors. Across all three groups, search efficiency (indexed by reaction time slopes) was higher for faces and airplanes than for cars and butterflies. Notably, the search slope for car targets was considerably shallower in the car experts than in nonexperts. Although the mean face slope was slightly steeper among the DPs than in the other two groups, most of the DPs' search slopes were well within the normative range. This pattern of results suggests that expertise in object detection is indeed associated with expertise at the subordinate level, that it is not specific to faces, and that the two types of expertise are distinct facilities. We discuss the potential role of experience in bridging between low-level discriminative features and high-level naturalistic categories. C1 [Golan, Tal; Bentin, Shlomo] Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, IL-91905 Jerusalem, Israel. [Bentin, Shlomo] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [DeGutis, Joseph M.] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Robertson, Lynn C.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Robertson, Lynn C.] VA Northern Calif Healthcare Syst, Martinez, CA USA. [Harel, Assaf] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [DeGutis, Joseph M.] Harvard Univ, Vis Sci Lab, Cambridge, MA 02138 USA. RP Golan, T (reprint author), Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, IL-91905 Jerusalem, Israel. EM tal.golan@alice.nc.huji.ac.il RI Golan, Tal/E-6406-2017; OI Golan, Tal/0000-0002-7940-7473; Harel, Assaf/0000-0002-4899-6156 FU NIMH NIH HHS [R01 MH064458] NR 72 TC 5 Z9 5 U1 2 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1943-3921 EI 1943-393X J9 ATTEN PERCEPT PSYCHO JI Atten. Percept. Psychophys. PD FEB PY 2014 VL 76 IS 2 BP 391 EP 406 DI 10.3758/s13414-013-0562-6 PG 16 WC Psychology; Psychology, Experimental SC Psychology GA AF1SH UT WOS:000334493200010 PM 24338355 ER PT J AU Maranhao, B Biswas, P Duncan, JL Branham, KE Silva, GA Naeem, MA Khan, SN Riazuddin, S Hejtmancik, JF Heckenlively, JR Riazuddin, SA Lee, PL Ayyagari, R AF Maranhao, B. Biswas, P. Duncan, J. L. Branham, K. E. Silva, G. A. Naeem, M. A. Khan, S. N. Riazuddin, S. Hejtmancik, J. F. Heckenlively, J. R. Riazuddin, S. A. Lee, P. L. Ayyagari, R. TI exomeSuite: Whole exome sequence variant filtering tool for rapid identification of putative disease causing SNVs/indels SO GENOMICS LA English DT Article DE Exome; Filtering; Software; Mendelian disease; Homozygosity mapping ID FUNDUS-ALBIPUNCTATUS; LDL RECEPTOR; MUTATIONS; GENE; CONE; ANNOTATION; COMMON; ROD AB Exome and whole-genome analyses powered by next-generation sequencing (NGS) have become invaluable tools in identifying causal mutations responsible for Mendelian disorders. Given that individual exomes contain several thousand single nucleotide variants and insertions/deletions, it remains a challenge to analyze large numbers of variants from multiple exomes to identify causal alleles associated with inherited conditions. To this end, we have developed user-friendly software that analyzes variant calls from multiple individuals to facilitate identification of causal mutations. The software, termed exomeSuite, filters for putative causative variants of monogenic diseases inherited in one of three forms: dominant, recessive caused by a homozygous variant, or recessive caused by two compound heterozygous variants. In addition, exomeSuite can perform homozygosity mapping and analyze the variant data of multiple unrelated individuals. Here we demonstrate that filtering of variants with exomeSuite reduces datasets to a fraction of a percent of their original size. To the best of our knowledge this is the first freely available software developed to analyze variant data from multiple individuals that rapidly assimilates and filters large data sets based on pattern of inheritance. (C) 2014 Elsevier Inc All rights reserved. C1 [Maranhao, B.; Biswas, P.; Silva, G. A.; Lee, P. L.; Ayyagari, R.] Univ Calif San Diego, UC Jacobs Retina Ctr, Dept Ophthalmol, La Jolla, CA 92037 USA. [Maranhao, B.; Silva, G. A.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Duncan, J. L.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. [Branham, K. E.; Heckenlively, J. R.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Silva, G. A.] Univ Calif San Diego, Grad Program Neurosci, La Jolla, CA 92093 USA. [Naeem, M. A.; Khan, S. N.; Riazuddin, S.; Riazuddin, S. A.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Hejtmancik, J. F.] NIH, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Riazuddin, S. A.] Johns Hopkins Univ, Wilmer Eye Inst, Sch Med, Baltimore, MD 21287 USA. RP Ayyagari, R (reprint author), Univ Calif San Diego, UC Jacobs Retina Ctr, Dept Ophthalmol, 9415 Campus Point Dr, La Jolla, CA 92037 USA. EM bmaranha@ucsd.edu; pbiswas@ucsd.edu; duncanj@vision.ucsf.edu; haag@med.umich.edu; gsilva@ucsd.edu; f3h@helix.nih.gov; jrheck@umich.edu; plee@scripps.edu; rayyagari@ucsd.edu RI Nasim Khan, Shaheen/F-2135-2015 FU NEI NIH HHS [R01 EY021237, P30 EY022589]; NIGMS NIH HHS [T32 GM007198] NR 34 TC 7 Z9 7 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD FEB-MAR PY 2014 VL 103 IS 2-3 BP 169 EP 176 DI 10.1016/j.ygeno.2014.02.006 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AF6KH UT WOS:000334823500002 PM 24603341 ER PT J AU Canton, M Menazza, S Di Lisa, F AF Canton, Marcella Menazza, Sara Di Lisa, Fabio TI Oxidative stress in muscular dystrophy: from generic evidence to specific sources and targets SO JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY LA English DT Review DE Oxidative stress; Muscular dystrophy; Myofilament proteins; Mitochondria; Monoamine oxidase ID FACTOR-KAPPA-B; PROTEIN THIOL OXIDATION; LIPID-PEROXIDATION PRODUCTS; COLLAGEN-VI DEFICIENCY; NITRIC-OXIDE SYNTHASE; CARDIAC TROPONIN-C; SKELETAL-MUSCLE; MDX MICE; MONOAMINE-OXIDASE; MITOCHONDRIAL DYSFUNCTION AB Muscular dystrophies (MDs) are a heterogeneous group of diseases that share a common end-point represented by muscular wasting. MDs are caused by mutations in a variety of genes encoding for different molecules, including extracellular matrix, transmembrane and membrane-associated proteins, cytoplasmic enzymes and nuclear proteins. However, it is still to be elucidated how genetic mutations can affect the molecular mechanisms underlying the contractile impairment occurring in these complex pathologies. The intracellular accumulation of reactive oxygen species (ROS) is widely accepted to play a key role in contractile derangements occurring in the different forms of MDs. However, scarce information is available concerning both the most relevant sources of ROS and their major molecular targets. This review focuses on (i) the sources of ROS, with a special emphasis on monoamine oxidase, a mitochondrial enzyme, and (ii) the targets of ROS, highlighting the relevance of the oxidative modification of myofilament proteins. C1 [Canton, Marcella; Di Lisa, Fabio] Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy. [Menazza, Sara] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Di Lisa, Fabio] Univ Padua, Inst Neurosci, CNR, I-35131 Padua, Italy. RP Canton, M (reprint author), Univ Padua, Dept Biomed Sci, Viale G Colombo 3, I-35131 Padua, Italy. EM marcella.canton@unipd.it OI Di Lisa, Fabio/0000-0001-9757-8818 FU University of Padova; Italian Ministry for University and Research; Association francaise contre les myopathies; CNR; Telethon Foundation [GGP11082] FX This work was supported by grants from the University of Padova (Fondazione Cariparo, Fabio Di Lisa), Italian Ministry for University and Research (PRIN, Marcella Canton), Association francaise contre les myopathies (AFM, Marcella Canton), CNR and Telethon Foundation (GGP11082, Fabio Di Lisa). We acknowledge the editorial assistance of the NIH Fellows Editorial Board for the careful editing of the manuscript and the insightful comments. NR 131 TC 8 Z9 9 U1 2 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0142-4319 EI 1573-2657 J9 J MUSCLE RES CELL M JI J. Muscle Res. Cell Motil. PD FEB PY 2014 VL 35 IS 1 SI SI BP 23 EP 36 DI 10.1007/s10974-014-9380-2 PG 14 WC Cell Biology SC Cell Biology GA AG4IZ UT WOS:000335384500004 PM 24619215 ER PT J AU Esser, L Yu, CA Xia, D AF Esser, Lothar Yu, Chang-An Xia, Di TI Structural Basis of Resistance to Anti-Cytochrome bc(1) Complex Inhibitors: Implication for Drug Improvement SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE cyt bc(1) complex; mechanism of inhibition; crystal structure; resistance; inhibitors ID IRON-SULFUR PROTEIN; BOVINE HEART-MITOCHONDRIA; X-RAY-STRUCTURE; ELECTRON-TRANSFER; SACCHAROMYCES-CEREVISIAE; RESPIRATORY-CHAIN; CRYSTAL-STRUCTURE; C OXIDOREDUCTASE; DOMAIN MOVEMENT; B(6)F COMPLEX AB The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc(1) complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc(1) inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc(1) complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc(1) by various quinol oxidation- and reduction-site inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives. C1 [Esser, Lothar; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Chang-An] Oklahoma State Univ, Dept Biochem, Stillwater, OK 74074 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Bldg 37,Room 2122C, Bethesda, MD 20892 USA. EM dixia@helix.nih.gov FU Intramural NIH HHS [Z01 BC010319-10] NR 108 TC 4 Z9 4 U1 0 U2 12 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD FEB PY 2014 VL 20 IS 5 BP 704 EP 724 PG 21 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE9EA UT WOS:000334306300004 PM 23688079 ER PT J AU Ford, DW Jensen, GL Still, C Wood, C Mitchell, DC Erickson, P Bailey, R Smiciklas-Wright, H Coffman, DL Hartman, TJ AF Ford, D. W. Jensen, G. L. Still, C. Wood, C. Mitchell, D. C. Erickson, P. Bailey, R. Smiciklas-Wright, H. Coffman, D. L. Hartman, T. J. TI THE ASSOCIATIONS BETWEEN DIET QUALITY, BODY MASS INDEX (BMI) AND HEALTH AND ACTIVITY LIMITATION INDEX (HALEX) IN THE GEISINGER RURAL AGING STUDY (GRAS) SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Diet quality; quality of life; HALex; aging ID OF-LIFE; OLDER-ADULTS; POPULATION; DISABILITY; NUTRITION; ADHERENCE; MORTALITY; OBESITY AB Objectives: to determine the associations between diet quality, body mass index (BMI), and health-related quality of life (HRQOL) as assessed by the health and activity limitation index (HALex) in older adults. Design: Multivariate linear regression models were used to analyze associations between Dietary screening tool (DST) scores, BMI and HALex score, after controlling for gender, age, education, living situation, smoking, disease burden and self-vs. proxy reporting. Setting: Geisinger rural aging study, Pennsylvania. Participants: 5,993 Gras participants were mailed HRQOL and DST questionnaires with 4,009 (1,722 male, 2,287 female; mean age 81.5 +/- 4.4) providing complete data. Results: HALex scores were significantly lower for participants with dietary intakes categorized as unhealthy (<60) (0.70, 95% CI 0.69, 0.72, p<0.05) or borderline (60-75) (0.71, 95% CI 0.70, 0.73, p<0.05) compared to those scoring in the healthy range (>75) (0.75, 95% CI 0.73, 0.77) based on DST scores. HALex scores were significantly lower for underweight (0.67, 95% CI 0.63, 0.72, p<0.05), obese class II (0.68, 95% CI 0.66, 0.71, p<0.05) and class III participants (0.62 95% CI 0.57, 0.67, p<0.05) compared to those with BMI 18.5-24.9. Conclusions: Poor diet quality, as assessed by the DST, is associated with lower HRQOL in adults >= 74 years of age. C1 [Ford, D. W.; Jensen, G. L.; Mitchell, D. C.; Smiciklas-Wright, H.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Still, C.] Geisinger Hlth Syst, Geisinger Obes Inst, Danville, PA 17882 USA. [Erickson, P.] Dept Publ Hlth Sci Penn State Hershey, Hershey, PA 17033 USA. [Bailey, R.] NIH, Off Dietary supplements, Bethesda, MD 20892 USA. [Coffman, D. L.] Penn State Univ, Methodol Ctr, State Coll, PA 16801 USA. [Hartman, T. J.] Emory Clin, Dept Epidemiol, Atlanta, GA 30322 USA. RP Ford, DW (reprint author), Penn State Univ, Dept Nutr Sci, Chandlee Lab 110, University Pk, PA 16802 USA. EM djw5083@psu.edu FU USDA grant [1950-51530-010-00] FX Ford, Jensen, Mitchell and Smiciklas-Wright: Money for this research was paid to my institution through a USDA grant. (USDA #1950-51530-010-00); still, Wood, Erickson, and Bailey: no conflict to disclose; Coffman: Money for this research was paid to my institution and myself through a USDA grant; Hartman: Money for this research was paid to my institution through a USDA grant. I serve as a consultant for the international Life sciences institute of north American for the analysis of caffeine in beverages consumed in the US population. NR 24 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 EI 1760-4788 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD FEB PY 2014 VL 18 IS 2 BP 167 EP 170 PG 4 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA AF0JZ UT WOS:000334401400009 PM 24522469 ER PT J AU Crowley, RW Dumont, AS Asthagiri, AR Torner, JC Medel, R Jane, JA Jane, JA Kassell, NF AF Crowley, R. Webster Dumont, Aaron S. Asthagiri, Ashok R. Torner, James C. Medel, Ricky Jane, John A., Jr. Jane, John A. Kassell, Neal F. TI Intraoperative Ultrasound Guidance for the Placement of Permanent Ventricular Cerebrospinal Fluid Shunt Catheters: A Single-Center Historical Cohort Study SO WORLD NEUROSURGERY LA English DT Article DE Cerebrospinal fluid shunts; Hydrocephalus; Image-guided surgery ID TECHNICAL NOTE; EXPERIENCE; NEUROSURGERY; MULTICENTER; INSERTION; SYSTEM AB OBJECTIVE: Despite the frequency with which ventriculoperitoneal shunts are placed, ventricular catheter revision rates remains as high as 30%-40% at 1 year. Many neurosurgeons place ventricular catheters "blindly"depending on anatomical landmarks and personal experience. To determine whether intraoperative ultrasonography is beneficial for ventricular catheter placement, we performed a historical cohort study comparing shunts placed with intraoperative ultrasound (US) guidance to those placed blindly. METHODS: We reviewed all shunts placed by the Department of Neurosurgery at the University of Virginia from January 2005 to January 2007. During that time 211 patients underwent 242 shunts, with US use determined by surgeon's preference. Ninety-two shunts were placed by the use of US guidance, and 150 were placed without US. Adults received 176 shunts, 56 with US. Children received 66 shunts, 36 with US. Mean follow-up was 21.6 months. The primary end points examined were shunt revision, ventricular catheter revision (VCR), and acute VCR (revision within 1 week for an improperly-placed catheter). RESULTS: The use of US was associated with a statistically significant decrease in shunt revisions (odds ratio 0.492; 95% confidence interval 0.253-0.958). Of the shunts placed with US guidance, 21.7% required revision, compared with 29.3% without US. VCRs and acute VCRs occurred in 9.8% and 2.2%, respectively, for US shunts, compared with 14% and 5.3% without US. Pediatric revision rates were 30.6% with US versus 53.3% without, whereas adult rates were 16.1% and 23.3%, respectively. The benefit of US was more profound for occipital shunts. CONCLUSIONS: The use of US for the placement of permanent cerebrospinal fluid shunt catheters is associated with a decreased risk of shunt revision. C1 [Crowley, R. Webster; Medel, Ricky; Jane, John A., Jr.; Jane, John A.; Kassell, Neal F.] Univ Virginia, Sch Med, Dept Neurol Surg, Charlottesville, VA 22908 USA. [Dumont, Aaron S.] Thomas Jefferson Univ, Dept Neurol Surg, Philadelphia, PA 19107 USA. [Asthagiri, Ashok R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. [Torner, James C.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. RP Crowley, RW (reprint author), Univ Virginia, Sch Med, Dept Neurol Surg, Charlottesville, VA 22908 USA. EM webster.crowley@bnaneuro.net NR 18 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD FEB PY 2014 VL 81 IS 2 BP 397 EP 403 DI 10.1016/j.wneu.2013.01.039 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AE6IU UT WOS:000334094900055 PM 23321382 ER PT J AU Beane, JD Yang, JC White, D Steinberg, S Rosenberg, SA Rudloff, U AF Beane, J. D. Yang, J. C. White, D. Steinberg, S. Rosenberg, S. A. Rudloff, U. TI Efficacy of Adjuvant Radiation Therapy in the Treatment of Soft Tissue Sarcomas of the Extremity: 20-year follow-up of a Randomized Prospective Trial SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 67th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 12-15, 2014 CL Phoenix, AZ SP Soc Surg Oncol C1 [Beane, J. D.; Yang, J. C.; White, D.; Rosenberg, S. A.; Rudloff, U.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Steinberg, S.] NCI, Biostat Sect, Bethesda, MD 20892 USA. [Steinberg, S.] NCI, Data Management Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2014 VL 21 SU 1 BP S6 EP S7 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA AE7WC UT WOS:000334209100005 ER PT J AU Inchauste, SM Alvarez-Downing, MM Atay, SM Steinberg, S Phan, GQ Sherry, RM Royal, RE Rosenberg, SA Hughes, MS Pandalai, P AF Inchauste, S. M. Alvarez-Downing, M. M. Atay, S. M. Steinberg, S. Phan, G. Q. Sherry, R. M. Royal, R. E. Rosenberg, S. A. Hughes, M. S. Pandalai, P. TI Small Bowel Metastasectomy for Adoptive Immunotherapy in Metastatic Melanoma: A Single Institution Experience SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 67th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 12-15, 2014 CL Phoenix, AZ SP Soc Surg Oncol C1 [Inchauste, S. M.; Alvarez-Downing, M. M.; Atay, S. M.; Steinberg, S.; Phan, G. Q.; Sherry, R. M.; Royal, R. E.; Rosenberg, S. A.; Hughes, M. S.; Pandalai, P.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2014 VL 21 SU 1 BP S118 EP S119 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA AE7WC UT WOS:000334209100327 ER PT J AU Wagman, LD Geller, DA Jacobs, SA Petrelli, NJ Allegra, CJ Buyse, M Wolmark, N O'Connell, MJ AF Wagman, L. D. Geller, D. A. Jacobs, S. A. Petrelli, N. J. Allegra, C. J. Buyse, M. Wolmark, N. O'Connell, M. J. TI NSABP FC-6: Phase II Study to Determine Surgical Conversion Rate in Patients (pts) Receiving Neoadjuvant (NA) mFOLFOX7 Plus Dose-escalating Cetuximab (C) for Unresectable K-RAS Wild-type (WT) Colorectal Cancer with Metastases (mCRC) Confined to the Liver SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 67th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 12-15, 2014 CL Phoenix, AZ SP Soc Surg Oncol C1 [Wagman, L. D.] Natl Surg Adjuvant Breast & Bowel Project NSABP, Orange, CA USA. [Wagman, L. D.] St Joseph Hosp, Orange, CA USA. [Geller, D. A.] NSABP, Pittsburgh, PA USA. [Geller, D. A.] Univ Pittsburgh, Med Ctr, UPMC Liver Canc Ctr, Pittsburgh, PA USA. [Jacobs, S. A.] Univ Pittsburgh, Sch Med, NSABP, Pittsburgh, PA USA. [Jacobs, S. A.] Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA USA. [Petrelli, N. J.; Allegra, C. J.] NSABP, Newark, DE USA. [Petrelli, N. J.] Helen F Graham Canc Ctr, Christiana Care Hlth Serv, Newark, DE USA. [Allegra, C. J.] Univ Florida, Gainesville, FL USA. [Buyse, M.] Int Inst Drug Dev, Brussels, Belgium. [Wolmark, N.; O'Connell, M. J.] NSABP, Pittsburgh, PA USA. [Wolmark, N.] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2014 VL 21 SU 1 BP S13 EP S13 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA AE7WC UT WOS:000334209100023 ER PT J AU Titmarsh, GJ McMullin, MF McShane, CM Clarke, M Engels, EA Anderson, LA AF Titmarsh, Glen J. McMullin, Mary Frances McShane, Charlene M. Clarke, Mike Engels, Eric A. Anderson, Lesley A. TI Community-acquired infections and their association with myeloid malignancies SO CANCER EPIDEMIOLOGY LA English DT Article DE Infection; Myeloid Malignancy; SEER-Medicare ID MYELODYSPLASTIC SYNDROMES; HEMATOLOGICAL MALIGNANCY; MEDICAL CONDITIONS; LEUKEMIA; RISK; NEOPLASMS; SYSTEM; CANCER AB Introduction: Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown. Materials and methods: Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n = 8489), CML (n = 3626) diagnosed 1992-2005; MDS (n = 3072) and MPNs (n = 2001) diagnosed 2001-2005; and controls (200,000 for AML/ CML and 97,681 for MDS/ MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality. Results: Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14-1.26], 1.25 [95% CI: 1.16-1.36]), influenza (ORs 1.16 [95% CI: 1.071.25], 1.29 [95% CI: 1.16-1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06-1.21], 1.22 [95% CI: 1.11-1.35]), pneumonia (ORs 1.28 [95% CI: 1.21-1.36], 1.52 [95% CI: 1.40-1.66]), sinusitis (ORs 1.23 [95% CI: 1.161.30], 1.25 [95% CI: 1.15-1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07-1.18], 1.26 [95% CI: 1.17-1.36]). Cellulitis (OR 1.51 [95% CI: 1.39-1.64]), herpes zoster (OR 1.31 [95% CI: 1.14-1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17-1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12-1.31]), pneumonia (OR 1.49 [95% CI: 1.37-1.62]), sinusitis (OR 1.19 [95% CI: 1.09-1.29]) and cellulitis (OR 1.43 [95% CI: 1.32-1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21-1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded. Discussion: Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Titmarsh, Glen J.; McShane, Charlene M.; Clarke, Mike; Anderson, Lesley A.] Queens Univ Belfast, Royal Victoria Hosp, Inst Clin Sci, Ctr Publ Hlth, Belfast BT12 6BA, Antrim, North Ireland. [McMullin, Mary Frances] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7BL, Antrim, North Ireland. [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Anderson, LA (reprint author), Inst Clin Sci, Ctr Publ Hlth, Canc Epidemiol & Hlth Serv Res Grp, Block B,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM l.anderson@qub.ac.uk OI Anderson, Lesley/0000-0002-1000-3649 FU Intramural Research Program of the National Cancer Institute; MPD Voice; Department for Learning and Employment (Northern Ireland) scholarship FX The authors would like to thank the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumour registries in the creation of the SEER-Medicare database. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. This study was supported, in part, by the Intramural Research Program of the National Cancer Institute. GJT is a PhD candidate at Queen's University Belfast supported by funding from MPD Voice. CMcS is a PhD candidate at Queen's University Belfast and is in receipt of a Department for Learning and Employment (Northern Ireland) scholarship. NR 34 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD FEB PY 2014 VL 38 IS 1 BP 56 EP 61 DI 10.1016/j.canep.2013.10.009 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AE5LF UT WOS:000334029800009 PM 24275260 ER PT J AU Caudle, KE Klein, TE Hoffman, JM Muller, DJ Whirl-Carrillo, M Gong, L McDonagh, EM Sangkuhl, K Thorn, CF Schwab, M Agundez, JAG Freimuth, RR Huser, V Lee, MTM Iwuchukwu, OF Crews, KR Scott, SA Wadelius, M Swen, JJ Tyndale, RF Stein, CM Roden, D Relling, MV Williams, MS Johnson, SG AF Caudle, Kelly E. Klein, Teri E. Hoffman, James M. Mueller, Daniel J. Whirl-Carrillo, Michelle Gong, Li McDonagh, Ellen M. Sangkuhl, Katrin Thorn, Caroline F. Schwab, Matthias Agundez, Jose A. G. Freimuth, Robert R. Huser, Vojtech Lee, Ming Ta Michael Iwuchukwu, Otito F. Crews, Kristine R. Scott, Stuart A. Wadelius, Mia Swen, Jesse J. Tyndale, Rachel F. Stein, C. Michael Roden, Dan Relling, Mary V. Williams, Marc S. Johnson, Samuel G. TI Incorporation of Pharmacogenomics into Routine Clinical Practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process SO CURRENT DRUG METABOLISM LA English DT Article DE Clinical practice guideline; guideline; pharmacogenetics; pharmacogenomics ID THIOPURINE METHYLTRANSFERASE GENOTYPE; HLA-B GENOTYPE; CLOPIDOGREL THERAPY; CYP2C19 GENOTYPE; RESEARCH NETWORK; 2013 UPDATE AB The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines. C1 [Caudle, Kelly E.; Hoffman, James M.; Crews, Kristine R.; Relling, Mary V.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Klein, Teri E.; Whirl-Carrillo, Michelle; Gong, Li; McDonagh, Ellen M.; Sangkuhl, Katrin; Thorn, Caroline F.] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Mueller, Daniel J.; Tyndale, Rachel F.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Mueller, Daniel J.; Tyndale, Rachel F.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Schwab, Matthias] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Schwab, Matthias] Univ Hosp, Inst Expt & Clin Pharmacol & Toxicol, Dept Clin Pharmacol, Tubingen, Germany. [Agundez, Jose A. G.] Univ Extremadura, Dept Pharmacol, Caceres, Spain. [Freimuth, Robert R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Huser, Vojtech] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. [Lee, Ming Ta Michael] RIKEN Ctr Integrat Med Sci, Lab Int Alliance Genom Res, Yokohama, Kanagawa, Japan. [Lee, Ming Ta Michael] Acad Sinica, Inst Biomed Sci, Natl Ctr Genome Med, Taipei, Taiwan. [Lee, Ming Ta Michael] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Iwuchukwu, Otito F.; Stein, C. Michael; Roden, Dan] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Scott, Stuart A.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA. [Wadelius, Mia] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Swen, Jesse J.] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands. [Stein, C. Michael; Roden, Dan] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Johnson, Samuel G.] Univ Colorado, Dept Clin Pharm, Skaggs Sch Pharm & Pharmaceut Sci, Denver, CO 80202 USA. [Johnson, Samuel G.] Kaiser Permanente Colorado, Clin Pharm Serv, Denver, CO USA. RP Caudle, KE (reprint author), 262 Danny Thomas Pl MS 313, Memphis, TN 38105 USA. EM cpic@pharmgkb.org RI Wadelius, Mia/C-7740-2016; Agundez, Jose/A-5503-2008 OI Agundez, Jose/0000-0001-6895-9160; Wadelius, Mia/0000-0002-6368-2622; FU National Institutes of Health/National Institute of General Medical Science (NIH/NIGMS) (PAAR4Kids) [UO1 GM92666]; National Institutes of Health/National Institute of General Medical Science (NIH/NIGMS) (PharmGKB) [R24 GM61374]; Brain & Behavior Research Foundation Award; CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia; Ontario Mental Health Foundation New Investigator Fellowship; Ministry of Research and Innovation of Ontario; Swedish Research Council [523-2008-5568, 521-2011-2440]; Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Madrid, Spain [PI12/00241, RETICS RD12/0013/0002]; NIH [T32 GM007569/GM/NIGMS]; NIH NIGMS [K23GM104401]; NIH/NIGMS [U19 GM61388]; [U19 HL065962] FX We acknowledge the critical input of members of the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network, funded by the National Institutes of Health/National Institute of General Medical Science (NIH/NIGMS) (PAAR4Kids (UO1 GM92666) and PharmGKB (R24 GM61374)). D.J.M receives support from the Brain & Behavior Research Foundation Award, CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia, and Ontario Mental Health Foundation New Investigator Fellowship and an Early Researcher Award by the Ministry of Research and Innovation of Ontario. M.W. receives support from the Swedish Research Council (Medicine 523-2008-5568 and 521-2011-2440). J.A.G.A. receives support from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Madrid, Spain (PI12/00241 and RETICS RD12/0013/0002). O.F.I. receives support from the NIH (T32 GM007569/GM/NIGMS). S.A.S receives support from the NIH NIGMS (K23GM104401). RRF supported by NIH/NIGMS U19 GM61388. D.R. supported by U19 HL065962. NR 23 TC 55 Z9 56 U1 5 U2 9 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2002 EI 1875-5453 J9 CURR DRUG METAB JI Curr. Drug Metab. PD FEB PY 2014 VL 15 IS 2 BP 209 EP 217 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AE1RV UT WOS:000333748300006 PM 24479687 ER PT J AU Andersen, NJ Mondal, TK Preissler, MT Freed, BM Stockinger, S Bell, E Druschel, C Louis, GMB Lawrence, DA AF Andersen, Nancy J. Mondal, Tapan Kumar Preissler, Mark T. Freed, Brian M. Stockinger, Sabine Bell, Erin Druschel, Charlotte Louis, Germaine M. Buck Lawrence, David A. TI Detection of immunoglobulin isotypes from dried blood spots SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Dried blood spots; IgE; Immunoglobulin isotypes; Newborn; Cord blood ID INTESTINAL EPITHELIAL-CELLS; FC-EPSILON-RI; CYTOKINE PRODUCTION; SUBSEQUENT DEVELOPMENT; SUBCLASS ANTIBODIES; IL-13 PRODUCTION; ATOPIC DISEASE; IGG SUBCLASSES; IN-VIVO; LIFE AB The study was designed to determine the sensitivity and reproducibility of recovering immunoglobulin (Ig) isotypes (IgG subclasses, IgA, IgE and IgM classes) from dried blood spots (DBS), a methodologic subcomponent of the Upstate KIDS Study. A multiplexed Luminex assay was used for IgG1/2/3/4, IgA and IgM analysis; an ELISA was used for IgE. Plasma samples from de-identified patients were used to compare the Luminex assay with nephelometry, which is routinely used to quantify IgA, IgG and IgM in clinical samples. The IgE ELISA was compared to an immunofluorescence assay. Prior to evaluation of punches from newborn dried blood spots (NDBSs), recoveries of Ig from punches of cord blood DBSs (CBDBSs) vs. plasma from the same cord bloods were compared. Although the recoveries of Ig from plasma and DBSs were not comparable, which could be due to cell lysates in the DBS samples, the analyses were reproducible. Additionally, the levels of IgA, IgG2, IgG4, and IgM recovered from CBDBSs positively correlated with those in plasma. The DBS data is a relative value since it is not equivalent to the plasma concentration. The majority of Ig concentrations recovered from 108 newborns of the Upstate KIDs Study were within the range of newborn plasma Ig levels with the exception of IgG3. The IgG4 values displayed the greatest variance with a wide range (0.01-319 mg/dl), whereas, IgG1 values had the narrowest range (85.2-960.4 mg/dl). (C) 2014 Elsevier B.V. All rights reserved. C1 [Andersen, Nancy J.; Mondal, Tapan Kumar; Lawrence, David A.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12208 USA. [Preissler, Mark T.] Albany Med Ctr, Serol Immunol Lab, Albany, NY 12208 USA. [Freed, Brian M.; Stockinger, Sabine] Univ Colorado, ClinImmune Labs, Aurora, CO 80045 USA. [Bell, Erin] SUNY Albany, Sch Publ Hlth, Rensselaer, NY 12144 USA. [Druschel, Charlotte] NYSDOH, Congenital Malformat Registry, New York, NY USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. RP Lawrence, DA (reprint author), David Axelrod Inst, 120 New Scotland Ave, Albany, NY 12208 USA. EM David.Lawrence@Wadsworth.org OI Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200005C, HHSN267200700019C] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C). We thank Jeffrey S. Kennedy, M.D. for his assistance in obtaining the NDBS punches and Tiffany Tryniszewski for her assistance with the Luminex analysis of CB plasma and CBDBS punches. NR 38 TC 8 Z9 8 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB PY 2014 VL 404 BP 24 EP 32 DI 10.1016/j.jim.2013.12.001 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AE3DN UT WOS:000333857300003 PM 24333851 ER PT J AU Grodzinski, P Torchilin, V AF Grodzinski, Piotr Torchilin, Vladimir TI Cancer nanotechnology Preface SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Editorial Material C1 [Grodzinski, Piotr] Natl Canc Inst, Bethesda, MD 20892 USA. [Torchilin, Vladimir] Northeastern Univ, Boston, MA USA. RP Grodzinski, P (reprint author), Natl Canc Inst, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD FEB PY 2014 VL 66 BP 1 EP 1 DI 10.1016/j.addr.2013.09.011 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AE3JN UT WOS:000333872900001 ER PT J AU DeGrazia, D AF DeGrazia, David TI Persons, Dolphins, and Human-Nonhuman Chimeras SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [DeGrazia, David] NIH, Bethesda, MD USA. [DeGrazia, David] George Washington Univ, Washington, DC 20052 USA. RP DeGrazia, D (reprint author), George Washington Univ, Dept Philosophy, Phillips 525, Washington, DC 20052 USA. EM ddd@gwu.edu FU National Institutes of Health Clinical Center FX This work was supported, in part, by intramural funds from the National Institutes of Health Clinical Center. The views expressed are the author's own. They do not represent the position or policy of the National Institutes of Health, the U.S. Public Health Service, or the Department of Health and Human Services. NR 5 TC 1 Z9 1 U1 1 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD FEB 1 PY 2014 VL 14 IS 2 BP 17 EP 18 DI 10.1080/15265161.2014.869434 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AA8GL UT WOS:000331333500006 PM 24521328 ER PT J AU Steele-Mortimer, O Subtil, A AF Steele-Mortimer, Olivia Subtil, Agathe TI Host-microbe interactions: bacteria. War and peace: the fragile equilibrium between bacteria and host SO CURRENT OPINION IN MICROBIOLOGY LA English DT Editorial Material C1 [Steele-Mortimer, Olivia] NIAID, Hamilton, MT 59840 USA. [Subtil, Agathe] Inst Pasteur, Unite Biol Interact Cellulaires, Paris, France. [Subtil, Agathe] CNRS, URA 2582, Paris, France. RP Steele-Mortimer, O (reprint author), NIAID, Hamilton, MT 59840 USA. EM omortimer@niaid.nih.gov; asubtil@pasteur.fr RI Subtil, Agathe/C-7464-2017 OI Subtil, Agathe/0000-0002-7481-4846 FU Intramural NIH HHS [Z01 AI000909-07, Z01 AI000909-06, Z99 AI999999] NR 0 TC 0 Z9 0 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2014 VL 17 BP V EP VII DI 10.1016/j.mib.2014.01.001 PG 3 WC Microbiology SC Microbiology GA AD8DG UT WOS:000333496100001 PM 24503282 ER PT J AU Otto, M AF Otto, Michael TI Staphylococcus aureus toxins SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID VALENTINE LEUKOCIDIN GENES; HUMAN NEUTROPHILS; DELTA-TOXIN; ALPHA-TOXIN; VIRULENCE; PROTEIN; STAPHYLOKINASE; INFECTIONS; PNEUMONIA; PEPTIDES AB Staphylococcus aureus is a dangerous pathogen that causes a variety of severe diseases. The virulence of S. aureus is defined by a large repertoire of virulence factors, among which secreted toxins play a preeminent role. Many S. aureus toxins damage biological membranes, leading to cell death. In particular, S. aureus produces potent hemolysins and leukotoxins. Among the latter, some were recently identified to lyse neutrophils after ingestion, representing an especially powerful weapon against bacterial elimination by innate host defense. Furthermore, S. aureus secretes many factors that inhibit the complement cascade or prevent recognition by host defenses. Several further toxins add to this multi-faceted program of S. aureus to evade elimination in the host. This review will give an overview over S. aureus toxins focusing on recent advances in our understanding of how leukotoxins work in receptor-mediated or receptorindependent fashions. C1 NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 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 Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH). NR 49 TC 82 Z9 87 U1 5 U2 44 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2014 VL 17 BP 32 EP 37 DI 10.1016/j.mib.2013.11.004 PG 6 WC Microbiology SC Microbiology GA AD8DG UT WOS:000333496100006 PM 24581690 ER PT J AU Morissette, R Merke, DP McDonnell, NB AF Morissette, Rachel Merke, Deborah P. McDonnell, Nazli B. TI Transforming growth factor-beta (TGF-beta) pathway abnormalities in tenascin-X deficiency associated with CAH-X syndrome SO EUROPEAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE CAH; Tenascin-X deficiency; TGF-beta pathway; Cleft palate; Cardiac abnormalities ID EHLERS-DANLOS-SYNDROME; AORTIC-ANEURYSM; MARFAN-SYNDROME; HYPERMOBILITY TYPE; HEART DEVELOPMENT; MUTATIONS; MATRIX; MICE; PALATE; COLLAGEN AB Patients with congenital adrenal hyperplasia (CAH) with tenascin-X deficiency (CAH-X syndrome) have both endocrine imbalances and characteristic Ehlers Danlos syndrome phenotypes. Unlike other subtypes, tenascin-X-related Ehlers Danlos syndrome is caused by an extracellular matrix protein deficiency rather than a defect in fibrillar collagen or a collagen-modifying enzyme, and the understanding of the disease mechanisms is limited. We hypothesized that transforming growth factor-beta pathway dysregulation may, in part, be responsible for connective tissue phenotypes observed in CAH-X, due to this pathway's known role in connective tissue disorders. Fibroblasts and direct tissue from human skin biopsies from CAH-X probands and age- and sex-matched controls were screened for transforming growth factor-beta biomarkers known to be dysregulated in other hereditary disorders of connective tissue. In CAH-X fibroblast lines and dermal tissue, pSmad1/5/8 was significantly upregulated compared to controls, suggesting involvement of the bone morphogenetic protein pathway. Additionally, CAH-X samples compared to controls exhibited significant increases in fibroblast-secreted TGF-beta 3, a cytokine important in secondary palatal development, and in plasma TGF-beta 2, a cytokine involved in cardiac function and development, as well as palatogenesis. Finally, MMP-13, a matrix metalloproteinase important in secondary palate formation and tissue remodeling, had significantly increased mRNA and protein expression in CAH-X fibroblasts and direct tissue. Collectively, these results demonstrate that patients with CAH-X syndrome exhibit increased expression of several transforming growth factor-beta biomarkers and provide a novel link between this signaling pathway and the connective tissue dysplasia phenotypes associated with tenascin-X deficiency. Published by Elsevier Masson SAS. C1 [Morissette, Rachel; McDonnell, Nazli B.] NIA, NIH, Clin Unit, Baltimore, MD 21225 USA. [Morissette, Rachel; Merke, Deborah P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP McDonnell, NB (reprint author), NIA, NIH, Clin Unit, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM morissetter@mail.nih.gov; nazli.mcdonnell@gmail.com FU Diurnal Limited, Ltd.; Intramural Research Programs of the National Institutes of Health, National Institute on Aging; NIH Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Dr. Justyna Fert-Bober and Dr. Jennifer van Eyk (Johns Hopkins Proteomics Center, Baltimore, MD) for technical support with the plasma TGF-beta 3 assay. R. Morissette and N.B. McDonnell declare no conflict of interest. D.P. Merke received research funds from Diurnal Limited, Ltd. This work was supported by the Intramural Research Programs of the National Institutes of Health, National Institute on Aging, the NIH Clinical Center, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 35 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1769-7212 EI 1878-0849 J9 EUR J MED GENET JI Eur. J. Med. Genet. PD FEB PY 2014 VL 57 IS 2-3 BP 95 EP 102 DI 10.1016/j.ejmg.2013.12.004 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA AE2OT UT WOS:000333813500009 PM 24380766 ER PT J AU Griffith, LM Cowan, MJ Notarangelo, LD Kohn, DB Puck, JM Pai, SY Ballard, B Bauer, SC Bleesing, JJH Boyle, M Brower, A Buckley, RH van der Burg, M Burroughs, LM Candotti, F Cant, AJ Chatila, T Cunningham-Rundles, C Dinauer, MC Dvorak, CC Filipovich, AH Fleisher, TA Gaspar, HB Gungor, T Haddad, E Hovermale, E Huang, F Hurley, A Hurley, M Iyengar, S Kang, EM Logan, BR Long-Boyle, JR Malech, HL McGhee, SA Modell, F Modell, V Ochs, HD O'Reilly, RJ Parkman, R Rawlings, DJ Routes, JM Shearer, WT Small, TN Smith, H Sullivan, KE Szabolcs, P Thrasher, A Torgerson, TR Veys, P Weinberg, K Zuniga-Pflucker, JC AF Griffith, Linda M. Cowan, Morton J. Notarangelo, Luigi D. Kohn, Donald B. Puck, Jennifer M. Pai, Sung-Yun Ballard, Barbara Bauer, Sarah C. Bleesing, Jack J. H. Boyle, Marcia Brower, Amy Buckley, Rebecca H. van der Burg, Mirjam Burroughs, Lauri M. Candotti, Fabio Cant, Andrew J. Chatila, Talal Cunningham-Rundles, Charlotte Dinauer, Mary C. Dvorak, Christopher C. Filipovich, Alexandra H. Fleisher, Thomas A. Gaspar, Hubert Bobby Gungor, Tayfun Haddad, Elie Hovermale, Emily Huang, Faith Hurley, Alan Hurley, Mary Iyengar, Sumathi Kang, Elizabeth M. Logan, Brent R. Long-Boyle, Janel R. Malech, Harry L. McGhee, Sean A. Modell, Fred Modell, Vicki Ochs, Hans D. O'Reilly, Richard J. Parkman, Robertson Rawlings, David J. Routes, John M. Shearer, William T. Small, Trudy N. Smith, Heather Sullivan, Kathleen E. Szabolcs, Paul Thrasher, Adrian Torgerson, Troy R. Veys, Paul Weinberg, Kenneth Zuniga-Pflucker, Juan Carlos CA Workshop Participants TI Primary Immune Deficiency Treatment Consortium (PIDTC) report SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allogeneic hematopoietic cell transplantation; gene therapy; primary immunodeficiency; clinical trial ID STEM-CELL TRANSPLANTATION; SEVERE COMBINED IMMUNODEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; WISKOTT-ALDRICH-SYNDROME; UMBILICAL-CORD BLOOD; BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVAL; GENE-THERAPY; UNRELATED DONOR; CONDITIONING REGIMEN AB The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives. C1 [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Cowan, Morton J.; Puck, Jennifer M.; Dvorak, Christopher C.] Univ Calif San Francisco, Div Allergy Immunol & Blood & Marrow Transplantat, Dept Pediat, San Francisco, CA 94143 USA. [Cowan, Morton J.; Puck, Jennifer M.; Dvorak, Christopher C.] Univ Calif San Francisco, UCSF Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Notarangelo, Luigi D.] Childrens Hosp, Div Immunol, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Immunol, Los Angeles, CA USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Mol Genet, Los Angeles, CA USA. [Puck, Jennifer M.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Pai, Sung-Yun; Chatila, Talal] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Ballard, Barbara; Boyle, Marcia; Hovermale, Emily] Immune Deficiency Fdn, Towson, MD USA. [Bauer, Sarah C.] Lurie Childrens Hosp Chicago, Northwestern Feinberg Sch Med, Chicago, IL USA. [Bleesing, Jack J. H.; Rawlings, David J.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Brower, Amy] Amer Coll Med Genet & Genom, Newborn Screening Translat Res Network, Bethesda, MD USA. [Buckley, Rebecca H.] Duke Univ, Sch Med, Durham, NC 27706 USA. [van der Burg, Mirjam] Erasmus MC, Rotterdam, Netherlands. [Burroughs, Lauri M.] Univ Washington, Fred Hutchinson Canc Res Ctr, Sch Med, Seattle, WA 98195 USA. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Cant, Andrew J.] Newcastle Gen Hosp, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. [Cunningham-Rundles, Charlotte] Mt Sinai Sch Med, New York, NY USA. [Dinauer, Mary C.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Filipovich, Alexandra H.] Cincinnati Childrens Hosp Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. [Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Gaspar, Hubert Bobby] UCL, Great Ormond St Hosp, Inst Child Hlth, Ctr Immunodeficiency, London WC1E 6BT, England. [Gungor, Tayfun] Univ Zurich, Childrens Hosp Zurich, CH-8006 Zurich, Switzerland. [Haddad, Elie] Mother & Child Ste Justine Hosp, Montreal, PQ, Canada. [Huang, Faith] Mt Sinai Med Ctr, New York, NY 10029 USA. [Hurley, Alan; Hurley, Mary] Chron Granulomatous Dis Assoc, San Marino, CA USA. [Iyengar, Sumathi] Wiskott Aldrich Fdn, Smyrna, GA USA. [Kang, Elizabeth M.; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Logan, Brent R.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Long-Boyle, Janel R.] Univ Calif San Francisco, Sch Pharm, Dept Clin Pharm, San Francisco, CA 94143 USA. [McGhee, Sean A.] Stanford Univ, Med Ctr, Lucile Packard Childrens Hosp, Stanford, CA 94305 USA. [Modell, Fred; Modell, Vicki] Jeffrey Modell Fdn, New York, NY USA. [Ochs, Hans D.] Univ Washington, Sch Med, Ctr Immun & Immunotherapy, Seattle Childrens Hosp Res Inst, Seattle, WA USA. [O'Reilly, Richard J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Parkman, Robertson] Childrens Hosp Los Angeles, Div Res Immunol BMT, Los Angeles, CA 90027 USA. [Rawlings, David J.; Torgerson, Troy R.] Univ Washington, Sch Med, Seattle Childrens Res Inst, Seattle, WA USA. [Routes, John M.] Med Coll Wisconsin, Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA. [Shearer, William T.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Small, Trudy N.] Mem Sloan Kettering Canc Ctr, Pediat Bone Marrow Transplant Serv, New York, NY 10021 USA. [Smith, Heather] SCID Angels Life Fdn, Lakeland, FL USA. [Sullivan, Kathleen E.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Szabolcs, Paul] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. [Thrasher, Adrian] UCL, Great Ormond St Hosp, Inst Child Hlth, Ctr Immunodeficiency, London WC1E 6BT, England. [Veys, Paul] Great Ormond St Hosp Sick Children, Inst Child Hlth, London, England. [Weinberg, Kenneth] Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Stanford, CA 94305 USA. [Zuniga-Pflucker, Juan Carlos] Univ Toronto, Toronto, ON M5S 1A1, Canada. RP Griffith, LM (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, 6610 Rockledge Dr,Rm 6716, Bethesda, MD 20892 USA. EM LGriffith@niaid.nih.gov RI Volpi, Stefano/O-3717-2014; Notarangelo, Luigi/F-9718-2016; Kohn, Donald/N-5085-2016; OI Volpi, Stefano/0000-0002-7129-868X; Notarangelo, Luigi/0000-0002-8335-0262; Kohn, Donald/0000-0003-1840-6087; , Jacob/0000-0003-4036-2105; Malech, Harry/0000-0001-5874-5775; Zuniga-Pflucker, Juan Carlos/0000-0003-2538-3178 FU Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases; Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Md [U54-AI082973, U54-NS064808, R13-AI094943]; Immune Deficiency Foundation, Towson, Md; Jeffrey Modell Foundation, New York, NY; Robert A. Good Immunology Society, St Petersburg, Fla; Manton Center for Orphan Disease Research; Children's Hospital Translational Research Program, Children's Hospital, Boston, Mass; Baxter International, Deerfield, Ill; CSL Behring, King of Prussia, Pa; Sigma-Tau Pharmaceuticals, Gaithersburg, Md; Talecris Biotherapeutics, Research Triangle Park, NC FX Supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Allergy and Infectious Diseases; and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Md; U54-AI082973 (primary investigator: M. J. Cowan); U54-NS064808 (primary investigator: J. P. Krischer); R13-AI094943 (primary investigators: M. J. Cowan and L. D. Notarangelo). Workshops in April 2011 (San Francisco, Calif) and April 2012 (Boston, Mass) were also supported in part by the Immune Deficiency Foundation, Towson, Md; the Jeffrey Modell Foundation, New York, NY; the Robert A. Good Immunology Society, St Petersburg, Fla; the Manton Center for Orphan Disease Research and the Children's Hospital Translational Research Program, Children's Hospital, Boston, Mass; Baxter International, Deerfield, Ill; CSL Behring, King of Prussia, Pa; Sigma-Tau Pharmaceuticals, Gaithersburg, Md; and Talecris Biotherapeutics, Research Triangle Park, NC. NR 79 TC 22 Z9 23 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2014 VL 133 IS 2 BP 335 EP + DI 10.1016/j.jaci.2013.07.052 PG 24 WC Allergy; Immunology SC Allergy; Immunology GA AC3EF UT WOS:000332397100005 PM 24139498 ER PT J AU Rose, DM Atkins, J Holland, SM Infante, AJ AF Rose, David M. Atkins, Jane Holland, Steven M. Infante, Anthony J. TI A novel mutation in IFN-gamma receptor 1 presenting as multisystem Mycobacterium intracellulare infection SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID INTERFERON-GAMMA; DEFICIENCY; DOMINANT C1 [Rose, David M.] JBSA Lackland, Dept Allergy & Immunol, Wilford Hall Ambulatory Surg Ctr, Lackland AFB, TX 78236 USA. [Atkins, Jane] Pediat Infect Dis, San Antonio, TX USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Infante, Anthony J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA. RP Rose, DM (reprint author), JBSA Lackland, Dept Allergy & Immunol, Wilford Hall Ambulatory Surg Ctr, Lackland AFB, TX 78236 USA. EM infantea@uthscsa.edu NR 8 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2014 VL 133 IS 2 BP 591 EP 592 DI 10.1016/j.jaci.2013.07.054 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA AC3EF UT WOS:000332397100042 PM 24220318 ER PT J AU Haddad, E Allakhverdi, Z Griffith, LM Cowan, MJ Notarangelo, LD AF Haddad, Elie Allakhverdi, Zoulfia Griffith, Linda M. Cowan, Morton J. Notarangelo, Luigi D. TI Survey on retransplantation criteria for patients with severe combined immunodeficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID STEM-CELL TRANSPLANTATION; RECONSTITUTION C1 [Haddad, Elie] Univ Montreal, Dept Pediat, Div Pediat Immunol Allergy & Rheumatol, Montreal, PQ H3C 3J7, Canada. [Haddad, Elie; Allakhverdi, Zoulfia] CHU St Justine, Res Ctr, Montreal, PQ, Canada. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Cowan, Morton J.] Univ Calif San Francisco, Benioff Childrens Hosp, Div Pediat Allergy Immunol & Blood & Marrow Trans, San Francisco, CA 94143 USA. [Notarangelo, Luigi D.] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Notarangelo, Luigi D.] Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. RP Haddad, E (reprint author), Univ Montreal, Dept Pediat, Div Pediat Immunol Allergy & Rheumatol, Montreal, PQ H3C 3J7, Canada. EM elie.haddad@umontreal.ca RI Notarangelo, Luigi/F-9718-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; Haddad, Elie/0000-0003-2446-6879 FU NIAID NIH HHS [R13 AI094943, U54 AI082973]; NINDS NIH HHS [U54 NS064808] NR 11 TC 3 Z9 3 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2014 VL 133 IS 2 BP 597 EP 599 DI 10.1016/j.jaci.2013.10.022 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA AC3EF UT WOS:000332397100045 PM 24331379 ER PT J AU Ackerman, WE Adamson, L Carter, AM Collins, S Cox, B Elliot, MG Ermini, L Gruslin, A Hoodless, PA Huang, J Kniss, DA McGowen, MR Post, M Rice, G Robinson, W Sadovsky, Y Salafia, C Salomon, C Sled, JG Todros, T Wildman, DE Zamudio, S Lash, GE AF Ackerman, W. E. Adamson, L. Carter, A. M. Collins, S. Cox, B. Elliot, M. G. Ermini, L. Gruslin, A. Hoodless, P. A. Huang, J. Kniss, D. A. McGowen, M. R. Post, M. Rice, G. Robinson, W. Sadovsky, Y. Salafia, C. Salomon, C. Sled, J. G. Todros, T. Wildman, D. E. Zamudio, S. Lash, G. E. TI IFPA Meeting 2013 Workshop Report II: Use of 'omics' in understanding placental development, bioinformatics tools for gene expression analysis, planning and coordination of a placenta research network, placental imaging, evolutionary approaches to understanding pre-eclampsia SO PLACENTA LA English DT Article DE 'Omics' technologies; Placenta research network; Bioinformatics; Placental evolution; Placental pathologies; Placental imaging AB Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At the IFPA meeting 2013 twelve themed workshops were presented, five of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of new technologies for placenta research: 1) use of ;omics' in understanding placental development and pathologies; 2) bioinformatics and use of omics technologies; 3) planning and coordination of a placenta research network; 4) clinical imaging and pathological outcomes; 5) placental evolution. (C) 2013 Published by IFPA and Elsevier Ltd. C1 [Ackerman, W. E.; Huang, J.; Kniss, D. A.] Ohio State Univ, Dept Obstet & Gynecol, Div Maternal Fetal Med, Columbus, OH 43210 USA. [Ackerman, W. E.; Huang, J.; Kniss, D. A.] Ohio State Univ, Dept Obstet & Gynecol, Lab Perinatal Res, Columbus, OH 43210 USA. [Adamson, L.] Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Adamson, L.] Univ Toronto, Dept Obstet & Gynaecol, Toronto, ON, Canada. [Carter, A. M.] Univ Southern Denmark, Inst Mol Med, Odense, Denmark. [Collins, S.] Univ Oxford, Dept Obstet & Gynaecol, Oxford, England. [Cox, B.] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Elliot, M. G.] Simon Fraser Univ, Dept Biol Sci, Burnaby, BC V5A 1S6, Canada. [Ermini, L.; Post, M.] Hosp Sick Children, Res Inst, Physiol & Expt Med Program, Toronto, ON M5G 1X8, Canada. [Gruslin, A.] Univ Ottawa, Dept Obstet & Gynaecol, Ottawa Hosp, Div Maternal Fetal Med,Res Inst, Ottawa, ON, Canada. [Gruslin, A.] Univ Ottawa, Dept Cellular & Mol Med, Ottawa Hosp, Div Maternal Fetal Med,Res Inst, Ottawa, ON, Canada. [Hoodless, P. A.] BC Canc Agcy, Terry Fox Lab, Vancouver, BC, Canada. [Hoodless, P. A.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [McGowen, M. R.; Wildman, D. E.] Wayne State Univ, Sch Med, Dept Obstet & Gynaecol, Ctr Mol Med & Genet, Detroit, MI USA. [Post, M.] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada. [Post, M.] Univ Toronto, Dept Paediat & Physiol, Toronto, ON, Canada. [Rice, G.; Salomon, C.] Univ Queensland, Clin Res Ctr, Ctr Clin Diagnost, Herston, Qld, Australia. [Robinson, W.] Univ British Columbia, Dept Med Genet, Child & Family Res Inst, Vancouver, BC, Canada. [Sadovsky, Y.] Magee Womens Res Inst, Pittsburgh, PA USA. [Salafia, C.] Placental Analyt LLC, New York, NY USA. [Salafia, C.] Inst Basic Res Dev Disabil, New York, NY USA. [Sled, J. G.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Sled, J. G.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Todros, T.] Univ Turin, St Anna Hosp, Dept Obstet & Gynecol, Turin, Italy. [Wildman, D. E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Zamudio, S.] Hackensack Univ, Dept Obstet & Gynaecol, Med Ctr, Hackensack, NJ USA. [Lash, G. E.] Newcastle Univ, Inst Cellular Med, Reprod & Vasc Biol Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. RP Lash, GE (reprint author), Newcastle Univ, Inst Cellular Med, 3rd Floor,William Leech Bldg, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. EM gendie.lash@ncl.ac.uk RI Salomon, Carlos/L-2167-2013; Sled, John/D-8268-2012; RICE, GREGORY/F-2412-2010; Robinson, Wendy/I-9590-2014 OI Salomon, Carlos/0000-0003-4474-0046; Sled, John/0000-0002-4461-283X; RICE, GREGORY/0000-0001-7177-0246; Robinson, Wendy/0000-0002-2010-6174 NR 0 TC 1 Z9 1 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD FEB PY 2014 VL 35 SU A BP S10 EP S14 DI 10.1016/j.placenta.2013.11.011 PG 5 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA AD8DF UT WOS:000333496000004 PM 24315655 ER PT J AU Greig, NH Lahiri, DK AF Greig, Nigel H. Lahiri, Debomoy K. TI Advances in Understanding Alzheimer's Disease, and the Contributions of Current Alzheimer Research: Ten Years on and Beyond SO CURRENT ALZHEIMER RESEARCH LA English DT Editorial Material ID GENOME; MARS C1 [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Lab Translat Gerontol, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Mol Neurogenet Lab, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. RP Lahiri, DK (reprint author), Indiana Univ Sch Med, Mol Neurogenet Lab, Dept Psychiat, Inst Psychiat Res, 791 Union Dr, Indianapolis, IN 46202 USA. EM dlahiri@iupui.edu FU Intramural NIH HHS [ZIA AG000311-14] NR 23 TC 2 Z9 3 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 EI 1875-5828 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD FEB PY 2014 VL 11 IS 2 BP 107 EP 109 DI 10.2174/156720501102140313162901 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AD4DC UT WOS:000333195900001 PM 24661146 ER PT J AU Day, PM Schelhaas, M AF Day, Patricia M. Schelhaas, Mario TI Concepts of papillomavirus entry into host cells SO CURRENT OPINION IN VIROLOGY LA English DT Article ID MINOR CAPSID PROTEIN; VIRUS-LIKE PARTICLES; SURFACE HEPARAN-SULFATE; SORTING NEXIN 17; HUMAN KERATINOCYTES; EXTRACELLULAR-MATRIX; INFECTIOUS ENTRY; CELLULAR ENTRY; LATE ENDOSOMES; L2 AB Papillomaviruses enter basal cells of stratified epithelia. Assembly of new virions occurs in infected cells during terminal differentiation. This unique biology is reflected in the mechanism of entry. Extracellularly, the interaction of nonenveloped capsids with several host cell proteins, after binding, results in discrete conformational changes. Asynchronous internalization occurs over several hours by an endocytic mechanism related to, but distinct from macropinocytosis. Intracellular trafficking leads virions through the endosomal system, and from late endosomes to the trans-Golgi-network, before nuclear delivery. Here, we discuss the existing data with the aim to synthesize an integrated model of the stepwise process of entry, thereby highlighting key open questions. Additionally, we relate data from experiments with cultured cells to in vivo results. C1 [Day, Patricia M.] NCI, Lab Cellular Oncol, NIH, Bethesda, MD 20892 USA. [Schelhaas, Mario] Univ Munster, Inst Mol Virol & Med Biochem, ZMBE, Emmy Noether Grp Virus Endocytosis, D-48149 Munster, Germany. [Schelhaas, Mario] CiM, Munster, Germany. RP Schelhaas, M (reprint author), Univ Munster, Inst Mol Virol & Med Biochem, ZMBE, Emmy Noether Grp Virus Endocytosis, D-48149 Munster, Germany. EM schelhaas@uni-muenster.de FU German Research Foundation (DFG) [SCHE 1552/2-1, SFB629/A16, EXC 1003] FX We would like to thank Lena Kuhling for assistance with generating a schematic depiction of PV entry and members of the Schelhaas lab for critical comments on the manuscript. We apologize to all individuals who have advanced the field of PV entry and who were not mentioned in the manuscript due to space limitations. Research in the laboratory of MS is supported by the German Research Foundation (DFG, Grants SCHE 1552/2-1, SFB629/A16, and partly by EXC 1003). NR 87 TC 18 Z9 18 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD FEB PY 2014 VL 4 BP 24 EP 31 DI 10.1016/j.coviro.2013.11.002 PG 8 WC Virology SC Virology GA AD8CI UT WOS:000333493700006 PM 24525291 ER PT J AU Taylor, KW Hoffman, K Thayer, KA Daniels, JL AF Taylor, Kyla W. Hoffman, Kate Thayer, Kristina A. Daniels, Julie L. TI Polyfluoroalkyl Chemicals and Menopause among Women 20-65 Years of Age (NHANES) SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PERFLUOROOCTANOATE PFOA CONCENTRATIONS; FLUOROCHEMICAL PRODUCTION WORKERS; NATIONAL-HEALTH; PERFLUORINATED COMPOUNDS; PERFLUOROALKYL ACIDS; SERUM CONCENTRATIONS; NATURAL MENOPAUSE; SULFONATE PFOS; US POPULATION; EXPOSURE AB BACKGROUND: Polyfluoroalkyl chemicals (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluoro-octanoate (PFOA) have been associated with early menopause. However, previous crosssectional studies have lacked adequate data to investigate possible reverse causality (i. e., higher serum concentrations due to decreased excretion after menopause). OBJECTIVES: We investigated the association between PFOS, PFOA, perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) and age at natural menopause among women 20-65 years of age in NHANES (National Health and Nutrition Examination Survey). METHODS: We used proportional hazard models to estimate hazard ratios (HRs) for the onset of natural menopause as a function of age and serum PFC levels, and to investigate reverse causation by estimating associations between PFC levels and the rate of hysterectomy. We also used multivariable linear regression to determine whether time since menopause predicted serum PFC levels. RESULTS: After adjusting for age at survey, race/ ethnicity, education, ever smoking, and parity, women with higher levels of PFCs had earlier menopause than did women with the lowest PFC levels. We observed a monotonic association with PFHxS: The HR was 1.42 (95% CI: 1.08, 1.87) for serum concentrations in tertile 2 versus tertile 1, and 1.70 (95% CI: 1.36, 2.12) for tertile 3 versus tertile 1. We also found evidence of reverse causation: PFCs were positively associated with rate of hysterectomy, and time since natural menopause was positively associated with serum PFCs. CONCLUSIONS: Our findings suggest a positive association between PFCs and menopause; however, at least part of the association may be due to reverse causation. Regardless of underlying cause, women appear to have higher PFC concentrations after menopause. C1 [Taylor, Kyla W.; Thayer, Kristina A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIH,US Dept HHS, Res Triangle Pk, NC 27709 USA. [Hoffman, Kate; Daniels, Julie L.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Taylor, KW (reprint author), NIEHS, Natl Toxicol Program, POB 12233,MD K2-04, Res Triangle Pk, NC 27709 USA. EM taylorkw@niehs.nih.gov NR 43 TC 22 Z9 23 U1 3 U2 20 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2014 VL 122 IS 2 BP 145 EP 150 DI 10.1289/ehp.1306707 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AC6QY UT WOS:000332650500017 PM 24280566 ER PT J AU Engel, LS Satagopan, J Sima, CS Orlow, I Mujumdar, U Coble, J Roy, P Yoo, S Sandler, DP Alavanja, MC AF Engel, Lawrence S. Satagopan, Jaya Sima, Camelia S. Orlow, Irene Mujumdar, Urvi Coble, Joseph Roy, Pampa Yoo, Sarah Sandler, Dale P. Alavanja, Michael C. TI Sun Exposure, Vitamin D Receptor Genetic Variants, and Risk of Breast Cancer in the Agricultural Health Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID POSTMENOPAUSAL WOMEN; SUNLIGHT EXPOSURE; DIETARY-INTAKE; POPULATION; POLYMORPHISMS; MORTALITY; COHORT; REPRODUCIBILITY; MECHANISMS; RADIATION AB BACKGROUND: Epidemiologic evidence suggests a negative relation between sunlight exposure and breast cancer risk. The hypothesized mechanism is sunlight-induced cutaneous synthesis of vitamin D. OBJECTIVES: Our goal was to examine sun exposure and its inter-action with vitamin D receptor (VDR) gene variants on breast cancer risk. METHODS: We examined sun exposure and breast cancer incidence among 31,021 private pesticide applicators' wives, including 578 cases, enrolled in the prospective Agricultural Health Study cohort and followed 8.6 years on average. We estimated inter-actions between sun exposure, VDR variants, and breast cancer in a nested case-control study comprising 293 cases and 586 matched controls. Information on sun exposure was obtained by questionnaire at cohort enrollment. Relative risks were estimated using Cox proportional hazards regression for the cohort data and conditional logistic regression for the nested case-control data. RESULTS: We observed a small decrease in breast cancer risk in association with usual sun exposure of >= 1 hr/ day (versus < 1 hr/ day) 10 years before the start of follow-up among all participants [ hazard ratio (HR) = 0.8; 95% CI: 0.6, 1.0]. The association appeared to be slightly stronger in relation to estrogen receptor-positive tumors (HR = 0.7; 95% CI: 0.5, 0.9) than estrogen receptor-negative tumors (HR = 1.1; 95% CI: 0.6, 2.1). The HR for joint exposure >= 1 hr/ day of sunlight and one VDR haplotype was less than expected given negative HRs for each individual exposure (inter-action p-value = 0.07). CONCLUSION: Our results suggest that sun exposure may be associated with reduced risk of breast cancer, but we did not find clear evidence of modification by VDR variants. Larger studies are warranted, particularly among populations in whom low levels of usual sun exposure can be more precisely characterized. C1 [Engel, Lawrence S.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Satagopan, Jaya; Sima, Camelia S.; Orlow, Irene; Mujumdar, Urvi; Roy, Pampa; Yoo, Sarah] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Coble, Joseph; Alavanja, Michael C.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Sandler, Dale P.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Engel, LS (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Campus Box 7435, Chapel Hill, NC 27599 USA. EM Larry.Engel@unc.edu OI Satagopan, Jaya/0000-0001-7102-5633; Sandler, Dale/0000-0002-6776-0018; Orlow, Irene/0000-0001-6234-6961; Engel, Lawrence/0000-0001-9268-4830 FU American Cancer Society [RSG-06-016-01-CNE to L.S.E.]; Intramural Research Program of the National Institutes of Health [Z01-ES049030]; National Cancer Institute [Z01-CP010119]; National Cancer Institute Research Grant [R01CA137420] FX This research was supported by the American Cancer Society (RSG-06-016-01-CNE to L.S.E.), the Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences (Z01-ES049030) and National Cancer Institute (NCI; Z01-CP010119), and by a Research Grant from the NCI (R01CA137420) to J.S.]. The Memorial Sloan-Kettering Cancer Center (MSKCC) Sequenom facility is supported by the Anbinder Fund, a private philanthropic fund. NR 59 TC 7 Z9 7 U1 0 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2014 VL 122 IS 2 BP 165 EP 171 DI 10.1289/ehp.1206274 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AC6QY UT WOS:000332650500020 PM 24252436 ER PT J AU Vermeulen, R Silverman, DT Garshick, E Vlaanderen, J Portengen, L Steenland, K AF Vermeulen, Roel Silverman, Debra T. Garshick, Eric Vlaanderen, Jelle Portengen, Lutzen Steenland, Kyle TI Exposure-Response Estimates for Diesel Engine Exhaust and Lung Cancer Mortality Based on Data from Three Occupational Cohorts SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID TRUCKING INDUSTRY; ELEMENTAL CARBON; AIR-POLLUTION; POTASH MINERS; GLOBAL BURDEN; DISEASE; WORKERS; METAANALYSIS; BRITAIN AB Background: Diesel engine exhaust (DEE) has recently been classified as a known human carcinogen. Objective: We derived a meta-exposure-response curve (ERC) for DEE and lung cancer mortality and estimated lifetime excess risks (ELRs) of lung cancer mortality based on assumed occupational and environmental exposure scenarios. Methods: We conducted a meta-regression of lung cancer mortality and cumulative exposure to elemental carbon (EC), a proxy measure of DEE, based on relative risk (RR) estimates reported by three large occupational cohort studies (including two studies of workers in the trucking industry and one study of miners). Based on the derived risk function, we calculated ELRs for several lifetime occupational and environmental exposure scenarios and also calculated the fractions of annual lung cancer deaths attributable to DEE. Results: We estimated a lnRR of 0.00098 (95% CI: 0.00055, 0.0014) for lung cancer mortality with each 1-mu g/m(3)-year increase in cumulative EC based on a linear meta-regression model. Corresponding lnRRs for the individual studies ranged from 0.00061 to 0.0012. Estimated numbers of excess lung cancer deaths through 80 years of age for lifetime occupational exposures of 1, 10, and 25 mu g/m(3) EC were 17, 200, and 689 per 10,000, respectively. For lifetime environmental exposure to 0.8 mu g/m3 EC, we estimated 21 excess lung cancer deaths per 10,000. Based on broad assumptions regarding past occupational and environmental exposures, we estimated that -approximately 6% of annual lung cancer deaths may be due to DEE exposure. Conclusions: Combined data from three U. S. occupational cohort studies suggest that DEE at levels common in the workplace and in outdoor air appear to pose substantial excess lifetime risks of lung cancer, above the usually acceptable limits in the United States and Europe, which are generally set at 1/1,000 and 1/100,000 based on lifetime exposure for the occupational and general population, respectively. C1 [Vermeulen, Roel; Vlaanderen, Jelle; Portengen, Lutzen] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Utrecht, Netherlands. [Silverman, Debra T.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Garshick, Eric] Vet Affairs Boston Healthcare Syst, Med Serv, Pulm & Crit Care Med Sect, Boston, MA USA. [Garshick, Eric] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Garshick, Eric] Harvard Univ, Sch Med, Boston, MA USA. [Vlaanderen, Jelle] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Steenland, Kyle] Emory Univ, Dept Environm & Occupat Hlth, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Vermeulen, R (reprint author), Yalelaan 2, NL-3584 CM Utrecht, Netherlands. EM R.C.H.Vermeulen@uu.nl RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 33 TC 33 Z9 33 U1 10 U2 125 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2014 VL 122 IS 2 BP 172 EP 177 DI 10.1289/ehp.1306880 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AC6QY UT WOS:000332650500021 PM 24273233 ER PT J AU Golding, J Steer, CD Lowery, T Hibbeln, JR AF Golding, Jean Steer, Colin D. Lowery, Tony Hibbeln, Joseph R. TI ALSPAC Mercury Study and Fish Consumers: Golding et al. Respond SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID UK TOTAL DIET; CONSUMPTION; EXPOSURE; COHORT C1 [Golding, Jean; Steer, Colin D.] Univ Bristol, Ctr Child & Adolescent Hlth, Bristol, Avon, England. [Lowery, Tony] NOAA, Natl Seafood Inspect Lab, Natl Marine Fisheries Serv, Pascagoula, MS USA. [Hibbeln, Joseph R.] NIAAA, NIH, US Dept HHS, Bethesda, MD USA. RP Golding, J (reprint author), Univ Bristol, Ctr Child & Adolescent Hlth, Bristol, Avon, England. EM jean.golding@bristol.ac.uk NR 7 TC 0 Z9 0 U1 2 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2014 VL 122 IS 2 BP A38 EP A39 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AC6QY UT WOS:000332650500003 PM 24486699 ER PT J AU Ostroumova, E Rozhko, A Hatch, M Furukawa, K Polyanskaya, O McConnell, RJ Nadyrov, E Petrenko, S Romanov, G Yauseyenka, V Drozdovitch, V Minenko, V Prokopovich, A Savasteeva, I Zablotska, LB Mabuchi, K Brenner, AV AF Ostroumova, Evgenia Rozhko, Alexander Hatch, Maureen Furukawa, Kyoji Polyanskaya, Olga McConnell, Robert J. Nadyrov, Eldar Petrenko, Sergey Romanov, George Yauseyenka, Vasilina Drozdovitch, Vladimir Minenko, Viktor Prokopovich, Alexander Savasteeva, Irina Zablotska, Lydia B. Mabuchi, Kiyohiko Brenner, Alina V. TI Iodine-131 and Thyroid Function: Ostroumova et al. Respond SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID BELARUSIAN CHILDREN; RADIATION; ACCIDENT C1 [Ostroumova, Evgenia; Hatch, Maureen; Drozdovitch, Vladimir; Mabuchi, Kiyohiko; Brenner, Alina V.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rozhko, Alexander; Polyanskaya, Olga; Nadyrov, Eldar; Romanov, George; Yauseyenka, Vasilina; Prokopovich, Alexander; Savasteeva, Irina] Republican Res Ctr Radiat Med & Human Ecol, Gomel, Byelarus. [Furukawa, Kyoji] Radiat Effects Res Fdn, Dept Stat, Hiroshima, Japan. [McConnell, Robert J.] Columbia Univ, Thyroid Ctr, New York, NY USA. [Petrenko, Sergey] Int Sakharov Environm Univ, Dept Anthropoecol & Epidemiol, Minsk, Byelarus. [Minenko, Viktor] Belarusian Med Acad Postgrad Educ, Minsk, Byelarus. [Zablotska, Lydia B.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Ostroumova, E (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM ostroume@mail.nih.gov NR 6 TC 0 Z9 0 U1 1 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2014 VL 122 IS 2 BP A40 EP A41 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AC6QY UT WOS:000332650500005 PM 24486619 ER PT J AU Patz, EF Pinsky, P Gatsonis, C Sicks, JD Kramer, BS Tammemagi, MC Chiles, C Black, WC Aberle, DR AF Patz, Edward F., Jr. Pinsky, Paul Gatsonis, Constantine Sicks, JoRean D. Kramer, Barnett S. Tammemaegi, Martin C. Chiles, Caroline Black, William C. Aberle, Denise R. CA NLST Overdiagnosis Manuscript Writ TI Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer SO JAMA INTERNAL MEDICINE LA English DT Article ID FOLLOW-UP; PROJECT; BIAS; MORTALITY; PROGRAM AB IMPORTANCE Screening for lung cancer has the potential to reduce mortality, but in addition to detecting aggressive tumors, screening will also detect indolent tumors that otherwise may not cause clinical symptoms. These overdiagnosis cases represent an important potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment. OBJECTIVE To estimate overdiagnosis in the National Lung Screening Trial (NLST). DESIGN, SETTING, AND PARTICIPANTS We used data from the NLST, a randomized trial comparing screening using low-dose computed tomography (LDCT) vs chest radiography (CXR) among 53 452 persons at high risk for lung cancer observed for 6.4 years, to estimate the excess number of lung cancers in the LDCT arm of the NLST compared with the CXR arm. MAIN OUTCOMES AND MEASURES We calculated 2 measures of overdiagnosis: the probability that a lung cancer detected by screening with LDCT is an overdiagnosis (P-S), defined as the excess lung cancers detected by LDCT divided by all lung cancers detected by screening in the LDCT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent 1 death from lung cancer. RESULTS During follow-up, 1089 lung cancers were reported in the LDCT arm and 969 in the CXR arm of the NLST. The probability is 18.5% (95% CI, 5.4%-30.6%) that any lung cancer detected by screening with LDCT was an overdiagnosis, 22.5% (95% CI, 9.7%-34.3%) that a non-small cell lung cancer detected by LDCT was an overdiagnosis, and 78.9% (95% CI, 62.2%-93.5%) that a bronchioalveolar lung cancer detected by LDCT was an overdiagnosis. The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent 1 death from lung cancer was 1.38. CONCLUSIONS AND RELEVANCE More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer. C1 [Patz, Edward F., Jr.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Patz, Edward F., Jr.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Pinsky, Paul; Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Gatsonis, Constantine; Sicks, JoRean D.] Brown Sch Publ Hlth, Ctr Stat Sci, Providence, RI USA. [Gatsonis, Constantine] Brown Sch Publ Hlth, Dept Biostat, Providence, RI USA. [Tammemaegi, Martin C.] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [Chiles, Caroline] Wake Forest Univ, Hlth Sci Ctr, Dept Radiol, Winston Salem, NC 27109 USA. [Black, William C.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Radiol, Hanover, NH 03756 USA. [Aberle, Denise R.] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. RP Patz, EF (reprint author), Duke Univ, Med Ctr, Dept Radiol, Box 3808, Durham, NC 27710 USA. EM patz0002@mc.duke.edu OI Aberle, Denise/0000-0002-8858-3401 FU National Institutes of Health [U01 CA079778, U01 CA080098, N01-CN-25511, N01-CN-25512, N01-CN-25513, N01-CN-25514, N01-CN-25515, N01-CN-25516, N01-CN-25518, N01-CN-25522, N01-CN-25524, N01-CN-75022, N01-CN-25476, N02-CN-63300] FX This research was supported by the National Institutes of Health (grants U01 CA079778 and U01 CA080098 and contracts N01-CN-25511, N01-CN-25512, N01-CN-25513, N01-CN-25514, N01-CN-25515, N01-CN-25516, N01-CN-25518, N01-CN-25522, N01-CN-25524, N01-CN-75022, N01-CN-25476, and N02-CN-63300). NR 19 TC 162 Z9 163 U1 4 U2 23 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD FEB PY 2014 VL 174 IS 2 BP 269 EP 274 DI 10.1001/jamainternmed.2013.12738 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA AD2FM UT WOS:000333049200022 PM 24322569 ER PT J AU Kepka, D Breen, N King, JB Benard, VB Saraiya, M AF Kepka, Deanna Breen, Nancy King, Jessica B. Benard, Vicki B. Saraiya, Mona TI Overuse of Papanicolaou Testing Among Older Women and Among Women Without a Cervix SO JAMA INTERNAL MEDICINE LA English DT Letter ID CANCER C1 [Kepka, Deanna] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Kepka, Deanna] Univ Utah, Coll Nursing, Salt Lake City, UT 84112 USA. [Kepka, Deanna; Breen, Nancy] NCI, Hlth Serv & Econ Branch, NIH, Rockville, MD USA. [King, Jessica B.] Ctr Dis Control & Prevent, Canc Surveillance Branch, Atlanta, GA USA. [Benard, Vicki B.; Saraiya, Mona] Ctr Dis Control & Prevent, Epidemiol & Appl Res Branch, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Kepka, D (reprint author), Univ Utah, Coll Nursing, Huntsman Canc Inst, 2000 Circle Hope,Room 4144, Salt Lake City, UT 84112 USA. EM deanna.kepka@hci.utah.edu FU Intramural CDC HHS [CC999999] NR 6 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD FEB PY 2014 VL 174 IS 2 BP 293 EP 296 DI 10.1001/jamainternmed.2013.12607 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AD2FM UT WOS:000333049200031 PM 24276745 ER PT J AU Lima, FO Furie, KL Silva, GS Lev, MH Camargo, ECS Singhal, AB Harris, GJ Halpern, EF Koroshetz, WJ Smith, WS Nogueira, RG AF Lima, Fabricio O. Furie, Karen L. Silva, Gisele S. Lev, Michael H. Camargo, Erica C. S. Singhal, Aneesh B. Harris, Gordon J. Halpern, Elkan F. Koroshetz, Walter J. Smith, Wade S. Nogueira, Raul G. TI Prognosis of Untreated Strokes Due to Anterior Circulation Proximal Intracranial Arterial Occlusions Detected by Use of Computed Tomography Angiography SO JAMA NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; ENDOVASCULAR TREATMENT; RANDOMIZED-TRIAL; THROMBECTOMY AB IMPORTANCE Limited data exist regarding the natural history of proximal intracranial arterial occlusions. OBJECTIVE To investigate the outcomes of patients who had an acute ischemic stroke attributed to an anterior circulation proximal intracranial arterial occlusion. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study at 2 university-based hospitals from 2003 to 2005 in which nonenhanced computed tomography scans and computed tomography angiograms were obtained at admission of all adult patients suspected of having an ischemic stroke in the first 24 hours of symptom onset. EXPOSURE Anterior circulation proximal intracranial arterial occlusion. MAIN OUTCOMES AND MEASURES Frequency of good outcome (defined as a modified Rankin Scale score of <= 2) and mortality at 6 months. RESULTS A total of 126 patients with a unilateral complete occlusion of the intracranial internal carotid artery (ICA; 26 patients: median National Institutes of Health Stroke Scale [NIHSS] score, 11 [interquartile range, 5-17]), of the M1 segment of the middle cerebral artery (MCA; 52 patients: median NIHSS score, 13 [interquartile range, 6-16]), or of the M2 segment of the MCA (48 patients: median NIHSS score, 7 [interquartile range, 4-15]) were included. Of these 3 groups of patients, 10 (38.5%), 20 (38.5%), and 26 (54.2%) with ICA, MCA-M1, and MCA-M2 occlusions, respectively, achieved a modified Rankin Scale score of 2 or less, and 6 (23.1%), 12 (23.1%), and 10 (20.8%) were dead at 6 months. Worse outcomes were seen in patients with a baseline NIHSS score of 10 or higher, with a modified Rankin Scale score of 2 or less achieved in only 7.1% (1 of 14), 23.5% (8 of 34), and 22.7% (5 of 22) of patients and mortality rates of 35.7% (5 of 14), 32.4% (11 of 34), and 40.9% (9 of 22) among patients with ICA, MCA-M1, and MCA-M2 occlusions, respectively. Age (odds ratio, 0.94 [95% CI, 0.91-0.98]), NIHSS score (odds ratio, 0.73 [95% CI, 0.64-0.83]), and strength of leptomeningeal collaterals (odds ratio, 2.37 [95% CI, 1.08-5.20]) were independently associated with outcome, whereas the level of proximal intracranial arterial occlusion (ICA vs MCA-M1 vs MCA-M2) was not. CONCLUSIONS AND RELEVANCE The natural history of proximal intracranial arterial occlusion is variable, with poor outcomes overall. Stroke severity and collateral flow appear to be more important than the level of proximal intracranial arterial occlusion in determining outcomes. Our results provide useful data for proper patient selection and sample size calculations in the design of new clinical trials aimed at recanalization therapies. C1 [Lima, Fabricio O.] Univ Estadual Campinas, Dept Neurol, Neurovasc Serv, Sao Paulo, Brazil. [Furie, Karen L.] Brown Univ, Dept Neurol, Providence, RI 02912 USA. [Silva, Gisele S.] Univ Fed Sao Paulo, Dept Neurol, Neurovasc Serv, Sao Paulo, Brazil. [Lev, Michael H.; Harris, Gordon J.; Halpern, Elkan F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Camargo, Erica C. S.] Boston Univ, Boston Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Singhal, Aneesh B.] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. [Smith, Wade S.] Univ Calif San Francisco, Dept Neurol, Neurovasc Serv, San Francisco, CA USA. [Nogueira, Raul G.] Emory Univ, Grady Mem Hosp, Sch Med, Neuroendovasc & Neurocrit Care Serv,Marcus Stroke, Atlanta, GA USA. RP Nogueira, RG (reprint author), Emory Univ, Sch Med, Grady Mem Hosp, Neuroendovasc & Neurocrit Care Serv,Marcus Stroke, 80 Jesse Hill Dr SE,Room 398, Atlanta, GA 30303 USA. EM raul.g.nogueira@emory.edu FU US Department of Health and Human Services/Agency for Healthcare Research and Quality [RO1-HS011392-O1A1] FX This research was funded by grant RO1-HS011392-O1A1 from the US Department of Health and Human Services/Agency for Healthcare Research and Quality. NR 16 TC 27 Z9 30 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD FEB PY 2014 VL 71 IS 2 BP 151 EP 157 DI 10.1001/jamaneurol.2013.5007 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AC9BY UT WOS:000332830300004 PM 24323077 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, Collen Ballard-Barbash, Rachel Irwin, Melinda L. Hollenbeck, Albert Gierach, Gretchen L. Brinton, Louise A. Pfeiffer, Ruth M. Matthews, Charles E. TI Comparative Proteome Analysis Revealing an 11-Protein Signature for Aggressive Triple-Negative Breast Cancer Response SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID BODY-MASS INDEX; SURVIVAL C1 [Arem, Hannah; Park, Yikyung; Pelser, Collen; 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. [Irwin, Melinda L.] Yale Univ, Sch Publ Hlth, Yale Canc Ctr, New Haven, CT USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Arem, H (reprint author), 9609 Med Ctr Dr,Rm 6E324, Rockville, MD 20892 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 NR 4 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD FEB PY 2014 VL 106 IS 2 AR djt377 DI 10.1093/jnci/djt377 PG 1 WC Oncology SC Oncology GA AD2UL UT WOS:000333090800011 PM 24389423 ER PT J AU Freidlin, B Korn, EL AF Freidlin, Boris Korn, Edward L. TI A Model Too Far SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CANCER C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov FU Cancer Research UK [10118] NR 11 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD FEB PY 2014 VL 106 IS 2 AR djt368 DI 10.1093/jnci/djt368 PG 2 WC Oncology SC Oncology GA AD2UL UT WOS:000333090800002 PM 24399851 ER PT J AU Salomon, D AF Salomon, David TI Transforming Growth Factor beta in Cancer: Janus, the Two-Faced God SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID TGF-BETA; STEM-CELLS; MEMBERS; ROLES C1 NCI, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Salomon, D (reprint author), NCI, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Bldg 560 Rm 12-67, Frederick, MD 21702 USA. EM salomond@mail.nih.gov NR 16 TC 2 Z9 2 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD FEB PY 2014 VL 106 IS 2 AR djt441 DI 10.1093/jnci/djt441 PG 2 WC Oncology SC Oncology GA AD2UL UT WOS:000333090800025 PM 24511109 ER PT J AU Trabert, B Ness, RB Lo-Ciganic, WH Murphy, MA Goode, EL Poole, EM Brinton, LA Webb, PM Nagle, CM Jordan, SJ Risch, HA Rossing, MA Doherty, JA Goodman, MT Lurie, G Kjaer, SK Hogdall, E Jensen, A Cramer, DW Terry, KL Vitonis, A Bandera, EV Olson, S King, MG Chandran, U Anton-Culver, H Ziogas, A Menon, U Gayther, SA Ramus, SJ Gentry-Maharaj, A Wu, AH Pearce, CL Pike, MC Berchuck, A Schildkraut, JM Wentzensen, N AF Trabert, Britton Ness, Roberta B. Lo-Ciganic, Wei-Hsuan Murphy, Megan A. Goode, Ellen L. Poole, Elizabeth M. Brinton, Louise A. Webb, Penelope M. Nagle, Christina M. Jordan, Susan J. Risch, Harvey A. Rossing, Mary Anne Doherty, Jennifer A. Goodman, Marc T. Lurie, Galina Kjaer, Susanne K. Hogdall, Estrid Jensen, Allan Cramer, Daniel W. Terry, Kathryn L. Vitonis, Allison Bandera, Elisa V. Olson, Sara King, Melony G. Chandran, Urmila Anton-Culver, Hoda Ziogas, Argyrios Menon, Usha Gayther, Simon A. Ramus, Susan J. Gentry-Maharaj, Aleksandra Wu, Anna H. Pearce, Celeste Leigh Pike, Malcolm C. Berchuck, Andrew Schildkraut, Joellen M. Wentzensen, Nicolas CA Australian Ovarian Canc Study Grp Ovarian Canc Assoc Consortium TI Aspirin, Nonaspirin Nonsteroidal Anti-inflammatory Drug, and Acetaminophen Use and Risk of Invasive Epithelial Ovarian Cancer: A Pooled Analysis in the Ovarian Cancer Association Consortium SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; INCESSANT OVULATION; ENDOMETRIAL CANCER; PRIMARY PREVENTION; ANALGESIC DRUGS; SCREENING TRIAL; HORMONE-THERAPY; WOMENS HEALTH; UNITED-STATES; INFLAMMATION AB Background Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. Methods We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11 843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. Results Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (>= 500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). Conclusions Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use. C1 [Trabert, Britton; Brinton, Louise A.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Lo-Ciganic, Wei-Hsuan] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Murphy, Megan A.; Poole, Elizabeth M.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Murphy, Megan A.; Poole, Elizabeth M.; Cramer, Daniel W.; Terry, Kathryn L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Webb, Penelope M.; Nagle, Christina M.; Jordan, Susan J.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. Peter MacCallum Canc Ctr, East Melbourne, Australia. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Rossing, Mary Anne; Doherty, Jennifer A.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Doherty, Jennifer A.] Dartmouth Med Sch, Sect Biostat & Epidemiol, Dept Community & Family Med, Lebanon, NH USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Lurie, Galina] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Kjaer, Susanne K.; Hogdall, Estrid; Jensen, Allan] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Kjaer, Susanne K.] Copenhagen Univ Hosp, Gynaecol Clin, Copenhagen, Denmark. [Bandera, Elisa V.; King, Melony G.; Chandran, Urmila] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Olson, Sara] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, EGA Inst Womens Hlth, Dept Womens Canc, London, England. [Gayther, Simon A.; Ramus, Susan J.; Pike, Malcolm C.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. RP Trabert, B (reprint author), Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Ste 550,MSC 7234, Rockville, MD 20852 USA. EM britton.trabert@nih.gov RI Bandera, Elisa/M-4169-2014; Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015; Bowtell, David/H-1007-2016; OI Bandera, Elisa/0000-0002-8789-2755; Brinton, Louise/0000-0003-3853-8562; Bowtell, David/0000-0001-9089-7525; Ramus, Susan/0000-0003-0005-7798; Kjaer, Susanne/0000-0002-8347-1398; Webb, Penelope/0000-0003-0733-5930 FU Ovarian Cancer Research Fund; Intramural Research Program of the National Institutes of Health (NIH); US Army Medical Research and Material Command [DAMD17-01-1-0729]; National Health and Medical Research Council of Australia [199600, 400413]; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Queensland; Cancer Council of South Australia; Cancer Council of Tasmania; Cancer Foundation of Western Australia; Department of Defense (DOD) [DAMD17-02-1-0669]; Danish Cancer Society, Copenhagen, Denmark [94 222 52]; Mermaid I project; DOD [DAMD17-02-1-0666, W81XWH-10-1-02802]; National Cancer Institute [K07 CA095666, R01 CA83918, K22CA138563]; Cancer Institute of New Jersey; Lon V Smith Foundation [LVS-39420]; Cancer Research UK; Eve Appeal; OAK Foundation; California Cancer Research Program [00-01389V-20170, R03 CA113148, R03 CA115195, N01 CN25403, 2II0200]; [T32 CA 09001]; [R01 CA122443]; [P50-CA136393]; [R01 CA074850]; [R01 CA080742]; [R01 CA112523]; [R01 CA87538]; [R01 CA58598]; [N01 CN55424]; [N01 PC67001]; [R01 CA95023]; [R01 CA61107]; [R01 CA76016]; [R01 CA54419]; [P50 CA105009]; [R01 CA58860]; [R01 CA92044]; [PSA 042205]; [R01 CA17054]; [R01 CA14089]; [R01 CA61132]; [N01-PC-67010]; [P01 CA17054] FX The Ovarian Cancer Association Consortium was supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith. This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). Elizabeth Poole and Megan Murphy are both supported in part by training grant T32 CA 09001. Ellen Goode is supported by R01 CA122443 and P50-CA136393. The Australian Ovarian Cancer Study and Australian Cancer Study were funded by the US Army Medical Research and Material Command (DAMD17-01-1-0729), National Health and Medical Research Council of Australia (199600, 400413), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia. The Connecticut Ovarian Cancer Study was funded by R01 CA074850 and R01 CA080742. The Diseases of the Ovary and their Evaluation Study was funded by R01 CA112523 and R01 CA87538. The Hawaii Ovarian Cancer Case-Control Study was funded by R01 CA58598, N01 CN55424 and N01 PC67001. The Hormones and Ovarian Cancer Prediction Study was funded by R01 CA95023 and Department of Defense (DOD) grant DAMD17-02-1-0669. The Malignant Ovarian Cancer Study was funded by R01 CA61107, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark, and the Mermaid I project. The North Carolina Ovarian Cancer Study was funded by R01 CA76016 and DOD grant DAMD17-02-1-0666. The New England Case-Control Study of Ovarian Cancer was funded by R01 CA54419, P50 CA105009, and DOD grant W81XWH-10-1-02802. The New Jersey Ovarian Cancer Study was funded by the National Cancer Institute (K07 CA095666, R01 CA83918, and K22CA138563) and the Cancer Institute of New Jersey. The University of California, Irvine Ovarian Cancer Study was funded by R01 CA58860, R01 CA92044, PSA 042205, and the Lon V Smith Foundation grant LVS-39420. The United Kingdom Ovarian Cancer Population Study was funded by Cancer Research UK, the Eve Appeal and the OAK Foundation. The University of Southern California, Study of Lifestyle and Women's Health was funded by R01 CA17054, R01 CA14089, R01 CA61132, N01-PC-67010, P01 CA17054, California Cancer Research Program (00-01389V-20170, R03 CA113148, R03 CA115195, N01 CN25403), and California Cancer Research Program (2II0200) (USC). The funding agencies did not have any role in conducting the study or preparing the manuscript for publication. NR 61 TC 31 Z9 33 U1 4 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD FEB PY 2014 VL 106 IS 2 AR djt431 DI 10.1093/jnci/djt431 PG 11 WC Oncology SC Oncology GA AD2UL UT WOS:000333090800016 PM 24503200 ER PT J AU Parker, SE Troisi, R Wise, LA Palmer, JR Titus-Ernstoff, L Strohsnitter, WC Hatch, EE AF Parker, Samantha E. Troisi, Rebecca Wise, Lauren A. Palmer, Julie R. Titus-Ernstoff, Linda Strohsnitter, William C. Hatch, Elizabeth E. TI Menarche, Menopause, Years of Menstruation, and the Incidence of Osteoporosis: The Influence of Prenatal Exposure to Diethylstilbestrol SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; IN-UTERO; REPRODUCTIVE FACTORS; ESTROGEN EXPOSURE; FRACTURE RISK; US WOMEN; AGE; HISTORY; PREVENTION AB Context: Estrogen is critical for bone formation and growth in women. Estrogen exposures occur throughout life, including prenatally, and change with reproductive events, such as menarche and menopause. Objective: The objective of this study was to investigate the association between age at menarche, age at menopause, and years of menstruation with incidence of osteoporosis and assess the impact of prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, on such associations. Design, Setting, and Participants: Participants were 5573 women in the National Cancer Institute Combined Cohort Study of DES (1994-2006). Data on reproductive history and medical conditions were collected through questionnaires at baseline in 1994 and subsequently in 1997, 2001, and 2006. Age-stratified Cox regression models were used to calculate multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Effect measure modification by prenatal DES exposure was assessed using cubic restricted spline regression models. Main Outcome Measure: Osteoporosis was the main outcome measure. Results: The IRRs for osteoporosis incidence with age at menarche less than 11 years and age at menopause of 50 years or younger were 0.82 (CI 0.59, 1.14) and 0.61 (CI 0.40, 0.92), respectively. Fewer than 25 years of menstruation was associated with an increased incidence of osteoporosis (IRR 1.80; CI 1.14, 2.86) compared with 35 years or more of menstruation. Associations were stronger among women who had not been prenatally exposed to DES. Conclusions: Our data support the hypothesis that lifetime cumulative exposure to estrogens is protective against osteoporosis. Furthermore, prenatal exposure to estrogen appears to modify these associations, although the mechanism by which this occurs is unknown. C1 [Parker, Samantha E.; Wise, Lauren A.; Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH 03756 USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Pediat, Lebanon, NH 03756 USA. Norris Cotton Canc Ctr, Lebanon, NH 03756 USA. [Strohsnitter, William C.] Tufts Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. [Wise, Lauren A.; Palmer, Julie R.; Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. RP Parker, SE (reprint author), Slone Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. EM separker@bu.edu OI /0000-0002-7193-077X FU National Institutes of Health [T32 HD052458] FX S.E.P. was a predoctoral trainee supported by National Institutes of Health Grant T32 HD052458 (to the Boston University Reproductive, Perinatal and Pediatric Epidemiology training program). NR 37 TC 8 Z9 8 U1 3 U2 11 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2014 VL 99 IS 2 BP 594 EP 601 DI 10.1210/jc.2013-2954 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AD7QS UT WOS:000333460300059 PM 24248183 ER PT J AU Ellis, RJ Wang, YH Stevenson, HS Boufraqech, M Patel, D Nilubol, N Davis, S Edelman, DC Merino, MJ He, M Zhang, LS Meltzer, PS Kebebew, E AF Ellis, Ryan J. Wang, Yonghong Stevenson, Holly S. Boufraqech, Myriem Patel, Dhaval Nilubol, Naris Davis, Sean Edelman, Daniel C. Merino, Maria J. He, Mei Zhang, Lisa Meltzer, Paul S. Kebebew, Electron TI Genome-Wide Methylation Patterns in Papillary Thyroid Cancer Are Distinct Based on Histological Subtype and Tumor Genotype SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BRAF V600E MUTATION; DNA METHYLATION; FOLLICULAR VARIANT; SUPPRESSOR GENES; CELL-LINES; CARCINOMA; 5-AZA-2'-DEOXYCYTIDINE; DIFFERENTIATION; ASSOCIATION; EXPRESSION AB Context: Aberrant DNA methylation is known to be a major factor in oncogenesis and cancer progression, but effects of methylation in papillary thyroid cancer (PTC) are not well defined. Objective: The objective of the study was to identify altered methylation patterns, which may be associated with PTC disease behavior. Design: This study was a genome-wide methylation analysis of PTC. Setting: The study was conducted at the National Institutes of Health Clinical Center. Patients: PTC tissue from 51 patients were analyzed and compared with normal thyroid tissue from seven patients. Interventions: CpG methylation status was assessed using advanced genome-wide methylation bead chips. Outcome Measures: Altered methylation patterns in PTC were analyzed by stage, recurrence, histological subtype of tumor, and tumor genotype. Results: PTC is globally hypomethylated compared with normal thyroid with 2837 differentially methylated CpG sites. The follicular variant of PTC demonstrated less differential methylation with only 569 differentially methylated CpG sites. Tumors with mutations in BRAF, RET/PTC, and RAS demonstrated a 3.6-fold increase in the number of differentially methylated sites compared with wild-type tumors. The differentially methylated genes were associated with oncological pathways including cellular movement, growth, and proliferation. Conclusion: PTC is epigenetically distinct from the follicular variant of PTC and by gene mutation status (BRAF, RET/PTC, and RAS). C1 [Ellis, Ryan J.; Boufraqech, Myriem; Patel, Dhaval; Nilubol, Naris; He, Mei; Zhang, Lisa; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Yonghong; Stevenson, Holly S.; Davis, Sean; Edelman, Daniel C.; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Ellis, Ryan J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Room 3-5581, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Boufraqech, Myriem/E-4823-2016; OI Davis, Sean/0000-0002-8991-6458; Patel, Dhaval/0000-0002-5744-568X FU Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 39 TC 10 Z9 11 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2014 VL 99 IS 2 BP E329 EP E337 DI 10.1210/jc.2013-2749 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AD7QS UT WOS:000333460300019 PM 24423287 ER PT J AU Jung, CK Little, MP Lubin, JH Brenner, AV Wells, SA Sigurdson, AJ Nikiforov, YE AF Jung, Chan Kwon Little, Mark P. Lubin, Jay H. Brenner, Alina V. Wells, Samuel A., Jr. Sigurdson, Alice J. Nikiforov, Yuri E. TI The Increase in Thyroid Cancer Incidence During the Last Four Decades Is Accompanied by a High Frequency of BRAF Mutations and a Sharp Increase in RAS Mutations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PAPILLARY CARCINOMAS; HEPATOCELLULAR CARCINOMAS; RET/PTC REARRANGEMENTS; CLINICAL-IMPLICATIONS; EXTERNAL RADIATION; FOLLICULAR VARIANT; K-RAS-2 MUTATIONS; HIGH PREVALENCE; GENE-MUTATIONS; VINYL-CHLORIDE AB Context: Thyroid cancer incidence rates in the United States and globally have increased steadily over the last 40 years, primarily due to a tripling of the incidence of papillary thyroid carcinoma (PTC). Objective: The purpose of this study was to analyze trends in demographic, clinical, pathologic, and molecular characteristics of PTC from 1974 to 2009. Design and Setting: We identified and histologically reviewed 469 consecutive cases of PTC from one US institution from 4 preselected periods (1974 to 1985, 1990 to 1992, 2000, and 2009) and assessed BRAF and RAS point mutations and RET/PTC rearrangements among 341 tumors >= 0.3 cm in size. Changes over time were analyzed using polytomous and binary logistic regression; all analyses were adjusted for age and sex. Results: During this period, the median age of patients at diagnosis increased from 37 to 53 years (P < .001) and the percentage of microcarcinomas (<= 1.0 cm) increased from 33% to 51% (P < .001), whereas extrathyroidal extension and advanced tumor stage decreased from 40% to 21% (P = .005) and from 43% to 28% (P = .036), respectively. Changes in tumor histopathology showed a decrease in classic PTC and an increase in the follicular variant (P < .001). The proportion of tumors with a BRAF mutation was stable (similar to 46%) but increased from 50% to 77% (P = .008) within classic papillary PTCs. The proportion of tumors with RAS mutations increased from 3% to 25% and within follicular pattern tumors from 18% to 44% (P < .001). The proportion of RET/PTC rearrangements decreased from 11% to 2% (P = .038). Conclusions: Similar to US national trends, we found an increasing age at diagnosis and greater detection of smaller-sized intrathyroidal PTCs. However, the overall proportion of BRAF mutations remained stable. Sharply rising percentages of the follicular variant histology and RAS mutations after 2000 suggest new and more recent etiologic factors. The increased incidence is not likely to be due to environmental or therapeutic radiation because the percentage of RET/PTC rearrangements decreased. C1 [Jung, Chan Kwon; Nikiforov, Yuri E.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Jung, Chan Kwon] Catholic Univ Korea, Dept Hosp Pathol, Seoul 137701, South Korea. [Little, Mark P.; Lubin, Jay H.; Brenner, Alina V.; Sigurdson, Alice J.] NCI, Radiat Epidemiol & Biostat Branches, NIH, Bethesda, MD 20892 USA. [Wells, Samuel A., Jr.] NCI, Div Canc Epidemiol, NIH, Bethesda, MD 20892 USA. [Wells, Samuel A., Jr.] NCI, Genet & Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Nikiforov, YE (reprint author), Univ Pittsburgh, Dept Pathol, PUH, 200 Lothrop St,Room C-606, Pittsburgh, PA 15213 USA. EM nikiforovye@upmc.edu OI Little, Mark/0000-0003-0980-7567 FU Intramural Research Program of the National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics; NCI [HSSN261200900017C/N02CP-90017]; [5-312-0212208] FX This work was supported by the Intramural Research Program of the National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics and NCI contract HSSN261200900017C/N02CP-90017 with subcontract 5-312-0212208 to the University of Pittsburgh. NR 50 TC 66 Z9 72 U1 0 U2 13 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2014 VL 99 IS 2 BP E276 EP E285 DI 10.1210/jc.2013-2503 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AD7QS UT WOS:000333460300013 PM 24248188 ER PT J AU London, E Rothenbuhler, A Lodish, M Gourgari, E Keil, M Lyssikatos, C Sierra, MD Patronas, N Nesterova, M Stratakis, CA AF London, Edra Rothenbuhler, Anya Lodish, Maya Gourgari, Evgenia Keil, Meg Lyssikatos, Charalampos Sierra, Maria de la Luz Patronas, Nicolas Nesterova, Maria Stratakis, Constantine A. TI Differences in Adiposity in Cushing Syndrome Caused by PRKAR1A Mutations: Clues for the Role of Cyclic AMP Signaling in Obesity and Diagnostic Implications SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PROTEIN-KINASE-A; NODULAR ADRENOCORTICAL DISEASE; RII-BETA-SUBUNIT; MACRONODULAR ADRENAL-HYPERPLASIA; REGULATORY SUBUNIT; CARNEY COMPLEX; TARGETED DISRUPTION; TUMORS; EXPRESSION; MICE AB Context: The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias. Bilateral adrenocortical hyperplasia is often associated with ACTH-independent Cushing syndrome (CS) and may be caused by mutations in genes such as PRKAR1A, which is responsible for primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A regulates cAMP-dependent protein kinase (PKA), an essential enzyme in the regulation of adiposity. Although CS is invariably associated with obesity, its different forms, including those associated with PKA defects, have not been compared. Objective: The purpose of this study was to characterize the phenotypic and molecular differences in periadrenal adipose tissue (PAT) between patients with CS with and without PRKAR1A mutations. Design and Setting: Samples from adrenalectomies of 51 patients were studied: patients with CS with (n = 13) and without (n = 32) PRKAR1A mutations and a comparison group with aldosterone-producing adenomas (APAs) (n = 6). In addition, clinical data from a larger group of patients with Cushing disease (n = 89) and hyperaldosteronism (n = 26) were used for comparison. Methods: Body mass index (BMI), abdominal computed tomography scans, and cortisol data were collected preoperatively. PAT was assayed for PKA activity, cAMP levels, and PKA subunit expression. Results: BMI was lower in adult patients with CS with PRKAR1A mutations. cAMP and active PKA levels in PAT were elevated in patients with CS with PRKAR1A mutations. Conclusions: Increased PKA signaling in PAT was associated with lower BMI in CS. Differences in fat distribution may contribute to phenotypic differences between patients with CS with and without PRKAR1A mutations. The observed differences are in agreement with the known roles of cAMP signaling in regulating adiposity, but this is the first time that germline defects of PKA are linked to variable obesity phenotypes in humans. C1 [London, Edra; Rothenbuhler, Anya; Lodish, Maya; Gourgari, Evgenia; Keil, Meg; Lyssikatos, Charalampos; Sierra, Maria de la Luz; Nesterova, Maria; Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Canc Ctr, Bethesda, MD 20892 USA. [Gourgari, Evgenia] Interinst Pediat Endocrinol Training Program, Clin Res Ctr, NIH, Bethesda, MD 20892 USA. [Patronas, Nicolas; Stratakis, Constantine A.] NIH, Dept Diagnost Radiol, Clin Res Ctr, Bethesda, MD 20892 USA. [Rothenbuhler, Anya] Univ Paris 11, Hop Bicetre, Serv Endocrinol Pediat, F-94270 Le Kremlin Bicetre, France. RP London, E (reprint author), NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Canc Ctr,East Labs, Room 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM londonec@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program FX This work was supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program. NR 29 TC 6 Z9 6 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2014 VL 99 IS 2 BP E303 EP E310 DI 10.1210/jc.2013-1956 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AD7QS UT WOS:000333460300016 PM 24248186 ER PT J AU Jakeman, LB Williams, KE Brautigam, B AF Jakeman, Lyn B. Williams, Kent E. Brautigam, Bryan TI In the presence of danger: the extracellular matrix defensive response to central nervous system injury SO NEURAL REGENERATION RESEARCH LA English DT Article DE nerve regeneration; glial scar; proteoglycan; axon growth; spinal cord injury; contusion; inhibitory; inflammation; astrocyte; macrophage; neural regeneration ID SPINAL-CORD-INJURY; CHONDROITIN SULFATE PROTEOGLYCANS; CELLULAR INFLAMMATORY RESPONSE; BLOOD-BRAIN-BARRIER; PERINEURONAL NETS; REACTIVE ASTROCYTES; CONTUSION INJURY; GROWTH-FACTOR; FUNCTIONAL RECOVERY; SECONDARY INJURY AB Glial cells in the central nervous system (CNS) contribute to formation of the extracellular matrix, which provides adhesive sites, signaling molecules, and a diffusion barrier to enhance efficient neurotransmission and axon potential propagation. In the normal adult CNS, the extracellular matrix (ECM) is relatively stable except in selected regions characterized by dynamic remodeling. However, after trauma such as a spinal cord injury or cortical contusion, the lesion epicenter becomes a focus of acute neuroinflammation. The activation of the surrounding glial cells leads to a dramatic change in the composition of the ECM at the edges of the lesion, creating a perilesion environment dominated by growth inhibitory molecules and restoration of the peripheral/central nervous system border. An advantage of this response is to limit the invasion of damaging cells and diffusion of toxic molecules into the spared tissue regions, but this occurs at the cost of inhibiting migration of endogenous repair cells and preventing axonal regrowth. The following review was prepared by reading and discussing over 200 research articles in the field published in PubMed and selecting those with significant impact and/or controversial points. This article highlights structural and functional features of the normal adult CNS ECM and then focuses on the reactions of glial cells and changes in the perilesion border that occur following spinal cord or contusive brain injury. Current research strategies directed at modifying the inhibitory perilesion microenvironment without eliminating the protective functions of glial cell activation are discussed. C1 [Jakeman, Lyn B.; Williams, Kent E.; Brautigam, Bryan] Ohio State Univ, Dept Physiol & Cell Biol, Wexner Med Ctr, Columbus, OH 43210 USA. [Jakeman, Lyn B.; Williams, Kent E.] Ohio State Univ, Neurosci Grad Studies Program, Wexner Med Ctr, Columbus, OH 43210 USA. [Jakeman, Lyn B.; Brautigam, Bryan] Ohio State Univ, Biomed Res Grad Program, Wexner Med Ctr, Columbus, OH 43210 USA. [Jakeman, Lyn B.; Williams, Kent E.; Brautigam, Bryan] Ohio State Univ, OSU Ctr Brain & Spinal Cord Repair, Wexner Med Ctr, Columbus, OH 43210 USA. RP Jakeman, LB (reprint author), NINDS, 6001 Execut USA, Bethesda, MD 20892 USA. EM lbjake01@gmail.com FU NIH/NINDS [R01-NS043246, P30-NS045758]; International Spinal Research Trust [STR-100]; Ohio State University College of Medicine FX The study was supported by NIH/NINDS R01-NS043246, P30-NS045758, the International Spinal Research Trust (STR-100) and the Ohio State University College of Medicine. NR 66 TC 4 Z9 5 U1 0 U2 15 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 1673-5374 EI 1876-7958 J9 NEURAL REGEN RES JI Neural Regen. Res. PD FEB PY 2014 VL 9 IS 4 SI SI BP 377 EP 384 DI 10.4103/1673-5374.128238 PG 8 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA AD3LD UT WOS:000333139700005 PM 24999352 ER PT J AU Clore, GM AF Clore, GM TI Interplay between conformational selection and induced fit in multidomain protein-ligand binding probed by paramagnetic relaxation enhancement SO BIOPHYSICAL CHEMISTRY LA English DT Review DE Paramagnetic relaxation enhancement; Sparsely-populated transient state; Conformational selection; Induced fit; Maltose binding protein; Calmodulin ID NMR-SPECTROSCOPY; ALLOSTERIC TRANSITIONS; DOMAIN REORIENTATION; PEPTIDE COMPLEX; CALMODULIN; TRANSIENT; APO; CA2+-CALMODULIN; MACROMOLECULES; RECOGNITION AB The binding of ligands and substrates to proteins has been extensively studied for many years and can be described, in its simplest form, by two limiting mechanisms: conformational selection and induced fit. Conformational selection involves the binding of ligand to a pre-existing sparsely-populated conformation of the free protein that is the same as that in the final protein-ligand complex. In the case of induced fit, the ligand binds to the major conformation of the free protein and only subsequent to binding undergoes a conformational change to the final protein-ligand complex. While these two mechanisms can be dissected and distinguished by transient kinetic measurements, direct direction, characterization and visualization of transient, sparsely-populated states of proteins are experimentally challenging. Unless trapped, sparsely-populated states are generally invisible to conventional structural and biophysical techniques, including crystallography and most NMR measurements. In this review we summarize some recent developments in the use of paramagnetic relaxation enhancement to directly study sparsely-populated states of proteins and illustrate the application of this approach to two proteins, maltose binding protein and calmodulin, both of which undergo large rigid body conformational rearrangements upon ligand binding from an open apo state to a closed ligand-bound hobo state. We show that the apo state ensemble comprises a small population of partially-closed configurations that are similar but not identical to that of the holo state. These results highlight the complementarity and interplay of induced fit and conformational selection and suggest that the existence of partially-closed states in the absence of ligand facilitates the transition to the closed ligand-bound state. Published by Elsevier B.V. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the NIH; Intramural Program of the NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX G.M.C. thanks members of his laboratory, past and present, and colleagues who have made significant contributions to the development of the PRE to detect sparsely-populated states, in particular, J. Iwahara, C. Tang, C.D. Schwieters, J.-Y. Suh, N. Fawzi, Y. Takayama and N. Anthis. This work was supported by funds from the Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 45 TC 16 Z9 16 U1 6 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 EI 1873-4200 J9 BIOPHYS CHEM JI Biophys. Chem. PD FEB PY 2014 VL 186 SI SI BP 3 EP 12 DI 10.1016/j.bpc.2013.08.006 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA AC3PX UT WOS:000332434800002 PM 24070540 ER PT J AU Nussinov, R Ma, BY Tsai, CJ AF Nussinov, Ruth Ma, Buyong Tsai, Chung-Jung TI Multiple conformational selection and induced fit events take place in allosteric propagation SO BIOPHYSICAL CHEMISTRY LA English DT Review DE Conformational selection; Induced fit; Allostery; Allosteric; Binding; Molecular recognition ID CELL-RECEPTOR ZETA; POPULATION-SHIFT; MOLECULAR RECOGNITION; ENERGY LANDSCAPES; SIGNALING PROTEIN; BINDING CASCADES; FOLDING FUNNELS; DRUG DISCOVERY; PATHWAYS; DOMAIN AB The fact that we observe a single conformational selection event during binding does not necessarily mean that only a single conformational selection event takes place, even though this is the common assumption. Here we suggest that conformational selection takes place not once in a given binding/allosteric event, but at every step along the allosteric pathway. This view generalizes conformational selection and makes it applicable also to other allosteric events, such as post-translational modifications (PTMs) and photon absorption. Similar to binding, at each step along a propagation pathway, conformational selection is coupled with induced fit which optimizes the interactions. Thus, as in binding, the allosteric effects induced by PTMs and light relate not only to population shift; but to conformational selection as well. Conformational selection and population shift take place conjointly. (c) 2013 Elsevier B.V. All rights reserved. C1 [Nussinov, Ruth; Ma, Buyong; Tsai, Chung-Jung] NCI, Leidos Biomed Res Inc, Frederick Natl Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Bldg 469,Rm 151, Frederick, MD 21702 USA. EM NussinoR@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH; Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 110 TC 29 Z9 29 U1 14 U2 54 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 EI 1873-4200 J9 BIOPHYS CHEM JI Biophys. Chem. PD FEB PY 2014 VL 186 SI SI BP 22 EP 30 DI 10.1016/j.bpc.2013.10.002 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA AC3PX UT WOS:000332434800004 PM 24239303 ER PT J AU Chuenchor, W Jin, T Ravilious, G Xiao, TS AF Chuenchor, Watchalee Jin, Tengchuan Ravilious, Geoffrey Xiao, T. Sam TI Structures of pattern recognition receptors reveal molecular mechanisms of autoinhibition, ligand recognition and oligomerization SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID TOLL-LIKE RECEPTOR-3; INNATE IMMUNE RECOGNITION; DOUBLE-STRANDED-RNA; SENSORS RIG-I; CRYSTAL-STRUCTURE; INFLAMMASOME ACTIVATION; AIM2 INFLAMMASOME; TLR4-MD-2 COMPLEX; ADAPTER PROTEIN; MDA5 AB Pattern recognition receptors (PRRs) are essential sentinels for pathogens or tissue damage and integral components of the innate immune system. Recent structural studies have provided unprecedented insights into the molecular mechanisms of ligand recognition and signal transduction by several PRR families at distinct subcellular compartments. Here we highlight some of the recent discoveries and summarize the common themes that are emerging from these exciting studies. Better mechanistic understanding of the structure and function of the PRRs will improve future prospects of therapeutic targeting of these important innate immune receptors. C1 [Chuenchor, Watchalee; Jin, Tengchuan; Ravilious, Geoffrey; Xiao, T. Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Xiao, TS (reprint author), NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM xiaot@niaid.nih.gov RI Xiao, Tsan/A-8590-2010; OI Xiao, Tsan/0000-0001-9688-475X; jin, tengchuan/0000-0002-1395-188X FU Division of Intramural Research; NIAID; NIH FX We thank members of the Xiao lab for critical reading of the manuscript. We apologize for omission of references due to space constraints. T.S.X is supported by the Division of Intramural Research, NIAID, NIH. NR 56 TC 5 Z9 5 U1 2 U2 15 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2014 VL 26 BP 14 EP 20 DI 10.1016/j.coi.2013.10.009 PG 7 WC Immunology SC Immunology GA AD1NV UT WOS:000333001600004 PM 24419035 ER PT J AU Moran, ME Weisinger, B Ludovici, K McAdams, H Greenstein, D Gochman, P Miller, R Clasen, L Rapoport, J Gogtay, N AF Moran, Marcel E. Weisinger, Brian Ludovici, Katharine McAdams, Harrison Greenstein, Deanna Gochman, Pete Miller, Rachel Clasen, Liv Rapoport, Judith Gogtay, Nitin TI At the boundary of the self: The insular cortex in patients with childhood-onset schizophrenia, their healthy siblings, and normal volunteers SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE Psychiatry; Schizophrenia; Neuroimaging; Psychosis ID GEOMETRICALLY ACCURATE; PERSONALITY-DISORDERS; NONPSYCHOTIC SIBLINGS; CORTICAL THICKNESS; BRAIN; MRI; METAANALYSIS; VOLUME; HALLUCINATIONS; ABNORMALITIES AB The insular cortex (insula), whose normal function involves delineating the boundary between self and non-self stimuli, has been implicated in the pathophysiology of the positive symptoms of schizophrenia, including hallucinations and delusions. Childhood-onset schizophrenia (COS), that includes the onset of psychosis before age 13, is a severe and continuous form of the illness which shows profound and global progressive cortical brain abnormalities during adolescence which merge in the adult pattern with age. Using prospectively acquired anatomic brain magnetic resonance imaging (MRI) scans, a matched sample of COS patients, their nonpsychotic full siblings and healthy volunteers, we measured insular volume using the FreeSurfer automated software. COS patients (n=98; 234 scans) had significantly lower right (p = 0.003), left (p < 0.001), and total (p < 0.001) insular volumes than healthy volunteers (n=100; 248 scans). Right insular volume negatively correlated with positive symptoms as measured by the Scale for the Assessment of Positive Symptoms (SAPS) (p = 0.02), while both left (p = 0.01) and right (p = 0.006) insula volumes were positively correlated with overall functioning, as measured by the Children's Global Assessment Scale (CGAS) scores. COS siblings (n = 71; 153 scans), on the other hand, did not differ significantly from normal volunteers suggesting that the insular deficits are more related to the illness state than a familial endophenotype. These results also highlight the salience of the insula in positive symptoms of schizophrenia perhaps resulting from the inability to discriminate between self from the non-self in COS. Further work to connect insular deficits to other neurocircuitries is warranted. Published by Elsevier Ltd. on behalf of ISDN. C1 [Moran, Marcel E.; Weisinger, Brian; Ludovici, Katharine; McAdams, Harrison; Greenstein, Deanna; Gochman, Pete; Miller, Rachel; Clasen, Liv; Rapoport, Judith; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Moran, ME (reprint author), 10 Ctr Dr,Bldg 10,RM 3N202, Bethesda, MD 20894 USA. EM marcel.moran@nih.gov RI Gogtay, Nitin/A-3035-2008 FU Intramural Research Program (IRP) at the National Institutes of Mental Health in Bethesda, Maryland FX The present research was funded by the Intramural Research Program (IRP) at the National Institutes of Mental Health in Bethesda, Maryland. NR 40 TC 6 Z9 6 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 EI 1873-474X J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD FEB PY 2014 VL 32 SI SI BP 58 EP 63 DI 10.1016/j.ijdevneu.2013.05.010 PG 6 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA AD1NW UT WOS:000333001700007 PM 23770018 ER PT J AU Dogan, RI Leaman, R Lu, ZY AF Dogan, Rezarta Islamaj Leaman, Robert Lu, Zhiyong TI NCBI disease corpus: A resource for disease name recognition and concept normalization SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Disease name recognition; Named entity recognition; Disease name normalization; Corpus annotation; Disease name corpus ID ANNOTATED CORPUS; INFORMATION EXTRACTION; BIOMEDICAL LITERATURE; ENTITY RECOGNITION; GENE NORMALIZATION; TEXT; SYSTEM; ONTOLOGY; UMLS; TASK AB Information encoded in natural language in biomedical literature publications is only useful if efficient and reliable ways of accessing and analyzing that information are available. Natural language processing and text mining tools are therefore essential for extracting valuable information, however, the development of powerful, highly effective tools to automatically detect central biomedical concepts such as diseases is conditional on the availability of annotated corpora. This paper presents the disease name and concept annotations of the NCBI disease corpus, a collection of 793 PubMed abstracts fully annotated at the mention and concept level to serve as a research resource for the biomedical natural language processing community. Each PubMed abstract was manually annotated by two annotators with disease mentions and their corresponding concepts in Medical Subject Headings (MeSH(R)) or Online Mendelian Inheritance in Man (OMIM(R)). Manual curation was performed using PubTator, which allowed the use of pre-annotations as a pre-step to manual annotations. Fourteen annotators were randomly paired and differing annotations were discussed for reaching a consensus in two annotation phases. In this setting, a high inter-annotator agreement was observed. Finally, all results were checked against annotations of the rest of the corpus to assure corpus-wide consistency. The public release of the NCBI disease corpus contains 6892 disease mentions, which are mapped to 790 unique disease concepts. Of these, 88% link to a MeSH identifier, while the rest contain an OMIM identifier. We were able to link 91% of the mentions to a single disease concept, while the rest are described as a combination of concepts. In order to help researchers use the corpus to design and test disease identification methods, we have prepared the corpus as training, testing and development sets. To demonstrate its utility, we conducted a benchmarking experiment where we compared three different knowledge-based disease normalization methods with a best performance in F-measure of 63.7%. These results show that the NCBI disease corpus has the potential to significantly improve the state-of-the-art in disease name recognition and normalization research, by providing a high-quality gold standard thus enabling the development of machine-learning based approaches for such tasks. The NCBI disease corpus, guidelines and other associated resources are available at: http://www.ncbi.nlm.nih.gov/CBBresearch/Dogan/DISEASE/. Published by Elsevier Inc. C1 [Dogan, Rezarta Islamaj; Leaman, Robert; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Leaman, Robert] Arizona State Univ, Dept Comp Sci & Engn, Tempe, AZ 85287 USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov FU NIH, National Library of Medicine FX We thank the team of 14 annotators for their time and expertise during the annotation of this corpus, and Francois Lang, Lan Aronson, and Jim Mork for help with Metamap, UMLS and other library tools. Funding: This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 45 TC 35 Z9 36 U1 4 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2014 VL 47 BP 1 EP 10 DI 10.1016/j.jbi.2013.12.006 PG 10 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA AD1OY UT WOS:000333004500001 PM 24393765 ER PT J AU Varadhan, R Yao, WL Matteini, A Beamer, BA Xue, QL Yang, HL Manwani, B Reiner, A Jenny, N Parekh, N Fallin, MD Newman, A Bandeen-Roche, K Tracy, R Ferrucci, L Walston, J AF Varadhan, Ravi Yao, Wenliang Matteini, Amy Beamer, Brock A. Xue, Qian-li Yang, Huanle Manwani, Bhavish Reiner, Alexander Jenny, Nancy Parekh, Neel Fallin, M. Daniele Newman, Anne Bandeen-Roche, Karen Tracy, Russell Ferrucci, Luigi Walston, Jeremy TI Simple Biologically Informed Inflammatory Index of Two Serum Cytokines Predicts 10 Year All-Cause Mortality in Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Inflammation; Cytokine; Mortality; Aging ID C-REACTIVE PROTEIN; CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; INTERLEUKIN-6; ATHEROSCLEROSIS; MARKERS; ASSOCIATION; RECEPTORS; INCHIANTI; SURVIVAL AB Background. Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways. Methods. In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-alpha receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI. Results. The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-alpha receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality. Conclusion. A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-alpha receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured. C1 [Varadhan, Ravi; Yao, Wenliang; Matteini, Amy; Xue, Qian-li; Yang, Huanle; Manwani, Bhavish; Parekh, Neel; Walston, Jeremy] Johns Hopkins Univ, Div Geriatr Med & Gerontol, Ctr Aging & Hlth, Baltimore, MD USA. [Beamer, Brock A.] Baltimore VA Med Ctr, Dept Geriatr, Baltimore, MD 21201 USA. [Reiner, Alexander] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Jenny, Nancy; Tracy, Russell] Univ Vermont, Dept Pathol, Colchester, Essex, England. [Fallin, M. Daniele] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Newman, Anne] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Newman, Anne] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Bandeen-Roche, Karen] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Walston, J (reprint author), Johns Hopkins Asthma & Allergy Ctr, 5501 Hopkins Bayview Circle,Rm 1A-62, Baltimore, MD 21224 USA. EM jwalston@jhmi.edu FU National Institute of Aging (NIA) [R01 AG027236]; Johns Hopkins Older Americans Independence Center [P30AG021334]; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079, N01-HC-75150, N01-HC-45133]; NHLBI [HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); NIA [AG-023629, AG-15928, AG-20098, AG-027058]; Italian Ministry of Health; U.S. National Institute on Aging, National Institutes of Health [263 MD 9164, 263 MD 821336]; U.S. National Institute on Aging [N.1-AG-1-1, N.1-AG-1-2111] FX This research was supported by National Institute of Aging (NIA; R01 AG027236) and the Johns Hopkins Older Americans Independence Center (P30AG021334), 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 (NINDS) and AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. The InCHIANTI study baseline (1998-2000) was supported by the Italian Ministry of Health and the U.S. National Institute on Aging, National Institutes of Health (Contracts 263 MD 9164 and 263 MD 821336). The InCHIANTI Follow-up (2001-2003) was funded by the U.S. National Institute on Aging (Contracts N.1-AG-1-1 and N.1-AG-1-2111). NR 39 TC 39 Z9 39 U1 2 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2014 VL 69 IS 2 BP 165 EP 173 DI 10.1093/gerona/glt023 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AD6QA UT WOS:000333384700006 PM 23689826 ER PT J AU Maruyama, SR Castro-Jorge, LA Ribeiro, JMC Gardinassi, LG Garcia, GR Brandao, LG Rodrigues, AR Okada, MI Abrao, EP Ferreira, BR da Fonseca, BAL de Miranda-Santos, IKF AF Maruyama, Sandra Regina Castro-Jorge, Luiza Antunes Chaves Ribeiro, Jose Marcos Gardinassi, Luiz Gustavo Garcia, Gustavo Rocha Brandao, Lucinda Giampietro Rodrigues, Aline Rezende Okada, Marcos Ituo Abrao, Emiliana Pereira Ferreira, Beatriz Rossetti Lopes da Fonseca, Benedito Antonio Ferreira de Miranda-Santos, Isabel Kinney TI Characterisation of divergent flavivirus NS3 and NS5 protein sequences detected in Rhipicephalus microplus ticks from Brazil SO MEMORIAS DO INSTITUTO OSWALDO CRUZ LA English DT Article DE Rhipicephalus microplus; tick; NS3; NS5; flavivirus ID CODON ADAPTATION INDEX; BORNE ENCEPHALITIS-VIRUS; WEST-NILE-VIRUS; PHYLOGENETIC-RELATIONSHIPS; BOOPHILUS-MICROPLUS; DISEASE RESERVOIRS; GENUS FLAVIVIRUS; COMPLEX-SYSTEMS; RNA-POLYMERASE; USAGE BIAS AB Transcripts similar to those that encode the nonstructural (NS) proteins NS3 and NS5 from flaviviruses were found in a salivary gland (SG) complementary DNA (cDNA) library from the cattle tick Rhipicephalus microplus. Tick extracts were cultured with cells to enable the isolation of viruses capable of replicating in cultured invertebrate and vertebrate cells. Deep sequencing of the viral RNA isolated from culture supernatants provided the complete coding sequences for the NS3 and NS5 proteins and their molecular characterisation confirmed similarity with the NS3 and NS5 sequences from other flaviviruses. Despite this similarity, phylogenetic analyses revealed that this potentially novel virus may be a highly divergent member of the genus Flavivirus. Interestingly, we detected the divergent NS3 and NS5 sequences in ticks collected from several dairy farms widely distributed throughout three regions of Brazil. This is the first report of flavivirus-like transcripts in R. microplus ticks. This novel virus is a potential arbovirus because it replicated in arthropod and mammalian cells; furthermore, it was detected in a cDNA library from tick SGs and therefore may be present in tick saliva. It is important to determine whether and by what means this potential virus is transmissible and to monitor the virus as a potential emerging tick-borne zoonotic pathogen. C1 [Maruyama, Sandra Regina; Castro-Jorge, Luiza Antunes; Gardinassi, Luiz Gustavo; Garcia, Gustavo Rocha; Brandao, Lucinda Giampietro; Abrao, Emiliana Pereira; Lopes da Fonseca, Benedito Antonio; Ferreira de Miranda-Santos, Isabel Kinney] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Ferreira, Beatriz Rossetti] Univ Sao Paulo, Escola Enfermagem Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Chaves Ribeiro, Jose Marcos] NIAID, NIH, Rockville, MD USA. [Brandao, Lucinda Giampietro; Okada, Marcos Ituo] Fac Tecnol, Aracatuba, SP, Brazil. [Rodrigues, Aline Rezende] Vallee SA, Sao Paulo, Brazil. [Rodrigues, Aline Rezende] Laticinios Vale Buritis, Buritis, MG, Brazil. [Okada, Marcos Ituo] Vetmais Med Anim, Campinas, SP, Brazil. RP de Miranda-Santos, IKF (reprint author), Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. EM imsantos@fmrp.usp.br RI Garcia, Gustavo/E-5182-2013; Ferreira, Beatriz/C-2003-2012; Ribeiro, Jose/J-7011-2015; de Miranda Santos, Isabel/D-5261-2016; de Miranda Santos, Isabel/B-7597-2012; OI Ferreira, Beatriz/0000-0002-6781-2236; de Miranda Santos, Isabel/0000-0002-0438-4430; Gardinassi, Luiz Gustavo/0000-0002-9027-2688; Maruyama, Sandra/0000-0001-6807-1452; Ribeiro, Jose/0000-0002-9107-0818 FU FAPESP [2004/09992-7, 2009/53645-3, 2012/06374-7]; CNPq [559603/2009-6, 471946/2010-9, 420067/2005-1, 505810/2004-2]; SRM [2006/54041-6, 2007/59357-4/FAPESP]; LACJ [143354/2008-6/CNPq]; GRG [2009/51212-2/FAPESP]; NIAID FX FAPESP (2004/09992-7, 2009/53645-3, 2012/06374-7), CNPq (559603/2009-6, 471946/2010-9, 420067/2005-1, 505810/2004-2); This work fulfils part of the Master's and PhD program requirements for SRM (scholarships 2006/54041-6, 2007/59357-4/FAPESP), LACJ (scholarship 143354/2008-6/CNPq) and GRG (scholarship 2009/51212-2/FAPESP). JMCR was supported by the Intramural Research Program of the NIAID. NR 69 TC 9 Z9 9 U1 0 U2 7 PU FUNDACO OSWALDO CRUZ PI RIO DE JANEIRO, RJ PA AV BRASIL 4365, 21045-900 RIO DE JANEIRO, RJ, BRAZIL SN 0074-0276 EI 1678-8060 J9 MEM I OSWALDO CRUZ JI Mem. Inst. Oswaldo Cruz PD FEB PY 2014 VL 109 IS 1 BP 38 EP + DI 10.1590/0074-0276130166 PG 34 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA AD2BU UT WOS:000333038700006 PM 24626302 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 (vol 59, pg 287, 2013) SO METHODS LA English DT Correction C1 [Inagaki, Sayaka; Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Rockville, MD 20852 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20814 USA. RP Ghirlando, R (reprint author), NIDDK, 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 NR 1 TC 1 Z9 1 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD FEB PY 2014 VL 65 IS 3 SI SI BP 367 EP 368 DI 10.1016/j.ymeth.2013.08.029 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC3PY UT WOS:000332434900012 ER PT J AU Chiang, HC Shin, W Zhao, WD Hamid, E Sheng, JS Baydyuk, M Wen, PJ Jin, A Momboisse, F Wu, LG AF Chiang, Hsueh-Cheng Shin, Wonchul Zhao, Wei-Dong Hamid, Edaeni Sheng, Jiansong Baydyuk, Maryna Wen, Peter J. Jin, Albert Momboisse, Fanny Wu, Ling-Gang TI Post-fusion structural changes and their roles in exocytosis and endocytosis of dense-core vesicles SO NATURE COMMUNICATIONS LA English DT Article ID ADRENAL CHROMAFFIN CELLS; KISS-AND-RUN; FROG NEUROMUSCULAR-JUNCTION; FUSION PORE; SYNAPTIC-TRANSMISSION; QUANTAL SIZE; NEUROTRANSMITTER RELEASE; CAPACITANCE MEASUREMENTS; TRANSMITTER RELEASE; SECRETORY GRANULES AB Vesicle fusion with the plasma membrane generates an Omega-shaped membrane profile. Its pore is thought to dilate until flattening (full-collapse), followed by classical endocytosis to retrieve vesicles. Alternatively, the pore may close (kiss-and-run), but the triggering mechanisms and its endocytic roles remain poorly understood. Here, using confocal and stimulated emission depletion microscopy imaging of dense-core vesicles, we find that fusion-generated O-profiles may enlarge or shrink while maintaining vesicular membrane proteins. Closure of fusion-generated Omega-profiles, which produces various sizes of vesicles, is the dominant mechanism mediating rapid and slow endocytosis within similar to 1-30 s. Strong calcium influx triggers dynamin-mediated closure. Weak calcium influx does not promote closure, but facilitates the merging of Omega-profiles with the plasma membrane via shrinking rather than full-collapse. These results establish a model, termed Omega-exo-endocytosis, in which the fusion-generated Omega-profile may shrink to merge with the plasma membrane, change in size or change in size then close in response to calcium, which is the main mechanism to retrieve dense-core vesicles. C1 [Chiang, Hsueh-Cheng; Shin, Wonchul; Zhao, Wei-Dong; Hamid, Edaeni; Sheng, Jiansong; Baydyuk, Maryna; Wen, Peter J.; Momboisse, Fanny; Wu, Ling-Gang] NINDS, Bethesda, MD 20892 USA. [Jin, Albert] NIBIB, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), NINDS, 35 Convent Dr,Bldg 35,Room 2B,1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov OI Jin, Albert/0000-0003-3826-1081 FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX We thank Dr. Fujun Luo for comments on the manuscript. We thank Drs. Carolyn Smith and Lei Xue for technical assistance in imaging. We thank Drs. Justin Taraska and Ronald Holz for providing NPY-EGFP and VAMP2-EGFP plasmids, respectively. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 66 TC 15 Z9 15 U1 3 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2014 VL 5 AR 3356 DI 10.1038/ncomms4356 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC6XN UT WOS:000332669600011 PM 24561832 ER PT J AU Hu, ZH Yu, DN Gu, QH Yang, YQ Tu, K Zhu, J Li, Z AF Hu, Zhonghua Yu, Danni Gu, Qin-hua Yang, Yanqin Tu, Kang Zhu, Jun Li, Zheng TI miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression SO NATURE COMMUNICATIONS LA English DT Article ID DENDRITIC SPINES; AMPA RECEPTORS; PROTEIN-SYNTHESIS; MORPHOLOGICAL PLASTICITY; RECYCLING ENDOSOMES; HIPPOCAMPAL-NEURONS; MICRORNA EXPRESSION; NMDA RECEPTORS; IN-VIVO; LTP AB Activity-dependent modification of dendritic spines, subcellular compartments accommodating postsynaptic specializations in the brain, is an important cellular mechanism for brain development, cognition and synaptic pathology of brain disorders. NMDA receptor-dependent long-term depression (NMDAR-LTD), a prototypic form of synaptic plasticity, is accompanied by prolonged remodelling of spines. The mechanisms underlying long-lasting spine remodelling in NMDAR-LTD, however, are largely unclear. Here we show that LTD induction causes global changes in miRNA transcriptomes affecting many cellular activities. Specifically, we show that expression changes of miR-191 and miR-135 are required for maintenance but not induction of spine restructuring. Moreover, we find that actin depolymerization and AMPA receptor exocytosis are regulated for extended periods of time by miRNAs to support long-lasting spine plasticity. These findings reveal a miRNA-mediated mechanism and a role for AMPA receptor exocytosis in long-lasting spine plasticity, and identify a number of candidate miRNAs involved in LTD. C1 [Hu, Zhonghua; Gu, Qin-hua; Li, Zheng] Natl Inst Mental Hlth, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. [Yu, Danni] Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA. [Yang, Yanqin; Tu, Kang; Zhu, Jun] NHLBI, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Li, Z (reprint author), Natl Inst Mental Hlth, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. EM lizheng2@mail.nih.gov RI Hu, Zhonghua/F-9493-2014; Li, Zheng/I-8016-2014; Hu, Zhonghua/J-1169-2016 OI Li, Zheng/0000-0002-2978-2531; Hu, Zhonghua/0000-0002-0117-7081 FU NIMH; NHLBI Intramural Programs FX We thank Dr Song Jiao for help with preparation of acute hippocampal slices, Dr Heinz Arnheiter for intense discussions of this study and critical reading of the manuscript and Dr Elizabeth J. Sherman for a close reading and editing of the manuscript. This work was supported by the NIMH and the NHLBI Intramural Programs. NR 70 TC 21 Z9 23 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2014 VL 5 AR 3263 DI 10.1038/ncomms4263 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC6WX UT WOS:000332667600010 PM 24535612 ER PT J AU Shi, JX Marconett, CN Duan, JB Hyland, PL Li, P Wang, ZM Wheeler, W Zhou, BY Campan, M Lee, DS Huang, J Zhou, WY Triche, T Amundadottir, L Warner, A Hutchinson, A Chen, PH Chung, BSI Pesatori, AC Consonni, D Bertazzi, PA Bergen, AW Freedman, M Siegmund, KD Berman, BP Borok, Z Chatterjee, N Tucker, MA Caporaso, NE Chanock, SJ Laird-Offringa, IA Landi, MT AF Shi, Jianxin Marconett, Crystal N. Duan, Jubao Hyland, Paula L. Li, Peng Wang, Zhaoming Wheeler, William Zhou, Beiyun Campan, Mihaela Lee, Diane S. Huang, Jing Zhou, Weiyin Triche, Tim Amundadottir, Laufey Warner, Andrew Hutchinson, Amy Chen, Po-Han Chung, Brian S. I. Pesatori, Angela C. Consonni, Dario Bertazzi, Pier Alberto Bergen, Andrew W. Freedman, Mathew Siegmund, Kimberly D. Berman, Benjamin P. Borok, Zea Chatterjee, Nilanjan Tucker, Margaret A. Caporaso, Neil E. Chanock, Stephen J. Laird-Offringa, Ite A. Landi, Maria Teresa TI Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue SO NATURE COMMUNICATIONS LA English DT Article ID DNA METHYLATION; SUSCEPTIBILITY LOCUS; CANCER-RISK; EXPRESSION QTLS; HUMAN GENOME; CTCF; DISEASE; TWINS; RNA; HYPERMETHYLATION AB The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF-binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, four of the five established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome. C1 [Shi, Jianxin; Hyland, Paula L.; Li, Peng; Wang, Zhaoming; Zhou, Weiyin; Amundadottir, Laufey; Hutchinson, Amy; Chatterjee, Nilanjan; Tucker, Margaret A.; Caporaso, Neil E.; Chanock, Stephen J.; Landi, Maria Teresa] NCI, Div Canc Epidemiol, NIH, DHHS, Bethesda, MD 20892 USA. [Marconett, Crystal N.; Campan, Mihaela; Lee, Diane S.; Chen, Po-Han; Chung, Brian S. I.; Laird-Offringa, Ite A.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Surg, Los Angeles, CA 90089 USA. [Marconett, Crystal N.; Campan, Mihaela; Lee, Diane S.; Chen, Po-Han; Chung, Brian S. I.; Borok, Zea; Laird-Offringa, Ite A.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA. [Duan, Jubao] Univ Chicago, North Shore Univ, Pritzker Sch Med, Hlth Syst Res Inst,Ctr Psychiat Genet,Dept Psychi, Evanston, IL 60201 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD 20852 USA. [Zhou, Beiyun; Borok, Zea] Univ So Calif, Keck Sch Med, Will Rogers Inst Pulm, Res Ctr,Div Pulm Crit Care & Sleep Med, Los Angeles, CA 90089 USA. [Huang, Jing] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. [Triche, Tim; Siegmund, Kimberly D.; Berman, Benjamin P.] Univ So Calif, Dept Prevent Med, Bioinformat Div, Los Angeles, CA 90089 USA. [Warner, Andrew] Frederick Natl Lab Canc Res, Pathol Histotechnol Lab, Lab Anim Sci Program, Frederick, MD 21702 USA. [Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto] Univ Milan, IRCCS Fdn Ca Granda Osped Maggiore Policlin, Dept Clin Sci & Community Hlth, Epidemiol Unit, I-20122 Milan, Italy. [Bergen, Andrew W.] SRI, Ctr Hlth Sci, Mol Genet Program, Menlo Pk, CA 94025 USA. [Freedman, Mathew] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Freedman, Mathew] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Dept Med Oncol, Boston, MA 02115 USA. [Berman, Benjamin P.] Univ So Calif, Norris Comprehens Canc Ctr, Epigenome Ctr, Los Angeles, CA 90089 USA. RP Landi, MT (reprint author), NCI, Div Canc Epidemiol, NIH, DHHS, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Huang, Jing/A-2566-2009; Consonni, Dario/K-7943-2016; Amundadottir, Laufey/L-7656-2016; bertazzi, pietro alberto/D-5039-2017; OI Huang, Jing/0000-0002-7163-5156; Consonni, Dario/0000-0002-8935-3843; Amundadottir, Laufey/0000-0003-1859-8971; bertazzi, pietro alberto/0000-0003-3475-2449; Triche, Tim/0000-0001-5665-946X; Marconett, Crystal/0000-0002-8463-7126; Borok, Zea/0000-0001-8673-8177; pesatori, angela/0000-0002-0261-3252 FU Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics; NCI [P30CA014089]; Trandisciplinary Research in Cancer of the Lung (TRICL); Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19CA148127]; NCI; NIH [HSN261200800001E, 1 R01 HL114094, 1 P30 H101258, R37HL062569-13]; Whittier Foundation; Hastings Foundation; Ralph Edgington Chair in Medicine; ACS/Canary postdoctoral fellowship [PFTED-10-207-01-SIED] FX This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA (http://biowulf.nih.gov). We are grateful to the EAGLE participants and the large number of EAGLE collaborators (listed in http://dceg.cancer.gov/eagle), The Cancer Genome Atlas project for the genotype and methylation data and the ENCODE project for the regulatory region data. This work was supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics and, in part, by the Norris Comprehensive Cancer Center core grant (P30CA014089) from NCI, the Trandisciplinary Research in Cancer of the Lung (TRICL) and the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network (U19CA148127). A.W., Z.W., W.Z. and A.H. were also funded by the NCI, NIH (HSN261200800001E). I.A.L.-O. and Z.B. were also funded by NIH grants (1 R01 HL114094, 1 P30 H101258, and R37HL062569-13), Whittier Foundation and Hastings Foundation. Z.B. was also funded by the Ralph Edgington Chair in Medicine. C.N.M. was funded by ACS/Canary postdoctoral fellowship (PFTED-10-207-01-SIED). NR 63 TC 37 Z9 37 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2014 VL 5 AR 3365 DI 10.1038/ncomms4365 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC6XO UT WOS:000332669900001 PM 24572595 ER PT J AU Tabet, F Vickers, KC Torres, LFC Wiese, CB Shoucri, BM Lambert, G Catherinet, C Prado-Lourenco, L Levin, MG Thacker, S Sethupathy, P Barter, PJ Remaley, AT Rye, KA AF Tabet, Fatiha Vickers, Kasey C. Torres, Luisa F. Cuesta Wiese, Carrie B. Shoucri, Bassem M. Lambert, Gilles Catherinet, Claire Prado-Lourenco, Leonel Levin, Michael G. Thacker, Seth Sethupathy, Praveen Barter, Philip J. Remaley, Alan T. Rye, Kerry-Anne TI HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells SO NATURE COMMUNICATIONS LA English DT Article ID HIGH-DENSITY-LIPOPROTEINS; APOLIPOPROTEIN-A-I; COLONY-STIMULATING FACTOR; CARDIOVASCULAR-DISEASES; INFLAMMATORY RESPONSE; ADHESION MOLECULE-1; PROGENITOR CELLS; FREE-CHOLESTEROL; VIVO; VITRO AB High-density lipoproteins (HDL) have many biological functions, including reducing endothelial activation and adhesion molecule expression. We recently reported that HDL transport and deliver functional microRNAs (miRNA). Here we show that HDL suppresses expression of intercellular adhesion molecule 1 (ICAM-1) through the transfer of miR-223 to endothelial cells. After incubation of endothelial cells with HDL, mature miR-223 levels are significantly increased in endothelial cells and decreased on HDL. However, miR-223 is not transcribed in endothelial cells and is not increased in cells treated with HDL from miR-223(-/-) mice. HDL inhibit ICAM-1 protein levels, but not in cells pretreated with miR-223 inhibitors. ICAM-1 is a direct target of HDL-transferred miR-223 and this is the first example of an extracellular miRNA regulating gene expression in cells where it is not transcribed. Collectively, we demonstrate that HDL's anti-inflammatory properties are conferred, in part, through HDLmiR-223 delivery and translational repression of ICAM-1 in endothelial cells. C1 [Tabet, Fatiha; Torres, Luisa F. Cuesta; Prado-Lourenco, Leonel; Barter, Philip J.; Rye, Kerry-Anne] Univ New S Wales, Ctr Vasc Res, Sydney, NSW 2052, Australia. [Tabet, Fatiha; Torres, Luisa F. Cuesta; Catherinet, Claire; Barter, Philip J.; Rye, Kerry-Anne] Heart Res Inst, Lipid Res Grp, Sydney, NSW 2042, Australia. [Tabet, Fatiha; Barter, Philip J.; Rye, Kerry-Anne] Univ Sydney, Fac Med, Sydney, NSW 2006, Australia. [Vickers, Kasey C.; Shoucri, Bassem M.; Levin, Michael G.; Thacker, Seth; Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20814 USA. [Vickers, Kasey C.; Wiese, Carrie B.] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, Nashville, TN 37232 USA. [Lambert, Gilles] Univ Nantes, Fac Med, Lab Inserm U957, Nantes, France. [Sethupathy, Praveen] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. RP Tabet, F (reprint author), Univ New S Wales, Ctr Vasc Res, Sydney, NSW 2052, Australia. EM f.tabet@unsw.edu.au FU NHMRC program [1037903]; NIH NHLBI Intramural Research Program; CIHR Postdoctoral Fellowship; NIH K22 [1K22HL113039-02]; NIDDK/NIH [5R00DK091318-03] FX This work was supported by NHMRC program grant 1037903 (PJB and KAR) and NIH NHLBI Intramural Research Program (A. T. R). F. T. was supported by a CIHR Postdoctoral Fellowship. K. C. V. is supported by a NIH K22 grant 1K22HL113039-02. P. S. is supported by a NIDDK/NIH grant 5R00DK091318-03. We would specifically like to thank Michael P. Anderson, Robert C. Taylor, Stuart R. Landstreet, Steve Demosky, John Stonik, Jeremie Rossy and Yeliz Cakan for their advice and assistance in the lab. We thank Fernando D. Camargo (Massachusetts Institute of Technology) and Stuart Lipton and Scott R. McKercher (Sanford-Burnham Medical Research Institute) for the 223-/- mice. This work was completed with assistance from the NHLBI DNA Sequencing Core Facility (Jun Zhu, PhD) and NHLBI Genomics Core Facility (Nalini Raghavachari). NR 68 TC 71 Z9 76 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2014 VL 5 AR 3292 DI 10.1038/ncomms4292 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC6WX UT WOS:000332667600039 PM 24576947 ER PT J AU Yu, Y Fuscoe, JC Zhao, C Guo, C Jia, MW Qing, T Bannon, DI Lancashire, L Bao, WJ Du, TT Luo, H Su, ZQ Jones, WD Moland, CL Branham, WS Qian, F Ning, BT Li, Y Hong, HX Guo, L Mei, N Shi, TL Wang, KY Wolfinger, RD Nikolsky, Y Walker, SJ Duerksen-Hughes, P Mason, CE Tong, WD Thierry-Mieg, J Thierry-Mieg, D Shi, LM Wang, C AF Yu, Ying Fuscoe, James C. Zhao, Chen Guo, Chao Jia, Meiwen Qing, Tao Bannon, Desmond I. Lancashire, Lee Bao, Wenjun Du, Tingting Luo, Heng Su, Zhenqiang Jones, Wendell D. Moland, Carrie L. Branham, William S. Qian, Feng Ning, Baitang Li, Yan Hong, Huixiao Guo, Lei Mei, Nan Shi, Tieliu Wang, Kevin Y. Wolfinger, Russell D. Nikolsky, Yuri Walker, Stephen J. Duerksen-Hughes, Penelope Mason, Christopher E. Tong, Weida Thierry-Mieg, Jean Thierry-Mieg, Danielle Shi, Leming Wang, Charles TI A rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages SO NATURE COMMUNICATIONS LA English DT Article ID MOUSE GENE-EXPRESSION; GENOME; LIVER; IDENTIFICATION; INFORMATION; LANDSCAPE; MODENCODE; ELEMENTS; DATABASE; DISEASE AB The rat has been used extensively as a model for evaluating chemical toxicities and for understanding drug mechanisms. However, its transcriptome across multiple organs, or developmental stages, has not yet been reported. Here we show, as part of the SEQC consortium efforts, a comprehensive rat transcriptomic BodyMap created by performing RNA-Seq on 320 samples from 11 organs of both sexes of juvenile, adolescent, adult and aged Fischer 344 rats. We catalogue the expression profiles of 40,064 genes, 65,167 transcripts, 31,909 alternatively spliced transcript variants and 2,367 non-coding genes/non-coding RNAs (ncRNAs) annotated in AceView. We find that organ-enriched, differentially expressed genes reflect the known organ-specific biological activities. A large number of transcripts show organ-specific, age-dependent or sex-specific differential expression patterns. We create a web-based, open-access rat BodyMap database of expression profiles with crosslinks to other widely used databases, anticipating that it will serve as a primary resource for biomedical research using the rat model. C1 [Yu, Ying; Zhao, Chen; Jia, Meiwen; Qing, Tao; Du, Tingting; Luo, Heng; Shi, Leming] Fudan Univ, Sch Life Sci & Pharm, Ctr Pharmacogen, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Yu, Ying; Zhao, Chen; Jia, Meiwen; Qing, Tao; Du, Tingting; Luo, Heng; Shi, Leming] Fudan Univ, Sch Life Sci & Pharm, MOE Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China. [Fuscoe, James C.; Su, Zhenqiang; Moland, Carrie L.; Branham, William S.; Qian, Feng; Ning, Baitang; Li, Yan; Hong, Huixiao; Guo, Lei; Mei, Nan; Tong, Weida; Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 92079 USA. [Bannon, Desmond I.] Army Inst Publ Hlth, US Army Publ Hlth Command, Aberdeen Proving Ground, MD 21010 USA. [Lancashire, Lee] IP & Sci Thomson Reuters, London EC1N 8JS, England. [Bao, Wenjun; Wolfinger, Russell D.] SAS Inst Inc, Cary, NC 27513 USA. [Jones, Wendell D.] Express Anal Inc, Durham, NC 27713 USA. [Shi, Tieliu] Coll Life Sci, Ctr Bioinformat, Shanghai 200241, Peoples R China. [Shi, Tieliu] Coll Life Sci, Inst Biomed Sci, Shanghai 200241, Peoples R China. [Wang, Kevin Y.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Walker, Stephen J.] Wake Forest Univ Hlth Sci, Wake Forest Inst Regenerat Med, Winston Salem, NC 27157 USA. [Duerksen-Hughes, Penelope] Loma Linda Univ, Sch Med, Dept Basic Sci, Loma Linda, CA 92350 USA. [Mason, Christopher E.] Cornell Univ, Dept Physiol & Biophys, New York, NY 10021 USA. [Mason, Christopher E.] Cornell Univ, Inst Computat Biomed, New York, NY 10021 USA. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Shi, Leming] Fudan Zhangjiang Ctr Clin Genom, Shanghai 201203, Peoples R China. [Shi, Leming] Zhangjiang Ctr Translat Med, Shanghai 201203, Peoples R China. [Wang, Charles] Loma Linda Univ, Sch Med, Ctr Genom & Div Microbiol Mol Genet, Loma Linda, CA 92350 USA. RP Wang, C (reprint author), Loma Linda Univ, Sch Med, Ctr Genom & Div Microbiol Mol Genet, Loma Linda, CA 92350 USA. EM leming.shi@gmail.com; oxwang@gmail.com RI Guo, Chao/B-2647-2010; mei, nan/E-8915-2011; Luo, Heng/D-3616-2016; THIERRY-MIEG, Jean/F-1975-2017 OI Guo, Chao/0000-0002-6673-0933; mei, nan/0000-0002-3501-9014; Luo, Heng/0000-0001-5192-8878; THIERRY-MIEG, Jean/0000-0002-0396-6789 FU US Food and Drug Administrative Agency (FDA); FDA Office of Women's Health, China's Program of Global Experts; National Institutes of Health's (NIH) Intramural Research Program; National 973 Key Basic Research Program of China [2010CB945401]; National Natural Science Foundation of China [31240038, 31071162]; Science and Technology Commission of Shanghai Municipality [11DZ2260300]; China's National Super-computing Center of Tianjin; NIH/NCBI's Supercomputing Center; USA FDA's Supercomputing Center FX The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as an endorsement. This work was supported in part by the US Food and Drug Administrative Agency (FDA), the FDA Office of Women's Health, China's Program of Global Experts, the National Institutes of Health's (NIH) Intramural Research Program, the National 973 Key Basic Research Program of China (2010CB945401), the National Natural Science Foundation of China (31240038 and 31071162) and the Science and Technology Commission of Shanghai Municipality (11DZ2260300). We gratefully acknowledge support by the China's National Super-computing Center of Tianjin, the NIH/NCBI's Supercomputing Center and the USA FDA's Supercomputing Center. We also thank Drs. Keely Walker, David Klein, Marina Bessarabova and Donna Mendrick for critical review of an earlier version of the manuscript. NR 43 TC 50 Z9 52 U1 2 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2014 VL 5 AR 3230 DI 10.1038/ncomms4230 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC6WG UT WOS:000332665700005 PM 24510058 ER PT J AU Yuan, HJ Hansen, KB Zhang, J Pierson, TM Markello, TC Fajardo, KVF Holloman, CM Golas, G Adams, DR Boerkoel, CF Gahl, WA Traynelis, SF AF Yuan, Hongjie Hansen, Kasper B. Zhang, Jing Pierson, Tyler Mark Markello, Thomas C. Fajardo, Karin V. Fuentes Holloman, Conisha M. Golas, Gretchen Adams, David R. Boerkoel, Cornelius F. Gahl, William A. Traynelis, Stephen F. TI Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy SO NATURE COMMUNICATIONS LA English DT Article ID D-ASPARTATE RECEPTOR; VOLTAGE-DEPENDENT BLOCK; NMDA RECEPTOR; STRUCTURAL DETERMINANTS; ENDOPLASMIC-RETICULUM; EXTRACELLULAR VESTIBULE; TRANSMEMBRANE PROTEINS; IDIOPATHIC EPILEPSIES; GLUTAMATE RECEPTORS; SPECTRUM DISORDERS AB NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy. C1 [Yuan, Hongjie; Hansen, Kasper B.; Zhang, Jing; Traynelis, Stephen F.] Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Regenerat Med Inst, Los Angeles, CA 90048 USA. [Pierson, Tyler Mark; Markello, Thomas C.; Fajardo, Karin V. Fuentes; Holloman, Conisha M.; Golas, Gretchen; Adams, David R.; Boerkoel, Cornelius F.; Gahl, William A.] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20892 USA. [Pierson, Tyler Mark; Markello, Thomas C.; Fajardo, Karin V. Fuentes; Holloman, Conisha M.; Golas, Gretchen; Adams, David R.; Boerkoel, Cornelius F.; Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Yuan, HJ (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Rollins Res Ctr, Atlanta, GA 30322 USA. EM hyuan@emory.edu RI Hansen, Kasper/C-4062-2008 OI Hansen, Kasper/0000-0002-3303-4819 FU NINDS [NS036654]; NIH Undiagnosed Diseases Program [HSN268201300162P]; Intramural Research Program of the National Human Genome Research Institute; Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases FX We are grateful to Anel Tankovic, Phuong Le and Kevin Ogden for technical assistance. We are also grateful to Eric D. Marsh and Dimitre R. Simeonov for assistance with the clinical and molecular evaluation of the patient. This work was supported by the NINDS (NS036654, S.F.T.), by the NIH Undiagnosed Diseases Program (HSN268201300162P, H.Y.) and by the Intramural Research Program of the National Human Genome Research Institute. TMP was also supported by the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. NR 72 TC 30 Z9 31 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2014 VL 5 AR 3251 DI 10.1038/ncomms4251 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC6WP UT WOS:000332666700009 PM 24504326 ER PT J AU North, KN Wang, CH Clarke, N Jungbluth, H Vainzof, M Dowling, JJ Amburgey, K Quijano-Roy, S Beggs, AH Sewry, C Laing, NG Bonnemann, CG AF North, Kathryn N. Wang, Ching H. Clarke, Nigel Jungbluth, Heinz Vainzof, Mariz Dowling, James J. Amburgey, Kimberly Quijano-Roy, Susana Beggs, Alan H. Sewry, Caroline Laing, Nigel G. Boennemann, Carsten G. CA Int Stand Care Comm Congenital Myo TI Approach to the diagnosis of congenital myopathies SO NEUROMUSCULAR DISORDERS LA English DT Article DE Congenital myopathy; Diagnosis; Guidelines ID FIBER-TYPE DISPROPORTION; RECESSIVE NEMALINE MYOPATHY; CENTRAL CORE DISEASE; ALPHA-ACTIN GENE; LINKED MYOTUBULAR MYOPATHY; MYOSIN STORAGE MYOPATHY; DNM2-RELATED CENTRONUCLEAR MYOPATHY; MUSCLE RYANODINE RECEPTOR; MULTI-MINICORE DISEASE; ONSET DISTAL MYOPATHY AB Over the past decade there have been major advances in defining the genetic basis of the majority of congenital myopathy subtypes. However the relationship between each congenital myopathy, defined on histological grounds, and the genetic cause is complex. Many of the congenital myopathies are due to mutations in more than one gene, and mutations in the same gene can cause different muscle pathologies. The International Standard of Care Committee for Congenital Myopathies performed a literature review and consulted a group of experts in the field to develop a summary of (1) the key features common to all forms of congenital myopathy and (2) the specific features that help to discriminate between the different genetic subtypes. The consensus statement was refined by two rounds of on-line survey, and a three-day workshop. This consensus statement provides guidelines to the physician assessing the infant or child with hypotonia and Weakness. We summarise the clinical features that are most suggestive of a congenital myopathy, the major differential diagnoses and the features on clinical examination, investigations, muscle pathology and muscle imaging that are suggestive of a specific genetic diagnosis to assist in prioritisation of genetic testing of known genes. As next generation sequencing becomes increasingly used as a diagnostic tool in clinical practise, these guidelines will assist in determining which sequence variations are likely to be pathogenic. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved. C1 [North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic 3052, Australia. [North, Kathryn N.; Clarke, Nigel] Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW 2006, Australia. [Wang, Ching H.] Driscoll Childrens Hosp, Corpus Christi, TX USA. [Jungbluth, Heinz] Evelina Childrens Hosp, Dept Paediat Neurol, London, England. [Jungbluth, Heinz] Kings Coll London, Muscle Signalling Sect, Randall Div Cell & Mol Biophys, London WC2R 2LS, England. [Jungbluth, Heinz] IoP, Clin Neurosci Div, London, England. [Vainzof, Mariz] Univ Sao Paulo, Human Genome Res Ctr, Sao Paulo, Brazil. [Dowling, James J.; Amburgey, Kimberly] Hosp Sick Children, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada. [Quijano-Roy, Susana] Raymond Poincare Univ Hosp UVSQ, AP HP, Garches Neuromuscular Reference Ctr GNMH, Dept Pediat, Garches, France. [Beggs, Alan H.] Childrens Hosp, Boston, MA 02115 USA. [Sewry, Caroline] Dubowitz Neuromuscular Ctr, London, England. [Sewry, Caroline] RJAH Orthopaed Hosp, Wolfson Ctr Inherited Neuromuscular Dis, Oswestry, Shrops, England. [Laing, Nigel G.] Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia. [Laing, Nigel G.] Harry Perkins Inst Med Res, QEII Med Ctr, Nedlands, WA 6009, Australia. [Boennemann, Carsten G.] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, Bethesda, MD 20892 USA. RP North, KN (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Melbourne, Vic 3052, Australia. EM kathryn.north@mcri.edu.au RI laporte, jocelyn/J-7008-2012; Fapesp-Cepid, CEGH-CEL/J-3613-2015; Vainzof, Mariz/J-7150-2012; Laporte, Jocelyn/H-6801-2016; Jungbluth, Heinz/B-8893-2012; Silva, Helga/D-8959-2012; Ferreiro, Ana/F-5371-2011; North, Kathryn/K-6476-2012; OI Koumbourlis, Anastassios/0000-0002-4400-4885; Connolly, Anne/0000-0002-9193-2457; Beggs, Alan/0000-0001-8818-0568; Vainzof, Mariz/0000-0002-2797-0782; Silva, Helga/0000-0002-9372-7019; North, Kathryn/0000-0003-0841-8009; Morrison, Leslie/0000-0002-0092-193X; Sejersen, Thomas/0000-0001-5961-7097 FU A Foundation Building Strength; TREAT-NMD FX This project is supported by grants from: A Foundation Building Strength (www.buildingstrength.org/) and TREAT-NMD (www.treat-nmd.edu). NR 92 TC 40 Z9 42 U1 5 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD FEB PY 2014 VL 24 IS 2 BP 97 EP 116 DI 10.1016/j.nmd.2013.11.003 PG 20 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AD2NI UT WOS:000333072000001 PM 24456932 ER PT J AU Farhat, T Iannotti, RJ Caccavale, LJ AF Farhat, Tilda Iannotti, Ronald J. Caccavale, Laura J. TI Adolescent Overweight, Obesity and Chronic Disease-Related Health Practices: Mediation by Body Image SO OBESITY FACTS LA English DT Article DE Adolescents; Obesity; Body image; Chronic disease-related health practices ID PHYSICAL-ACTIVITY; RISK-FACTORS; MASS INDEX; BREAKFAST CONSUMPTION; WEIGHT; CHILDREN; BEHAVIOR; YOUTH; GIRLS; DISSATISFACTION AB Background/Aims: To examine whether body image mediates the association between overweight/obesity and chronic disease-related health practices (CDRHP), including lack of physical activity (PA), infrequent breakfast consumption (IBC), screen-based media use (SBM), and smoking. Methods: The 2006 Health Behaviors in School-Age Children survey was administered to a nationally representative sample of US students (n = 8,028) in grades 6-10 (mean age = 14.3 years). Outcome variables included self-reported measures of PA, SBM, IBC, and smoking. Body image was assessed with 5 items from the Body Investment Scale (alpha = 0.87) asking for agreement/disagreement with statements about one's body. Stratifying on gender, an initial regression model estimated the association between overweight/obesity and CDRHP. Mediation models that included body image were then compared to the initial model to determine the role of body image in the relationship between overweight/obesity and CDRHP. Results: Among boys, body image mediated the relationships of overweight/obesity with SBM, and of obesity with IBC. Among girls, it mediated the relationships of obesity with PA, IBC, and smoking, and of overweight with SBM. Conclusion: As the prevalence of overweight/obesity among adolescent boys and girls remains high, efforts to improve their body image could result in less frequent engagement in CDRHP. (C) 2013 S. Karger GmbH, Freiburg C1 [Farhat, Tilda; Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, NIH, Bethesda, MD USA. [Caccavale, Laura J.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. RP Farhat, T (reprint author), NCI, Ctr Reduce Canc Hlth Dispar, NIH, 6909 Med Ctr Dr, Bethesda, MD 20892 USA. EM farhatti@mail.nih.gov FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-5-3401]; Maternal and Child Health Bureau of the Health Resources and Services Administration FX This research was supported in part by the intramural research program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract N01-HD-5-3401), and by the Maternal and Child Health Bureau of the Health Resources and Services Administration. NR 42 TC 4 Z9 4 U1 1 U2 15 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1662-4025 EI 1662-4033 J9 OBESITY FACTS JI Obes. Facts PD FEB PY 2014 VL 7 IS 1 BP 1 EP 14 DI 10.1159/000357601 PG 14 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AD1CO UT WOS:000332971600001 PM 24356530 ER PT J AU Alam, MM Bufano, MK Xu, P Kalsy, A Yu, Y Freeman, YW Sultana, T Rashu, MR Desai, I Eckhoff, G Leung, DT Charles, RC LaRocque, RC Harris, JB Clements, JD Calderwood, SB Qadri, F Vann, WF Kovac, P Ryan, ET AF Alam, Mohammad Murshid Bufano, Megan Kelly Xu, Peng Kalsy, Anuj Yu, Y. Freeman, Y. Wu Sultana, Tania Rashu, Md. Rasheduzzaman Desai, Ishaan Eckhoff, Grace Leung, Daniel T. Charles, Richelle C. LaRocque, Regina C. Harris, Jason B. Clements, John D. Calderwood, Stephen B. Qadri, Firdausi Vann, W. F. Kovac, Pavol Ryan, Edward T. TI Evaluation in Mice of a Conjugate Vaccine for Cholera Made from Vibrio cholerae O1 (Ogawa) O-Specific Polysaccharide SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MEMORY B-CELL; INFECTION-DERIVED IMMUNITY; ORAL KILLED CHOLERA; FREE MOUSE MODEL; ANTIBODY-RESPONSES; SEROTYPE OGAWA; DETOXIFIED LIPOPOLYSACCHARIDE; TRANSCUTANEOUS IMMUNIZATION; PROTECTIVE IMMUNITY; HOUSEHOLD CONTACTS AB Background Protective immunity against cholera is serogroup specific. Serogroup specificity in Vibrio cholerae is determined by the O-specific polysaccharide (OSP) of lipopolysaccharide (LPS). Generally, polysaccharides are poorly immunogenic, especially in young children. Methodology Here we report the evaluation in mice of a conjugate vaccine for cholera (OSP:TThc) made from V. cholerae O1 Ogawa O-Specific Polysaccharide-core (OSP) and recombinant tetanus toxoid heavy chain fragment (TThc). We immunized mice intramuscularly on days 0, 21, and 42 with OSP:TThc or OSP only, with or without dmLT, a non-toxigenic immunoadjuvant derived from heat labile toxin of Escherichia coli. Principal Findings We detected significant serum IgG antibody responses targeting OSP following a single immunization in mice receiving OSP:TThc with or without adjuvant. Anti-LPS IgG responses were detected following a second immunization in these cohorts. No anti-OSP or anti-LPS IgG responses were detected at any time in animals receiving un-conjugated OSP with or without immunoadjuvant, and in animals receiving immunoadjuvant alone. Responses were highest following immunization with adjuvant. Serum anti-OSP IgM responses were detected in mice receiving OSP:TThc with or without immunoadjuvant, and in mice receiving unconjugated OSP. Serum anti-LPS IgM and vibriocidal responses were detected in all vaccine cohorts except in mice receiving immunoadjuvant alone. No significant IgA anti-OSP or anti-LPS responses developed in any group. Administration of OSP:TThc and adjuvant also induced memory B cell responses targeting OSP and resulted in 95% protective efficacy in a mouse lethality cholera challenge model. Conclusion We describe a protectively immunogenic cholera conjugate in mice. Development of a cholera conjugate vaccine could assist in inducing long-term protective immunity, especially in young children who respond poorly to polysaccharide antigens. Author Summary Cholera is a severe dehydrating diarrheal illness of humans caused by organisms Vibrio cholerae serogroups O1 or O139 serogroup organisms. Protective immunity against cholera is serogroup specific. Serogroup specificity in V. cholerae is determined by the O-specific polysaccharide (OSP) of lipopolysaccharide (LPS). Generally, polysaccharides are poorly immunogenic, especially in young children. Unfortunately, children bear a large burden of cholera globally. Here we describe a novel cholera conjugate vaccine and show that it induces immune responses in mice, including memory responses, to OSP, the T cell-independent antigen that probably is the target of protective immunity to cholera. These responses were highest following immunization of the vaccine with a novel immunoadjuvant, dmLT. We also show that immunization of mice with this conjugate vaccine protects against challenge with wild-type V. cholerae. A protectively immunogenic cholera conjugate vaccine that induces long-term memory responses could have particular utility in young children who are most at risk of cholera. C1 [Alam, Mohammad Murshid; Bufano, Megan Kelly; Kalsy, Anuj; Yu, Y.; Freeman, Y. Wu; Sultana, Tania; Rashu, Md. Rasheduzzaman; Desai, Ishaan; Eckhoff, Grace; Leung, Daniel T.; Charles, Richelle C.; LaRocque, Regina C.; Harris, Jason B.; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Alam, Mohammad Murshid; Sultana, Tania; Rashu, Md. Rasheduzzaman; Leung, Daniel T.; Qadri, Firdausi] ICDDR B, Dhaka, Bangladesh. [Xu, Peng; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. [Leung, Daniel T.; Charles, Richelle C.; LaRocque, Regina C.; Calderwood, Stephen B.; Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Clements, John D.] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA USA. [Vann, W. F.] US FDA, CBER, Lab Bacterial Toxins, Bethesda, MD 20014 USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Alam, MM (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM etryan@partners.org RI Kovac, Pavol/B-8813-2008; Xu, Peng/K-7036-2012; OI Kovac, Pavol/0000-0001-5044-3449; leung, daniel/0000-0001-8401-0801 FU icddr,b; Intramural Research Program of the National Institutes of Health; NIDDK; National Institutes of Health; National Institute of Allergy & Infectious Diseases [AI077883, AI106878, AI058935]; career development awards [K08 AI089721, K08 AI100923]; Fogarty International Center Training Grant in Vaccine Development and Public Health [TW005572]; FIC Career Development Awards [K01 TW07409, TW07144]; Swedish International Development Cooperation Agency; Howard Hughes Medical Institute; American Society for Tropical Medicine & Hygiene - Burroughs Wellcome Fund FX This research was supported by the icddr,b, by the Intramural Research Program of the National Institutes of Health, NIDDK, and extramural grants from the National Institutes of Health, including the National Institute of Allergy & Infectious Diseases (AI077883, AI106878, AI058935 [SBC, ETR, and FQ], and career development awards K08 AI089721 [RCC] and K08 AI100923 [DTL]), a Fogarty International Center Training Grant in Vaccine Development and Public Health (TW005572 [MMA, TS, MRR and FQ]), FIC Career Development Awards (K01 TW07409 [JBH], TW07144 [RCL]), as well as by the Swedish International Development Cooperation Agency (FQ), a Physician Scientist Early Career Award from the Howard Hughes Medical Institute (RCL), and a Postdoctoral Fellowship in Tropical Infectious Diseases from the American Society for Tropical Medicine & Hygiene - Burroughs Wellcome Fund (DTL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 5 Z9 5 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2014 VL 8 IS 2 AR e2683 DI 10.1371/journal.pntd.0002683 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AB8CK UT WOS:000332017500019 PM 24516685 ER PT J AU Liebman, KA Stoddard, ST Reiner, RC Perkins, TA Astete, H Sihuincha, M Halsey, ES Kochel, TJ Morrison, AC Scott, TW AF Liebman, Kelly A. Stoddard, Steven T. Reiner, Robert C., Jr. Perkins, T. Alex Astete, Helvio Sihuincha, Moises Halsey, Eric S. Kochel, Tadeusz J. Morrison, Amy C. Scott, Thomas W. TI Determinants of Heterogeneous Blood Feeding Patterns by Aedes aegypti in Iquitos, Peru SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MOSQUITO-BORNE DISEASE; PUERTO-RICO; POPULATION-DYNAMICS; HOST SELECTION; HUMAN MOVEMENT; DENGUE VECTOR; CULICIDAE; DIPTERA; TRANSMISSION; IDENTIFICATION AB Background Heterogeneous mosquito biting results in different individuals in a population receiving an uneven number of bites. This is a feature of many vector-borne disease systems that, if understood, could guide preventative control efforts toward individuals who are expected to contribute most to pathogen transmission. We aimed to characterize factors determining biting patterns of Aedes aegypti, the principal mosquito vector of dengue virus. Methodology/Principal Findings Engorged female Ae. aegypti and human cheek swabs were collected from 19 houses in Iquitos, Peru. We recorded the body size, age, and sex of 275 consenting residents. Movement in and out of the house over a week (time in house) and mosquito abundance were recorded on eight separate occasions in each household over twelve months. We identified the individuals bitten by 96 engorged mosquitoes over this period by amplifying specific human microsatellite markers in mosquito blood meals and human cheek swabs. Using a multinomial model assuming a saturating relationship (power), we found that, relative to other residents of a home, an individual's likelihood of being bitten in the home was directly proportional to time spent in their home and body surface area (p<0.05). A linear function fit the relationship equally well (AIC<1). Conclusions/Significance Our results indicate that larger people and those who spend more time at home are more likely to receive Ae. aegypti bites in their homes than other household residents. These findings are consistent with the idea that measurable characteristics of individuals can inform predictions of the extent to which different people will be bitten. This has implications for an improved understanding of heterogeneity in different people's contributions to pathogen transmission, and enhanced interventions that include the people and places that contribute most to pathogen amplification and spread. Author Summary We studied the biting habits of Aedes aegypti, the principal vector of dengue virus, to determine why certain people are bitten more often by this day-active mosquito. Over one year in dengue-endemic Iquitos, Peru, we collected blood fed mosquitoes from 19 households. Mosquito blood meals were then matched to household residents using genetic fingerprinting. We found that within a household, larger individuals and those spending more time in the home were bitten more often than other household residents. Importantly, our results show that one's probability of being bitten is dependent on the characteristics of other household residents and visitors. These results indicate that measurable characteristics of individuals do predict who is most exposed to mosquito-borne pathogens, which contributes to our understanding of pathogen transmission processes, informs development of mathematical disease models, and can enhance the design of targeted control programs. C1 [Liebman, Kelly A.; Stoddard, Steven T.; Reiner, Robert C., Jr.; Perkins, T. Alex; Morrison, Amy C.; Scott, Thomas W.] Univ Calif Davis, Davis, CA 95616 USA. [Reiner, Robert C., Jr.; Perkins, T. Alex; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Astete, Helvio; Morrison, Amy C.] Naval Med Res Unit 6, Iquitos, Peru. [Sihuincha, Moises] Hosp Apoyo, Iquitos, Peru. [Halsey, Eric S.] Naval Med Res Unit 6, Lima, Peru. [Kochel, Tadeusz J.] Naval Med Res Ctr, Silver Spring, MD USA. RP Liebman, KA (reprint author), Univ Calif Davis, Davis, CA 95616 USA. EM kelly.liebman@gmail.com FU National Institutes of Health [R01 AI069341]; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This research was supported by National Institutes of Health Grant R01 AI069341. TWS received support from the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 38 TC 10 Z9 10 U1 2 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2014 VL 8 IS 2 AR e2702 DI 10.1371/journal.pntd.0002702 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AB8CK UT WOS:000332017500031 PM 24551262 ER PT J AU Vlkova, M Sima, M Rohousova, I Kostalova, T Sumova, P Volfova, V Jaske, EL Barbian, KD Gebre-Michael, T Hailu, A Warburg, A Ribeiro, JMC Valenzuela, JG Jochim, RC Volf, P AF Vlkova, Michaela Sima, Michal Rohousova, Iva Kostalova, Tatiana Sumova, Petra Volfova, Vera Jaske, Erin L. Barbian, Kent D. Gebre-Michael, Teshome Hailu, Asrat Warburg, Alon Ribeiro, Jose M. C. Valenzuela, Jesus G. Jochim, Ryan C. Volf, Petr TI Comparative Analysis of Salivary Gland Transcriptomes of Phlebotomus orientalis Sand Flies from Endemic and Non-endemic Foci of Visceral Leishmaniasis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID FLY LUTZOMYIA-LONGIPALPIS; DELAYED-TYPE HYPERSENSITIVITY; INDUCED PLATELET-AGGREGATION; ANTIGENIC CROSS-REACTIVITY; CANINE ANTIBODY-RESPONSE; CUTANEOUS LEISHMANIASIS; IMMUNE-RESPONSE; BRAZILIENSIS INFECTION; HYALURONIDASE ACTIVITY; PHYLOGENETIC ANALYSIS AB Background In East Africa, Phlebotomus orientalis serves as the main vector of Leishmania donovani, the causative agent of visceral leishmaniasis (VL). Phlebotomus orientalis is present at two distant localities in Ethiopia; Addis Zemen where VL is endemic and Melka Werer where transmission of VL does not occur. To find out whether the difference in epidemiology of VL is due to distant compositions of P. orientalis saliva we established colonies from Addis Zemen and Melka Werer, analyzed and compared the transcriptomes, proteomes and enzymatic activity of the salivary glands. Methodology/Principal Findings Two cDNA libraries were constructed from the female salivary glands of P. orientalis from Addis Zemen and Melka Werer. Clones of each P. orientalis library were randomly selected, sequenced and analyzed. In P. orientalis transcriptomes, we identified members of 13 main protein families. Phylogenetic analysis and multiple sequence alignments were performed to evaluate differences between the P. orientalis colonies and to show the relationship with other sand fly species from the subgenus Larroussius. To further compare both colonies, we investigated the humoral antigenicity and cross-reactivity of the salivary proteins and the activity of salivary apyrase and hyaluronidase. Conclusions This is the first report of the salivary components of P. orientalis, an important vector sand fly. Our study expanded the knowledge of salivary gland compounds of sand fly species in the subgenus Larroussius. Based on the phylogenetic analysis, we showed that P. orientalis is closely related to Phlebotomus tobbi and Phlebotomus perniciosus, whereas Phlebotomus ariasi is evolutionarily more distinct species. We also demonstrated that there is no significant difference between the transcriptomes, proteomes or enzymatic properties of the salivary components of Addis Zemen (endemic area) and Melka Werer (non-endemic area) P. orientalis colonies. Thus, the different epidemiology of VL in these Ethiopian foci cannot be attributed to the salivary gland composition. Author SummaryPhlebotomus orientalis is the vector of visceral leishmaniasis (VL) caused by Leishmania donovani in Northeast Africa. Immunization with sand fly saliva or with individual salivary proteins has been shown to protect against leishmaniasis in different hosts, warranting the intensive study of salivary proteins of sand fly vectors. In our study, we characterize the salivary compounds of P. orientalis, thereby broadening the repertoire of salivary proteins of sand fly species belonging to the subgenus Larroussius. In order to find out whether there is any connection between the composition of P. orientalis saliva and the epidemiology of VL in two distinct Ethiopian foci, Addis Zemen and Melka Werer, we studied the transcriptomes, proteomes, enzymatic activities, and the main salivary antigens in two P. orientalis colonies originating from these areas. We did not detect any significant difference between the saliva of female sand flies originating in Addis Zemen (endemic area) and Melka Werer (non-endemic area). Therefore, the different epidemiology of VL in these Ethiopian foci cannot be related to the distant salivary gland protein composition. Identifying the sand fly salivary gland compounds will be useful for future research focused on characterizing suitable salivary proteins as potential anti-Leishmania vaccine candidates. C1 [Vlkova, Michaela; Sima, Michal; Rohousova, Iva; Kostalova, Tatiana; Sumova, Petra; Volfova, Vera; Volf, Petr] Charles Univ Prague, Fac Sci, Dept Parasitol, Prague, Czech Republic. [Jaske, Erin L.; Barbian, Kent D.] NIAID, Rocky Mt Labs, Res Technol Sect, Genom Unit, Hamilton, MT 59840 USA. [Gebre-Michael, Teshome] Univ Addis Ababa, Aklilu Lemma Inst Pathobiol, Addis Ababa, Ethiopia. [Hailu, Asrat] Univ Addis Ababa, Fac Med, Dept Microbiol Immunol & Parasitol, Addis Ababa, Ethiopia. [Warburg, Alon] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Parasitol, Kuvin Ctr Study Infect & Trop Dis, IL-91010 Jerusalem, Israel. [Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Valenzuela, Jesus G.; Jochim, Ryan C.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Vlkova, M (reprint author), Charles Univ Prague, Fac Sci, Dept Parasitol, Prague, Czech Republic. EM jvalenzuela@niaid.nih.gov; ryan.c.jochim.ctr@mail.mil; volf@cesnet.cz RI Ribeiro, Jose/J-7011-2015; Rohousova, Iva/B-4852-2011; Sima, Michal/F-2961-2016; Spitzova, Tatiana/C-3302-2017; Volf, Petr/C-4300-2012; OI Rohousova, Iva/0000-0003-1830-0813; Volf, Petr/0000-0003-1790-1123; Ribeiro, Jose/0000-0002-9107-0818 FU Bill and Melinda Gates Foundation Global Health Program [OPPGH5336]; EU [FP7-261504 EDENext]; Czech Science Foundation [13-05292S]; Grant Agency of Charles University [GAUK-675012/2012]; UNCE [204017]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX The research was supported by Bill and Melinda Gates Foundation Global Health Program (grant number OPPGH5336). This study was partially funded by EU grant FP7-261504 EDENext and is catalogued by the EDENext Steering Committee as EDENext176 (http://www.edenext.eu). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. The Czech team was also supported by Czech Science Foundation (13-05292S), by Grant Agency of Charles University (GAUK-675012/2012), and by UNCE (204017). JMCR and JGV were supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 117 TC 13 Z9 13 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2014 VL 8 IS 2 AR e2709 DI 10.1371/journal.pntd.0002709 PG 19 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AB8CK UT WOS:000332017500009 PM 24587463 ER PT J AU Gruver-Yates, AL Quinn, MA Cidlowski, JA AF Gruver-Yates, Amanda L. Quinn, Matthew A. Cidlowski, John A. TI Analysis of Glucocorticoid Receptors and Their Apoptotic Response to Dexamethasone in Male Murine B Cells During Development SO ENDOCRINOLOGY LA English DT Article ID BONE-MARROW; IN-VITRO; EXPRESSION; SUBPOPULATIONS; THYMOCYTES; MOUSE AB Glucocorticoids have an important role in the resolution of inflammation and clinically they are routinely used to treat allergies, asthma, sepsis, and autoimmune diseases. In addition, glucocorticoids are well recognized to negatively impact the development and function of T cells in the immune system by inducing apoptosis. Less is known however about glucocorticoid function in B lymphocytes. Herein, we demonstrate that the glucocorticoid receptor (GR) is present in B-cell populations isolated from both the spleen and the bone marrow. B-cell populations were found to express more GR than non-B-cell populations from both the spleen and the bone marrow. GR protein was found in all B-cell (B220+) developmental subsets (Mature IgM+IgD+, Immature IgM+IgD-, and Pro/Pre IgM-IgD-) isolated from spleen. GR staining intensity was varied among the B-cell developmental subsets and was found to be higher in B cells isolated from the spleen (secondary lymphoid organ) versus the bone marrow (primary lymphoid organ). Ex vivo cell culture of murine splenocytes and bone marrow lymphocytes indicated that dexamethasone stimulated apoptosis in all B-cell developmental subsets demonstrating glucocorticoid responsiveness. Furthermore, in vivo administration of dexamethasone to adrenalectomized mice reduced B-cell numbers in both spleen and bone marrow. These data suggest that glucocorticoid signaling has an important understudied role in B-cell life-or-death decisions. C1 [Gruver-Yates, Amanda L.; Quinn, Matthew A.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences/NIH FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences/NIH. NR 22 TC 14 Z9 15 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2014 VL 155 IS 2 BP 463 EP 474 DI 10.1210/en.2013-1473 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AC2YQ UT WOS:000332382600013 PM 24196358 ER PT J AU Krieger, CC Gershengorn, MC AF Krieger, Christine C. Gershengorn, Marvin C. TI A Modified ELISA Accurately Measures Secretion of High Molecular Weight Hyaluronan (HA) by Graves' Disease Orbital Cells SO ENDOCRINOLOGY LA English DT Article ID THYROID-ASSOCIATED OPHTHALMOPATHY; THYROTROPIN RECEPTOR EXPRESSION; TSH RECEPTOR; ROOSTER COMB; FIBROBLASTS; DIFFERENTIATION; INTERLEUKIN-1-BETA; ADIPOGENESIS; TISSUE; PROTEOGLYCAN AB Excess production of hyaluronan (hyaluronic acid [ HA]) in the retro-orbital space is a major component of Graves' ophthalmopathy, and regulation of HA production by orbital cells is a major research area. In most previous studies, HA was measured by ELISAs that used HA-binding proteins for detection and rooster comb HA as standards. We show that the binding efficiency of HA-binding protein in the ELISA is a function of HA polymer size. Using gel electrophoresis, we show that HA secreted from orbital cells is primarily comprised of polymers more than 500 000. We modified a commercially available ELISA by using 1 million molecular weight HA as standard to accurately measure HA of this size. We demonstrated that IL-1 beta-stimulated HA secretion is at least 2-fold greater than previously reported, and activation of the TSH receptor by an activating antibody M22 from a patient with Graves' disease led to more than 3-fold increase in HA production in both fibroblasts/preadipocytes and adipocytes. These effects were not consistently detected with the commercial ELISA using rooster comb HA as standard and suggest that fibroblasts/preadipocytes may play a more prominent role in HA remodeling in Graves' ophthalmopathy than previously appreciated. C1 [Krieger, Christine C.; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, NIH, 50 South Dr,Room 4134, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov OI Krieger, Christine/0000-0002-1856-415X FU National Institutes of Health Intramural Research Program [1Z01 K011006] FX This work was supported by the National Institutes of Health Intramural Research Program 1Z01 K011006. NR 36 TC 11 Z9 11 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2014 VL 155 IS 2 BP 627 EP 634 DI 10.1210/en.2013-1890 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AC2YQ UT WOS:000332382600027 PM 24302624 ER PT J AU Xi, HB Kurtoglu, M Lampidis, TJ AF Xi, Haibin Kurtoglu, Metin Lampidis, Theodore J. TI The wonders of 2-deoxy-d-glucose SO IUBMB LIFE LA English DT Review DE 2-deoxy-d-glucose; endoplasmic reticulum stress; glycosylation; autophagy; viral replication; apoptosis; hypoxia ID UNFOLDED PROTEIN RESPONSE; LIPID-LINKED OLIGOSACCHARIDES; ISOLATED RAT HEPATOCYTES; HUMAN CEREBRAL GLIOMAS; NORMOXIC TUMOR-CELLS; ENDOPLASMIC-RETICULUM; GLYCOLYTIC INHIBITORS; OXIDATIVE STRESS; PROSTATE-CANCER; IN-VITRO AB Through the eons of time, out of all possible configurations, nature has selected glucose not only as a vital source of energy to sustain life but also as the molecule who's structure supplies the appropriate elements required for a cell to grow and multiply. This understanding, at least in part, explains the profound effects that the analog of glucose, 2-deoxy-d-glucose, has been shown to have on as common and widespread diseases as cancer, viral infection, aging-related morbidity, epilepsy, and others. This review is confined to summarizing some of the salient findings of this remarkable compound as they relate mainly to cancer. (c) 2014 IUBMB Life, 66(2):110-121, 2014 C1 [Xi, Haibin] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. [Xi, Haibin] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA. [Kurtoglu, Metin] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Lampidis, Theodore J.] Univ Miami, Miller Sch Med, Dept Cell Biol, Miami, FL 33101 USA. [Lampidis, Theodore J.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33101 USA. RP Lampidis, TJ (reprint author), Univ Miami, Miller Sch Med, Dept Cell Biol, R-124,POB 016960, Miami, FL 33101 USA. EM tlampidi@med.miami.edu FU National Cancer Institute [CA37109]; Pap Corps award FX The authors are grateful to Huaping Liu for her input and helpful discussions. The research on 2-DG in the Lampidis lab has been supported by two consecutive 5-year National Cancer Institute grant awards #CA37109 and a Pap Corps award to T.J.L. NR 102 TC 21 Z9 21 U1 0 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1521-6543 EI 1521-6551 J9 IUBMB LIFE JI IUBMB Life PD FEB PY 2014 VL 66 IS 2 BP 110 EP 121 DI 10.1002/iub.1251 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AC8KJ UT WOS:000332781600006 PM 24578297 ER PT J AU Baquet, CR Middleton, TM AF Baquet, Claudia R. Middleton, Thomas McLain (Mac) TI 25th Anniversary Supplement of the Journal of Health Care for the Poor and Underserved SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Editorial Material ID PREVENTION; ACT C1 [Baquet, Claudia R.] Univ Maryland, Sch Med, College Pk, MD 20742 USA. [Baquet, Claudia R.] Univ Maryland Baltimore, Ctr Hlth Policy Hlth Serv Res, Baltimore, MD USA. [Baquet, Claudia R.] NCI, Bethesda, MD 20892 USA. RP Baquet, CR (reprint author), Univ Maryland, Sch Med, College Pk, MD 20742 USA. FU NCI NIH HHS [U01 CA086249, U01 CA114650]; NIMHD NIH HHS [P60 MD000532] NR 13 TC 0 Z9 0 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2014 VL 25 IS 1 SU S BP X EP XIV PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AC3RL UT WOS:000332438800002 PM 24583497 ER PT J AU Ghitza, UE Tai, B AF Ghitza, Udi E. Tai, Betty TI Challenges and Opportunities for Integrating Preventive Substance-Use-Care Services in Primary Care through the Affordable Care Act SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Substance use disorders; Affordable Care Act; addiction treatment; drug abuse treatment; primary care; medical settings; electronic health record; health information technology; prevention; medical home; implementation science; health care reform; health services research; patient-centered medical home; electronic medical record ID ABUSE TREATMENT; MENTAL-HEALTH; USE DISORDERS; REFORM AB Undertreated or untreated substance use disorders (SUD) remain a pervasive, medically-harmful public health problem in the United States, particularly in medically underserved and low-income populations lacking access to appropriate treatment. The need for greater access to SUD treatment was expressed as policy in the Final Rule on standards related to essential health benefits, required to be covered through the 2010 Affordable Care Act (ACA) health insurance exchanges. SUD treatment services have been included as an essential health benefit, in a manner that complies with the Mental Health Parity and Addiction Equity Act (MHPAEA) of 2008. Consequently, with the ACA, a vast expansion of SUD-care services in primary care is looming. This commentary discusses challenges and opportunities under the ACA for equipping health care professionals with appropriate workforce training, infrastructure, and resources to support and guide science-based Screening, Brief Intervention, and Referral to Treatment (SBIRT) for SUD in primary care. C1 [Ghitza, Udi E.; Tai, Betty] NIDA, Ctr Clin Trials Network, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, Ctr Clin Trials Network, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 24 TC 16 Z9 16 U1 1 U2 21 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2014 VL 25 IS 1 SU S BP 36 EP 45 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AC3RL UT WOS:000332438800008 PM 24583486 ER PT J AU Walcott, FL Dunn, BK DeShields, M Baquet, C AF Walcott, Farzana L. Dunn, Barbara K. DeShields, Mary Baquet, Claudia TI The Affordable Care Act and Genetic Testing for Inheritable Cancer Syndromes: Impact on High-Risk Underserved Minorities SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Affordable Care Act; Patient Protection and Affordable Care Act; genetic testing; disparities; high-risk; minorities; BRCA; Lynch Syndrome; prostate cancer; endometrial cancer; breast cancer; colorectal cancer; African Americans; Hispanics; HBOC ID NEGATIVE BREAST-CANCER; BRCA2 MUTATION CARRIERS; COLORECTAL-CANCER; AFRICAN-AMERICANS; OVARIAN-CANCER; MICROSATELLITE INSTABILITY; HEALTH DISPARITIES; GERMLINE MUTATIONS; FAMILY-HISTORY; LYNCH SYNDROME AB Genetic testing for inheritable cancer syndromes is becoming a critical part of preventive health services.. The Patient Protection and Affordable Care Act (PPACA) Essential Health Benefits package addresses breast cancer susceptibility-gene testing for women who are unaffected by cancer. The absence of provisions for 1) men, 2) cancer patients, 3) other inheritable cancer syndromes, and 4) risk-reducing interventions are limitations of PPACA. We discuss provisions and limitations of PPACA pertaining to genetic testing and effects on high-risk populations, in particular minorities. The PPACA is the beginning of an ongoing process of incorporating genetic testing in the armamentarium of cancer prevention. Future efforts should focus on ensuring equitable access to genetic testing as a preventive service under PPACA to high-risk populations other than women. Consideration should also be given to provisions for risk-reducing interventions, especially in underserved minority populations, who are known to underutilize genetic testing and may have limited financial resources for medical intervention. C1 [Walcott, Farzana L.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Dunn, Barbara K.] NCI, Chemoprevent Agents Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Baquet, Claudia] Univ Maryland, Sch Med, Bioeth & Hlth Dispar Res Ctr, College Pk, MD USA. RP Walcott, FL (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. NR 58 TC 2 Z9 2 U1 1 U2 13 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2014 VL 25 IS 1 SU S BP 46 EP 62 PG 17 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AC3RL UT WOS:000332438800009 PM 24583487 ER PT J AU Seshamani, S Cheng, X Fogtmann, M Thomason, ME Studholme, C AF Seshamani, Sharmishtaa Cheng, Xi Fogtmann, Mads Thomason, Moriah E. Studholme, Colin TI A Method for handling intensity inhomogenieties in fMRI sequences of moving anatomy of the early developing brain SO MEDICAL IMAGE ANALYSIS LA English DT Article DE FMRI; Fetal imaging; Bias correction ID INHOMOGENEITY CORRECTION; MR-IMAGES; NONUNIFORMITY CORRECTION; TISSUE CLASSIFICATION; SEGMENTATION; RECONSTRUCTION; INFORMATION AB This paper presents a method for intensity inhomogeniety removal in fMRI studies of a moving subject. In such studies, subtle changes in signal as the subject moves in the presence of a bias field can be a significant confound for BOLD signal analysis. The proposed method avoids the need for a specific tissue model or assumptions about tissue homogeneity by making use of the multiple views of the underlying bias field provided by the subject's motion. A parametric bias field model is assumed and a regression model is used to estimate the basis function weights of this model. Quantitative evaluation of the effects of motion and noise in motion estimates are performed using simulated data. Results demonstrate the strength and robustness of the new method compared to the state of the art 4D nonparametric bias estimator (N4ITK). We also qualitatively demonstrate the impact of the method on resting state neuroimage analysis of a moving adult brain with simulated motion and bias fields, as well as on in vivo moving fetal fMRI. (C) 2013 Elsevier B.V. All rights reserved. C1 [Seshamani, Sharmishtaa; Cheng, Xi; Fogtmann, Mads; Studholme, Colin] Univ Washington, Dept Pediat, Biomed Image Comp Grp, Seattle, WA 98195 USA. [Seshamani, Sharmishtaa; Cheng, Xi; Fogtmann, Mads; Studholme, Colin] Univ Washington, Dept Bioengn, Biomed Image Comp Grp, Seattle, WA 98195 USA. [Seshamani, Sharmishtaa; Cheng, Xi; Fogtmann, Mads; Studholme, Colin] Univ Washington, Dept Radiol, Biomed Image Comp Grp, Seattle, WA 98195 USA. [Thomason, Moriah E.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI USA. [Thomason, Moriah E.] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Thomason, Moriah E.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RP Seshamani, S (reprint author), Univ Washington, Dept Pediat, Biomed Image Comp Grp, Seattle, WA 98195 USA. EM seshaman@uw.edu FU NIH [NIH/NINDS R01 NS 061957, NIH/NINDS R01 EB017133, NIH/NINDS R01 NS 055064]; Merrill Palmer Skillman Institute for Child and Family Development; Department of Pediatrics at Wayne State University (WSU) School of Medicine; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services; WSUs Perinatology Virtual Discovery [P3018205]; W.K. Kellogg Foundation; Research Grant Program awards FX This research was supported by NIH Grants NIH/NINDS R01 NS 061957, NIH/NINDS R01 EB017133 and NIH/NINDS R01 NS 055064, the Merrill Palmer Skillman Institute for Child and Family Development, the Department of Pediatrics at Wayne State University (WSU) School of Medicine, and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. This project was also supported by WSUs Perinatology Virtual Discovery Grant P3018205 (made possible by the W.K. Kellogg Foundation) and Research Grant Program awards to MET. NR 35 TC 9 Z9 9 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD FEB PY 2014 VL 18 IS 2 BP 285 EP 300 DI 10.1016/j.media.2013.10.011 PG 16 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AC0OM UT WOS:000332194600004 PM 24317121 ER PT J AU Bolduc, V Zou, YQ Ko, DY Bonnemann, CG AF Bolduc, Veronique Zou, Yaqun Ko, Dayoung Boennemann, Carsten G. TI siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE allele-specific siRNA; collagen type VI; dominant negative; Ullrich congenital muscular dystrophy ID COLLAGEN VI MYOPATHIES; IN-FRAME DELETION; BETHLEM MYOPATHY; EXTRACELLULAR-MATRIX; FIBROBLASTS; MUSCLE; SECRETION; ORGANIZATION; INHERITANCE; DEFICIENCY AB Congenital muscular dystrophy type Ullrich (UCMD) is a severe disorder of early childhood onset for which currently there is no effective treatment. UCMD commonly is caused by dominant-negative mutations in the genes coding for collagen type VI, a major microfibrillar component of the extracellular matrix surrounding the muscle fibers. To explore RNA interference (RNAi) as a potential therapy for UCMD, we designed a series of small interfering RNA (siRNA) oligos that specifically target the most common mutations resulting in skipping of exon 16 in the COL6A3 gene and tested them in UCMD-derived dermal fibroblasts. Transcript analysis by semiquantitative and quantitative reverse transcriptase PCR showed that two of these siRNAs were the most allele-specific, i.e., they efficiently knocked down the expression from the mutant allele, without affecting the normal allele. In HEK293T cells, these siRNAs selectively suppressed protein expression from a reporter construct carrying the mutation, with no or minimal suppression of the wild-type (WT) construct, suggesting that collagen VI protein levels are as also reduced in an allele-specific manner. Furthermore, we found that treating UCMD fibroblasts with these siRNAs considerably improved the quantity and quality of the collagen VI matrix, as assessed by confocal microscopy. Our current study establishes RNAi as a promising molecular approach for treating dominant COL6-related dystrophies. C1 [Bolduc, Veronique; Zou, Yaqun; Ko, Dayoung; Boennemann, Carsten G.] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Bonnemann, CG (reprint author), NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 2A-116,35 Convent Dr, Bethesda, MD 20892 USA. EM carsten.bonnemann@nih.gov FU Canadian Institutes of Health Research fellowship; Muscular Dystrophy Association (USA); NINDS intramural research program FX We thank Ying Hu for technical assistance, as well as Sungyoung Auh, Ami Mankodi, Carlo Rinaldi, and Laura Bott for critical review of the manuscript and helpful discussions. We thank Mon-Li Chu for sharing antibodies. V. B. is the recipient of a Canadian Institutes of Health Research fellowship. This study was initially supported by a grant from the Muscular Dystrophy Association (USA) to C.G.B., and then by funds of the NINDS intramural research program to C.G.B. The authors declared no conflict of interest. NR 42 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD FEB PY 2014 VL 3 AR e147 DI 10.1038/mtna.2013.74 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC4DO UT WOS:000332471000003 PM 24518369 ER PT J AU Malik, R Bevan, S Nalls, MA Holliday, EG Devan, WJ Cheng, YC Ibrahim-Verbaas, CA Verhaaren, BFJ Bis, JC Joon, AY de Stefano, AL Fornage, M Psaty, BM Ikram, MA Launer, LJ van Duijn, CM Sharma, P Mitchell, BD Rosand, J Meschia, JF Levi, C Rothwell, PM Sudlow, C Markus, HS Seshadri, S Dichgans, M AF Malik, Rainer Bevan, Steve Nalls, Michael A. Holliday, Elizabeth G. Devan, William J. Cheng, Yu-Ching Ibrahim-Verbaas, Carla A. Verhaaren, Benjamin F. J. Bis, Joshua C. Joon, Aron Y. de Stefano, Anita L. Fornage, Myriam Psaty, Bruce M. Ikram, M. Arfan Launer, Lenore J. van Duijn, Cornelia M. Sharma, Pankaj Mitchell, Braxton D. Rosand, Jonathan Meschia, James F. Levi, Christopher Rothwell, Peter M. Sudlow, Cathie Markus, Hugh S. Seshadri, Sudha Dichgans, Martin CA Wellcome Trust Case Control TI Multilocus Genetic Risk Score Associates With Ischemic Stroke in Case-Control and Prospective Cohort Studies SO STROKE LA English DT Article DE genetics; polymorphism; genetic; risk assessment; risk factors ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; ATRIAL-FIBRILLATION; ATHEROSCLEROTIC STROKE; SUSCEPTIBILITY LOCI; BLOOD-PRESSURE; PREDICTION; VARIANTS; HEART AB Background and Purpose Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. Methods Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. Results A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. Conclusions A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small. C1 [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Bevan, Steve; Markus, Hugh S.] St Georges Univ London, Stroke & Dementia Res Ctr, London, England. [Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Holliday, Elizabeth G.] Univ Newcastle, Sch Med & Publ Hlth, Ctr Clin Epidemiol & Biostat, Callaghan, NSW 2308, Australia. [Levi, Christopher] Univ Newcastle, Ctr Translat Neurosci & Mental Hlth Res, Callaghan, NSW 2308, Australia. [Holliday, Elizabeth G.] Hunter Med Res Inst, Ctr Bioinformat Biomarker Discovery & Informat Ba, New Lambton, NSW, Australia. [Devan, William J.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Baltimore Geriatr Res Educ & Clin Ctr GRECC, Dept Vet Affairs, Baltimore, MD USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Baltimore Geriatr Res Educ & Clin Ctr GRECC, Vet Affairs Med Ctr, Baltimore, MD USA. [Ibrahim-Verbaas, Carla A.; Verhaaren, Benjamin F. J.; Ikram, M. Arfan; van Duijn, Cornelia M.] Erasmus MC Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ibrahim-Verbaas, Carla A.; Ikram, M. Arfan] Erasmus MC Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Verhaaren, Benjamin F. J.; Ikram, M. Arfan] Erasmus MC Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Joon, Aron Y.; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [de Stefano, Anita L.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [de Stefano, Anita L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [de Stefano, Anita L.; Seshadri, Sudha] NHLBI, Framingham Heart Study, Framingham, MA USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Ikram, M. Arfan; van Duijn, Cornelia M.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England. [Rosand, Jonathan] Harvard Univ, Sch Med, Boston, MA USA. [Rosand, Jonathan] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Levi, Christopher] Hunter Med Res Inst, New Lambton, NSW, Australia. [Rothwell, Peter M.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford OX3 9DU, England. [Sudlow, Cathie] Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Sudlow, Cathie] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. RP Dichgans, M (reprint author), Klinikum Univ Munich, Inst Stroke & Dementia Res, D-81377 Munich, Germany. EM martin.dichgans@med.uni-muenchen.de OI Seshadri, Sudha/0000-0001-6135-2622; Ikram, Mohammad Arfan/0000-0003-0372-8585; Bevan, Steve/0000-0003-0490-6830; Mitchell, Braxton/0000-0003-4920-4744 FU University of Newcastle; Australian National and Medical Health Research Council (NHMRC) [569257]; Australian National Heart Foundation (NHF) [G 04S 1623]; Gladys M. Brawn Fellowship scheme; Vincent Fairfax Family Foundation in Australia; Australian NHMRC Fellowship scheme; Department of Health (United Kingdom); UK-India Education Research Initiative from the British Council; National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI), Gene-Environment Association Studies (GENEVA) consortium under GEI [U01 HG004436]; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; NIH [HHSN268200782096C, HSN268200625226C]; Division of Adult and Community Health, Centers for Disease Control and Prevention; National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS45012, U01 NS069208-01]; National Institute on Aging (NIA), NIH [Z01 AG-000954-06, Z01 AG-000015-50]; NIH-NINDS [R01 NS-42733, R01 NS-39987]; NINDS [U01 NS069208, NS17950]; American Heart Association (AHA)/Bugher Foundation Centers for Stroke Prevention Research [0775010 N]; National Heart, Lung, and Blood Institute's (NHLBI) SNP Typing for Association [R01 HL087676]; National Center for Research Resources [U54 RR020278]; Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z]; MRC; Stroke Association; Dunhill Medical Trust; National Institute of Health Research (NIHR); NIHR Biomedical Research Centre, Oxford; Binks Trust; Scottish Funding Council; Chief Scientist Office; Netherlands Organization of Scientific Research [175.010.2005.011]; Netherlands Genomics Initiative/Netherlands Organization for Scientific Research Netherlands Consortium for Healthy Ageing [050-060-810]; Nederlandse Hartstichting [2009B102]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN2682011 00009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01HG004402]; NIA [AG-023629, AG-15928, AG-20098, AG-027058, AG08122, AG033193]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease [DK063491]; NHLBI's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278, U01 HL096917, R01 HL093029]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; NHLBI. [U01 HL096917, R01HL087641, R01HL59367, R01HL086694, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641] FX Australian Stroke Genetics Collaboration Australian population control data were derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National and Medical Health Research Council (NHMRC project grant ID: 569257), the Australian National Heart Foundation (NHF project grant ID: G 04S 1623), the University of Newcastle, the Gladys M. Brawn Fellowship scheme, and the Vincent Fairfax Family Foundation in Australia. E. G. Holliday is supported by the Australian NHMRC Fellowship scheme. Bio-Repository of DNA in Stroke is partly funded by a Senior Fellowship from the Department of Health (United Kingdom) to P. Sharma, the Henry Smith Charity, and the UK-India Education Research Initiative from the British Council. Genetics of Early Onset Stroke Study, Baltimore, MD, was supported by the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) Grant U01 HG004436, as part of the Gene-Environment Association Studies (GENEVA) consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488), and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research, which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract number HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) was supported in part by the Intramural Research Program of the National Institute on Aging (NIA), NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000015-50, human subjects protocol number 2003-078. The ISGS study was funded by NIH-NINDS grant R01 NS-42733 (J. F. Meschia). The SWISS study was funded by NIH-NINDS grant R01 NS-39987 (J. F. Meschia). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov). MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS) was supported by the NINDS (U01 NS069208), the American Heart Association (AHA)/Bugher Foundation Centers for Stroke Prevention Research 0775010 N, the NIH and the National Heart, Lung, and Blood Institute's (NHLBI) SNP Typing for Association with Multiple Phenotypes from Existing Epidemiological Data 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. Funding for the Wellcome Trust Case Control Consortium 2 was provided by the Wellcome Trust (grants 085475/B/08/Z and 085475/Z/08/Z). The Stroke Association provided additional support for collection of some of the St George's, London cases. The Oxford cases were collected as part of the Oxford Vascular Study, which is funded by the MRC, Stroke Association, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Biomedical Research Centre, Oxford. The Edinburgh Stroke Study was supported by the Wellcome Trust (clinician scientist award to C. Sudlow), and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre (www.sbirc.ed.ac.uk), Division of Clinical Neurosciences, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility and part of the Scottish Imaging Network-A Platform for Scientific Excellence collaboration (www.sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. Collection of the Munich cases and data analysis was supported by the Vascular Dementia Research Foundation. The Rotterdam study was supported by The Netherlands Organization of Scientific Research (175.010.2005.011), the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research Netherlands Consortium for Healthy Ageing (050-060-810), Nederlandse Hartstichting (2009B102), the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission, and the Municipality of Rotterdam to the Rotterdam Study. The Atherosclerosis Risk in Communities Study (ARIC) is performed as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN2682011 00009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; NIH contract HHSN268200625226C, and NHLBI contracts(Mosley). Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. ARIC analyses performed as part of this project were supported by grant HL-093029 to M. Fornage. This Cardiovascular Health Study (CHS) research was supported by the NHLBI contracts 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, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, and HL105756 with additional contribution from the 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 at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176 and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS) research was supported by the NHLBI's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (contract no. N02-HL-6-4278) and grants (U01 HL096917 and R01 HL093029). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. This study was also supported by grants from the NINDS (NS17950) and the National Institute of Aging (AG08122, AG033193). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, the NHLBI, the NIA, the NIH, or the AHA. NR 47 TC 18 Z9 19 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD FEB PY 2014 VL 45 IS 2 BP 394 EP 402 DI 10.1161/STROKEAHA.113.002938 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 298GP UT WOS:000330312500023 PM 24436234 ER PT J AU Ibrahim-Verbaas, CA Fornage, M Bis, JC Choi, SH Psaty, BM Meigs, JB Rao, M Nalls, M Fontes, JD O'Donnell, CJ Kathiresan, S Ehret, GB Fox, CS Malik, R Dichgans, M Schmidt, H Lahti, J Heckbert, SR Lumley, T Rice, K Rotter, JI Taylor, KD Folsom, AR Boerwinkle, E Rosamond, WD Shahar, E Gottesman, RF Koudstaal, PJ Amin, N Wieberdink, RG Dehghan, A Hofman, A Uitterlinden, AG DeStefano, AL Debette, S Xue, LT Beiser, A Wolf, PA DeCarli, C Ikram, MA Seshadri, S Mosley, TH Longstreth, WT van Duijn, CM Launer, LJ AF Ibrahim-Verbaas, Carla A. Fornage, Myriam Bis, Joshua C. Choi, Seung Hoan Psaty, Bruce M. Meigs, James B. Rao, Madhu Nalls, Mike Fontes, Joao D. O'Donnell, Christopher J. Kathiresan, Sekar Ehret, Georg B. Fox, Caroline S. Malik, Rainer Dichgans, Martin Schmidt, Helena Lahti, Jari Heckbert, Susan R. Lumley, Thomas Rice, Kenneth Rotter, Jerome I. Taylor, Kent D. Folsom, Aaron R. Boerwinkle, Eric Rosamond, Wayne D. Shahar, Eyal Gottesman, Rebecca F. Koudstaal, Peter J. Amin, Najaf Wieberdink, Renske G. Dehghan, Abbas Hofman, Albert Uitterlinden, Andre G. DeStefano, Anita L. Debette, Stephanie Xue, Luting Beiser, Alexa Wolf, Philip A. DeCarli, Charles Ikram, M. Arfan Seshadri, Sudha Mosley, Thomas H., Jr. Longstreth, W. T., Jr. van Duijn, Cornelia M. Launer, Lenore J. TI Predicting Stroke Through Genetic Risk Functions The CHARGE Risk Score Project SO STROKE LA English DT Article DE genetic epidemiology; risk factors; stroke ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; INTEGRATED DISCRIMINATION IMPROVEMENT; CARDIOVASCULAR EVENTS; ATHEROSCLEROSIS RISK; ISCHEMIC-STROKE; BLOOD-PRESSURE; FRAMINGHAM; DESIGN; EPIDEMIOLOGY AB Background and Purpose Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. Methods The study includes 4 population-based cohorts with 2047 first incident strokes from 22 720 initially stroke-free European origin participants aged 55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. Results In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: joint area under the curve=0.016, P=2.3x10(-6); ischemic stroke: joint area under the curve=0.021, P=3.7x10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). Conclusions The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke. C1 [Ibrahim-Verbaas, Carla A.; Koudstaal, Peter J.; Amin, Najaf; Wieberdink, Renske G.; Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ibrahim-Verbaas, Carla A.; Koudstaal, Peter J.; Wieberdink, Renske G.; Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Ibrahim-Verbaas, Carla A.; Amin, Najaf; van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.; Heckbert, Susan R.; Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Choi, Seung Hoan; DeStefano, Anita L.; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Choi, Seung Hoan; DeStefano, Anita L.; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Fontes, Joao D.] Boston Univ, Sch Med, Cardiol Sect, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Choi, Seung Hoan; Fontes, Joao D.; O'Donnell, Christopher J.; Fox, Caroline S.; DeStefano, Anita L.; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A.; Seshadri, Sudha] NHLBI, Framingham Heart Study, Framingham, MA USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Div Gen Med, Boston, MA USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Rao, Madhu] Tufts Univ, Sch Med, Tufts Med Ctr, Div Nephrol,Tufts Evidence Practice Ctr, Boston, MA 02111 USA. [Nalls, Mike] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Kathiresan, Sekar] Broad Inst Harvard & Massachusetts Inst Technol M, Program Med & Populat Genet, Cambridge, MD USA. [Ehret, Georg B.] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Gottesman, Rebecca F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1011 Lausanne, Switzerland. Univ Lausanne, Lausanne, Switzerland. [Ehret, Georg B.] Univ Hosp Geneva, Dept Specialties Internal Med, Div Cardiol, Geneva, Switzerland. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol, Boston, MA 02115 USA. [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res ISD, Munich, Germany. [Schmidt, Helena] Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, Graz, Austria. [Lahti, Jari] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Lahti, Jari] Folkhalsan Res Ctr, Helsinki, Finland. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Rotter, Jerome I.; Taylor, Kent D.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Rosamond, Wayne D.] Univ N Carolina, Dept Epidemiol, Sch Med, Chapel Hill, NC USA. [Shahar, Eyal] Univ Arizona, Div Epidemiol & Biostat, Tucson, AZ USA. [Hofman, Albert; Uitterlinden, Andre G.; Ikram, M. Arfan; van Duijn, Cornelia M.] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [Debette, Stephanie] Univ Versailles, Dept Epidemiol, Paris, France. [Debette, Stephanie] Lariboisiere Hosp, Dept Neurol, Paris, France. [Debette, Stephanie] INSERM, Dept Neuroepidemiol, Paris, France. [DeCarli, Charles] Univ Calif Davis, Dept Neurol & Neurosci, Sacramento, CA 95817 USA. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Med & Neurol, Jackson, MS USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol & Populat Sci, 7201 Wisconsin Ave,Gateway Bldg Suite C-309, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov OI Seshadri, Sudha/0000-0001-6135-2622; Ikram, Mohammad Arfan/0000-0003-0372-8585; Beiser, Alexa/0000-0001-8551-7778; Lahti, Jari/0000-0002-4310-5297; Dehghan, Abbas/0000-0001-6403-016X FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN2682011 00008C, HHSN268201100009C, HHSN268201100010C, HHSN 268201100011C, HHSN268201100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694, N01HC85079, N01HC85080]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C]; NIH [UL1RR025005, K24 DK080140]; NIH Roadmap for Medical Research [UL1RR025005]; National Institute of Neurological Disorders and Stroke; National Institute of Aging [AG023629, AG15928, AG20098, AG027058, AG033193, AG081220, AG16495]; National Center for Research Resources [UL1RR033176]; Clinical and Translational Science Institute [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease [DK063491]; Affymetrix, Inc. [N02-HL-6-4278, U01 HL096917, R01 HL093029]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Neurological Disorders and Stroke [NS17950]; Netherlands Consortium for Healthy Ageing (NGI/NWO-NCHA) [050-060-810]; Erasmus Medical Center; Erasmus University; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Zoll LifeCor; Medtronic; NIH, National Institute on Aging [Z01 AG000954-06]; Netherlands Organisation for Scientific Research (NOW) [916.12.154]; Erasmus University Rotterdam (EUR); Agence National de la Recherche; National Heart, Lung, and Blood Institute (NHLBI). [N01HC85081, N01HC85082, N01HC85083, N01HC85084, N01HC85085, N01HC85086, N01HC35129, N01HC15103, N01HC55222, N01HC75150, N01HC45133, N01HC85239, HHSN268201200036C, HL080295, HL087652, HL105756, N01-HC-25195] FX The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN2682011 00008C, HHSN268201100009C, HHSN268201100010C, HHSN 268201100011C, and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. Infrastructure was partly supported by grant No. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This CHS research was supported by NHLBI contracts N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85084, N01HC85085, N01HC85086; N01HC35129, N01HC15103, N01HC55222, N01HC75150, N01HC45133, N01HC85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke. Additional support was provided through AG023629, AG15928, AG20098, and AG027058 from the National Institute of Aging. See also http://chs-nhlbi.org. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR000124, in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. This work was supported by the NHLBI's Framingham Heart Study research (contract No. N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (contract No. N02-HL-6-4278) and grants (U01 HL096917 and R01 HL093029). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (AG033193, AG081220, AG16495). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS, NHLBI, NIA, NIH, or American Heart Association. The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organisation of Scientific Research (NWO) Investments (No. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Ageing (NGI/NWO-NCHA; project No. 050-060-810). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam.; Dr Psaty serves on a Data Safety Monitoring Board for a clinical trial of a device funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Medtronic. Dr Meigs is supported by NIH grant K24 DK080140. Drs Launer and Nalls' participation was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging (Z01 AG000954-06), and portions of Dr Nalls' contribution utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (http://bio-wulf.nih.gov). Dr Dehghan is supported by Netherlands Organisation for Scientific Research (NOW) grant (veni, 916.12.154) and the Erasmus University Rotterdam (EUR) Fellowship. Dr Debette is a recipient of a "Chaire d'Excellence grant from the Agence National de la Recherche." The study sponsors played no role in the design and conduct of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript. NR 32 TC 23 Z9 23 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD FEB PY 2014 VL 45 IS 2 BP 403 EP 412 DI 10.1161/STROKEAHA.113.003044 PG 10 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 298GP UT WOS:000330312500024 PM 24436238 ER PT J AU Mirasol, RV Bokkers, RPH Hernandez, DA Merino, JG Luby, M Warach, S Latour, LL AF Mirasol, Raymond V. Bokkers, Reinoud P. H. Hernandez, Daymara A. Merino, Jose G. Luby, Marie Warach, Steven Latour, Lawrence L. TI Assessing Reperfusion With Whole-Brain Arterial Spin Labeling A Noninvasive Alternative to Gadolinium SO STROKE LA English DT Article DE magnetic resonance imaging; perfusion imaging ID CEREBRAL-BLOOD-FLOW; ASSOCIATION/AMERICAN-STROKE-ASSOCIATION; DYNAMIC SUSCEPTIBILITY CONTRAST; ACUTE ISCHEMIC-STROKE; PERFUSION MRI; TRANSIT-TIME; INVERSION; ACQUISITION; DISEASE; REGIONS AB Background and Purpose Arterial spin labeling (ASL) is a perfusion imaging technique that does not require gadolinium. The study aimed to assess the reliability of ASL for evaluating reperfusion in acute ischemic stroke in comparison with dynamic susceptibility contrast (DSC) imaging. Methods The study included 24 patients with acute ischemic stroke on admission and 24-hour follow-up ASL and DSC scans. Two readers rated images for interpretability and evidence of reperfusion. Cohen unweighted was used to assess (1) inter-rater reliability between readers for determining interpretability and the presence of reperfusion, (2) agreement between ASL and DSC for determining reperfusion for individual raters, and (3) agreement between ASL and DSC for determining reperfusion after consensus. Results Inter-rater reliability for both ASL and DSC was moderate to good ( of 0.67 versus 0.55, respectively). Reader 1 rated 16 patients as having interpretable ASL and DSC when compared with 15 patients for reader 2. The between ASL and DSC for determining reperfusion was 0.50 for reader 1 and 0.595 for reader 2. After consensus, 18 ASL and 17 DSC image sets were rated interpretable for reperfusion and 13 had both interpretable ASL and DSC scans, yielding a for assessment of reperfusion of 0.8. Conclusions Inter-rater reliability of ASL and DSC was moderate to good. Agreement between ASL and DSC for determining reperfusion was moderate for each individual rater and increased substantially after consensus. ASL is a noninvasive and practical alternative to DSC for reperfusion assessments in patients with confirmed acute ischemic stroke. C1 [Mirasol, Raymond V.; Hernandez, Daymara A.; Merino, Jose G.; Luby, Marie; Warach, Steven; Latour, Lawrence L.] NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. [Mirasol, Raymond V.] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurodegenerat, Stockholm, Sweden. [Bokkers, Reinoud P. H.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Bokkers, Reinoud P. H.] Gelre Hosp, Dept Radiol, Apeldoorn, Netherlands. [Mirasol, Raymond V.] Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20817 USA. [Warach, Steven] UT Southwestern Med Ctr, Seton UT Southwestern Clin Res Inst Austin, Dept Neurol & Neurotherapeut, Dallas, TX USA. RP Mirasol, RV (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, LFMI 10 Ctr Dr,Bldg 10,Rm 1D48,MSC1065, Bethesda, MD 20892 USA. EM mirasolrv@mail.nih.gov OI Merino, Jose/0000-0002-6676-0008 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 22 TC 9 Z9 12 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD FEB PY 2014 VL 45 IS 2 BP 456 EP 461 DI 10.1161/STROKEAHA.113.004001 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 298GP UT WOS:000330312500032 PM 24385278 ER PT J AU Wolf, PA AF Wolf, Philip A. TI Awareness of the Role of Atrial Fibrillation as a Cause of Ischemic Stroke SO STROKE LA English DT Editorial Material DE atrial fibrillation; history; stroke ID RISK C1 [Wolf, Philip A.] Boston Univ, Sch Med, Framingham Heart Study, NHLBI, Boston, MA 02118 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Framingham Heart Study, Dept Neurol, Boston, MA 02118 USA. RP Wolf, PA (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 72 E Concord St,B-6, Boston, MA 02118 USA. EM pawolf@bu.edu FU National Heart, Lung, and Blood Institute Framingham Heart Study [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [NS17950] FX This work was supported by the National Heart, Lung, and Blood Institute Framingham Heart Study (N01-HC-25195) and the National Institute of Neurological Disorders and Stroke (NS17950). NR 12 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD FEB PY 2014 VL 45 IS 2 BP E19 EP E21 DI 10.1161/STROKEAHA.113.003282 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 298GP UT WOS:000330312500003 PM 24357657 ER PT J AU Bao, R Esser, L Poole, S McVeigh, A Chen, YX Savarino, SJ Xia, D AF Bao, Rui Esser, Lothar Poole, Steven McVeigh, Annette Chen, Yu-xing Savarino, Stephen J. Xia, Di TI Preliminary X-ray diffraction analysis of CfaA, a molecular chaperone essential for the assembly of CFA/I fimbriae of human enterotoxigenic Escherichia coli SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID FACTOR ANTIGEN-I; COLONIZATION FACTOR; STRUCTURAL BASIS; PROTEIN CRYSTALS; YERSINIA-PESTIS; RECOGNITION; DIARRHEA; ADHESIN; PATHWAY; ETEC AB Understanding of pilus bioassembly in Gram-negative bacteria stems mainly from studies of P pili and type 1 fimbriae of uropathogenic Escherichia coli, which are mediated by the classic chaperone-usher pathway (CUP). However, CFA/I fimbriae, a class 5 fimbria and intestinal colonization factor for enterotoxigenic E. coli (ETEC), are proposed to assemble via the alternate chaperone pathway (ACP). Both CUP and ACP fimbrial bioassembly pathways require the function of a periplasmic chaperone, but their corresponding proteins share very low similarity in primary sequence. Here, the crystallization of the CFA/I periplasmic chaperone CfaA by the hanging-drop vapor-diffusion method is reported. X-ray diffraction data sets were collected from a native CfaA crystal to 2 angstrom resolution and to 1.8 and 2.8 angstrom resolution, respectively, from a lead and a platinum derivative. These crystals displayed the symmetry of space group C2, with unit-cell parameters a = 103.6, b = 28.68, c = 90.60 angstrom, beta = 119.7 degrees. Initial phases were derived from multiple isomorphous replacement with anomalous scattering experiments using the data from the platinum and lead derivatives. This resulted in an interpretable electron-density map showing one CfaA molecule in an asymmetric unit. Sequence assignments were aided by anomalous signals from the heavy-atom derivatives. Refinement of the atomic model of CfaA is ongoing, which is expected to further understanding of the essential aspects and allowable variations in tertiary structure of the greater family of chaperones involved in chaperone-usher mediated bioassembly. C1 [Bao, Rui; Esser, Lothar; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Poole, Steven; McVeigh, Annette; Savarino, Stephen J.] Naval Med Res Ctr, Infect Dis Directorate, Enter Dis Dept, Silver Spring, MD 20895 USA. [Chen, Yu-xing] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China. [Chen, Yu-xing] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China. [Savarino, Stephen J.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Trans-NIH/FDA Intramural Biodefense Program; US Army Military Infectious Diseases Research Program Work Unit [A0307]; Henry M. Jackson Foundation for the Advancement of Military Medicine FX The authors wish to thank the beamline staff of the SER-CAT at APS, ANL for their assistance in data collection. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by a grant from the Trans-NIH/FDA Intramural Biodefense Program (to DX), by the US Army Military Infectious Diseases Research Program Work Unit Number A0307 (to SJS) and by the Henry M. Jackson Foundation for the Advancement of Military Medicine (SJS). NR 25 TC 0 Z9 0 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD FEB PY 2014 VL 70 BP 196 EP 199 DI 10.1107/S2053230X13033967 PN 2 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AC1BM UT WOS:000332229200010 PM 24637755 ER PT J AU Henske, EP Rasooly, R Siroky, B Bissler, J AF Henske, Elizabeth P. Rasooly, Rebekah Siroky, Brian Bissler, John TI Tuberous sclerosis complex, mTOR, and the kidney: report of an NIDDK-sponsored workshop SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE angiomyolipoma; cyst; mTOR; tuberous sclerosis complex ID SPORADIC LYMPHANGIOLEIOMYOMATOSIS; RENAL ANGIOMYOLIPOMATA; SIROLIMUS; RAPAMYCIN; DISEASE; GENE; EVEROLIMUS; PROTEINS; PATHWAY; GROWTH AB Remarkable basic and translational advances have elucidated the role of the mammalian target of rapamycin (mTOR) signaling network in the pathogenesis of renal disease. Many of these advances originated from studies of the genetic disease tuberous sclerosis complex (TSC), leading to one of the clearest therapeutic opportunities to target mTOR with rapamycin and its analogs ("rapalogs"), which effectively inhibit mTOR complex 1 (mTORC1) by an allosteric mechanism. Clinical trials based on these discoveries have provided strongly positive therapeutic results in TSC (Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. N Engl J Med 358: 140-151, 2008; Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN. N Engl J Med 363: 1801-1811, 2010; McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC. N Engl J Med 364: 1595-1606, 2011). In June 2013, the National Institute of Diabetes and Digestive and Kidney Diseases convened a small panel of physicians and scientists working in the field to identify key unknowns and define possible "next steps" in advancing understanding of TSC-and mTOR-dependent renal phenotypes. TSC-associated renal disease, which affects > 85% of TSC patients, and was a major topic of discussion, focused on angiomyolipomas and epithelial cysts. The third major topic was the role of mTOR and mTOR inhibition in the pathogenesis and therapy of chronic renal disease. Renal cell carcinoma, while recognized as a manifestation of TSC that occurs in a small fraction of patients, was not the primary focus of this workshop and thus was omitted from panel discussions and from this report. C1 [Henske, Elizabeth P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Rasooly, Rebekah] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Siroky, Brian] Univ Cincinnati, Med Ctr, Cincinnati Childrens Hosp, Div Nephrol & Hypertens, Cincinnati, OH 45267 USA. [Bissler, John] Univ Tennessee, Le Bonheur Childrens Hosp, Coll Med, Tuberous Sclerosis Complex Ctr Excellence, Memphis, TN USA. RP Henske, EP (reprint author), Karp Bldg,6th Floor,One Blackfan Circle, Boston, MA 02115 USA. EM EHenske@Partners.org OI Rasooly, Rebekah/0000-0002-6357-5528 FU NIDDK NIH HHS [R01 DK096556] NR 25 TC 4 Z9 4 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2014 VL 306 IS 3 BP F279 EP F283 DI 10.1152/ajprenal.00525.2013 PG 5 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AB7DE UT WOS:000331948700001 PM 24226526 ER PT J AU Hoffert, JD Pisitkun, T Saeed, F Wilson, JL Knepper, MA AF Hoffert, Jason D. Pisitkun, Trairak Saeed, Fahad Wilson, Justin L. Knepper, Mark A. TI Global analysis of the effects of the V2 receptor antagonist satavaptan on protein phosphorylation in collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE inner medullary collecting duct; iTRAQ; mass spectrometry; phosphoproteomics; vasopressin ID VASOPRESSIN V-2-RECEPTOR ANTAGONIST; RENAL PRINCIPAL CELLS; LONG-TERM TREATMENT; MASS-SPECTROMETRY; ARGININE-VASOPRESSIN; SIGNALING NETWORK; LC-MS/MS; AQUAPORIN-2; HYPONATREMIA; PHOSPHOPROTEOMICS AB Satavaptan (SR121463) is a vasopressin V2 receptor antagonist that has been shown to improve hyponatremia in patients with cirrhosis, congestive heart failure, and syndrome of inappropriate antidiuresis. While known to inhibit adenylyl cyclase-mediated accumulation of intracellular cyclic AMP and potentially recruit beta-arrestin in kidney cell lines, very little is known regarding the signaling pathways that are affected by this drug. To this end, we carried out a global quantitative phosphoproteomic analysis of native rat inner medullary collecting duct cells pretreated with satavaptan or vehicle control followed by the V2 receptor agonist desmopressin (dDAVP) for 0.5, 2, 5, or 15 min. A total of 2,449 unique phosphopeptides from 1,160 proteins were identified. Phosphopeptides significantly changed by satavaptan included many of the same kinases [protein kinase A, phosphoinositide 3-kinase, mitogen-activated protein kinase kinase kinase 7 (TAK1), and calcium/calmodulin-dependent kinase kinase 2] and channels (aquaporin-2 and urea transporter UT-A1) regulated by vasopressin. Time course clustering and kinase motif analysis suggest that satavaptan blocks dDAVP-mediated activation of basophilic kinases, while also blocking dDAVP-mediated inhibition of proline-directed kinases. Satavaptan affects a variety of dDAVP-mediated processes including regulation of cell-cell junctions, actin cytoskeleton dynamics, and signaling through Rho GTPases. These results demonstrate that, overall, satavaptan acts as a selective V2 receptor antagonist and affects many of the same signaling pathways regulated by vasopressin. This study represents the first "systems-wide" analysis of a "vaptan"-class drug and provides a wealth of new data regarding the effects of satavaptan on vasopressin-mediated phosphorylation events. C1 [Hoffert, Jason D.; Pisitkun, Trairak; Saeed, Fahad; Wilson, Justin L.; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, Bethesda, MD 20892 USA. [Pisitkun, Trairak] Chulalongkorn Univ, Fac Med, Bangkok 10330, Thailand. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N260,10 Ctr Dr, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU National Heart, Lung, and Blood Institute [ZO1-HL-001285] FX This work was supported by the National Heart, Lung, and Blood Institute intramural budget (ZO1-HL-001285). NR 49 TC 2 Z9 2 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2014 VL 306 IS 4 BP F410 EP F421 DI 10.1152/ajprenal.00497.2013 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AC3IO UT WOS:000332410700005 PM 24259510 ER PT J AU Miranda, CA Lee, JW Chou, CL Knepper, MA AF Miranda, Carlos A. Lee, Jae Wook Chou, Chung-Lin Knepper, Mark A. TI Tolvaptan as a tool in renal physiology SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin-2; Brattleboro; osmotic minipump; urea channel; vasopressin ID THICK ASCENDING LIMB; MEDULLARY COLLECTING DUCT; RAT-KIDNEY; NA-K-2CL COTRANSPORTER; MEDIATED REGULATION; DIABETES-INSIPIDUS; UREA TRANSPORTERS; HEART-FAILURE; VASOPRESSIN; AQUAPORIN-2 AB For decades, the Brattleboro rat has been a useful model in kidney physiology. These animals manifest central diabetes insipidus (lack of circulating vasopressin) due to a mutation in the vasopressin-neurophysin gene. V2 receptor-mediated vasopressin actions in the kidney can be assessed in these animals by infusing the V2-selective vasopressin analog 1-desamino-8-D-arginine vasopressin (dDAVP). However, the major commercial supplier in the United States has ceased production, creating the need for another reliable experimental model of V2 receptor-mediated vasopressin action in rodents. We designed an in vivo protocol to investigate vasopressin responses in the rat kidney using osmotic minipumps loaded with tolvaptan, a nonpeptide competitive inhibitor of the vasopressin V2 receptor. Tolvaptan-infused rats had a mean urinary osmolality of <300 vs. >2,000 mosmol/kgH(2)O in vehicle-infused rats. The tolvaptan infusion produced large decreases in the renal abundance of aquaporin-2 (AQP2), aquaporin-3 (AQP3), the beta-subunit of the epithelial sodium channel (beta-ENaC), and gamma-ENaC that were comparable to the differences seen in vehicleinfused vs. vasopressin-infused Brattleboro rats. Thus we conclude that tolvaptan infusion in rats provides an additional model (besides dDAVP-infusion in the Brattleboro rat) for the assessment of V2 receptor-mediated vasopressin actions in the kidney. We also provide ancillary in vitro data in rat inner-medullary-collecting-duct suspensions showing that tolvaptan can block vasopressin's effects on phosphorylation of the water channel AQP2 in vitro. Specifically, tolvaptan almost completely inhibited the ability of vasopressin to increase AQP2 phosphorylation at Ser256, Ser264, and Ser269, while strongly inhibiting a vasopressin-induced decrease in AQP2 phosphorylation at Ser261. C1 [Miranda, Carlos A.; Lee, Jae Wook; Chou, Chung-Lin; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU National Heart, Lung, and Blood Institute [ZO1-HL001285]; NIH; Pfizer, Inc. FX The study was carried out in the intramural program of the National Heart, Lung, and Blood Institute (Project ZO1-HL001285, M. A. Knepper). C. A. Miranda was a member of the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH, and generous contributions to the Foundation for the NIH from Pfizer, Inc., The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. NR 39 TC 8 Z9 8 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2014 VL 306 IS 3 BP F359 EP F366 DI 10.1152/ajprenal.00330.2013 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AB7DE UT WOS:000331948700011 PM 24305472 ER PT J AU Gul, A Miskulin, D Gassman, J Harford, A Horowitz, B Chen, J Paine, S Bedrick, E Kusek, JW Unruh, M Zager, P AF Gul, Ambreen Miskulin, Dana Gassman, Jennifer Harford, Antonia Horowitz, Bruce Chen, Joline Paine, Susan Bedrick, Edward Kusek, John W. Unruh, Mark Zager, Philip CA BID Pilot Study Investigators TI Design of the Blood Pressure Goals in Dialysis Pilot Study SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Blood pressure; Cardiac MRI; Dialysis; Randomized controlled trial ID LEFT-VENTRICULAR HYPERTROPHY; STAGE RENAL-DISEASE; QUALITY-OF-LIFE; HEMODIALYSIS-PATIENTS; KIDNEY-DISEASE; HYPERTENSION; MORTALITY; SURVIVAL; TRIAL; EPIDEMIOLOGY AB Background:Cardiovascular disease (CVD) is markedly increased among hemodialysis (HD) patients. Optimizing blood pressure (BP) among HD patients may present an important opportunity to reduce the disparity in CVD rates between HD patients and the general population. The optimal target predialysis systolic BP (SBP) among HD patients is unknown. Current international guidelines, calling for a predialysis SBP < 140 mm Hg, are based on the opinion and extrapolation from the general population. Existing randomized controlled trials (RCTs) were small and did not include prespecified BP targets.Methods:The authors described the design of the Blood Pressure in Dialysis (BID) Study, a pilot, multicenter RCT where HD patients are randomized to either a target-standardized predialysis SBP of 110 to 140 mm Hg or 155 to 165 mm Hg. This is the first study to randomize HD patients to 2 different SBP targets.Results:Primary outcomes are feasibility and safety. Feasibility parameters include recruitment and retention rates, adherence with prescribed BP measurements and achievement and maintenance of selected BP targets. Safety parameters include rates of hypotension and other adverse and serious adverse events. The authors obtained preliminary data on changes in left ventricular mass, aortic pulse wave velocity, vascular access thromboses and health-related quality of life across study arms, which may be the secondary outcomes in the full-scale study.Conclusions:The data acquired in the pilot RCT will determine the feasibility and safety and inform the design of a full-scale trial, powered for hard outcomes, which may require 2000 participants. C1 [Gul, Ambreen; Harford, Antonia; Horowitz, Bruce; Bedrick, Edward; Zager, Philip] Univ New Mexico, Dept Med, Albuquerque, NM 87102 USA. [Miskulin, Dana] Tufts Univ, Dept Med, Boston, MA 02111 USA. [Gassman, Jennifer] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Chen, Joline] Boston Univ, Dept Med, Boston, MA 02215 USA. [Paine, Susan; Zager, Philip] Dialysis Clin Inc, Qual Management, Albuquerque, NM USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Unruh, Mark] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. RP Zager, P (reprint author), Univ New Mexico, Dept Med, 1500 Indian Sch Rd NE, Albuquerque, NM 87102 USA. EM pzag@unm.edu FU Dialysis Clinic, Inc; NIDDK [R01-DK083424-01] FX Supported by Dialysis Clinic, Inc, and NIDDK: Grant number R01-DK083424-01. NR 38 TC 7 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD FEB PY 2014 VL 347 IS 2 BP 125 EP 130 DI 10.1097/MAJ.0b013e31827daee5 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA AA7SB UT WOS:000331296100006 PM 23377167 ER PT J AU Wohlfarth, A Gandhi, AS Pang, SK Zhu, MS Scheidweiler, KB Huestis, MA AF Wohlfarth, Ariane Gandhi, Adarsh S. Pang, Shaokun Zhu, Mingshe Scheidweiler, Karl B. Huestis, Marilyn A. TI Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Synthetic cannabinoids; PB-22; 5F-PB-22; High resolution mass spectrometry; Metabolism ID URINARY METABOLITES; IDENTIFICATION; JWH-018; GLUTATHIONE; MIXTURES; AGONIST; CULTURE; MS/MS; SPICE; ACID AB PB-22 (1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid) and 5F-PB-22 (1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid) are new synthetic cannabinoids with a quinoline substructure and the first marketed substances with an ester bond linkage. No human metabolism data are currently available, making it difficult to document PB-22 and 5F-PB-22 intake from urine analysis, and complicating assessment of the drugs' pharmacodynamic and toxicological properties. We incubated 10 mu mol/l PB-22 and 5F-PB-22 with pooled cryopreserved human hepatocytes up to 3 h and analyzed samples on a TripleTOF 5600+ high-resolution mass spectrometer. Data were acquired via TOF scan, followed by information-dependent acquisition triggered product ion scans with mass defect filtering (MDF). The accurate mass full scan MS and MS/MS metabolite datasets were analyzed with multiple data processing techniques, including MDF, neutral loss and product ion filtering. The predominant metabolic pathway for PB-22 and 5F-PB-22 was ester hydrolysis yielding a wide variety of (5-fluoro)pentylindole-3-carboxylic acid metabolites. Twenty metabolites for PB-22 and 22 metabolites for 5F-PB-22 were identified, with the majority generated by oxidation with or without glucuronidation. For 5F-PB-22, oxidative defluorination occurred forming PB-22 metabolites. Both compounds underwent epoxide formation followed by internal hydrolysis and also produced a cysteine conjugate. Human hepatic metabolic profiles were generated for PB-22 and 5F-PB-22. Pentylindole-3-carboxylic acid, hydroxypentyl-PB-22 and PB-22 pentanoic acid for PB-22, and 5'-fluoropentylindole-3-carboxylic acid, PB-22 pentanoic acid and the hydroxy-5F-PB-22 metabolite with oxidation at the quinoline system for 5F-PB-22 are likely the best targets to incorporate into analytical methods for urine to document PB-22 and 5F-PB-22 intake. C1 [Wohlfarth, Ariane; Gandhi, Adarsh S.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Pang, Shaokun] AB SCIEX, Redwood City, CA 94404 USA. [Zhu, Mingshe] Bristol Myers Squibb Res & Dev, Dept Biotransformat, Princeton, NJ 08543 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health; AB SCIEX FX This research was funded by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health and AB SCIEX. NR 34 TC 39 Z9 39 U1 1 U2 30 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD FEB PY 2014 VL 406 IS 6 BP 1763 EP 1780 DI 10.1007/s00216-014-7668-0 PG 18 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AC2GK UT WOS:000332317400020 PM 24518903 ER PT J AU Molloy, AM Einri, CN Jain, D Laird, E Fan, RZ Wang, YF Scott, JM Shane, B Brody, LC Kirke, PN Mills, JL AF Molloy, Anne M. Einri, Caitriona Nic Jain, Divyanshu Laird, Eamon Fan, Ruzong Wang, Yifan Scott, John M. Shane, Barry Brody, Lawrence C. Kirke, Peadar N. Mills, James L. TI Is Low Iron Status a Risk Factor for Neural Tube Defects? SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE ferritin; iron; hemoglobin; neural tube defects ID FOLIC-ACID FORTIFICATION; DEFICIENCY ANEMIA; FORTIFIED POPULATION; PREGNANCY OUTCOMES; MOUSE EMBRYO; SPINA-BIFIDA; FOLATE; WOMEN; VITAMIN-B-12; PREVALENCE AB BackgroundFolic acid supplements can protect against neural tube defects (NTDs). Low folate and low vitamin B-12 status may be maternal risk factors for having an NTD affected pregnancy. However, not all NTDs are preventable by having an adequate folate/ B-12 status and other potentially modifiable factors may be involved. Folate and vitamin B-12 status have important links to iron metabolism. Animal studies support an association between poor iron status and NTDs, but human data are scarce. We examined the relevance of low iron status in a nested NTD case-control study of women within a pregnant population-based cohort. MethodsPregnant women were recruited between 1986 and 1990, when vitamin or iron supplementation in early pregnancy was rare. Blood samples, taken at an average of 14 weeks gestation, were used to measure ferritin and hemoglobin in 64 women during an NTD affected pregnancy and 207 women with unaffected pregnancies. ResultsNo significant differences in maternal ferritin or hemoglobin concentrations were observed between NTD affected and nonaffected pregnancies (case median ferritin 16.9 mu g/L and hemoglobin 12.4 g/dl versus 15.4 mu g/L and 12.3g/dl in controls). As reported previously, red cell folate and vitamin B-12 concentrations were significantly lower in cases. Furthermore, there was no significant association of iron status with type of NTD lesion (anencephaly or spina bifida). ConclusionWe conclude that low maternal iron status during early pregnancy is not an independent risk factor for NTDs. Adding iron to folic acid for periconceptional use may improve iron status but is not likely to prevent NTDs. Birth Defects Research (Part A) 100:100-106, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Molloy, Anne M.; Einri, Caitriona Nic; Jain, Divyanshu; Laird, Eamon] Univ Dublin Trinity Coll, Sch Med, Inst Mol Med, Dublin 2, Ireland. [Fan, Ruzong; Wang, Yifan; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Scott, John M.] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. [Shane, Barry] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Brody, Lawrence C.] NHGRI, NIH, Bethesda, MD 20892 USA. [Kirke, Peadar N.] Hlth Res Board, Dublin, Ireland. RP Molloy, AM (reprint author), Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Room 6-09,Pearse St, Dublin 2, Ireland. EM amolloy@tcd.ie OI Molloy, Anne/0000-0002-1688-9049; Laird, Eamon/0000-0003-4225-5223 FU Health Research Board, Ireland; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01HD33348] FX Supported by the Health Research Board, Ireland and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract: N01HD33348). NR 50 TC 0 Z9 1 U1 0 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD FEB PY 2014 VL 100 IS 2 BP 100 EP 106 DI 10.1002/bdra.23223 PG 7 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA AB2IM UT WOS:000331616400005 PM 24535840 ER PT J AU Stentz, R Osborne, S Horn, N Li, AWH Hautefort, I Bongaerts, R Rouyer, M Bailey, P Shears, SB Hemmings, AM Brearley, CA Carding, SR AF Stentz, Regis Osborne, Samantha Horn, Nikki Li, Arthur W. H. Hautefort, Isabelle Bongaerts, Roy Rouyer, Marine Bailey, Paul Shears, Stephen B. Hemmings, Andrew M. Brearley, Charles A. Carding, Simon R. TI A Bacterial Homolog of a Eukaryotic Inositol Phosphate Signaling Enzyme Mediates Cross-kingdom Dialog in the Mammalian Gut SO CELL REPORTS LA English DT Article ID OUTER-MEMBRANE VESICLES; POLYPHOSPHATE PHOSPHATASE; MAXIMUM-LIKELIHOOD; PHYTASES; EVOLUTION; PYROPHOSPHATES; ROLES; CELLS; IP6 AB Dietary InsP(6) can modulate eukaryotic cell proliferation and has complex nutritive consequences, but its metabolism in the mammalian gastrointestinal tract is poorly understood. Therefore, we performed phylogenetic analyses of the gastrointestinal microbiome in order to search for candidate InsP(6) phosphatases. We determined that prominent gut bacteria express homologs of the mammalian InsP(6) phosphatase (MINPP) and characterized the enzyme from Bacteroides thetaiotaomicron (BtMinpp). We show that BtMinpp has exceptionally high catalytic activity, which we rationalize on the basis of mutagenesis studies and by determining its crystal structure at 1.9 angstrom resolution. We demonstrate that BtMinpp is packaged inside outer membrane vesicles (OMVs) protecting the enzyme from degradation by gastrointestinal proteases. Moreover, we uncover an example of cross-kingdom cell-to-cell signaling, showing that the BtMinpp-OMVs interact with intestinal epithelial cells to promote intracellular Ca2+ signaling. Our characterization of BtMinpp offers several directions for understanding how the microbiome serves human gastrointestinal physiology. C1 [Stentz, Regis; Osborne, Samantha; Horn, Nikki; Hautefort, Isabelle; Bongaerts, Roy; Rouyer, Marine; Carding, Simon R.] Inst Food Res, Gut Hlth & Food Safety Programme, Norwich NR4 7UA, Norfolk, England. [Li, Arthur W. H.; Hemmings, Andrew M.; Brearley, Charles A.] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. [Hemmings, Andrew M.] Univ E Anglia, Sch Chem, Norwich NR4 7TJ, Norfolk, England. [Carding, Simon R.] Univ E Anglia, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England. [Bailey, Paul] John Innes Ctr, Dept Computat & Syst Biol, Norwich NR4 7UH, Norfolk, England. [Shears, Stephen B.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Brearley, CA (reprint author), Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. EM c.brearley@uea.ac.uk; simon.carding@ifr.ac.uk OI Brearley, Charles/0000-0001-6179-9109; Carding, Simon/0000-0002-2383-9701 FU Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J004529/1]; BBSRC [BB/F016816/1]; Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX We would like to thank Kathryn Cross for help with electron microscopy, Dr. Ida Porcelli for providing advice on periplasmic extraction, and Dr. Nathalie Juge for scientific discussions. This work was supported by institutional grants from Biotechnology and Biological Sciences Research Council (BBSRC; BB/J004529/1, S. R. C.), by a BBSRC postgraduate studentship (BB/F016816/1, S.O.), and by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences (S.B.S.). NR 39 TC 12 Z9 12 U1 0 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB PY 2014 VL 6 IS 4 BP 646 EP 656 DI 10.1016/j.celrep.2014.01.021 PG 11 WC Cell Biology SC Cell Biology GA AC3DO UT WOS:000332395400007 PM 24529702 ER PT J AU Qiao, GL Ying, HY Zhao, YX Liang, YR Guo, H Shen, HF Li, ZP Solway, J Tao, EX Chiang, YJ Lipkowitz, S Penninger, JM Langdon, WY Zhang, J AF Qiao, Guilin Ying, Haiyan Zhao, Yixia Liang, Yanran Guo, Hui Shen, Huifeng Li, Zhenping Solway, Julian Tao, Enxiang Chiang, Y. Jeffrey Lipkowitz, Stanley Penninger, Josef M. Langdon, Wallace Y. Zhang, Jian TI E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation SO CELL REPORTS LA English DT Article ID ACTIVATED MAST-CELLS; TRANSCRIPTION FACTOR; NEGATIVE REGULATION; CUTTING EDGE; STAT6; RECEPTOR; IL-4; EXPRESSION; RESPONSES; LINEAGE AB E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the T cell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation in vitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of T cell receptor (TCR)/CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb(-/-) mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation. C1 [Qiao, Guilin; Ying, Haiyan; Zhao, Yixia; Liang, Yanran; Guo, Hui; Li, Zhenping; Zhang, Jian] Univ Chicago, Dept Med, Nephrol Sect, Chicago, IL 60637 USA. [Solway, Julian] Univ Chicago, Dept Med, Sect Pulm & Crit Care, Chicago, IL 60637 USA. [Qiao, Guilin; Ying, Haiyan; Zhao, Yixia; Liang, Yanran; Zhang, Jian] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. [Solway, Julian; Zhang, Jian] Univ Chicago, Comm Mol Pathogenesis & Mol Med, Chicago, IL 60637 USA. [Zhao, Yixia; Liang, Yanran; Guo, Hui; Shen, Huifeng; Zhang, Jian] Ohio State Univ, Dept Microbial Infect & Immun, Columbus, OH 43210 USA. [Chiang, Y. Jeffrey] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lipkowitz, Stanley] NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Penninger, Josef M.] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. [Langdon, Wallace Y.] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA 6009, Australia. [Zhao, Yixia; Liang, Yanran] Cent S Univ, Dept Cardiol, Changsha 410008, Hunan, Peoples R China. [Tao, Enxiang] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Neurol, Guangzhou 510120, Guangdong, Peoples R China. RP Qiao, GL (reprint author), Univ Chicago, Dept Med, Nephrol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM glqiao@uic.edu; jian.zhang@osumc.edu RI Penninger, Josef/I-6860-2013; Zhang, Jian/A-2564-2008 OI Penninger, Josef/0000-0002-8194-3777; FU National Institutes of Health [R01 AR04775, AI090901]; American Heart Association [09GRNT2010084] FX We thank Drs. D. Bohmann, M. H. Kaplan, and K. Murphy for providing the His-tagged ubiquitin, Stat6, and pGFP-RV-GATA3 constructs that made this study possible. This work was supported by grants from the National Institutes of Health (R01 AR04775 and AI090901 to J.Z.) and the American Heart Association (09GRNT2010084 to J.Z.). J.Z. was an American Lung Association Career Investigator. NR 49 TC 17 Z9 17 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB PY 2014 VL 6 IS 4 BP 709 EP 723 DI 10.1016/j.celrep.2014.01.012 PG 15 WC Cell Biology SC Cell Biology GA AC3DO UT WOS:000332395400012 PM 24508458 ER PT J AU Fu, SM Cunningham-Rundles, C Diamond, B Rotrosen, D Stohl, W Terhorst, C AF Fu, Shu Man Cunningham-Rundles, Charlotte Diamond, Betty Rotrosen, Daniel Stohl, William Terhorst, Cox TI Lloyd Mayer, MD, 1952-2013, In Memoriam SO CLINICAL IMMUNOLOGY LA English DT Biographical-Item C1 [Fu, Shu Man] Univ Virginia, Dept Med, Charlottesville, VA USA. [Cunningham-Rundles, Charlotte] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Diamond, Betty] North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Ctr Autoimmune & Musculoskeletal Dis, Manhasset, NY USA. [Rotrosen, Daniel] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Stohl, William] Univ So Calif, Div Rheumatol, Los Angeles, CA USA. [Terhorst, Cox] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Immunol, Boston, MA 02215 USA. RP Fu, SM (reprint author), POB 800133, Charlottesville, VA 22908 USA. EM sf2e@virginia.edu; bdiamond@nshs.edu; Drotrosen@niaid.nih.gov; cterhors@bidmc.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD FEB PY 2014 VL 150 IS 2 BP A1 EP A2 DI 10.1016/j.clim.2014.01.001 PG 2 WC Immunology SC Immunology GA AC0OH UT WOS:000332194100001 ER PT J AU Moghtadaei, M Golpayegani, MRH Almasganj, F Etemadi, A Akbari, MR Malekzadeh, R AF Moghtadaei, Motahareh Golpayegani, Mohammad Reza Hashemi Almasganj, Farshad Etemadi, Arash Akbari, Mohammad R. Malekzadeh, Reza TI Predicting the risk of squamous dysplasia and esophageal squamous cell carcinoma using minimum classification error method SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE Early detection of cancer; Risk factors; Cancer prediction; Squamous dysplasia; Esophageal squamous cell carcinoma; Classification ID SPEECH RECOGNITION; CANCER STATISTICS; AREA; POPULATION; IRAN; PERFORMANCE; ALGORITHM AB Early detection of squamous dysplasia and esophageal squamous cell carcinoma is of great importance. Adopting computer aided algorithms in predicting cancer risk using its risk factors can serve in limiting the clinical screenings to people with higher risks. In the present study, we show that the application of an advanced classification method, the Minimum Classification Error, could considerably enhance the classification performance in comparison to the logistic regression model and the variable structure fuzzy neural network, as the latest successful methods. The results yield the accuracy of 89.65% for esophageal squamous cell carcinoma, and 88.42% for squamous dysplasia risk prediction. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Moghtadaei, Motahareh; Golpayegani, Mohammad Reza Hashemi] Amirkabir Univ Technol, Fac Biomed Engn, Complex Syst & Cybernet Control Lab, Tehran Polytech, Tehran, Iran. [Almasganj, Farshad] Amirkabir Univ Technol, Fac Biomed Engn, Speech Lab, Tehran Polytech, Tehran, Iran. [Etemadi, Arash] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Etemadi, Arash; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Ctr, Shariati Hosp, Tehran, Iran. [Akbari, Mohammad R.] Univ Toronto, Womens Coll Hosp, Womens Coll, Res Inst, Toronto, ON, Canada. [Akbari, Mohammad R.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. RP Golpayegani, MRH (reprint author), Amirkabir Univ Technol, Fac Biomed Engn, Complex Syst & Cybernet Control Lab, Tehran Polytech, POB 1591634311, Tehran, Iran. EM mrhashemigolpayegani@aut.ac.ir RI Etemadi, Arash/C-1386-2016; OI Etemadi, Arash/0000-0002-3458-1072; Malekzadeh, Reza/0000-0003-1043-3814 NR 27 TC 2 Z9 2 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 EI 1879-0534 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD FEB 1 PY 2014 VL 45 BP 51 EP 57 DI 10.1016/j.compbiomed.2013.11.011 PG 7 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA AC3PJ UT WOS:000332433400007 PM 24480163 ER PT J AU Thomas, CJ McKew, JC AF Thomas, Craig J. McKew, John C. TI Playing Well with Others! Initiating and Sustaining Successful Collaborations between Industry, Academia and Government SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Editorial Material C1 [Thomas, Craig J.; McKew, John C.] NIH, Div Preclin Innovat, NCATS, Bethesda, MD 20892 USA. RP Thomas, CJ (reprint author), NIH, Div Preclin Innovat, NCATS, Bldg 10, Bethesda, MD 20892 USA. EM craigt@mail.nih.gov; john.mckew@nih.gov FU Intramural NIH HHS [ZIA HG200319-06] NR 9 TC 4 Z9 4 U1 1 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 EI 1873-4294 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD FEB PY 2014 VL 14 IS 3 BP 291 EP 293 DI 10.2174/1568026613666131127125351 PG 3 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AA8XY UT WOS:000331379500001 PM 24283974 ER PT J AU Portilla, LM Rohrbaugh, ML AF Portilla, Lili M. Rohrbaugh, Mark L. TI Leveraging Public Private Partnerships to Innovate under Challenging Budget Times SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE Collaboration; de-risking; drug repurposing; drug rescue; public private partnerships; technology transfer; translational AB The National Institutes of Health (NIH), academic medical centers and industry have a long and productive history in collaborating together. Decreasing R&D budgets in both the private and public sector have made the need for such collaborations paramount to reduce the risk of further declines in the number of innovative drugs reaching the market to address pressing public health needs. Doing more with less has forced both industry and public sector research institutions (PSRIs) to leverage resources and expertise in order to de-risk projects. In addition, it provides an opportunity to envision and implement new approaches to accomplish these goals. We discuss several of these innovative collaborations and partnerships at the NIH that demonstrate how the NIH and industry are working together to strengthen the drug development pipeline. C1 [Portilla, Lili M.] NIH, Natl Ctr Adv Translat Sci, Off Strateg Alliances, Bethesda, MD 20892 USA. [Rohrbaugh, Mark L.] NIH, Off Technol Transfer, Rockville, MD 20852 USA. RP Portilla, LM (reprint author), NIH, Natl Ctr Adv Translat Sci, Off Strateg Alliances, 9800 Med Ctr Dr,Bldg B,Room B3005, Bethesda, MD 20892 USA. EM Lilip@nih.gov FU Intramural NIH HHS [ZIB TR000004-02] NR 3 TC 2 Z9 2 U1 1 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 EI 1873-4294 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD FEB PY 2014 VL 14 IS 3 BP 326 EP 329 DI 10.2174/1568026613666131127155703 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AA8XY UT WOS:000331379500006 PM 24283971 ER PT J AU Ottinger, EA Kao, ML Carrillo-Carrasco, N Yanjanin, N Shankar, RK Janssen, M Brewster, M Scott, I Xu, X Cradock, J Terse, P Dehdashti, SJ Marugan, J Zheng, W Portilla, L Hubbs, A Pavan, WJ Heiss, J Vite, CH Walkley, SU Ory, DS Silber, SA Porter, FD Austin, CP McKew, JC AF Ottinger, Elizabeth A. Kao, Mark L. Carrillo-Carrasco, Nuria Yanjanin, Nicole Shankar, Roopa Kanakatti Janssen, Marjo Brewster, Marcus Scott, Ilona Xu, Xin Cradock, Jim Terse, Pramod Dehdashti, Seameen J. Marugan, Juan Zheng, Wei Portilla, Lili Hubbs, Alan Pavan, William J. Heiss, John Vite, Charles H. Walkley, Steven U. Ory, Daniel S. Silber, Steven A. Porter, Forbes D. Austin, Christopher P. McKew, John C. TI Collaborative Development of 2-Hydroxypropyl-beta-Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE 2-hydroxypropyl-beta-cyclodextrin; Niemann-Pick disease type C1; neurodegenerative rare disease; translational research ID ORPHAN DRUG LEGISLATION; PHARMACEUTICAL APPLICATIONS; CHOLESTEROL HOMEOSTASIS; EVERY ORGAN; CYCLODEXTRINS; MOUSE; PROGRESSION; MIGLUSTAT; CHILDREN; DELIVERY AB In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-beta-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-beta-CD for the benefit of the NPC patient community. C1 [Ottinger, Elizabeth A.; Carrillo-Carrasco, Nuria; Xu, Xin; Cradock, Jim; Terse, Pramod; Dehdashti, Seameen J.; Marugan, Juan; Zheng, Wei; McKew, John C.] NIH, Div PreClin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Kao, Mark L.; Scott, Ilona; Silber, Steven A.] Janssen Res & Dev LLC, Titusville, NJ 08560 USA. [Yanjanin, Nicole; Shankar, Roopa Kanakatti; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Janssen, Marjo; Brewster, Marcus] Janssen Res & Dev LLC, B-2340 Beerse, Belgium. [Portilla, Lili] NIH, Off Policy Commun & Strateg Alliances, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Hubbs, Alan] NCI, Technol Transfer Off, NIH, Bethesda, MD 20892 USA. [Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Heiss, John] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Vite, Charles H.] Univ Penn, Sch Vet Med, Dept Clin Studies, Philadelphia, PA 19104 USA. [Walkley, Steven U.] Albert Einstein Coll Med, Rose F Kennedy Intellectual & Dev Disabil Res Ctr, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. [Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. [Austin, Christopher P.] NIH, Off Director, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Ottinger, EA (reprint author), NIH, Div PreClin Innovat, Natl Ctr Adv Translat Sci, MSC 3370, Rockville, MD 20850 USA. EM ottingerea@mail.nih.gov RI Carrillo-Carrasco, Nuria/B-9034-2009; Zheng, Wei/J-8889-2014 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808; Zheng, Wei/0000-0003-1034-0757 FU NIH [National Center for Advancing Translational Science (NCATS)]; NIH [Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)]; NIH [National Institute of Neurological Disorders & Stroke (NINDS)]; NIH [National Human Genome Research Institute (NHGRI)]; Janssen Research & Development, LLC part of the Janssen Pharmaceutical Companies of Johnson Johnson; Ara Parseghian Medical Research Foundation; National Niemann-Pick Disease Foundation; Dana's Angels Research Trust; Hide & Seek Foundation for Lysosomal Disease Research; Race for Adam FX Funding support was provided by NIH [National Center for Advancing Translational Science (NCATS), Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Neurological Disorders & Stroke (NINDS), and National Human Genome Research Institute (NHGRI)], Janssen Research & Development, LLC part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Ara Parseghian Medical Research Foundation (D.S.O., S. U. W., C. H. V., F. D. P.), National Niemann-Pick Disease Foundation (D.S.O., C. H. V., F. D. P.), Dana's Angels Research Trust (D.S.O., S. U. W., F. D. P., C. H. V.), the Hide & Seek Foundation for Lysosomal Disease Research (D.S.O., S. U. W., C. H. V.), and the Race for Adam (C.H.V). NR 58 TC 43 Z9 43 U1 1 U2 29 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 EI 1873-4294 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD FEB PY 2014 VL 14 IS 3 BP 330 EP 339 DI 10.2174/1568026613666131127160118 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AA8XY UT WOS:000331379500007 PM 24283970 ER PT J AU Lund, A McMillan, J Kelly, R Jabbarzadeh, S Mead, DG Burkot, TR Kitron, U Vazquez-Prokopec, GM AF Lund, Andrea McMillan, Joseph Kelly, Rosmarie Jabbarzadeh, Shirin Mead, Daniel G. Burkot, Thomas R. Kitron, Uriel Vazquez-Prokopec, Gonzalo M. TI Long term impacts of combined sewer overflow remediation on water quality and population dynamics of Culex quinquefasciatus, the main urban West Nile virus vector in Atlanta, GA SO ENVIRONMENTAL RESEARCH LA English DT Article DE Arbovirus; Culex quinquefasciatus; Risk factors; Urban pollution; Wastewater treatment ID COMBINED SEWAGE OVERFLOWS; LOUIS ENCEPHALITIS-VIRUS; DIPTERA-CULICIDAE; AVIAN HOST; TRANSMISSION; CHICAGO; EPIDEMIOLOGY; OVIPOSITION; CALIFORNIA; LANDSCAPE AB Background: Combined sewers are a significant source of urban water pollution due to periodic discharges into natural streams. Such events (called combined sewer overflows, or CSOs) contribute to the impairment of natural waterways and are associated with increased mosquito productivity and elevated risk of West Nile virus transmission. Objectives: We investigated the impact of CSOs on water quality and immature mosquito productivity in the city of Atlanta, Georgia, one year before and four years after CSO facility remediation. Methods: Water quality (ammonia, phosphate, nitrate and dissolved oxygen concentrations), immature mosquitoes (larvae and pupae), water temperature and rainfall were quantified biweekly between June-October at two urban creeks during 2008-2012. A before-after control-intervention design tested the impact of remediation on mosquito productivity and water quality, whereas generalized linear mixed-effect models quantified the factors explaining the long term impacts of remediation on mosquito productivity. Results: Ammonia and phosphate concentrations and late immature (fourth-instar and pupae) mosquito populations were significantly higher in CSO than in non-CSO creeks, while dissolved oxygen concentrations were lower. Remediation significantly improved water quality estimates (particularly ammonia and dissolved oxygen) and reduced the number of overflows, mosquito productivity and the overall contribution of CSO-affected streams as sources of vectors of West Nile virus. Conclusions: The quality of water in CSOs provided a suitable habitat for immature mosquitoes. Remediation of the CSO facility through the construction of a deep storage tunnel improved water quality indices and reduced the productivity of mosquito species that can serve as vectors of West Nile virus. (C) 2013 Elsevier Inc. All rights reserved. C1 [Lund, Andrea; McMillan, Joseph; Jabbarzadeh, Shirin; Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. [Kelly, Rosmarie] Georgia Dept Publ Hlth, Atlanta, GA USA. [Mead, Daniel G.] Univ Georgia, Athens, GA 30602 USA. [Burkot, Thomas R.] James Cook Univ, Cairns, Qld, Australia. [Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] Fogarty Int Ctr, Bethesda, MD USA. RP Vazquez-Prokopec, GM (reprint author), Emory Univ, Dept Environm Studies, Math & Sci Ctr, 400 Dowman Dr,5th Floor,Suite E530, Atlanta, GA 30322 USA. EM gmvazqu@emory.edu FU internal sources in the Department of Environmental Studies, Emory University FX This project was funded by internal sources in the Department of Environmental Studies, Emory University. NR 50 TC 8 Z9 8 U1 0 U2 39 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2014 VL 129 BP 20 EP 26 DI 10.1016/j.envres.2013.12.008 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AB6SZ UT WOS:000331921100003 PM 24528998 ER PT J AU Mortensen, ME Calafat, AM Ye, XY Wong, LY Wright, DJ Pirkle, JL Merrill, LS Moye, J AF Mortensen, Mary E. Calafat, Antonia M. Ye, Xiaoyun Wong, Lee-Yang Wright, David J. Pirkle, James L. Merrill, Lori S. Moye, John TI Urinary concentrations of environmental phenols in pregnant women in a pilot study of the National Children's Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE Environmental phenols; Biomonitoring; National children's study; National health and nutrition examination survey; Pregnancy ID BISPHENOL-A CONCENTRATIONS; NUTRITION EXAMINATION SURVEY; TEMPORAL VARIABILITY; US POPULATION; UNITED-STATES; EXPOSURE; TRICLOSAN; PREDICTORS; METABOLITE; HEALTH AB Environmental phenols are a group of chemicals with widespread uses in consumer and personal care products, food and beverage processing, and in pesticides. We assessed exposure to benzophenone-3, bisphenol A (BPA), triclosan, methyl- and propyl parabens, and 2,4- and 2,5-dichlorophenol or their precursors in 506 pregnant women enrolled in the National Children's Study (NCS) Vanguard Study. We measured the urinary concentrations of the target phenols by using online solid-phase extraction-isotope dilution high performance liquid chromatography-tandem mass spectrometry. NCS women results were compared to those of 524 similar-aged women in the National Health and Nutrition Examination Survey (NHANES) 2009-2010, and to 174 pregnant women in NHANES 2005-2010. In the NCS women, we found significant racial/ethnic differences (p<0.05) in regression adjusted mean concentrations of benzophenone-3, triclosan, 2,4- and 2,5-dichlorophenol, but not of BPA. Urinary 2,4- and 2,5-dichlorophenol concentrations were highly correlated (r=0.66, p<0.0001). Except for BPA and triclosan, adjusted mean concentrations were significantly different across the 7 study sites. Education was marginally significant for benzophenone-3, triclosan, propyl paraben, and 2,5-dichlorophenol. Urinary concentrations of target phenols in NCS pregnant women and U.S. women and pregnant women were similar. In NCS pregnant women, race/ethnicity and geographic location determined urinary concentrations of most phenols (except BPA), suggesting differential exposures. NCS Main Study protocols should collect urine biospecimens and information about exposures to environmental phenols. Published by Elsevier Inc. C1 [Mortensen, Mary E.; Calafat, Antonia M.; Ye, Xiaoyun; Wong, Lee-Yang; Pirkle, James L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. [Wright, David J.; Merrill, Lori S.] Westat Corp, Rockville, MD USA. [Moye, John] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NCS Program Off, NIH, Bethesda, MD USA. RP Mortensen, ME (reprint author), Div Sci Lab, MS F-20,4770 Buford Highway, Atlanta, GA 30341 USA. EM MMortensen@cdc.gov OI moye, john/0000-0001-9976-8586 FU National Institutes of Health, Department of Health and Human Services; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275200503414C, HHSN27-5200503411C, HHSN275200603416C, HHSN275200503415C, HHSN2-75200503413C, HHSN275200503410C, HSN275200503396C]; National Center for Environmental Health, Centers for Disease Control and Prevention FX This project has been funded from the National Institutes of Health, Department of Health and Human Services, administered by the Eunice Kennedy Shriver National Institute of Child Health and Human Development under Contract nos. HHSN275200503414C, HHSN27-5200503411C, HHSN275200603416C, HHSN275200503415C, HHSN2-75200503413C, HHSN275200503410C, and HHSN275200503396C. Funding for the biospecimen analyses was provided by the National Center for Environmental Health, Centers for Disease Control and Prevention. The manuscript was developed by a Writing Team identified by the National Children's Study Publications Committee for the purpose of timely sharing of centrally collected NCS data. We acknowledge the contributions of the following Vanguard Centers and Principal Investigators: Children's Hospital of Philadelphia, Jennifer Culhane; Mt Sinai Medical School, Phil. Landrigan; South Dakota State University, Bonny Specker; University of California at Irvine, James Swanson and Dean Baker; University of North Carolina at Chapel Hill, Barbara Entwisle and Nancy Dole; University of Utah School of Medicine, Ed Clark; University of Wisconsin, Maureen Durkin. We are grateful to the NHANES staff for the quality and completeness of their efforts conducting this complex survey and specimen collection. We appreciate the dedication and diligence of the NCEH laboratory staff that performed the analyses. NR 39 TC 29 Z9 31 U1 2 U2 44 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2014 VL 129 BP 32 EP 38 DI 10.1016/j.envres.2013.12.004 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AB6SZ UT WOS:000331921100005 PM 24529000 ER PT J AU Shriner, D Adeyemo, A Rotimi, CN AF Shriner, Daniel Adeyemo, Adebowale Rotimi, Charles N. TI Reconciling clinical importance and statistical significance SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID HEIGHT; LOCI C1 [Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Shriner, D (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. EM shrinerda@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU Intramural NIH HHS; NHGRI NIH HHS [Z01 HG200362]; NIMHD NIH HHS [P20 MD006899] NR 3 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD FEB PY 2014 VL 22 IS 2 BP 158 EP 159 DI 10.1038/ejhg.2013.110 PG 2 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 299SK UT WOS:000330415800004 PM 23695278 ER PT J AU Ciucci, T Bosselut, R AF Ciucci, Thomas Bosselut, Remy TI Gimap and T cells: A matter of life or death SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Editorial Material DE auto-immunity; Bcl-2; GTPase immune-associated proteins; lymphopenia; T-cell survival ID BB RAT; FAMILY; SURVIVAL; GTPASE; GENE; MUTATION; IMMUNITY; LYMPHOCYTES; ACTIVATION; PROTEINS AB GTPase immune-associated proteins (Gimap) genes encode evolutionarily conserved GTP-binding proteins that are preferentially expressed in immune cells. Specific members have been shown to be involved in lymphocyte development, or are associated with inflammatory and autoimmune diseases. However, the function of these proteins remains poorly understood, both at the cellular and molecular levels. A new study in this issue of the European Journal of Immunology [Eur. J. Immunol. 2014. 44: 561-572] points to the distinct but partly overlapping functions of two members of this family, Gimap3 and Gimap5, and offers new insight into their potential functions in T cells. C1 [Ciucci, Thomas; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bldg 37,Room 3032,37 Convent Dr, Bethesda, MD 20892 USA. EM remy@helix.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 26 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2014 VL 44 IS 2 BP 348 EP 351 DI 10.1002/eji.201344375 PG 4 WC Immunology SC Immunology GA AB6LX UT WOS:000331901200005 PM 24510500 ER PT J AU Li, WN Wang, LL Jiang, CL Li, H Zhang, K Xu, YJ Hao, Q Li, M Xue, XC Qin, X Zhang, C Wang, HX Zhang, W Zhang, YQ AF Li, Weina Wang, Lili Jiang, Changli Li, Hong Zhang, Kuo Xu, Yujin Hao, Qiang Li, Meng Xue, Xiaochang Qin, Xin Zhang, Cun Wang, Huixuan Zhang, Wei Zhang, Yingqi TI UXT is a novel regulatory factor of regulatory T cells associated with Foxp3 SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Cofactor; Foxp3; Immune suppression; Regulatory T (Treg) cell; UXT ID IMMUNOLOGICAL SELF-TOLERANCE; IN-VITRO PROLIFERATION; C VIRUS-INFECTION; TRANSCRIPTIONAL REPRESSOR; TARGET GENES; STIMULATION; INTERACTS; SCURFIN; COMPLEX; PROTEIN AB Regulatory T (Treg) cells are a constitutively immunosuppressive subtype of T cells that contribute to the maintenance of immunological self-tolerance and immune homeostasis. However, the molecular mechanisms involved in the regulation of Treg cells remain unclear. In the present study, we identified ubiquitously expressed transcript (UXT) to be a novel regulator of human Treg-cell function. In cultured human Treg cells, UXT associates with Foxp3 in the nucleus by interacting with the proline-rich domain in the N-terminus of Foxp3. Knockdown of UXT expression in Treg cells results in a less-suppressive phenotype, demonstrating that UXT is an important regulator of the suppressive actions of Treg cells. Depletion of UXT affects the localization stability of Foxp3 protein in the nucleus and downregulates the expression of Foxp3-related genes. Overall, our results show that UXT is a cofactor of Foxp3 and an important player in Treg-cell function. C1 [Li, Weina; Wang, Lili; Jiang, Changli; Zhang, Kuo; Xu, Yujin; Hao, Qiang; Li, Meng; Xue, Xiaochang; Qin, Xin; Zhang, Cun; Zhang, Wei; Zhang, Yingqi] Fourth Mil Med Univ, State Key Lab Canc Biol, Dept Biopharmaceut, Sch Pharm, Xian 710032, Shaanxi, Peoples R China. [Jiang, Changli; Wang, Huixuan] Chengdu Mil Command, Kunming Gen Hosp, Clin Lab, Kunming, Yunnan, Peoples R China. [Li, Hong] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Zhang, YQ (reprint author), Fourth Mil Med Univ, State Key Lab Canc Biol, Dept Biopharmaceut, Sch Pharm, Xian 710032, Shaanxi, Peoples R China. EM Zhangw90@fmmu.edu.cn; zhangyqh@fmmu.edu.cn RI xue, xiaochang/N-2985-2014 OI xue, xiaochang/0000-0001-9875-9821 FU Natural Science Foundation of China (NSFC) [30972672, 31000406, 81001182, 81171978, 31200657] FX This work was supported by grants from the Natural Science Foundation of China (NSFC numbers 30972672; 31000406; 81001182; 81171978; and 31200657). NR 31 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2014 VL 44 IS 2 BP 533 EP 544 DI 10.1002/eji.201343394 PG 12 WC Immunology SC Immunology GA AB6LX UT WOS:000331901200023 PM 24136450 ER PT J AU Pophali, PA Klotz, JK Ito, S Jain, NA Koklanaris, E Le, RQ Hourigan, CS Savani, BN Chawla, K Shanbhag, S Barrett, AJ Battiwalla, M AF Pophali, Priyanka A. Klotz, Jeffrey K. Ito, Sawa Jain, Natasha A. Koklanaris, Eleftheria Le, Robert Q. Hourigan, Christopher S. Savani, Bipin N. Chawla, Kamna Shanbhag, Sujata Barrett, A. John Battiwalla, Minoo TI Male survivors of allogeneic hematopoietic stem cell transplantation have a long term persisting risk of cardiovascular events SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID MARROW-TRANSPLANTATION; SIBLING DONOR; CHRONIC GVHD; HYPERTENSION; PREVALENCE; MORTALITY; DISEASE; COMPLICATIONS; PREVENTION; CARE AB Long-term survivors of allogeneic stem cell transplantation (SCT) have increased risk of cardiovascular disease. We retrospectively studied cardiovascular risk factors (CVRFs) in 109 SCT survivors (62 males, 47 females; median age 34 years) five years or more after bone marrow (15) or T cell depleted peripheral blood (94) SCT for CML (56), acute leukemia (29), MDS (13), and others (11). One death and two cardiovascular events were reported. At five and ten years after SCT, respectively, 44% and 52% had abnormal lipid profiles; 23% of 5-year survivors met the Adult Treatment Panel HI threshold for dyslipidemia treatment, which is substantially higher than the age-matched general population. There were significant increases in prevalence of hypertension (p < 0.001), diabetes (p = 0.018), and body mass index (p = 0.044) after SCT compared with baseline. The Framingham general cardiovascular risk score (FGCRS) in males at five years after SCT projected a doubling (median 10.4% vs. 5.4%) in the 10-year risk of cardiovascular events. Females received HRT after SCT, and none had increased FGCRS. Chronic GVHD and C-reactive protein were not associated with CVRF at any time. All CVRFs stabilized between five and ten years after SCT. Thus, SCT survivors have sustained elevations in CVRFs. Males have a significantly increased risk of cardiovascular events in their second and third decade after SCT. Published by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells. C1 [Pophali, Priyanka A.; Klotz, Jeffrey K.; Ito, Sawa; Jain, Natasha A.; Koklanaris, Eleftheria; Le, Robert Q.; Hourigan, Christopher S.; Chawla, Kamna; Barrett, A. John; Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Shanbhag, Sujata] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Battiwalla, M (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Pophali, Priyanka/P-8646-2016; Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU intramural research program of the National Institutes of Health Clinical Center; National Heart, Lung, and Blood Institute FX This work was supported by the intramural research program of the National Institutes of Health Clinical Center and the National Heart, Lung, and Blood Institute. NR 30 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2014 VL 42 IS 2 BP 83 EP 89 DI 10.1016/j.exphem.2013.07.003 PG 7 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AC0OF UT WOS:000332193900003 PM 24141092 ER PT J AU Wang, YM Wang, JT Rasoloson, D Stitzel, ML O' Connell, KF Smith, HE Seydoux, G AF Wang, Yuemeng Wang, Jennifer T. Rasoloson, Dominique Stitzel, Michael L. O' Connell, Kevin F. Smith, Harold E. Seydoux, Geraldine TI Identification of Suppressors of mbk-2/DYRK by Whole-Genome Sequencing SO G3-GENES GENOMES GENETICS LA English DT Article DE whole-genome sequencing; single nucleotide polymorphism mapping; suppressors; DYRK kinase; MBK-2; C; elegans ID TO-EMBRYO TRANSITION; CAENORHABDITIS-ELEGANS MEIOSIS; C.-ELEGANS; HOMOLOGOUS RECOMBINATION; SUBSTRATE RECOGNITION; FUNCTIONAL REDUNDANCY; CRISPR-CAS9 SYSTEM; KINASE; DEGRADATION; ASYMMETRY AB Screening for suppressor mutations is a powerful method to isolate genes that function in a common pathway or process. Because suppressor mutations often do not have phenotypes on their own, cloning of suppressor loci can be challenging. A method combining whole-genome sequencing (WGS) and single nucleotide polymorphism (SNP) mapping (WGS/SNP mapping) was developed to identify mutations with visible phenotypes in C. elegans. We show here that WGS/SNP mapping is an efficient method to map suppressor mutations without the need for previous phenotypic characterization. Using RNA-mediated interference to test candidate loci identified by WGS/SNP mapping, we identified 10 extragenic and six intragenic suppressors of mbk-2, a DYRK family kinase required for the transition from oocyte to zygote. Remarkably, seven suppressors are mutations in cell-cycle regulators that extend the timing of the oocyte-to-zygote transition. C1 [Wang, Yuemeng; Wang, Jennifer T.; Rasoloson, Dominique; Stitzel, Michael L.; Seydoux, Geraldine] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [O' Connell, Kevin F.; Smith, Harold E.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Seydoux, G (reprint author), Johns Hopkins Univ, Sch Med, 725 N Wolfe St 706 PCTB, Baltimore, MD 21205 USA. EM gseydoux@jhmi.edu OI Wang, Yuemeng/0000-0003-3928-6926; Wang, Jennifer/0000-0002-8506-5182; Seydoux, Geraldine/0000-0001-8257-0493 FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; Howard Hughes Medical Institute FX We gratefully acknowledge funding from the Intramural Research Program of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases (HS and KOC) and from the Howard Hughes Medical Institute (GS). NR 44 TC 7 Z9 7 U1 0 U2 4 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD FEB PY 2014 VL 4 IS 2 BP 231 EP 241 DI 10.1534/g3.113.009126 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AB2HW UT WOS:000331614800004 PM 24347622 ER PT J AU Takeuchi, N Kaneko, K Koonin, EV AF Takeuchi, Nobuto Kaneko, Kunihiko Koonin, Eugene V. TI Horizontal Gene Transfer Can Rescue Prokaryotes from Muller's Ratchet: Benefit of DNA from Dead Cells and Population Subdivision SO G3-GENES GENOMES GENETICS LA English DT Article DE environmental DNA; evolution of transformation; competence; structured population; soil bacteria ID STREPTOCOCCUS-PNEUMONIAE; ESCHERICHIA-COLI; BACTERIAL TRANSFORMATION; DELETERIOUS MUTATIONS; PSEUDOMONAS-STUTZERI; ASEXUAL POPULATIONS; ADAPTIVE EVOLUTION; METABOLIC NETWORKS; NONSTERILE SOIL; RECOMBINATION AB Horizontal gene transfer (HGT) is a major factor in the evolution of prokaryotes. An intriguing question is whether HGT is maintained during evolution of prokaryotes owing to its adaptive value or is a byproduct of selection driven by other factors such as consumption of extracellular DNA (eDNA) as a nutrient. One hypothesis posits that HGT can restore genes inactivated by mutations and thereby prevent stochastic, irreversible deterioration of genomes in finite populations known as Muller's ratchet. To examine this hypothesis, we developed a population genetic model of prokaryotes undergoing HGT via homologous recombination. Analysis of this model indicates that HGT can prevent the operation of Muller's ratchet even when the source of transferred genes is eDNA that comes from dead cells and on average carries more deleterious mutations than the DNA of recipient live cells. Moreover, if HGT is sufficiently frequent and eDNA diffusion sufficiently rapid, a subdivided population is shown to be more resistant to Muller's ratchet than an undivided population of an equal overall size. Thus, to maintain genomic information in the face of Muller's ratchet, it is more advantageous to partition individuals into multiple subpopulations and let them cross-reference each other's genetic information through HGT than to collect all individuals in one population and thereby maximize the efficacy of natural selection. Taken together, the results suggest that HGT could be an important condition for the long-term maintenance of genomic information in prokaryotes through the prevention of Muller's ratchet. C1 [Takeuchi, Nobuto; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Takeuchi, Nobuto; Kaneko, Kunihiko] Univ Tokyo, Dept Basic Sci, Grad Sch Arts & Sci, Tokyo 1538902, Japan. RP Takeuchi, N (reprint author), Univ Tokyo, KOMABA, Grad Sch Arts & Sci, Dept Basic Sci,Meguro Ku, Komaba 3-8-1, Tokyo 1538902, Japan. EM takeuchi.nobuto@gmail.com FU National Institutes of Health, National Library of Medicine; Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health; Japan Society for the Promotion of Science Research Fellowship for Young Scientists FX We thank Paulien Hogeweg, Alexander Lobkovsky, Nen Saito, and Yuri Wolf for helpful discussions. This research was in part supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, by the Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health, and by the Japan Society for the Promotion of Science Research Fellowship for Young Scientists. NR 96 TC 25 Z9 25 U1 6 U2 41 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD FEB PY 2014 VL 4 IS 2 BP 325 EP 339 DI 10.1534/g3.113.009845 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA AB2HW UT WOS:000331614800012 PM 24347631 ER PT J AU Garcia, FAR Cornelison, T Nuno, T Greenspan, DL Byron, JW Hsu, CH Alberts, DS Chow, HHS AF Garcia, Francisco A. R. Cornelison, Terri Nuno, Tomas Greenspan, David L. Byron, John W. Hsu, Chiu-Hsieh Alberts, David S. Chow, H. -H. Sherry TI Results of a phase II randomized, double-blind, placebo-controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Polyphenon E; Cervical intraepithelial neoplasia; HPV infection ID GREEN TEA EXTRACT; DYSPLASIA; GROWTH AB Objective. In vitro data and pilot data suggest that green tea catechins may possess chemopreventive activity for cervical cancer and precursor lesions. We conducted a randomized, double-blind, placebo-controlled trial of Polyphenon E (decaffeinated and enriched green tea catechin extract) in women with persistent human papillomavirus (HPV) infection and low-grade cervical intraepithelial neoplasia (CIN1) to evaluate the potential of Polyphenon E for cervical cancer prevention. Methods. Ninety-eight eligible women were randomized to receive either Polyphenon E (containing 800 mg epigallocatechin gallate) or placebo once daily for 4 months. The primary study outcome was oncogenic HPV clearance and clearance of CIN1. Results. Polyphenon E was shown to be acceptable, safe and well tolerated. There was no difference in the response rate by treatment allocation. Complete response, defined as negative for high-risk HPV and normal histopathology, was noted in 7 (17.1%) and 6 (14.6%) women in the Polyphenon E and placebo arms, respectively. Progression, defined as persistent oncogenic HPV with histopathologic evidence of progression, was more common in the Polyphenon E group than in the placebo group [6 (14.6%) vs. 3 (7.7%)]. Conclusion. Based on the largest randomized placebo-controlled trial of a green tea extract for HPV related cervical disease, we conclude that 4 months of Polyphenon E intervention did not promote the clearance of persistent high-risk HPV and related CIN1. Further studies may be necessary to better delineate the risk factors for persistent HPV infection and biology of the disease to facilitate the evaluation of chemopreventive strategies. (C) 2013 Elsevier Inc. All rights reserved. C1 [Garcia, Francisco A. R.; Nuno, Tomas] Univ Arizona, Ctr Excellence Womens Hlth, Tucson, AZ 85724 USA. [Garcia, Francisco A. R.; Nuno, Tomas; Hsu, Chiu-Hsieh; Alberts, David S.; Chow, H. -H. Sherry] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. [Cornelison, Terri] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Greenspan, David L.] Maricopa Integrated Hlth Syst, Phoenix, AZ 85008 USA. [Byron, John W.] Southern Pines Womens Hlth Ctr, Southern Pines, NC 28388 USA. RP Nuno, T (reprint author), Univ Arizona, Ctr Canc, 1515 N Campbell Ave,Rm 4985A,POB 245024, Tucson, AZ 85724 USA. EM tnuno@email.arizona.edu FU National Cancer Institute [N01-CN35158]; Arizona Cancer Center Support Grant [P30CA023074]; National Cancer Institute of the National Institutes of Health [R25CA078447] FX This work was supported by a contract (N01-CN35158) from the National Cancer Institute and the Arizona Cancer Center Support Grant (P30CA023074). This article was partially written using funding provided by the National Cancer Institute of the National Institutes of Health under Award Number R25CA078447. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 15 TC 7 Z9 7 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2014 VL 132 IS 2 BP 377 EP 382 DI 10.1016/j.ygyno.2013.12.034 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AC0NJ UT WOS:000332191700023 PM 24388920 ER PT J AU Mavrides, N Pao, M AF Mavrides, Nicole Pao, Maryland TI Updates in paediatric psycho-oncology SO INTERNATIONAL REVIEW OF PSYCHIATRY LA English DT Article ID CHILDHOOD-CANCER SURVIVOR; YOUNG-ADULT SURVIVORS; OF-THE-LITERATURE; FERTILITY PRESERVATION; CHILDREN; ADOLESCENTS; SYMPTOMS; DELIRIUM; CARE; PARENTS AB Childhood cancer accounts for less than 2% of all cancers diagnosed each year. About 12-14,000 children will be diagnosed in a given year with any type of cancer. Over the past fifty years, treatments and cure rates have improved from 10-20% five-year survival rates to between 80-85% five-year survival rates. Psychosocial support of children with cancer and their families has grown and has been more fully integrated into paediatric care over the past five decades. Increasing acceptance of the importance of addressing mental health has led to oncologists referring patients to specific resources and services. This paper provides updated information on psychosocial issues for those who treat children and adolescents with cancer and focuses on unique challenges for the paediatric psycho-oncologist. PubMed and PsycINFO databases were searched from January 2000 through June 2013 using key words: pediatrics, oncology, psychosocial care, family, siblings, cancer, psycho-oncology, psychosocial issues, depression, anxiety, survivorship, and end of life. C1 [Mavrides, Nicole] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Pao, Maryland] NIMH, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Mavrides, N (reprint author), Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. EM nmavrides@med.miami.edu FU Intramural NIH HHS [, ZIA MH002922-01] NR 55 TC 7 Z9 7 U1 2 U2 13 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0954-0261 EI 1369-1627 J9 INT REV PSYCHIATR JI Int. Rev. Psych. PD FEB PY 2014 VL 26 IS 1 BP 63 EP 73 DI 10.3109/09540261.2013.870537 PG 11 WC Psychiatry SC Psychiatry GA AB9QJ UT WOS:000332130100006 PM 24716501 ER PT J AU Thurber, KR Tycko, R AF Thurber, Kent R. Tycko, Robert TI On Mechanisms of Dynamic Nuclear Polarization in Solids SO ISRAEL JOURNAL OF CHEMISTRY LA English DT Review DE adiabatic rapid passage; cross effect; dynamic nuclear polarization; Landau-Zener; magic angle spinning; NMR spectroscopy; radicals; solid effect ID CROSS EFFECT MECHANISMS; THEORETICAL ASPECTS; TRITYL RADICALS; STATE; C-13; RESONANCE; TEMPERATURE; TRANSITION; SATURATION; SYSTEM AB Dynamic nuclear polarization (DNP) can dramatically increase the signal in nuclear magnetic resonance (NMR) experiments by transferring spin polarization from electrons to nuclei. We discuss quantum mechanical descriptions of the solid effect and cross effect mechanisms of DNP that typically occur in solid state NMR at high magnetic field, both with and without magic angle spinning (MAS). We present several extensions of recent theoretical descriptions, including (i) treatments of solid effect DNP and cross effect DNP with MAS, in which two nuclei change spin states simultaneously and (ii) a treatment of solid effect DNP in a two-spin system without MAS, in which the ratio of microwave field strength to hyperfine coupling strength can be arbitrary. We also briefly discuss factors that influence DNP efficiency in experiments, beyond the basic principles contained in simple quantum mechanical models. C1 [Thurber, Kent R.; Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Thurber, KR (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 116, Bethesda, MD 20892 USA. EM thurberk@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 39 TC 10 Z9 10 U1 8 U2 72 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0021-2148 EI 1869-5868 J9 ISR J CHEM JI Isr. J. Chem. PD FEB PY 2014 VL 54 IS 1-2 SI SI BP 39 EP 46 DI 10.1002/ijch.201300116 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA AB7ZI UT WOS:000332009500006 ER PT J AU Thompson, KM Gottesman, S AF Thompson, Karl M. Gottesman, Susan TI The MiaA tRNA Modification Enzyme Is Necessary for Robust RpoS Expression in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GENERAL STRESS-RESPONSE; DNA-DAMAGE RESPONSE; SIGMA-FACTOR RPOS; SALMONELLA-TYPHIMURIUM; HOST FACTOR; TRANSLATIONAL REGULATION; SHIGELLA-FLEXNERI; HEAT-SHOCK; Q-BETA; HF-I AB The stationary phase/general stress response sigma factor RpoS (sigma(S)) is necessary for adaptation and restoration of homeostasis in stationary phase. As a physiological consequence, its levels are tightly regulated at least at two levels. Multiple small regulatory RNA molecules modulate its translation, in a manner that is dependent on the RNA chaperone Hfq and the rpoS 5' untranslated region. ClpXP and the RssB adaptor protein degrade RpoS, unless it is protected by an anti-adaptor. We here find that, in addition to these posttranscriptional levels of regulation, tRNA modification also affects the steady-state levels of RpoS. We screened mutants of several RNA modification enzymes for an effect on RpoS expression and identified the miaA gene, encoding a tRNA isopentenyltransferase, as necessary for full expression of both an rpoS750-lacZ translational fusion and the RpoS protein. This effect is independent of rpoS, the regulatory RNAs, and RpoS degradation. RpoD steady-state levels were not significantly different in the absence of MiaA, suggesting that this is an RpoS-specific effect. The rpoS coding sequence is significantly enriched for leu codons that use MiaA-modified tRNAs, compared to rpoD and many other genes. Dependence on MiaA may therefore provide yet another way for RpoS levels to respond to growth conditions. C1 [Thompson, Karl M.] Howard Univ, Coll Med, Dept Microbiol, Washington, DC 20059 USA. [Gottesman, Susan] NCI, Biochem Genet Sect, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Thompson, KM (reprint author), Howard Univ, Coll Med, Dept Microbiol, Washington, DC 20059 USA. EM karl.thompson@howard.edu FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Howard University College of Medicine; Howard University College of Medicine Bridge Funds; Pilot Project Program; National Institute of General Medical Sciences of the National Institutes of Health [SC2 GM105419] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. K. M. T. was supported in part through startup funding from Howard University College of Medicine, Howard University College of Medicine Bridge Funds and Pilot Project Program, and by the National Institute of General Medical Sciences of the National Institutes of Health under award number SC2 GM105419. NR 56 TC 6 Z9 7 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2014 VL 196 IS 4 BP 754 EP 761 DI 10.1128/JB.01013-13 PG 8 WC Microbiology SC Microbiology GA AC6IU UT WOS:000332626300004 PM 24296670 ER PT J AU Pan, YM Cheng, TJ Wang, YL Bryant, SH AF Pan, Yongmei Cheng, Tiejun Wang, Yanli Bryant, Stephen H. TI Pathway Analysis for Drug Repositioning Based on Public Database Mining SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID CELL LUNG-CANCER; ACUTE PROMYELOCYTIC LEUKEMIA; TRANS-RETINOIC ACID; EXPERIMENTAL PANCREATIC-CANCER; INSTITUTES ANTICANCER SCREEN; GENE-EXPRESSION OMNIBUS; ADVANCED BREAST-CANCER; PHASE-II; DISEASE RELATIONSHIPS; BIOLOGICAL PATHWAYS AB Sixteen FDA-approved drugs were investigated to elucidate their mechanisms of action (MOAs) and clinical functions by pathway analysis based on retrieved drug targets interacting with or affected by the investigated drugs. Protein and gene targets and associated pathways were obtained by data-mining of public databases including the MMDB, PubChem BioAssay, GEO DataSets, and the BioSystems databases. Entrez E-Utilities were applied, and in-house Ruby scripts were developed for data retrieval and pathway analysis to identify and evaluate relevant pathways common to the retrieved drug targets. Pathways pertinent to clinical uses or MOAs were obtained for most drugs. Interestingly, some drugs identified pathways responsible for other diseases than their current therapeutic uses, and these pathways were verified retrospectively by in vitro tests, in vivo tests, or clinical trials. The pathway enrichment analysis based on drug target information from public databases could provide a novel approach for elucidating drug MOAs and repositioning, therefore benefiting the discovery of new therapeutic treatments for diseases. C1 [Pan, Yongmei; Cheng, Tiejun; Wang, Yanli; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Cheng, Tiejun/A-5344-2010 OI Cheng, Tiejun/0000-0002-4486-3356 FU National Institutes of Health (NIH), National Library of Medicine (NLM) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM). NR 120 TC 10 Z9 10 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD FEB PY 2014 VL 54 IS 2 BP 407 EP 418 DI 10.1021/ci4005354 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA AB7SW UT WOS:000331992000008 PM 24460210 ER PT J AU Luo, M Wang, XS Roth, BL Golbraikh, A Tropsha, A AF Luo, Man Wang, Xiang Simon Roth, Bryan L. Golbraikh, Alexander Tropsha, Alexander TI Application of Quantitative Structure-Activity Relationship Models of 5-HT1A Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT1A Ligands SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID ATYPICAL ANTIPSYCHOTIC-DRUGS; DOPAMINE RELEASE; QSAR; ARIPIPRAZOLE; VALIDATION; SELECTION; PROFILE; CHEMINFORMATICS; ANTAGONISTS; DISORDER AB The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP K-i database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 mu M. The most active compound, Lysergol, from the diversity library showed very high binding affinity (K-i) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs. C1 [Luo, Man; Roth, Bryan L.; Golbraikh, Alexander; Tropsha, Alexander] Univ N Carolina, Eshelman Sch Pharm, Lab Mol Modeling, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Luo, Man; Roth, Bryan L.; Golbraikh, Alexander; Tropsha, Alexander] Univ N Carolina, Eshelman Sch Pharm, Carolina Exploratory Ctr Cheminformat Res, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA. [Wang, Xiang Simon] Howard Univ, Dept Pharmaceut Sci, Coll Pharm, Washington, DE 20059 USA. RP Wang, XS (reprint author), Howard Univ, Dept Pharmaceut Sci, Coll Pharm, Washington, DE 20059 USA. EM x.simon.wang@gmail.com; alex_tropsha@unc.edu RI Tropsha, Alexander/G-6245-2014; Roth, Bryan/F-3928-2010 FU NIH [GM066940, GM096967]; NIMH Psychoactive Drug Screening Program; UNC-CH University Research Council [A3-12988]; [RO1MH61887] FX We acknowledge access to the computing facilities at the ITS Research Computing Division of the UNC-CH. The studies reported in this paper were supported in part by the NIH research grants GM066940 and GM096967 (A.T.), the NIMH Psychoactive Drug Screening Program and RO1MH61887 to B.L.R. and the UNC-CH University Research Council Research Grant A3-12988 to X.S.W. NR 55 TC 8 Z9 9 U1 2 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD FEB PY 2014 VL 54 IS 2 BP 634 EP 647 DI 10.1021/ci400460q PG 14 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA AB7SW UT WOS:000331992000029 PM 24410373 ER PT J AU Moussouttas, M Lai, EW Huynh, TT James, J Stocks-Dietz, C Dombrowski, K Khoury, J Pacak, K AF Moussouttas, Michael Lai, Edwin W. Huynh, Thanh T. James, Jerry Stocks-Dietz, Casey Dombrowski, Keith Khoury, John Pacak, Karel TI Association between acute sympathetic response, early onset vasospasm, and delayed vasospasm following spontaneous subarachnoid hemorrhage SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Catecholamines; Cerebral vasospasm; Delayed; Early; Subarachnoid hemorrhage; Sympathetic ID TRANSCRANIAL DOPPLER ULTRASONOGRAPHY; STELLATE GANGLION BLOCK; CEREBRAL VASOSPASM; SELECTIVE LESIONS; PREDICTORS; 3,4-DIHYDROXYPHENYLGLYCOL; NOREPINEPHRINE; INFARCTION; ISCHEMIA; PLASMA AB Subarachnoid hemorrhage (SAH) is accompanied by a marked acute sympathetic response, and evidence exists for sympathetic participation in the development of cerebral vasospasm (VS). The purpose of this observational investigation was to assess the association between acute central catecholaminergic activity, early VS and delayed VS following SAH. SAH grade 3-5 patients who received ventriculostomy, and in whom bilateral temporal transcranial insonation was performed, were enrolled. Cerebrospinal fluid (CSF) was sampled (<48 hours) and assayed for catecholamines, which were correlated to measures of early and delayed sonographic anterior circulation VS. Clinical independent predictors of early VS included age (odds ratio .946 [95% confidence interval .902-.991]), CT scan score (4.27 [1.30-14.0]) and neurogenic cardiomyopathy (6.5 [1.24-34.1]). Age (.925 [.859-.996]) and CT scan score (8.30 [1.33-5.17]) also independently predicted delayed VS. Any early VS independently predicted conventionally defined delayed VS (10.9 [2.64-45.0]), and severe delayed VS was independently predicted by any early VS (9.87 [2.45-39.7]) and by conventionally defined early VS (12.3 [2.80-54.1]). The norepinephrine:3,4-dihydroxyphenylglycol ratio (NE/DHPG) independently predicted severe delayed VS (3.38 [1.01-11.35]), for which DHPG was a negative predictor (.356 [.151-.839]). Epinephrine was a negative predictor of any early VS (.574 [.357-.921]), any delayed VS (.372 [.158-.875]), and delayed conventional VS (.402 [.200-.807]). Early and delayed VS appear to be related processes that are generally unrelated to the acute central sympathetic response following SAH. The one exception may be severe delayed VS which may be associated with noradrenergic activation. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Moussouttas, Michael] Capital Reg Med Ctr, Inst Neurosci, Neurocrit Care Div, Trenton, NJ 08638 USA. [Lai, Edwin W.; Huynh, Thanh T.; Pacak, Karel] NIH, Med Neuroendocrinol Sect, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [James, Jerry; Stocks-Dietz, Casey] Thomas Jefferson Hosp, Neurosonol Div, Philadelphia, PA USA. [Dombrowski, Keith; Khoury, John] Thomas Jefferson Med Ctr, Dept Neurol, Philadelphia, PA USA. RP Moussouttas, M (reprint author), Capital Reg Med Ctr, Inst Neurosci, Neurocrit Care Div, 750 Brunswick Ave, Trenton, NJ 08638 USA. EM moussouttas@hotmail.com FU Intramural Research Program of the NIH FX The authors express their gratitude to the nurses of the neurological intensive care unit from the Jefferson Hospital of Neurosciences at Thomas Jefferson University Medical Center for their assistance in this project. This work represents a collaboration between the Neurocritical Care Division at Thomas Jefferson Medical Center, and the Section on Neuroendocrinology of the Reproductive and Adult Endocrinology Program at the National Institutes of Health (NIH). Research sponsored in part by the Intramural Research Program of the NIH. NR 36 TC 4 Z9 5 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD FEB PY 2014 VL 21 IS 2 BP 256 EP 262 DI 10.1016/j.jocn.2013.03.036 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AC0NT UT WOS:000332192700014 PM 24119956 ER PT J AU Hammer, MB El Euch-Fayache, G Nehdi, H Feki, M Maamouri-Hicheri, W Hentati, F Amouri, R AF Hammer, Monia Benhamed El Euch-Fayache, Ghada Nehdi, Houda Feki, Moncef Maamouri-Hicheri, Wieme Hentati, Faycal Amouri, Rim TI Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE ABL; Ataxia; MTTP; Mutation; Tunisian ID TRIGLYCERIDE TRANSFER PROTEIN; NEUROPATHY; DEFECTS; SUBUNIT; DISEASE AB Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T > A, leading to a-truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9 + 2T > G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins. Published by Elsevier Ltd. C1 [Hammer, Monia Benhamed; El Euch-Fayache, Ghada; Nehdi, Houda; Maamouri-Hicheri, Wieme; Hentati, Faycal; Amouri, Rim] Natl Inst Neurol, Dept Mol Neurobiol & Neuropathol, Tunis, Tunisia. [Hammer, Monia Benhamed] Natl Inst Aging, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Feki, Moncef] Rabta Hosp, Biochem Lab, Tunis, Tunisia. RP Hammer, MB (reprint author), Natl Inst Neurol, Dept Mol Neurobiol & Neuropathol, Tunis, Tunisia. EM benhamadm@mail.nih.gov OI , Moncef/0000-0003-1585-4052 NR 22 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD FEB PY 2014 VL 21 IS 2 BP 311 EP 315 DI 10.1016/j.jocn.2013.04.016 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AC0NT UT WOS:000332192700025 PM 24139731 ER PT J AU Price, JD Beauchamp, NM Rahir, G Zhao, Y Rieger, CC Lau-Kilby, AW Tarbell, KV AF Price, Jeffrey D. Beauchamp, Nicole M. Rahir, Gwendoline Zhao, Yongge Rieger, Cosima C. Lau-Kilby, Annie W. Tarbell, Kristin V. TI CD8(+) dendritic cell-mediated tolerance of autoreactive CD4(+) T cells is deficient in NOD mice and can be corrected by blocking CD40L SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE type 1 diabetes; DEC-205; CD40; peripheral tolerance ID NONOBESE DIABETIC MICE; IN-VIVO; RECEPTOR DEC-205; DYING CELLS; IFN-GAMMA; ANTIGEN; EXPRESSION; UNRESPONSIVENESS; PATHOGENESIS; PEPTIDE AB NOD CD8(+) DCs express increased CD40; targeting of autoantigen to these cells induces Th1 responses, not tolerance, unless CD40/CD40L interactions are blocked. DCs are important mediators of peripheral tolerance for the prevention of autoimmunity. Chimeric DEC-205 antibodies with attached antigens allow in vivo antigen-specific stimulation of T cells by CD8(+) DCs, resulting in tolerance in nonautoimmune mice. However, it is not clear whether DC-mediated tolerance induction occurs in the context of ongoing autoimmunity. We assessed the role of CD8(+) DCs in stimulation of autoreactive CD4(+) T cells in the NOD mouse model of type 1 diabetes. Targeting of antigen to CD8(+) DCs via DEC-205 led to proliferation and expansion of -cell specific BDC2.5 T cells. These T cells also produced IL-2 and IFN- and did not up-regulate FoxP3, consistent with an activated rather than tolerant phenotype. Similarly, endogenous BDC peptide-reactive T cells, identified with I-A(g7) tetramers, did not become tolerant after antigen delivery via DEC-205: no deletion or Treg induction was observed. We observed that CD8(+) DCs from NOD mice expressed higher surface levels of CD40 than CD8(+) DCs from C57BL/6 mice. Blockade of CD40-CD40L interactions reduced the number of BDC2.5 T cells remaining in mice, 10 days after antigen targeting to CD8 DCs, and blocked IFN- production by BDC2.5 T cells. These data indicate that the ability of autoreactive CD4(+) T cells to undergo tolerance mediated by CD8(+) DCs is defective in NOD mice and that blocking CD40-CD40L interactions can restore tolerance induction. C1 [Price, Jeffrey D.; Beauchamp, Nicole M.; Rahir, Gwendoline; Zhao, Yongge; Rieger, Cosima C.; Lau-Kilby, Annie W.; Tarbell, Kristin V.] NIDDKD, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. RP Tarbell, KV (reprint author), NIDDK, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH, Bldg 10,CRC,West Labs 5-5940, Bethesda, MD 20892 USA. EM tarbellk@niddk.nih.gov OI Lau-Kilby, Annie/0000-0002-2666-1347; Tarbell, Kristin/0000-0003-3738-379X FU Intramural Research Programs of the NIDDK; Juvenile Diabetes Research Foundation FX This work was supported by the Intramural Research Programs of the NIDDK and the Juvenile Diabetes Research Foundation. We acknowledge Mrs. Alice Franks (Diabetes, Endocrinology, and Obesity Branch, NIDDK) for help with mouse husbandry, Ms. Jennifer King (Jennifer King Creative) for technical graphics support, and Drs. Michael Lenardo (National Institute of Allergy and Infectious Disease) and Giorgio Trinchieri (National Cancer Institute) for helpful discussions. NR 57 TC 7 Z9 7 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2014 VL 95 IS 2 BP 325 EP 336 DI 10.1189/jlb.0113013 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AB1OD UT WOS:000331560800016 PM 24082013 ER PT J AU Pereira-Manfro, WF Ribeiro-Gomes, FL Filardy, AA Vellozo, NS Guillermo, LVC Silva, EM Siegel, RM DosReis, GA Lopes, MF AF Pereira-Manfro, Wania F. Ribeiro-Gomes, Flavia L. Filardy, Alessandra Almeida Vellozo, Natalia S. Guillermo, Landi V. C. Silva, Elisabeth M. Siegel, Richard M. DosReis, George A. Lopes, Marcela F. TI Inhibition of caspase-8 activity promotes protective Th1-and Th2-mediated immunity to Leishmania major infection SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE apoptosis; CD4 T cells; FasL; FLIP; cytokines ID EXPERIMENTAL CUTANEOUS LEISHMANIASIS; TRYPANOSOMA-CRUZI INFECTION; IL-4-DEFICIENT BALB/C MICE; INDUCED CELL-DEATH; CD4 T-CELLS; TRANSGENIC MICE; VISCERAL LEISHMANIASIS; CYTOKINE INTERACTIONS; INTERFERON-GAMMA; DEFICIENT MICE AB T cell expression of caspase-8 inhibitor vFLIP provides a Th1 cytokine environment, along with a protective Th2 response that increases immunity to Leishmania major infection. We investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to Leishmania major parasites. Splenic CD4 T cells undergo activation-induced apoptosis, and blockade of FasL-Fas interaction increased IFN- and IL-4 cytokine responses to L. major antigens. To block death receptor-induced death, we used mice expressing a T cell-restricted transgene for vFLIP. Inhibition of caspase-8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. major infection, even in the Th1-prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. major infection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti-IL-4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase-8 activity in T cells improves immunity to L. major infection by promoting increased Th1 and Th2 responses. C1 [Pereira-Manfro, Wania F.; Ribeiro-Gomes, Flavia L.; Filardy, Alessandra Almeida; Vellozo, Natalia S.; Guillermo, Landi V. C.; Silva, Elisabeth M.; DosReis, George A.; Lopes, Marcela F.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941902 Rio De Janeiro, Brazil. [Ribeiro-Gomes, Flavia L.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Siegel, Richard M.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [DosReis, George A.] Inst Nacl Pesquisa Translac Saude & Ambiente Regi, Conselho Nacl Desenvolvimento Cient & Tecnol Mini, Rio De Janeiro, Brazil. RP Lopes, MF (reprint author), Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Ctr Ciencias Saude, Ilha Fundao, Av Carlos Chagas Filho 373, BR-21941902 Rio De Janeiro, Brazil. EM marcelal@biof.ufrj.br RI Ribeiro-Gomes, Flavia/F-7609-2015; lopes, marcela/E-2201-2012 OI lopes, marcela/0000-0002-4508-0505 FU United Nations Children's Fund (UNICEF)/United Nations Development Programme (UNDP)/World Bank/World Health Organization (WHO) Special Program for Research and Training in Tropical Diseases (TDR) [A60281]; Howard Hughes Medical Institute [55003669]; Brazilian National Research Council (CNPq); Rio de Janeiro State Science Foundation (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro; FAPERJ); National Institutes of Science and Technology-Instituto Nacional para Pesquisa Translacional em Saude e Ambiente na Regiao Amazonica (INCT-INPeTAm)/CNPq/Ministerio da Ciencia e Tecnologia (MCT); CNPq FX This investigation received financial support from United Nations Children's Fund (UNICEF)/United Nations Development Programme (UNDP)/World Bank/World Health Organization (WHO) Special Program for Research and Training in Tropical Diseases (TDR; grant A60281 to M. F. L.), Howard Hughes Medical Institute (grant 55003669 to G. A. D.), Brazilian National Research Council (CNPq), Rio de Janeiro State Science Foundation (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro; FAPERJ), and National Institutes of Science and Technology-Instituto Nacional para Pesquisa Translacional em Saude e Ambiente na Regiao Amazonica (INCT-INPeTAm)/CNPq/Ministerio da Ciencia e Tecnologia (MCT). W. F. P-M. received a Ph.D. fellowship from CNPq. M. F. L. and G. A. D. are research fellows at CNPq, Brazil. We thank Dr. David Sacks for supporting an experiment with vFLIP mice in his lab at U. S. National Institutes of Health and Dr. Francoise Meylan for genotyping mice. We also thank Edna Aleixo (UFRJ) for importing vFLIP mice from the United States and Jorgete Logullo for technical assistance. NR 66 TC 1 Z9 1 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2014 VL 95 IS 2 BP 347 EP 355 DI 10.1189/jlb.0912463 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AB1OD UT WOS:000331560800018 PM 24072877 ER PT J AU Hartung, AM Beutler, JA Navarro, HA Wiemer, DF Neighbors, JD AF Hartung, Alyssa M. Beutler, John A. Navarro, Hernan A. Wiemer, David F. Neighbors, Jeffrey D. TI Stilbenes as kappa-Selective, Non-nitrogenous Opioid Receptor Antagonists SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID VITRO BINDING-AFFINITY; SALVIA-DIVINORUM; NEOCLERODANE DITERPENES; DIOCLEA-GRANDIFLORA; SALVINORIN-A; CANNABINOID RECEPTORS; SCHWEINFURTHIN-F; PAWHUSKIN-C; ANALOGS; RESVERATROL AB The natural stilbene pawhuskin A has been shown to function as an opioid receptor antagonist, with preferential binding to the kappa receptor. This finding encouraged assembly of a set of analogues to probe the importance of key structural features. Assays on these compounds determined that one (compound 29) shows potent opioid receptor binding activity and significantly improved selectivity for the kappa receptor. These studies begin to illuminate the structural features of these non-nitrogenous opioid, receptor antagonists that are required for activity. C1 [Hartung, Alyssa M.; Wiemer, David F.; Neighbors, Jeffrey D.] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Wiemer, David F.] RTI Int, Discovery Sci, Res Triangle Pk, NC 27709 USA. RP Neighbors, JD (reprint author), Univ Iowa, Dept Chem, Chem Bldg, Iowa City, IA 52242 USA. EM jeffrey-neighbors@uiowa.edu FU National Institutes of Health [DA02-6573]; Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research; Roy J. Carver Charitable Trust as a Research Program of Excellence FX We thank Dr. R. J. Barney for his assistance with preparation of some early intermediates. Financial support from the National Institutes of Health (DA02-6573) is gratefully acknowledged. This research also was supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research, and the Roy J. Carver Charitable Trust as a Research Program of Excellence. NR 56 TC 4 Z9 4 U1 2 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2014 VL 77 IS 2 BP 311 EP 319 DI 10.1021/np4009046 PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA AC2SQ UT WOS:000332354700017 PM 24456556 ER PT J AU Glancy, B Hsu, LY Dao, L Bakalar, M French, S Chess, DJ Taylor, JL Picard, M Aponte, A Daniels, MP Esfahani, S Cushman, S Balaban, RS AF Glancy, Brian Hsu, Li-Yueh Dao, Lam Bakalar, Matthew French, Stephanie Chess, David J. Taylor, Joni L. Picard, Martin Aponte, Angel Daniels, Mathew P. Esfahani, Shervin Cushman, Samuel Balaban, Robert S. TI In Vivo Microscopy Reveals Extensive Embedding of Capillaries within the Sarcolemma of Skeletal Muscle Fibers SO MICROCIRCULATION LA English DT Article DE two-photon microscopy; 3D quantitative imaging; muscle mitochondria; myoglobin; vasculature; microcirculation; GLUT4 ID SCANNING-ELECTRON-MICROSCOPY; ISCHEMIA-REPERFUSION INJURY; NEUROMUSCULAR-JUNCTIONS; 2-PHOTON MICROSCOPY; OXYGEN-CONSUMPTION; NITRIC-OXIDE; BLOOD-FLOW; MYOGLOBIN; RAT; MITOCHONDRIA AB ObjectiveTo provide insight into mitochondrial function in vivo, we evaluated the 3D spatial relationship between capillaries, mitochondria, and muscle fibers in live mice. Methods3D volumes of in vivo murine TA muscles were imaged by MPM. Muscle fiber type, mitochondrial distribution, number of capillaries, and capillary-to-fiber contact were assessed. The role of Mb-facilitated diffusion was examined in Mb KO mice. Distribution of GLUT4 was also evaluated in the context of the capillary and mitochondrial network. ResultsMPM revealed that 43.63.3% of oxidative fiber capillaries had 50% of their circumference embedded in a groove in the sarcolemma, in vivo. Embedded capillaries were tightly associated with dense mitochondrial populations lateral to capillary grooves and nearly absent below the groove. Mitochondrial distribution, number of embedded capillaries, and capillary-to-fiber contact were proportional to fiber oxidative capacity and unaffected by Mb KO. GLUT4 did not preferentially localize to embedded capillaries. ConclusionsEmbedding capillaries in the sarcolemma may provide a regulatory mechanism to optimize delivery of oxygen to heterogeneous groups of muscle fibers. We hypothesize that mitochondria locate to PV regions due to myofibril voids created by embedded capillaries, not to enhance the delivery of oxygen to the mitochondria. C1 [Glancy, Brian; Hsu, Li-Yueh; Dao, Lam; Bakalar, Matthew; French, Stephanie; Chess, David J.; Taylor, Joni L.; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. [Picard, Martin] Childrens Hosp Philadelphia, Dept Lab Med, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Picard, Martin] Univ Penn, Philadelphia, PA 19104 USA. [Aponte, Angel] NHLBI, Prote Core Facil, Bethesda, MD 20892 USA. [Daniels, Mathew P.; Esfahani, Shervin] NHLBI, Electron Microscopy Core Facil, Bethesda, MD 20892 USA. [Cushman, Samuel] NIDDK, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD 20892 USA. RP Glancy, B (reprint author), NHLBI, NIH, 10 Ctr Dr Room B1D416, Bethesda, MD 20892 USA. EM glancybp@nhlbi.nih.gov RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU Division of Intramural Research, National Heart, Lung, and Blood Institute FX This study was supported by Intramural Funding of the Division of Intramural Research, National Heart, Lung, and Blood Institute. The authors thank Kathryn White (EM Research Services, Newcastle University) for expert technical assistance in preparing and visualizing the SEM samples and Dr. Bertrand Lucotte (NHLBI) for discussions and advice regarding the technical limitations of two-photon microscopy. In addition, they are grateful to Jurgen Schrader (Heinrich Heine Universitat) for kindly providing them the Mb KO mice. NR 88 TC 8 Z9 9 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-9688 EI 1549-8719 J9 MICROCIRCULATION JI Microcirculation PD FEB PY 2014 VL 21 IS 2 BP 131 EP 147 DI 10.1111/micc.12098 PG 17 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AA8IK UT WOS:000331339000001 PM 25279425 ER PT J AU Avenarius, MR Saylor, KW Lundeberg, MR Wilmarth, PA Shin, JB Spinelli, KJ Pagana, JM Andrade, L Kachar, B Choi, D David, LL Barr-Gillespie, PG AF Avenarius, Matthew R. Saylor, Katherine W. Lundeberg, Megan R. Wilmarth, Phillip A. Shin, Jung-Bum Spinelli, Kateri J. Pagana, James M. Andrade, Leonardo Kachar, Bechara Choi, Dongseok David, Larry L. Barr-Gillespie, Peter G. TI Correlation of Actin Crosslinker and Capper Expression Levels with Stereocilia Growth Phases SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID HAIR-CELL STEREOCILIA; GLYCOLYTIC-ENZYMES; CAPPING PROTEIN; BIRD COCHLEA; MASS-SPECTROMETRY; BINDING PROTEIN; SKELETAL-MUSCLE; BASILAR PAPILLA; CUTICULAR PLATE; HEARING-LOSS AB During development of the chick cochlea, actin crosslinkers and barbed-end cappers presumably influence growth and remodeling of the actin paracrystal of hair cell stereocilia. We used mass spectrometry to identify and quantify major actin-associated proteins of the cochlear sensory epithelium from E14 to E21, when stereocilia widen and lengthen. Tight actin crosslinkers (i.e. fascins, plastins, and espin) are expressed dynamically during cochlear epithelium development between E7 and E21, with FSCN2 replacing FSCN1 and plastins remaining low in abundance. Capping protein, a barbed-end actin capper, is located at stereocilia tips; it is abundant during growth phase II, when stereocilia have ceased elongating and are increasing in diameter. Capping protein levels then decline during growth phase III, when stereocilia reinitiate barbed-end elongation. Although actin crosslinkers are readily detected by electron microscopy in developing chick cochlea stereocilia, quantitative mass spectrometry of stereocilia isolated from E21 chick cochlea indicated that tight crosslinkers are present there in stoichiometric ratios relative to actin that are much lower than their ratios for vestibular stereocilia. These results demonstrate the value of quantitation of global protein expression in chick cochlea during stereocilia development. C1 [Avenarius, Matthew R.; Saylor, Katherine W.; Lundeberg, Megan R.; Shin, Jung-Bum; Spinelli, Kateri J.; Pagana, James M.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. [Avenarius, Matthew R.; Saylor, Katherine W.; Lundeberg, Megan R.; Shin, Jung-Bum; Spinelli, Kateri J.; Pagana, James M.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Wilmarth, Phillip A.; David, Larry L.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Andrade, Leonardo; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Choi, Dongseok] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. RP Barr-Gillespie, PG (reprint author), Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, L335A-3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. EM gillespp@ohsu.edu RI Andrade, Leonardo/C-9554-2011; OI Andrade, Leonardo/0000-0002-0004-5677; Spinelli, Kateri/0000-0002-6290-0886; Barr-Gillespie, Peter/0000-0002-9787-5860 FU National Institutes of Health [R01 DC011034, R01 DC002368, P30 DC005983, R01 EY007755] FX This work was supported by National Institutes of Health grants R01 DC011034 (PGBG), R01 DC002368 (PGBG), P30 DC005983 (PGBG), and R01 EY007755 (LLD). NR 53 TC 9 Z9 10 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD FEB PY 2014 VL 13 IS 2 BP 606 EP 620 DI 10.1074/mcp.M113.033704 PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AA8TX UT WOS:000331369000017 PM 24319057 ER PT J AU Leelahavanichkul, K Amornphimoltham, P Molinolo, AA Basile, JR Koontongkaew, S Gutkind, JS AF Leelahavanichkul, Kantima Amornphimoltham, Panomwat Molinolo, Alfredo A. Basile, John R. Koontongkaew, Sittichai Gutkind, J. Silvio TI A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis SO MOLECULAR ONCOLOGY LA English DT Article DE p38 MAPK; Head and neck cancer; Angiogenesis; Lymphangiogenesis; p38 Inhibitor; MAPK; JNK ID ACTIVATED PROTEIN-KINASES; CARCINOMA; PROLIFERATION; INHIBITION; P38-ALPHA; PATHWAY; JNK; STATISTICS; EXPRESSION; CYTOKINES AB We have recently gained a remarkable understanding of the mutational landscape of head and neck squamous cell carcinoma (HNSCC). However, the nature of the dysregulated signaling networks contributing to HNSCC progression is still poorly defined. Here, we have focused on the role of the family of mitogen activated kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun terminal kinase (INK) and p38 MAPK in HNSCC. Immunohistochemical analysis of a large collection of human HNSCC tissues revealed that the levels of the phosphorylated active form of ERK1/2 and JNK were elevated in less than 33% and 16% of the cases, respectively. Strikingly, however, high levels of active phospho-p38 were observed in most (79%) of hundreds of tissues analyzed. We explored the biological role of p38 in HNSCC cell lines using three independent approaches: treatment with a specific p38 inhibitor, SB203580; a retro-inhibition strategy consisting in the use of SB203580 combined with the expression of an inhibitor-insensitive mutant form of p38 alpha; and short-hairpin RNAs (shRNAs) targeting p38 alpha. We found that specific blockade of p38 signaling significantly inhibited the proliferation of HNSCC cells both in vitro and in vivo. Indeed, we observed that p38 inhibition in HNSCC cancer cells reduces cancer growth in tumor xenografts and a remarkable decrease in intratumoral blood and lymphatic vessels. We conclude that p38a functions as a positive regulator of HNSCC in the context of the tumor microenvironment, controlling cancer cell growth as well as tumor-induced angiogenesis and lymphangiogenesis. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. C1 [Leelahavanichkul, Kantima; Amornphimoltham, Panomwat; Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Basile, John R.] Univ Maryland, Sch Dent, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA. [Leelahavanichkul, Kantima; Koontongkaew, Sittichai] Thammasat Univ, Fac Dent, Pathum Thani, Thailand. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research [Z01DE00558] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research, project Z01DE00558. NR 38 TC 23 Z9 23 U1 1 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1574-7891 EI 1878-0261 J9 MOL ONCOL JI Mol. Oncol. PD FEB PY 2014 VL 8 IS 1 BP 105 EP 118 DI 10.1016/j.molonc.2013.10.003 PG 14 WC Oncology SC Oncology GA AB0VL UT WOS:000331510100011 PM 24216180 ER PT J AU Lake, AG Moalli, P Richter, HE Kim, HY Nager, CW Sirls, L Brubaker, L Kusek, JW Chai, TC AF Lake, AeuMuro G. Moalli, Pamela Richter, Holly E. Kim, Hae-Young Nager, Charles W. Sirls, Larry Brubaker, Linda Kusek, John W. Chai, Toby C. TI COMPARISON OF ROC CURVES FOR PREOPERATIVE VLPP, MUCP AND URINARY NTX AS PREDICTORS FOR MIDURETHRALSLING OUTCOMES SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Annual Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion (SUFU) CY FEB 25-MAR 01, 2014 CL Miami, FL SP Soc Urodynam, Female Pelv Med & Urogenital Reconstruct C1 [Lake, AeuMuro G.; Chai, Toby C.] Yale Univ, Sch Med, Dept Urol, New Haven, CT USA. [Lake, AeuMuro G.; Chai, Toby C.] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Moalli, Pamela] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Kim, Hae-Young] New England Res Inst, Watertown, MA 02172 USA. [Nager, Charles W.] Univ Calif San Diego, Dept Reprod Med, San Diego, CA 92103 USA. [Sirls, Larry] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Brubaker, Linda] Loyola Univ, Dept Urol, Chicago, IL 60611 USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2014 VL 33 IS 2 BP 166 EP 166 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AA3SO UT WOS:000331012800010 ER PT J AU Pezza, RJ Voloshin, ON Volodin, AA Boateng, KA Bellani, MA Mazin, AV Camerini-Otero, RD AF Pezza, Roberto J. Voloshin, Oleg N. Volodin, Alexander A. Boateng, Kingsley A. Bellani, Marina A. Mazin, Alexander V. Camerini-Otero, R. Daniel TI The dual role of HOP2 in mammalian meiotic homologous recombination SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA STRAND EXCHANGE; COLI RECA PROTEIN; ESCHERICHIA-COLI; ATP HYDROLYSIS; SACCHAROMYCES-CEREVISIAE; RAD51 RECOMBINASE; HOP2-MND1 COMPLEX; BASE-PAIRS; MEIOSIS; CHROMOSOMES AB Deletion of Hop2 in mice eliminates homologous chromosome synapsis and disrupts double-strand break (DSB) repair through homologous recombination. HOP2 in vitro shows two distinctive activities: when it is incorporated into a HOP2-MND1 complex it stimulates DMC1 and RAD51 recombination activities and the purified HOP2 alone is proficient in promoting strand invasion. We observed that a fraction of Mnd1(-/-) spermatocytes, which express HOP2 but apparently have inactive DMC1 and RAD51 due to lack of the HOP2-MND1 complex, exhibits a high level of chromosome synapsis and that most DSBs in these spermatocytes are repaired. This suggests that DSB repair catalyzed solely by HOP2 supports homologous chromosome pairing and synapsis. In addition, we show that in vitro HOP2 promotes the co-aggregation of ssDNA with duplex DNA, binds to ssDNA leading to unstacking of the bases, and promotes the formation of a three-strand synaptic intermediate. However, HOP2 shows distinctive mechanistic signatures as a recombinase. Namely, HOP2-mediated strand exchange does not require ATP and, in contrast to DMC1, joint molecules formed by HOP2 are more sensitive to mismatches and are efficiently dissociated by RAD54. We propose that HOP2 may act as a recombinase with specific functions in meiosis. C1 [Pezza, Roberto J.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Pezza, Roberto J.] Univ Oklahoma, Dept Cell Biol, Hlth Sci Ctr, Oklahoma City, OK 73126 USA. [Voloshin, Oleg N.; Volodin, Alexander A.; Boateng, Kingsley A.; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Volodin, Alexander A.] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. [Bellani, Marina A.] NIA, Biomed Res Ctr, Baltimore, MD 21224 USA. [Mazin, Alexander V.] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19102 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM rc10d@nih.gov FU National Institute of Diabetes, Digestive and Kidney Diseases; National Institute of General Medical Sciences of the National Institutes of Health [1P20GM103636]; OCAST [HR10-48 S]; National Institutes of Health (NIH) [CA100839, R03DA033981, R03MH097512]; Leukemia and Lymphoma Society Scholar Award [1054-09]; Russian Foundation for Basic Research [10-04-01057-a]; NIH FX Research reported in this publication was supported by the National Institute of Diabetes, Digestive and Kidney Diseases Intramural Research Program (to R.D.C.-O.); the National Institute of General Medical Sciences of the National Institutes of Health under award number 1P20GM103636 and by the OCAST grant [HR10-48 S to R.J.P.]; National Institutes of Health (NIH) grants [CA100839, R03DA033981, R03MH097512 to A. V. M.] and by a Leukemia and Lymphoma Society Scholar Award 1054-09 (to A. V. M.); the Russian Foundation for Basic Research (project 10-04-01057-a) (to A. A. V.). Funding for open access charge: NIH. NR 59 TC 14 Z9 14 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2014 VL 42 IS 4 BP 2346 EP 2357 DI 10.1093/nar/gkt1234 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC2YA UT WOS:000332381000029 PM 24304900 ER PT J AU Wu, H Mitra, M Naufer, MN McCauley, MJ Gorelick, RJ Rouzina, I Musier-Forsyth, K Williams, MC AF Wu, Hao Mitra, Mithun Naufer, M. Nabuan McCauley, Micah J. Gorelick, Robert J. Rouzina, Ioulia Musier-Forsyth, Karin Williams, Mark C. TI Differential contribution of basic residues to HIV-1 nucleocapsid protein's nucleic acid chaperone function and retroviral replication SO NUCLEIC ACIDS RESEARCH LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLUS-STRAND TRANSFER; TRIM5-ALPHA RESTRICTION FACTOR; MURINE LEUKEMIA-VIRUS; RNA PACKAGING SIGNAL; PRIMER BINDING-SITE; REVERSE TRANSCRIPTION; ZINC-FINGER; DNA-SYNTHESIS; STRUCTURAL DETERMINANTS AB The human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein contains 15 basic residues located throughout its 55-amino acid sequence, as well as one aromatic residue in each of its two CCHC-type zinc finger motifs. NC facilitates nucleic acid (NA) rearrangements via its chaperone activity, but the structural basis for this activity and its consequences in vivo are not completely understood. Here, we investigate the role played by basic residues in the N-terminal domain, the N-terminal zinc finger and the linker region between the two zinc fingers. We use in vitro ensemble and single-molecule DNA stretching experiments to measure the characteristics of wild-type and mutant HIV-1 NC proteins, and correlate these results with cell-based HIV-1 replication assays. All of the cationic residue mutations lead to NA interaction defects, as well as reduced HIV-1 infectivity, and these effects are most pronounced on neutralizing all five N-terminal cationic residues. HIV-1 infectivity in cells is correlated most strongly with NC's NA annealing capabilities as well as its ability to intercalate the DNA duplex. Although NC's aromatic residues participate directly in DNA intercalation, our findings suggest that specific basic residues enhance these interactions, resulting in optimal NA chaperone activity. C1 [Wu, Hao; Naufer, M. Nabuan; McCauley, Micah J.; Williams, Mark C.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Mitra, Mithun; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Dept Chem & Biochem, Columbus, OH 43210 USA. [Mitra, Mithun; Musier-Forsyth, Karin] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Rouzina, Ioulia] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. RP Williams, MC (reprint author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA. EM mark@neu.edu RI Mitra, Mithun/A-2133-2015; OI Williams, Mark C./0000-0003-3219-376X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc.; National Institutes of Health [GM065056, GM072462]; National Science Foundation [MCB-1243883] FX Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with Leidos Biomedical Research, Inc. (RJG); National Institutes of Health [GM065056 to K.M.-F. and GM072462 to M. C. W.]; National Science Foundation [MCB-1243883 to M. C. W]. Funding for open access charge: National Institutes of Health. NR 99 TC 11 Z9 11 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2014 VL 42 IS 4 BP 2525 EP 2537 DI 10.1093/nar/gkt1227 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC2YA UT WOS:000332381000044 PM 24293648 ER PT J AU Fonfara, I Le Rhun, A Chylinski, K Makarova, KS Lecrivain, AL Bzdrenga, J Koonin, EV Charpentier, E AF Fonfara, Ines Le Rhun, Anais Chylinski, Krzysztof Makarova, Kira S. Lecrivain, Anne-Laure Bzdrenga, Janek Koonin, Eugene V. Charpentier, Emmanuelle TI Phylogeny of Cas9 determines functional exchangeability of dual-RNA and Cas9 among orthologous type II CRISPR-Cas systems SO NUCLEIC ACIDS RESEARCH LA English DT Article ID COLI RIBONUCLEASE-III; STREPTOCOCCUS-THERMOPHILUS; ESCHERICHIA-COLI; NEISSERIA-MENINGITIDIS; STRUCTURE PREDICTION; GUIDED ENDONUCLEASE; SECONDARY STRUCTURE; GENE-EXPRESSION; IMMUNE-SYSTEM; GENOME AB The CRISPR-Cas-derived RNA-guided Cas9 endonuclease is the key element of an emerging promising technology for genome engineering in a broad range of cells and organisms. The DNA-targeting mechanism of the type II CRISPR-Cas system involves maturation of tracrRNA: crRNA duplex (dual-RNA), which directs Cas9 to cleave invading DNA in a sequence-specific manner, dependent on the presence of a Protospacer Adjacent Motif (PAM) on the target. We show that evolution of dual-RNA and Cas9 in bacteria produced remarkable sequence diversity. We selected eight representatives of phylogenetically defined type II CRISPR-Cas groups to analyze possible coevolution of Cas9 and dual-RNA. We demonstrate that these two components are interchangeable only between closely related type II systems when the PAM sequence is adjusted to the investigated Cas9 protein. Comparison of the taxonomy of bacterial species that harbor type II CRISPR-Cas systems with the Cas9 phylogeny corroborates horizontal transfer of the CRISPR-Cas loci. The reported collection of dual-RNA: Cas9 with associated PAMs expands the possibilities for multiplex genome editing and could provide means to improve the specificity of the RNA-programmable Cas9 tool. C1 [Fonfara, Ines; Le Rhun, Anais; Chylinski, Krzysztof; Lecrivain, Anne-Laure; Bzdrenga, Janek; Charpentier, Emmanuelle] Umea Univ, Dept Mol Biol, Umea Ctr Microbial Res, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden. [Fonfara, Ines; Le Rhun, Anais; Charpentier, Emmanuelle] Helmholtz Ctr Infect Res, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany. [Chylinski, Krzysztof] Univ Vienna, Dept Biochem & Cell Biol, Max F Perutz Labs, A-1030 Vienna, Austria. [Makarova, Kira S.; Koonin, Eugene V.] Natl Biotechnol Ctr, Natl Lib Med, NIH, Bethesda, MD 20894 USA. [Charpentier, Emmanuelle] Hannover Med Sch, D-30625 Hannover, Germany. RP Charpentier, E (reprint author), Umea Univ, Dept Mol Biol, Umea Ctr Microbial Res, Lab Mol Infect Med Sweden MIMS, S-90187 Umea, Sweden. EM emmanuelle.charpentier@helmholtz-hzi.de OI Le Rhun, Anais/0000-0003-2211-2153 FU Swedish Research Council [K2010-57X-21436-01-3, K2013-57X-21436-04-3, 621-2011-5752-LiMS]; Kempe Foundation; Umea University [223- 2728-10, 223-2836-10, 223-2989-10]; Laboratory for Molecular Infection Medicine Sweden; Helmholtz Association; US Department of Health and Human Services; Helmholtz Centre for Infection Research FX Swedish Research Council [K2010-57X-21436-01-3, K2013-57X-21436-04-3, 621-2011-5752-LiMS to E. C.]; the Kempe Foundation to E. C.; Umea University [Dnr: 223- 2728-10, Dnr: 223-2836-10, Dnr: 223-2989-10 to E. C.]; the Laboratory for Molecular Infection Medicine Sweden to E. C. and the Helmholtz Association to E. C., K. S. M. and E. V. K. are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). K. C. was a fellow of the Austrian Doctoral Program in RNA Biology. Funding for open access charge: Helmholtz Centre for Infection Research. NR 59 TC 80 Z9 99 U1 7 U2 33 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2014 VL 42 IS 4 BP 2577 EP 2590 DI 10.1093/nar/gkt1074 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC2YA UT WOS:000332381000048 PM 24270795 ER PT J AU Liu, AY Gu, DF Hixson, JE Rao, DC Shimmin, LC Jaquish, CE Liu, DP He, J Kelly, TN AF Liu, Angela Y. Gu, Dongfeng Hixson, James E. Rao, Dabeeru C. Shimmin, Lawrence C. Jaquish, Cashell E. Liu, De-Pei He, Jiang Kelly, Tanika N. TI Genome-Wide Linkage and Regional Association Study of Obesity-Related Phenotypes: The GenSalt Study SO OBESITY LA English DT Article ID BODY-MASS INDEX; ACTIVATED RECEPTOR-ALPHA; WAIST CIRCUMFERENCE; LEPTIN LEVELS; FAMILIES; TRAITS; SCAN; POLYMORPHISMS; POPULATIONS; VARIANTS AB Objective: To identify chromosomal regions harboring quantitative trait loci for waist circumference (WC) and body mass index (BMI). Design and Methods: A genome-wide linkage scan and regional association study WC and BMI among 633 Chinese families was conducted. Results: A significant linkage signal for WC was observed at 22q13.31-22q13.33 in the overall analysis (LOD = 3.13). Follow-up association study of 22q13.31-13.33 revealed an association between the TBC1D22A gene marker rs16996195 and WC (false discovery rate [FDR]-Q < 0.05). In gender-stratified analysis, suggestive linkage signals were attained for WC at 2p24.3-2q12.2 and 22q13.33 among females (LOD = 2.54 and 2.15, respectively). Among males, 6q12-6q13 was suggestively linked to BMI (LOD = 2.03). Single marker association analyses at these regions identified male-specific relationships of six single nucleotide polymorphisms (SNPs) at 2p24.3-2q12.2 (rs100955, rs13020676, rs13014034, rs12990515, rs17024325, and rs2192712) and five SNPs at 6q12-6q13 (rs7747318, rs7767301, rs12197115, rs12203049, and rs9454847) with the obesity-related phenotypes (all FDR-Q < 0.05). At chromosome 6q12-6q13, markers rs7755450 and rs11758293 predicted BMI in females (both FDR-Q < 0.05). Conclusions: Genomic regions on chromosomes 2, 6, and 22 which may harbor important obesity-susceptibility loci were described. Follow-up study of these regions revealed several novel variants associated with obesity related traits. Future work to confirm these promising findings is warranted. C1 [Liu, Angela Y.] Univ N Carolina, Dept Epidemiol, Sch Global Publ Hlth, Chapel Hill, NC USA. [Gu, Dongfeng] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100730, Peoples R China. [Gu, Dongfeng] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100730, Peoples R China. [Gu, Dongfeng; Liu, De-Pei] Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Dongfeng] Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing 100021, Peoples R China. [Hixson, James E.; Shimmin, Lawrence C.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. [Rao, Dabeeru C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Liu, De-Pei] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China. [He, Jiang; Kelly, Tanika N.] Tulane Univ, Sch Med, Dept Epidemiol, Dept Med, New Orleans, LA 70112 USA. [He, Jiang; Kelly, Tanika N.] Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA. RP Kelly, TN (reprint author), Tulane Univ, Sch Med, Dept Epidemiol, Dept Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. EM tkelly@tulane.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD [U01HL072507, R01HL087263, R01HL090682] FX The Genetic Epidemiology Network of Salt Sensitivity is supported by research grants (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. NR 37 TC 5 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD FEB PY 2014 VL 22 IS 2 BP 545 EP 556 DI 10.1002/oby.20469 PG 12 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AC0ZO UT WOS:000332224200032 PM 23526746 ER PT J AU Gill, R Cheung, YH Shen, YF Lanzano, P Mirza, NM Ten, S Maclaren, NK Motaghedi, R Han, JC Yanovski, JA Leibel, RL Chung, WK AF Gill, Richard Cheung, Yee Him Shen, Yufeng Lanzano, Patricia Mirza, Nazrat M. Ten, Svetlana Maclaren, Noel K. Motaghedi, Roja Han, Joan C. Yanovski, Jack A. Leibel, Rudolph L. Chung, Wendy K. TI Whole-Exome Sequencing Identifies Novel LEPR Mutations in Individuals with Severe Early Onset Obesity SO OBESITY LA English DT Article ID CONGENITAL LEPTIN DEFICIENCY; BODY-MASS INDEX; RECEPTOR; GENERATION; FRAMEWORK AB Objective: Obesity is a major public health problem that increases the risk for a broad spectrum of comorbid conditions. Despite evidence for a strong genetic contribution to susceptibility to obesity, previous efforts to discover the relevant genes using positional cloning have failed to account for most of the apparent genetic risk variance. Design and Methods: Deploying a strategy combining analysis of exome sequencing data in extremely obese members of four consanguineous families with segregation analysis, we screened for causal genetic variants. Filter-based analysis and homozygosity mapping were used to identify and prioritize putative functional variants. Results: Two novel frameshift mutations in the leptin receptor in two of the families were identified. Conclusions: These results provide proof-of-principle that whole-exome sequencing of families segregating for extreme obesity can identify causal pathogenic mutations. The methods described here can be extended to additional families segregating for extreme obesity and should enable the identification of mutations in novel genes that predispose to obesity. C1 [Gill, Richard; Cheung, Yee Him; Lanzano, Patricia; Leibel, Rudolph L.; Chung, Wendy K.] Columbia Univ Coll Phys & Surg, Dept Pediat, Div Mol Genet, Med Ctr, New York, NY 10032 USA. [Gill, Richard] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, Med Ctr, New York, NY USA. [Shen, Yufeng] Columbia Univ Coll Phys & Surg, Dept Biomed Informat, New York, NY 10032 USA. [Mirza, Nazrat M.; Han, Joan C.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Mirza, Nazrat M.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Ten, Svetlana] Maimonides Infants & Childrens Hosp Brooklyn, Div Pediat Endocrinol, Brooklyn, NY USA. [Ten, Svetlana] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Maclaren, Noel K.] Cornell Univ, Weill Med Coll, Dept Pediat, New York, NY 10021 USA. [Motaghedi, Roja] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. RP Chung, WK (reprint author), Columbia Univ Coll Phys & Surg, Dept Pediat, Div Mol Genet, Med Ctr, New York, NY 10032 USA. EM wkc15@columbia.edu OI Yanovski, Jack/0000-0001-8542-1637 FU NIH [DK52431-19, DK26687-31, UL1 RR024156]; Russell Berrie Foundation; NICHD, NIH [Z1A-HD-00641]; CIHR [DFSA-113549] FX This work was supported by NIH DK52431-19, DK26687-31, UL1 RR024156, the Russell Berrie Foundation, and the Intramural Research Program of NICHD, NIH, Z1A-HD-00641. RG is supported by funding from CIHR DFSA-113549. NR 34 TC 15 Z9 15 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD FEB PY 2014 VL 22 IS 2 BP 576 EP 584 DI 10.1002/oby.20492 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AC0ZO UT WOS:000332224200035 PM 23616257 ER PT J AU Manson, JE Chlebowski, RT Stefanick, ML Aragaki, AK Rossouw, JE Prentice, RL Anderson, G Howard, BV Thomson, CA LaCroix, AZ Wactawski-Wende, J Jackson, RD Limacher, M Margolis, KL Wassertheil-Smoller, S Beresford, SA Cauley, JA Eaton, CB Gass, M Hsia, J Johnson, KC Kooperberg, C Kuller, LH Lewis, CE Liu, S Martin, LW Ockene, JK O'Sullivan, MJ Powell, LH Simon, MS Van Horn, L Vitolins, MZ Wallace, RB AF Manson, JoAnn E. Chlebowski, Rowan T. Stefanick, Marcia L. Aragaki, Aaron K. Rossouw, Jacques E. Prentice, Ross L. Anderson, Garnet Howard, Barbara V. Thomson, Cynthia A. LaCroix, Andrea Z. Wactawski-Wende, Jean Jackson, Rebecca D. Limacher, Marian Margolis, Karen L. Wassertheil-Smoller, Sylvia Beresford, Shirley A. Cauley, Jane A. Eaton, Charles B. Gass, Margery Hsia, Judith Johnson, Karen C. Kooperberg, Charles Kuller, Lewis H. Lewis, Cora E. Liu, Simin Martin, Lisa W. Ockene, Judith K. O'Sullivan, Mary Jo Powell, Lynda H. Simon, Michael S. Van Horn, Linda Vitolins, Mara Z. Wallace, Robert B. TI Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women's Health Initiative Randomized Trials SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB The Women's Health Initiative (WHI) was a placebo-controlled randomized study that investigated the benefits and risks of 2 menopausal hormone regimens in healthy normal postmenopausal women. The present report provides a comprehensive, integrated overview of findings from the intervention and extended postintervention phases of 2 WHI trials: one used conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA), and the other used CEEs alone. Between 1993 and 1998, 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus were randomized to receive a regimen of CEEs (0.625 mg/d) plus MPA (2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy were randomized to receive CEEs alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention phase of the CEEs plus MPA trial lasted a median of 5.6 years, and that of the CEEs alone trial lasted a median of 7.2 years with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes for both trials were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index of other health outcomes included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. Benefits in the CEEs plus MPA intervention phase included decreased hip fractures, diabetes, and vasomotor symptoms. During the intervention phase in the CEEs plus MPA group, there were 196 CHD cases versus 159 for placebo (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.95-1.45), and 206 invasive breast cancer cases versus 155 for placebo (HR, 1.24; 95% CI, 1.01-1.53). Moreover, risks increased for stroke, pulmonary embolism, dementia (in women aged 65 years), gallbladder disease, and urinary incontinence. Among women in the CEEs plus MPA group, most risks and benefits dissipated after intervention, but there was persisting elevation in risk of breast cancer (434 cases vs 323 for placebo; HR, 1.28; 95% CI, 1.11-1.48). During the intervention phase in the CEEs alone group, risks and benefits were more balanced; there were 204 CHD cases versus 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 cases of invasive breast cancer compared with 135 for placebo (HR, 0.79; 95% CI, 0.61-1.02). Moreover, during cumulative follow-up, 168 cases of breast cancer were diagnosed in the CEEs alone group compared with 216 for the placebo; the HR was 0.79, with a 95% CI of 0.65 to 0.97. Other outcomes in this group were similar to the CEEs plus MPA group. All-cause mortality was not affected with either regimen. Younger women (aged 50-59 years) in the CEEs alone group had more favorable results during the intervention phase than older women for all-cause mortality, myocardial infarction, and the global index. Compared with placebo, absolute risks of adverse events in the CEEs plus MPA group assessed using global index data were lower in younger women: women aged 50 to 69 years had 12 more adverse events per 10,000 person-years, whereas those aged 70 to 79 years had 38 more. In the CEEs alone group, women aged 50 to 59 years had 19 fewer adverse events per 10,000 person-years, and women aged 70 to 79 years had 51 more adverse events. In both trials, results of quality-of-life outcomes were mixed. These findings do not support the use of CEEs plus MPA or CEEs alone in postmenopausal women for prevention of chronic disease. However, hormonal treatment may be beneficial in generally healthy women during early menopause for management of moderate to severe menopausal symptoms. C1 [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Stefanick, Marcia L.] Stanford Prevent Res Ctr, Stanford, CA USA. [Aragaki, Aaron K.; Prentice, Ross L.; Anderson, Garnet; LaCroix, Andrea Z.; Beresford, Shirley A.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Howard, Barbara V.] MedStar Hlth Res Inst, Washington, DC USA. [Howard, Barbara V.] Georgetown Univ Ctr Clin & Translat Sci, Washington, DC USA. [Howard, Barbara V.] Howard Univ Ctr Clin & Translat Sci, Washington, DC USA. [Thomson, Cynthia A.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Limacher, Marian] Univ Florida, Gainesville, FL USA. [Margolis, Karen L.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, New York, NY USA. [Cauley, Jane A.; Kuller, Lewis H.] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Family Med & Epidemiol, Providence, RI 02912 USA. [Gass, Margery] Cleveland Clin, North Amer Menopause Soc, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Hsia, Judith] AstraZeneca, Clin Res, Wilmington, DE USA. [Johnson, Karen C.] Univ Tennessee Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Providence, RI 02912 USA. [Martin, Lisa W.] George Washington Univ Sch Med & Hlth Sci, Div Cardiol, Washington, DC USA. [Ockene, Judith K.] Univ Massachusetts Med Sch, Worcester, MA USA. [O'Sullivan, Mary Jo] Univ Miami, Div Res, Dept Obstet & Gynecol, Miami, FL USA. [Powell, Lynda H.] Rush Univ Med Ctr, Dept Prevent Med, Chicago, IL USA. [Simon, Michael S.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Van Horn, Linda] Northwestern Univ Feinberg Sch Med, Chicago, IL USA. [Vitolins, Mara Z.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Wallace, Robert B.] Univ Iowa Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. RP Manson, JE (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RI Liu, Simin/I-3689-2014; OI Liu, Simin/0000-0003-2098-3844; Martin, Lisa Warsinger/0000-0003-4352-0914; Cauley, Jane A/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD FEB PY 2014 VL 69 IS 2 BP 83 EP 85 DI 10.1097/01.ogx.0000444679.66386.38 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AB1HK UT WOS:000331541900012 ER PT J AU Chagas, AC Oliveira, F Debrabant, A Valenzuela, JG Ribeiro, JMC Calvo, E AF Chagas, Andrezza C. Oliveira, Fabiano Debrabant, Alain Valenzuela, Jesus G. Ribeiro, Jose M. C. Calvo, Eric TI Lundep, a Sand Fly Salivary Endonuclease Increases Leishmania Parasite Survival in Neutrophils and Inhibits XIIa Contact Activation in Human Plasma SO PLOS PATHOGENS LA English DT Article ID LUTZOMYIA-LONGIPALPIS; EXTRACELLULAR TRAPS; INFECTION; FLIES; VECTOR; STREPTOCOCCUS; PROTECTION; MECHANISM; PROTEIN; GLANDS AB Neutrophils are the host's first line of defense against infections, and their extracellular traps (NET) were recently shown to kill Leishmania parasites. Here we report a NET-destroying molecule (Lundep) from the salivary glands of Lutzomyia longipalpis. Previous analysis of the sialotranscriptome of Lu. longipalpis showed the potential presence of an endonuclease. Indeed, not only was the cloned cDNA (Lundep) shown to encode a highly active ss- and dsDNAse, but also the same activity was demonstrated to be secreted by salivary glands of female Lu. longipalpis. Lundep hydrolyzes both ss- and dsDNA with little sequence specificity with a calculated DNase activity of 300000 Kunitz units per mg of protein. Disruption of PMA (phorbol 12 myristate 13 acetate)- or parasite-induced NETs by treatment with recombinant Lundep or salivary gland homogenates increases parasite survival in neutrophils. Furthermore, co-injection of recombinant Lundep with metacyclic promastigotes significantly exacerbates Leishmania infection in mice when compared with PBS alone or inactive (mutagenized) Lundep. We hypothesize that Lundep helps the parasite to establish an infection by allowing it to escape from the leishmanicidal activity of NETs early after inoculation. Lundep may also assist blood meal intake by lowering the local viscosity caused by the release of host DNA and as an anticoagulant by inhibiting the intrinsic pathway of coagulation. Author Summary Salivary components from disease vectors help the arthropod to acquire blood. Here we show that an arthropod vector salivary enzyme affects the innate immune system of the hostmainly the destruction of neutrophil trapsallowing the Leishmania parasite to evade the host immune response and to cause an infection. This work highlights the relevance of vector salivary components in parasite transmission and further suggests the inclusion of these proteins as components for an anti-Leishmania vaccine. Importantly, because salivary proteins are always present at the site of natural transmission, this work further encourages the testing of vaccine candidates using the natural route of transmissionthe bites of an arthropod vectorinstead of current practices based solely on needle injection of parasites. C1 [Chagas, Andrezza C.; Oliveira, Fabiano; Valenzuela, Jesus G.; Ribeiro, Jose M. C.; Calvo, Eric] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Debrabant, Alain] US FDA, Ctr Biol Evaluat & Res, Lab Emerging Pathogens, Bethesda, MD USA. RP Chagas, AC (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM ecalvo@niaid.nih.gov RI Oliveira, Fabiano/B-4251-2009; Ribeiro, Jose/J-7011-2015; OI Oliveira, Fabiano/0000-0002-7924-8038; Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, NIAID, National Institutes of Health FX This work was funded by the Division of Intramural Research, NIAID, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 17 Z9 17 U1 0 U2 3 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 FEB PY 2014 VL 10 IS 2 AR e1003923 DI 10.1371/journal.ppat.1003923 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AB9CC UT WOS:000332085900031 PM 24516388 ER PT J AU Chevalier, SA Turpin, J Cachat, A Afonso, PV Gessain, A Brady, JN Pise-Masison, CA Mahieux, R AF Chevalier, Sebastien A. Turpin, Jocelyn Cachat, Anne Afonso, Philippe V. Gessain, Antoine Brady, John N. Pise-Masison, Cynthia A. Mahieux, Renaud TI Gem-Induced Cytoskeleton Remodeling Increases Cellular Migration of HTLV-1-Infected Cells, Formation of Infected-to-Target T-Cell Conjugates and Viral Transmission SO PLOS PATHOGENS LA English DT Article ID VIRUS TYPE-I; GTP-BINDING PROTEINS; KAPPA-B ACTIVATION; LYMPHOTROPIC-VIRUS; VIROLOGICAL-SYNAPSE; HTLV-I; RGK FAMILY; RHO-KINASE; LEUKEMIA; TAX AB Efficient HTLV-1 viral transmission occurs through cell-to-cell contacts. The Tax viral transcriptional activator protein facilitates this process. Using a comparative transcriptomic analysis, we recently identified a series of genes up-regulated in HTLV-1 Tax expressing T-lymphocytes. We focused our attention towards genes that are important for cytoskeleton dynamic and thus may possibly modulate cell-to-cell contacts. We first demonstrate that Gem, a member of the small GTP-binding proteins within the Ras superfamily, is expressed both at the RNA and protein levels in Tax-expressing cells and in HTLV-1-infected cell lines. Using a series of ChIP assays, we show that Tax recruits CREB and CREB Binding Protein (CBP) onto a c-AMP Responsive Element (CRE) present in the gem promoter. This CRE sequence is required to drive Tax-activated gem transcription. Since Gem is involved in cytoskeleton remodeling, we investigated its role in infected cells motility. We show that Gem co-localizes with F-actin and is involved both in T-cell spontaneous cell migration as well as chemotaxis in the presence of SDF-1/CXCL12. Importantly, gem knock-down in HTLV-1-infected cells decreases cell migration and conjugate formation. Finally, we demonstrate that Gem plays an important role in cell-to-cell viral transmission. Author Summary HTLV-1 was the first human oncoretrovirus to be discovered. Five to ten million people are infected, and 1-6% will develop either Adult T-cell Leukemia, or Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). HTLV-1 infects primarily T-cells, but dendritic cells were also found to carry proviruses. Contrary to HIV-1, cell-free HTLV-1 viral particles are poorly infectious. Thus, efficient viral transmission relies on formation of virological synapses or formation and transfer of viral biofilm-like structures. The Tax viral transactivator plays a key role in both modes of transmission. Using transcriptomic analyses, we recently identified cellular genes that are deregulated following Tax expression in T-cells. We focused our attention on genes that are important for cell architecture and are thus likely to modulate cell-to-cell contacts and motility. We found that Gem was highly upregulated both at the RNA and protein levels in Tax-expressing cells and HTLV-1-infected cell lines. We further show that Tax binds cellular co-activators and transcription factor and activates transcription from the gem promoter. We demonstrated that Gem is involved in cellular migration of HTLV-1-infected cells. Importantly, gem knockdown decreases the rate of HTLV-1-infected cell migration and cell-to-cell conjugate formation. We also show that Gem plays an important role in HTLV-1 transmission through cell-to-cell contacts, the most efficient mode of viral infection. C1 [Chevalier, Sebastien A.; Turpin, Jocelyn; Cachat, Anne; Mahieux, Renaud] Univ Lyon 1, Ecole Normale Super Lyon, INSERM CNRS U1111 UMR5308,Equipe Oncogenese Retro, Int Ctr Res Infectiol,Equipe Labellisee Ligue Nat, F-69365 Lyon, France. [Afonso, Philippe V.; Gessain, Antoine] Inst Pasteur, CNRS UMR 3569, Paris, France. [Brady, John N.] NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Pise-Masison, Cynthia A.] NCI, Anim Models & Retroviral Vaccine Sect, Vaccine Branch, CCR,NIH, Bethesda, MD 20892 USA. RP Chevalier, SA (reprint author), Univ Lyon 1, Ecole Normale Super Lyon, INSERM CNRS U1111 UMR5308,Equipe Oncogenese Retro, Int Ctr Res Infectiol,Equipe Labellisee Ligue Nat, F-69365 Lyon, France. EM renaud.mahieux@ens-lyon.fr RI Afonso, Philippe/D-2234-2014; OI Afonso, Philippe/0000-0002-4828-3797; Turpin, Jocelyn/0000-0001-5177-2471 FU Ecole Normale Superieure de Lyon; Fondation pour la Recherche Medicale; InCa (Canceropole CLARA); FONDATION ARC; Association de Recherche sur le Cancer; La Ligue Contre le Cancer (equipe Labellisee) FX RM and AC are supported by Ecole Normale Superieure de Lyon. SAC was supported by Fondation pour la Recherche Medicale and InCa (Canceropole CLARA). JT was supported by FONDATION ARC. The authors acknowledge the support of Association de Recherche sur le Cancer and of La Ligue Contre le Cancer (equipe Labellisee). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 13 Z9 14 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2014 VL 10 IS 2 AR e1003917 DI 10.1371/journal.ppat.1003917 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AB9CC UT WOS:000332085900004 PM 24586148 ER PT J AU Lemey, P Rambaut, A Bedford, T Faria, N Bielejec, F Baele, G Russell, CA Smith, DJ Pybus, OG Brockmann, D Suchard, MA AF Lemey, Philippe Rambaut, Andrew Bedford, Trevor Faria, Nuno Bielejec, Filip Baele, Guy Russell, Colin A. Smith, Derek J. Pybus, Oliver G. Brockmann, Dirk Suchard, Marc A. TI Unifying Viral Genetics and Human Transportation Data to Predict the Global Transmission Dynamics of Human Influenza H3N2 SO PLOS PATHOGENS LA English DT Article ID PANDEMIC INFLUENZA; SPREAD; MODEL; VIRUS; SIMULATION; EVOLUTION; EPIDEMIC; ACCURATE; SCALE AB Information on global human movement patterns is central to spatial epidemiological models used to predict the behavior of influenza and other infectious diseases. Yet it remains difficult to test which modes of dispersal drive pathogen spread at various geographic scales using standard epidemiological data alone. Evolutionary analyses of pathogen genome sequences increasingly provide insights into the spatial dynamics of influenza viruses, but to date they have largely neglected the wealth of information on human mobility, mainly because no statistical framework exists within which viral gene sequences and empirical data on host movement can be combined. Here, we address this problem by applying a phylogeographic approach to elucidate the global spread of human influenza subtype H3N2 and assess its ability to predict the spatial spread of human influenza A viruses worldwide. Using a framework that estimates the migration history of human influenza while simultaneously testing and quantifying a range of potential predictive variables of spatial spread, we show that the global dynamics of influenza H3N2 are driven by air passenger flows, whereas at more local scales spread is also determined by processes that correlate with geographic distance. Our analyses further confirm a central role for mainland China and Southeast Asia in maintaining a source population for global influenza diversity. By comparing model output with the known pandemic expansion of H1N1 during 2009, we demonstrate that predictions of influenza spatial spread are most accurate when data on human mobility and viral evolution are integrated. In conclusion, the global dynamics of influenza viruses are best explained by combining human mobility data with the spatial information inherent in sampled viral genomes. The integrated approach introduced here offers great potential for epidemiological surveillance through phylogeographic reconstructions and for improving predictive models of disease control. Author Summary What explains the geographic dispersal of emerging pathogens? Reconstructions of evolutionary history from pathogen gene sequences offer qualitative descriptions of spatial spread, but current approaches are poorly equipped to formally test and quantify the contribution of different potential explanatory factors, such as human mobility and demography. Here, we use a novel phylogeographic method to evaluate multiple potential predictors of viral spread in human influenza dynamics. We identify air travel as the predominant driver of global influenza migration, whilst also revealing the contribution of other mobility processes at more local scales. We demonstrate the power of our inter-disciplinary approach by using it to predict the global pandemic expansion of H1N1 influenza in 2009. Our study highlights the importance of integrating evolutionary and ecological information when studying the dynamics of infectious disease. C1 [Lemey, Philippe; Faria, Nuno; Bielejec, Filip; Baele, Guy] Katholieke Univ Leuven, Dept Microbiol & Immunol, Louvain, Belgium. [Rambaut, Andrew; Bedford, Trevor] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Russell, Colin A.; Smith, Derek J.] Univ Cambridge, Dept Zool, Cambridge, England. [Russell, Colin A.; Smith, Derek J.] WHO, Collaborating Ctr Modeling Evolut & Control Emerg, Cambridge, England. [Smith, Derek J.] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Brockmann, Dirk] Northwestern Univ, Evanston, IL USA. [Brockmann, Dirk] Northwestern Inst Complex Syst, Evanston, IL USA. [Brockmann, Dirk] Robert Koch Inst, Berlin, Germany. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, UCLA Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA USA. RP Lemey, P (reprint author), Katholieke Univ Leuven, Dept Microbiol & Immunol, Louvain, Belgium. EM philippe.lemey@rega.kuleuven.be OI Bedford, Trevor/0000-0002-4039-5794; Pybus, Oliver/0000-0002-8797-2667; Rodrigues Faria, Nuno/0000-0002-9747-8822; Russell, Colin/0000-0002-2113-162X; Rambaut, Andrew/0000-0003-4337-3707 FU European Union [278433-PREDEMICS, 260864]; NSF [DMS 1264153]; NIH [R01 AI107034, R01 HG006139]; National Evolutionary Synthesis Center (NESCent) [NSF EF-0423641]; Wellcome Trust [092807]; Royal Society; EU [223498, 278976]; Human Frontier Science Program (HFSP) [P0050/2008]; NIH Director's Pioneer Award [DP1-OD000490-01]; National Institute of Allergy and Infectious Diseases NIH CEIRS [HHSN266200700010C] FX The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement no. 278433-PREDEMICS and ERC Grant agreement no. 260864. MAS is in part supported by NSF grant DMS 1264153 and NIH grants R01 AI107034 and R01 HG006139. Collaboration between MAS, AR and PL was supported by the National Evolutionary Synthesis Center (NESCent), NSF EF-0423641. This work was supported by the Wellcome Trust [092807] to AR. TB is supported by the Royal Society. DJS and CAR acknowledge EU FP7 programs EMPERIE (223498) and ANTIGONE (278976), Human Frontier Science Program (HFSP) program grant P0050/2008, Wellcome 087982AIA, NIH Director's Pioneer Award DP1-OD000490-01 and National Institute of Allergy and Infectious Diseases NIH CEIRS contract HHSN266200700010C. CAR was supported by a University Research Fellowship from the Royal Society. Further, research was partially completed while PL and MAS were visiting the Institute for Mathematical Sciences, National University of Singapore in 2011. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 60 Z9 61 U1 3 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2014 VL 10 IS 2 AR e1003932 DI 10.1371/journal.ppat.1003932 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AB9CC UT WOS:000332085900036 PM 24586153 ER PT J AU Pulloor, NK Nair, S Kostic, AD Bist, P Weaver, JD Riley, AM Tyagi, R Uchil, PD York, JD Snyder, SH Garcia-Sastre, A Potter, BVL Lin, RT Shears, SB Xavier, RJ Krishnan, MN AF Pulloor, Niyas Kudukkil Nair, Sajith Kostic, Aleksandar D. Bist, Pradeep Weaver, Jeremy D. Riley, Andrew M. Tyagi, Richa Uchil, Pradeep D. York, John D. Snyder, Solomon H. Garcia-Sastre, Adolfo Potter, Barry V. L. Lin, Rongtuan Shears, Stephen B. Xavier, Ramnik J. Krishnan, Manoj N. TI Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response SO PLOS PATHOGENS LA English DT Article ID DOUBLE-STRANDED-RNA; INNATE IMMUNE-RESPONSE; IRF-3 TRANSCRIPTION FACTOR; HEXAKISPHOSPHATE KINASE 1; SENSORS RIG-I; ANTIVIRAL RESPONSE; VIRUS-INFECTION; REGULATORY FACTOR-3; PP-INSP(5) KINASE; UBIQUITIN LIGASE AB The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon- production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7) were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by -phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications. Author Summary The innate immune system is critical for viral infection control by host organisms. The type I interferons are a family of major antiviral cytokines produced upon the activation of innate immune pattern recognition receptors (PRRs) by viruses. The RIG-I is a major PRR that uniquely detects RNA viruses within the cytoplasm. In this study, we aimed to discover cellular genes and pathways that play regulatory roles in the transcriptional induction of type I interferon- (IFN). Using a human genome wide RNA interference (RNAi) screening, we identified 226 genes whose expression is important for proper IFN production. Through bioinformatics-based mining of the RNAi screen results, we identified that the cellular pathway synthesizing inositol pyrophosphates, a class of inositol phosphates with high-energy diphosphates, is a key positive regulator of RIG-I mediated IFN production. The kinases IPPK, PPIP5K1 and PPIP5K2, that synthesize inositol pyrophosphate 1-IP7, regulated IFN response in a catalytically dependent manner. Mechanistic studies identified that 1-IP7 synthesis pathway was needed for efficient phosphorylation of IRF3. The DIPP family of inositol pyrophosphate hydrolases negatively regulated the IFN response, upon ectopic expression. In summary, this study generated a global view of the regulation of RIG-I signaling, and identified inositol pyrophosphates as important regulators of antiviral response. C1 [Pulloor, Niyas Kudukkil; Nair, Sajith; Bist, Pradeep; Krishnan, Manoj N.] DUKE NUS Grad Med Sch, Program Emerging Infect Dis, Singapore, Singapore. [Kostic, Aleksandar D.; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Weaver, Jeremy D.; Shears, Stephen B.] NIH, NIEHS, DHHS, Lab Signal Transduct,Inositol Signaling Grp, Res Triangle Pk, NC USA. [Riley, Andrew M.; Potter, Barry V. L.] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. [Tyagi, Richa; Snyder, Solomon H.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Tyagi, Richa; Snyder, Solomon H.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Tyagi, Richa; Snyder, Solomon H.] Johns Hopkins Univ, Sch Med, Dept Behav Sci, Baltimore, MD USA. [Uchil, Pradeep D.] Yale Univ, Sch Med, Sect Microbial Pathogenesis, New Haven, CT USA. [York, John D.] Vanderbilt Univ, Med Ctr, Dept Biochem, Nashville, TN USA. [Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, Dept Med, Div Infect Dis,Dept Microbiol, New York, NY USA. [Lin, Rongtuan] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. RP Pulloor, NK (reprint author), DUKE NUS Grad Med Sch, Program Emerging Infect Dis, Singapore, Singapore. EM manoj.krishnan@duke-nus.edu.sg RI Lin, Rongtuan/A-1442-2008; tyagi, richa/A-7261-2015; OI Lin, Rongtuan/0000-0002-2238-3503; Kostic, Aleksandar/0000-0002-0837-4360; Garcia-Sastre, Adolfo/0000-0002-6551-1827; McCaffrey, Kathleen/0000-0002-6544-2649 FU ASTAR; Ministry of Education; NIH [MH-18501]; Canadian Institutes of Health Research [MOP42562]; NIAID [U19AI083025]; CRIP (Center for Research on Influenza Pathogenesis); Center of Excellence for Influenza Research and Surveillance (CEIRS) [HHSN266200700010C]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; Wellcome Trust [082837, 101010] FX MNK was funded by ASTAR and Ministry of Education. SHS was funded by NIH grant MH-18501. RL was funded by the Canadian Institutes of Health Research grant MOP42562. AGS was funded by NIAID grant U19AI083025 and by CRIP (Center for Research on Influenza Pathogenesis), a NIAD-funded Center of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN266200700010C). SBS was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AMR and BVLP were funded by the Wellcome Trust (Programme Grant 082837). BVLP is a Wellcome Trust Senior Investigator (Grant 101010) NR 72 TC 25 Z9 25 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 FEB PY 2014 VL 10 IS 2 AR e1003981 DI 10.1371/journal.ppat.1003981 PG 16 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AB9CC UT WOS:000332085900052 PM 24586175 ER PT J AU Ruckwardt, TJ Malloy, AMW Morabito, KM Graham, BS AF Ruckwardt, Tracy J. Malloy, Allison M. W. Morabito, Kaitlyn M. Graham, Barney S. TI Quantitative and Qualitative Deficits in Neonatal Lung-Migratory Dendritic Cells Impact the Generation of the CD8+T Cell Response SO PLOS PATHOGENS LA English DT Article ID SYNCYTIAL VIRUS-INFECTION; CD4(+) T-CELLS; LYMPH-NODE; INFLUENZA-VIRUS; ANTIGEN; CD103(+); COSTIMULATION; IMMUNITY; SUBSETS; MICE AB CD103+ and CD11b+ populations of CD11c+MHCIIhi murine dendritic cells (DCs) have been shown to carry antigens from the lung through the afferent lymphatics to mediastinal lymph nodes (MLN). We compared the responses of these two DC populations in neonatal and adult mice following intranasal infection with respiratory syncytial virus. The response in neonates was dominated by functionally-limited CD103+ DCs, while CD11b+ DCs were diminished in both number and function compared to adults. Infecting mice at intervals through the first three weeks of life revealed an evolution in DC phenotype and function during early life. Using TCR transgenic T cells with two different specificities to measure the ability of CD103+ DC to induce epitope-specific CD8+ T cell responses, we found that neonatal CD103+ DCs stimulate proliferation in a pattern distinct from adult CD103+ DCs. Blocking CD28-mediated costimulatory signals during adult infection demonstrated that signals from this costimulatory pathway influence the hierarchy of the CD8+ T cell response to RSV, suggesting that limited costimulation provided by neonatal CD103+ DCs is one mechanism whereby neonates generate a distinct CD8+ T cell response from that of adults. Author Summary Respiratory syncytial virus (RSV) infection is most severe in infants under six months and the most common cause of hospitalization for lower respiratory tract infection in children under five years. Disease is a consequence of virus- and T-cell-mediated pathology. Adaptive immune responses to viral respiratory infections are initiated by dendritic cells (DCs) that traffic to lymph nodes from the infected lungs. We compared the phenotype and function of two lung-migratory DC populations, identified by high expression of MHC Class II and CD103+ (CD103+DCs) or CD11b+ (CD11b+DCs), in mice infected in early life or as adults. We found that DC subsets undergo dramatic quantitative and qualitative changes during the first weeks of life, and CD103+DCs from neonatal mediastinal lymph nodes induced a fundamentally different CD8+ T-cell response profile than CD103+DCs from adults. The adult response pattern required CD28-mediated costimulatory signals, which is a limiting functional property of neonatal CD103+DCs. Thus, the ability of neonatal CD103+DCs to provide sufficient costimulation to neonatal CD8+ T-cells can influence the immunodominance hierarchy and functional properties of neonatal CD8+ T-cell responses compared to those of adults. A better understanding of deficiencies in early life immunity will guide vaccine approaches that induce disease-sparing immune responses in infants. C1 [Ruckwardt, Tracy J.; Malloy, Allison M. W.; Morabito, Kaitlyn M.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Ruckwardt, TJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU National Institute of Allergy and Infectious Diseases FX This work was supported by intramural funding from the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript. NR 38 TC 19 Z9 21 U1 1 U2 2 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 FEB PY 2014 VL 10 IS 2 AR e1003934 DI 10.1371/journal.ppat.1003934 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AB9CC UT WOS:000332085900037 PM 24550729 ER PT J AU Padgett, L Rowland, J AF Padgett, Lynne Rowland, Julia TI The Cancer Psychosocial Matrix: Testing the Utility of a Tool for Addressing Capacity to Deliver Quality Cancer Care SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Padgett, Lynne; Rowland, Julia] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 11 EP 12 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700020 ER PT J AU Padgett, L Moser, R Ottenbacher, A Snider, R McDonald, P AF Padgett, Lynne Moser, Richard Ottenbacher, Allison Snider, Rachel McDonald, Paige TI Enabling the Comparison of Distress Measurement Through Community Engagement SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Padgett, Lynne; Moser, Richard; Ottenbacher, Allison; Snider, Rachel; McDonald, Paige] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 11 EP 11 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700019 ER PT J AU Sherman-Bien, S Patenaude, AF Battles, H Elkin, D Friebert, S Kearney, J Kupst, MJ Madan-Swain, A Mullins, L Pao, M Phipps, S Zadeh, S Wiener, L AF Sherman-Bien, Sandra Patenaude, Andrea Farkas Battles, Haven Elkin, David Friebert, Sarah Kearney, Julia Kupst, Mary Jo Madan-Swain, Avi Mullins, Larry Pao, Maryland Phipps, Sean Zadeh, Sima Wiener, Lori TI Meeting the Needs of Their Children: Correlates of Distress for Lone Parents of Children With Cancer SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Sherman-Bien, Sandra] Miller Childrens Hosp, Jonathan Jacques Childrens Canc Ctr, Long Beach, CA USA. [Patenaude, Andrea Farkas] Dana Farber Canc Inst, Boston, MA 02115 USA. [Battles, Haven; Pao, Maryland; Zadeh, Sima; Wiener, Lori] NCI, NIH, Bethesda, MD 20892 USA. [Elkin, David] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Friebert, Sarah] Akron Childrens Hosp, Akron, OH USA. [Kearney, Julia] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kupst, Mary Jo] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Madan-Swain, Avi] Univ Alabama Birmingham, Birmingham, AL USA. [Mullins, Larry] Oklahoma State Univ, Stillwater, OK 74078 USA. [Phipps, Sean] St Jude Childrens Res Hosp, Memphis, TN 38105 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 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 30 EP 31 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700052 ER PT J AU Corner, G Sweeney, C Wiener, L Roberts, K Loeb, R Zaider, T Tuman, M Craig, C Lichtenthal, W AF Corner, Geoffrey Sweeney, Corinne Wiener, Lori Roberts, Kailey Loeb, Rebecca Zaider, Talia Tuman, Malwina Craig, Caraline Lichtenthal, Wendy TI Factors Associated With Partner-Related Adjustment in Parents Bereaved by Cancer SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Corner, Geoffrey; Sweeney, Corinne; Wiener, Lori; Roberts, Kailey; Loeb, Rebecca; Zaider, Talia; Tuman, Malwina; Craig, Caraline; Lichtenthal, Wendy] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sweeney, Corinne] Fairleigh Dickinson Univ, Teaneck, NJ USA. [Wiener, Lori] NCI, Bethesda, MD 20892 USA. [Roberts, Kailey] New Sch, New York, NY 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 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 33 EP 33 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700057 ER PT J AU Padgett, L AF Padgett, Lynne TI The Cancer Psychosocial Care Matrix: A Resource for Implementing a Process of Care SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Padgett, Lynne] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 35 EP 35 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700060 ER PT J AU Wiener, L Loucas, C Pelletier, W Battles, H Vasserman-Stokes, E Zadeh, S Muriel, A AF Wiener, Lori Loucas, Caitlyn Pelletier, Wendy Battles, Haven Vasserman-Stokes, Elaina Zadeh, Sima Muriel, Anna TI Parental Dyadic Adjustment in the Face of Childhood Cancer SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Wiener, Lori; Battles, Haven; Vasserman-Stokes, Elaina; Zadeh, Sima] NCI, NIH, Bethesda, MD 20892 USA. [Loucas, Caitlyn; Muriel, Anna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pelletier, Wendy] Alberta Childrens Prov Gen Hosp, Calgary, AB, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 40 EP 41 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700071 ER PT J AU Zadeh, S Wiener, L Pao, M Osherow, J Lane, M AF Zadeh, Sima Wiener, Lori Pao, Maryland Osherow, Janet Lane, Mary TI The Use of a Distress Thermometer in a Pediatric Outpatient Setting: Evaluating Validity, Acceptability and Feasibility SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Zadeh, Sima; Wiener, Lori] NCI, Bethesda, MD 20892 USA. [Pao, Maryland] NIMH, Bethesda, MD 20892 USA. [Osherow, Janet; Lane, Mary] Medstar Georgetown Univ Hosp, Washington, DC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 52 EP 52 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700092 ER PT J AU Applebaum, A Son, T Bevans, M Hernandez, M DuHamel, K AF Applebaum, Allison Son, Tammy Bevans, Margaret Hernandez, Marisol DuHamel, Katherine TI The Experience of Caregivers of Outpatient Hematopoietic Stem Cell Transplant Patients: Lessons Learned From the Inpatient Hematopoietic Stem Cell Transplant Literature SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Applebaum, Allison; Son, Tammy; Hernandez, Marisol; DuHamel, Katherine] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Bevans, Margaret] NIH, Ctr Clin, 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 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 105 EP 105 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700185 ER PT J AU Prince, P Bevans, M AF Prince, Patricia Bevans, Margaret TI "Outside The Ring of Fire": Distress Screening for Cancer Caregivers During Survivorship SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Prince, Patricia; Bevans, Margaret] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 107 EP 107 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700189 ER PT J AU Loucas, C Muriel, A Zadeh, S Pelletier, W Battles, H Vasserman-Stokes, E Wiener, L AF Loucas, Caitlyn Muriel, Anna Zadeh, Sima Pelletier, Wendy Battles, Haven Vasserman-Stokes, Elaina Wiener, Lori TI He Loves Me, She Loves Me Not: Self-Reports of Parental Marital Stress and Closeness During Pediatric Cancer SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Loucas, Caitlyn; Muriel, Anna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zadeh, Sima; Battles, Haven; Vasserman-Stokes, Elaina; Wiener, Lori] NIH, Bethesda, MD 20892 USA. [Pelletier, Wendy] Alberta Childrens Prov Gen Hosp, Calgary, AB T2T 5C7, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2014 VL 23 SU 1 SI SI BP 108 EP 108 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AA4TI UT WOS:000331088700191 ER PT J AU Mousavi, K Zare, H Koulnis, M Sartorelli, V AF Mousavi, Kambiz Zare, Hossein Koulnis, Miroslav Sartorelli, Vittorio TI The emerging roles of eRNAs in transcriptional regulatory networks SO RNA BIOLOGY LA English DT Article DE transcription; enhancers; chromatin; eRNA; mRNA synthesis; histones ID MATRIX ATTACHMENT REGIONS; BETA-GLOBIN LOCUS; GENE-EXPRESSION; CHROMATIN ACCESSIBILITY; HUMAN GENOME; HUMAN-CELLS; INTERGENIC TRANSCRIPTION; PELVIC REDUCTION; SUPER-ENHANCERS; DISEASE RISK AB Following reports by ENCyclopedia Of DNA Elements (ENCODE; GENCODE) Consortium and others, it is now fairly evident that the majority (70-80%) of the mammalian genome has the potential to be transcribed into non-protein-coding RNAs (ncRNAs). Critical to our understanding of genetic processes is the mechanism by which ncRNAs exert their roles. Accordingly, ncRNAs are shown to regulate the expression of protein-coding loci (i.e., genes) at the transcriptional as well as post-transcriptional stages. We recently reported on a widespread transcription at the DNA enhancer elements in myogenic cells. In our study, we found certain enhancer RNAs (eRNAs) regulate chromatin accessibility of the transcriptional machinery at loci encoding master regulators of myogenesis (i.e., MyoD/MyoG), thus suggesting their significance and site-specific impact in cellular programming. Here, we examine recent discoveries pertinent to the proposed role(s) of eRNAs in regulating gene expression. We will highlight consistencies, discuss confounding observations, and consider a lack of critical information in a way to prioritize future objectives. C1 [Mousavi, Kambiz] Moderna Therapeut Inc, Cambridge, MA USA. [Zare, Hossein; Koulnis, Miroslav; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Mousavi, K (reprint author), Moderna Therapeut Inc, Cambridge, MA USA. EM kambiz.mousavi@modernatx.com; sartorev@mail.nih.gov NR 71 TC 10 Z9 10 U1 1 U2 9 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD FEB 1 PY 2014 VL 11 IS 2 BP 106 EP 110 DI 10.4161/rna.27950 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC0VG UT WOS:000332213000003 PM 24525859 ER PT J AU Satpathy, M Wang, LY Zielinski, R Qian, WP Lipowska, M Capala, J Lee, GY Xu, H Wang, YA Mao, H Yang, L AF Satpathy, Minati Wang, Liya Zielinski, Rafal Qian, Weiping Lipowska, Malgorzata Capala, Jacek Lee, Gee Young Xu, Hong Wang, Y. Andrew Mao, Hui Yang, Lily TI Active Targeting Using HER-2-Affibody-Conjugated Nanoparticles Enabled Sensitive and Specifi c Imaging of Orthotopic HER-2 Positive Ovarian Tumors SO SMALL LA English DT Article DE HER-2 targeted nanoparticles; HER-2 affibody; NIR-830 dye; Optical imaging; MRI; orthotopic ovarian tumor model ID MAGNETIC NANOPARTICLES; SHORTENED SURVIVAL; AFFIBODY MOLECULES; PANCREATIC-CANCER; HER2/NEU ONCOGENE; BREAST-CANCER; EXPRESSION; CARCINOMA; THERAPY; OVEREXPRESSION AB Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, HER-2 targeted magnetic iron oxide nanoparticles (IONPs) are developed by conjugating a high affinity and small size HER-2 affibody that is labeled with a unique near infrared dye (NIR-830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, it is shown that HER-2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non-invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. It is determined that HER-2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER-2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non-targeted IONPs into the mice bearing HER-2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER-2 low expressing OVCAR3 tumors after systemic delivery of HER-2 targeted-IONPs. Since HER-2 is expressed in a high percentage of ovarian cancers, the HER-2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image-guided therapy and surgery. C1 [Satpathy, Minati; Wang, Liya; Qian, Weiping; Lipowska, Malgorzata; Lee, Gee Young; Mao, Hui; Yang, Lily] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Capala, Jacek] NIH, Bethesda, MD 20892 USA. [Zielinski, Rafal] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Xu, Hong; Wang, Y. Andrew] Ocean Nanotech LLC, Springdale, AR USA. RP Yang, L (reprint author), Emory Univ, Sch Med, Atlanta, GA 30322 USA. EM Lyang02@emory.edu FU NIH/NCI [R01CA133722, U01CA151810]; Nancy Panoz Endowed Chair Funds FX We thank Drs. Daniela Matei and Neil Sidell for providing SKOV3-luc cell and OVCAR3 cell lines. This research project was supported by the following NIH/NCI grants, R01CA133722 (Yang) and U01CA151810 (Yang and Mao), and the Nancy Panoz Endowed Chair Funds (Yang). NR 61 TC 28 Z9 28 U1 2 U2 41 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD FEB PY 2014 VL 10 IS 3 BP 544 EP 555 DI 10.1002/smll.201301593 PG 12 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA AB7BM UT WOS:000331944300016 PM 24038985 ER PT J AU Barodka, V Mohanty, JG Mustafa, AK Santhanam, L Nyhan, A Bhunia, AK Sikka, G Nyhan, D Berkowitz, DE Rifkind, JM AF Barodka, Viachaslau Mohanty, Joy G. Mustafa, Asif K. Santhanam, Lakshmi Nyhan, Aoibhinn Bhunia, Anil K. Sikka, Gautam Nyhan, Daniel Berkowitz, Dan E. Rifkind, Joseph M. TI Nitroprusside inhibits calcium-induced impairment of red blood cell deformability SO TRANSFUSION LA English DT Article ID ACTIVATED POTASSIUM CHANNEL; RANDOMIZED CONTROLLED-TRIAL; SUICIDAL ERYTHROCYTE DEATH; NITRIC-OXIDE; S-NITROSYLATION; INTRACELLULAR CALCIUM; IN-VITRO; STORAGE; RATS; HYPERTENSION AB BACKGROUND: Red blood cell (RBC) deformation is critical for microvascular perfusion and oxygen delivery to tissues. Abnormalities in RBC deformability have been observed in aging, sickle cell disease, diabetes, and preeclampsia. Although nitric oxide (NO) prevents decreases in RBC deformability, the underlying mechanism is unknown. STUDY DESIGN AND METHODS: As an experimental model, we used ionophore A23187-mediated calcium influx in RBCs to reduce their deformability and investigated the role of NO donor sodium nitroprusside (SNP) and KCa3.1 (Gardos) channel blockers on RBC deformability (measured as elongation index [EI] by microfluidic ektacytometry). RBC intracellular Ca2+ and extracellular K+ were measured by inductively coupled plasma mass spectrometry and potassium ion selective electrode, respectively. RESULTS: SNP treatment of RBCs blocked the Ca2+ (approx. 10 mmol/L)-induced decrease in RBC deformability (EI 0.34 +/- 0.02 vs. 0.09 +/- 0.01, control vs. Ca2+ loaded, p < 0.001; and EI 0.37 +/- 0.02 vs. 0.30 +/- 0.01, SNP vs. SNP plus Ca2+ loaded) as well as Ca2+ influx and K+ efflux. The SNP effect was similar to that observed after pharmacologic blockade of the KCa3.1 channel (with charybdotoxin or extracellular medium containing isotonic K+ concentration). In RBCs from KCa3.1(-/-) mice, 10 mmol/L Ca2+ loading did not decrease cellular deformability. A preliminary attempt to address the molecular mechanism of SNP protection suggests the involvement of cell surface thiols. CONCLUSION: Our results suggest that nitroprusside treatment of RBCs may protect them from intracellular calcium increase-mediated stiffness, which may occur during microvascular perfusion in diseased states, as well as during RBC storage. C1 [Barodka, Viachaslau] Johns Hopkins Univ Hosp, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. RP Barodka, V (reprint author), Johns Hopkins Univ Hosp, Dept Anesthesiol & Crit Care Med, 600 North Wolfe St,Tower 711, Baltimore, MD 21287 USA. EM vbarodk1@jhmi.edu; mohantyj@mail.nih.gov FU NIH T32; Intramural Research Program of the NIH, National Institute on Aging FX Funded by NIH T32 to VB. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 54 TC 7 Z9 7 U1 4 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD FEB PY 2014 VL 54 IS 2 BP 434 EP 444 DI 10.1111/trf.12291 PG 11 WC Hematology SC Hematology GA AA8YY UT WOS:000331382100025 PM 23781865 ER PT J AU Wagner, SJ Glynn, SA Welniak, LA AF Wagner, Stephen J. Glynn, Simone A. Welniak, Lisbeth A. CA NHLBI Working Grp Strategies Optim TI Research opportunities in optimizing storage of red blood cell products SO TRANSFUSION LA English DT Article ID INTENSIVE-CARE-UNIT; NITRIC-OXIDE SYNTHASE; OLDER STORED-BLOOD; ACUTE LUNG INJURY; S-NITROSOHEMOGLOBIN; DI(2-ETHYLHEXYL) PHTHALATE; CARDIAC-SURGERY; ERYTHROCYTE CONSUMPTION; DEVELOPMENTAL TOXICITY; PHYSIOLOGICAL STATUS C1 Amer Red Cross, Rockville, MD 20855 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Wagner, SJ (reprint author), Amer Red Cross, Holland Lab, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM Stephen.wagner@redcross.org FU NIH [HL095463, HL095467, HL095468, HL095470, HL095479, HL098014, HL098031, HL098032] FX This work was sponsored in part by NIH Grants HL095463, HL095467, HL095468, HL095470, HL095479, HL098014, HL098031, and HL098032. NR 93 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD FEB PY 2014 VL 54 IS 2 BP 483 EP 494 DI 10.1111/trf.12244 PG 12 WC Hematology SC Hematology GA AA8YY UT WOS:000331382100031 PM 23676138 ER PT J AU Nelson, EE Lau, JYF Jarcho, JM AF Nelson, Eric E. Lau, Jennifer Y. F. Jarcho, Johanna M. TI Growing pains and pleasures: how emotional learning guides development SO TRENDS IN COGNITIVE SCIENCES LA English DT Review DE sensitive periods; amygdala; cortex; social ID MONKEYS MACACA-MULATTA; BRAIN MECHANISMS; SOCIAL-BEHAVIOR; RHESUS-MONKEYS; AMYGDALA RESPONSE; PREFRONTAL CORTEX; SENSITIVE PERIODS; MEMORY FORMATION; SEXUAL-BEHAVIOR; CEREBRAL-CORTEX AB The nervous system promotes adaptive responding to myriad environmental stimuli by ascribing emotion to specific stimulus domains. This affects the salience of different stimuli, facilitates learning, and likely involves the amygdala. Recent studies suggest a strong homology between adaptive responses that result from learning and those that emerge during development. As in motivated learning, developmental studies have found the salience of different classes of stimulus (e.g., peers) undergoes marked fluctuation across maturation and may involve differential amygdala engagement. In this review, by highlighting the importance of particular stimulus categories during sensitive periods of development, we suggest that variability in amygdala response to different stimulus domains has an active and functional role in shaping emerging cortical circuits across development. C1 [Nelson, Eric E.; Jarcho, Johanna M.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Lau, Jennifer Y. F.] Kings Coll London, Inst Psychiat, Dept Psychol, London WC2R 2LS, England. RP Nelson, EE (reprint author), NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. EM nelsone@mail.nih.gov OI Jarcho, Johanna/0000-0001-9075-6968; Nelson, Eric/0000-0002-3376-2453 FU National Institute of Mental Health; Economic and Social Research Council; Calleva Centre for Evolution and Human Science FX E.E.N. and J.M.J. were funded by the intramural research program of the National Institute of Mental Health. J.Y.F.L. received funding from the Economic and Social Research Council and from the Calleva Centre for Evolution and Human Science. NR 100 TC 16 Z9 16 U1 3 U2 24 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD FEB PY 2014 VL 18 IS 2 BP 99 EP 108 DI 10.1016/j.tics.2013.11.003 PG 10 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AC4NR UT WOS:000332498500011 PM 24405846 ER PT J AU Yeo, L AF Yeo, L. TI Re: The sonopartogram: a novel method for recording the progress of labor by ultrasound. W. A. Hassan, T. Eggebo, M. Ferguson, A. Gillett, J. Studd, D. Pasupathy and C. C. Lees. Ultrasound Obstet Gynecol 2014; 43: 189-194. SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Editorial Material C1 [Yeo, L.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Yeo, L.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Yeo, L (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. EM lyeo@med.wayne.edu NR 4 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0960-7692 EI 1469-0705 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD FEB PY 2014 VL 43 IS 2 DI 10.1002/uog.13300 PG 2 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA AA6XV UT WOS:000331242400003 PM 24497420 ER PT J AU Cuthbert, BN AF Cuthbert, Bruce N. TI The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology SO WORLD PSYCHIATRY LA English DT Article DE Psychiatric diagnosis; Research Domain Criteria; RDoC; NIMH; DSM-5; translational research ID PSYCHOTIC SYMPTOMS; MENTAL-DISORDERS; SCHIZOPHRENIA; BRAIN; CONSTRUCTS; PSYCHIATRY; CHALLENGES; DEPRESSION; TRAITS; FEAR AB In 2008, the National Institute of Mental Health (NIMH) included in its new Strategic Plan the following aim: Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures. The implementation of this aim was named the Research Domain Criteria project, or RDoC. RDoC is a programmatic initiative that will fund grants, contracts, early-phase trials, and similar activities for the purpose of generating studies to build a research literature that can inform future versions of psychiatric nosologies based upon neuroscience and behavioral science rather than descriptive phenomenology. RDoC departs markedly from the DSM and ICD processes, in which extensive workgroup meetings generate final and finely-honed sets of diagnoses that are modified in field tests only if problems with clinical utility arise. Rather, in keeping with its provenance as an experimental system, the RDoC provides a framework for conducting research in terms of fundamental circuit-based behavioral dimensions that cut across traditional diagnostic categories. While an important aim of the project is to validate particular dimensions as useful for eventual clinical work, an equally important goal is to provide information and experience about how to conceive and implement such an alternative approach to future diagnostic practices that can harness genetics and neuroscience in the service of more effective treatment and prevention. This paper summarizes the rationale for the RDoC project, its essential features, and potential methods of transitioning from DSM/ICD categories to dimensionally-oriented designs in research studies. C1 NIMH, Bethesda, MD 20892 USA. RP Cuthbert, BN (reprint author), NIMH, 6001 Execut Blvd, Bethesda, MD 20892 USA. NR 35 TC 215 Z9 221 U1 11 U2 62 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1723-8617 EI 2051-5545 J9 WORLD PSYCHIATRY JI World Psychiatry PD FEB PY 2014 VL 13 IS 1 BP 28 EP 35 DI 10.1002/wps.20087 PG 8 WC Psychiatry SC Psychiatry GA AA6YA UT WOS:000331242900006 PM 24497240 ER PT J AU Zhu, L Ma, Y Kiesewetter, DO Wang, Y Lang, LX Lee, S Niu, G Chen, XY AF Zhu, Lei Ma, Ying Kiesewetter, Dale O. Wang, Ye Lang, Lixin Lee, Seulki Niu, Gang Chen, Xiaoyuan TI Rational Design of Matrix Metalloproteinase-13 Activatable Probes for Enhanced Specificity SO ACS CHEMICAL BIOLOGY LA English DT Article ID IN-VIVO; PROTEASE; CELLS; INFLAMMATION; DOXORUBICIN; METABOLISM; EXPRESSION; PEPTIDES; CANCER; LIGHT AB Because of the important roles that matrix metalloproteinases (MMPs) play in tumor invasion and metastasis, various activatable optical probes have been developed to visualize MMP activities in vitro and in vivo. Our recently developed MMP-13 activatable probe, L-MMP-P12, has been successfully applied to image the expression and inhibition of MMPs in a xenografted tumor model [Zhu, L., et al. (2011) Theranostics 1, 18-27]. In this study, to further optimize the in vivo behavior of the proteinase activatable probe, we tracked and profiled the metabolites by a high-resolution liquid chromatography mass spectrometry (LC-MS) system. Two major-metabolites that contributed to the fluorescence recovery were identified. One was specifically cleaved between glycine (G(4)) and valine (V-5) by MMP, while the other one was generated by nonspecific cleavage between glycine (G(7)) and lysine (K-8). To visualize the MMP activity more accurately and specifically, a new probe, D-MMP-P12, was designed by replacing the L-lysine with D-lysine in the MMP substrate sequence. The metabolic profile of the new probe, D-MMP-P12, was further characterized by in vitro enzymatic assay, and no nonspecific metabolite was found by LC-MS. Our in vivo optical imaging also demonstrated that D-MMP-P12 had a tumor-to-background ratio (TBR, 5.55 +/- 0.75) significantly higher than that of L-MMP-P12 (3.73 +/- 0.31) 2 h postinjection. The improved MMP activatable probe may have the potential for drug screening, tumor diagnosis, and therapy response monitoring. Moreover, our research strategy can be further extended to study other protease activatable probes. C1 [Zhu, Lei] Xiamen Univ, Sch Publ Hlth, CMITM, Xiamen 361005, Peoples R China. [Zhu, Lei; Ma, Ying; Kiesewetter, Dale O.; Lang, Lixin; Lee, Seulki; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Wang, Ye] Jilin Univ, Coll Life Sci, Changchun 130000, Peoples R China. RP Niu, G (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM gang.niu@nih.gov; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU Major State Basic Research Development Program of China (973 Program) [2013CB733802, 2014CB744503]; National Science Foundation of China (NSFC) [51373144, 81201129, 81371596]; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the Major State Basic Research Development Program of China (973 Program) (2013CB733802 and 2014CB744503), the National Science Foundation of China (NSFC) (51373144, 81201129, and 81371596), and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 30 TC 8 Z9 8 U1 2 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD FEB PY 2014 VL 9 IS 2 BP 510 EP 516 DI 10.1021/cb400698s PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB6VG UT WOS:000331927000026 PM 24266806 ER PT J AU Iida, Y Kazuki, Y Hayashi, M Ueda, Y Hasegawa, M Kouprina, N Larionov, V Oshimura, M AF Iida, Yuichi Kazuki, Yasuhiro Hayashi, Masahiro Ueda, Yasuji Hasegawa, Mamoru Kouprina, Natalay Larionov, Vladimir Oshimura, Mitsuo TI Bi-HAC Vector System toward Gene and Cell Therapy SO ACS SYNTHETIC BIOLOGY LA English DT Article DE human artificial chromosome vector; gene expression; gene and cell therapy ID HUMAN ARTIFICIAL CHROMOSOME; CONDITIONAL CENTROMERE; DEFINED FACTORS; DIRECT CONVERSION; MOUSE; MICE; CONSTRUCTION; FIBROBLASTS; EXPRESSION; DELIVERY AB Genetic manipulations with mammalian cells often require introduction of two or more genes that have to be in trans-configuration. However, conventional gene delivery vectors have several limitations, including a limited cloning capacity and a risk of insertional mutagenesis. In this paper, we describe a novel gene expression system that consists of two differently marked HAC vectors containing unique gene loading sites. One HAC, 21HAC, is stably propagated during cell divisions; therefore, it is suitable for complementation of a gene deficiency. The other HAC, tet-O HAC, can be eliminated, providing a unique opportunity for transient gene expression (e.g., for cell reprogramming). Efficiency and accuracy of a novel bi-HAC vector system have been evaluated after loading of two different transgenes into these HACs. Based on analysis of transgenes expression and HACs. stability in the proof of principle experiments, the combination of two HAC vectors may provide a powerful tool toward gene and cell therapy. C1 [Iida, Yuichi; Kazuki, Yasuhiro; Hayashi, Masahiro; Oshimura, Mitsuo] Tottori Univ, Grad Sch Med Sci, Inst Regenerat Med & Biofunct, Dept Biomed Sci, Yonago, Tottori 6838503, Japan. [Kazuki, Yasuhiro; Oshimura, Mitsuo] Tottori Univ, Chromosome Engn Res Ctr, Tottori 680, Japan. [Ueda, Yasuji; Hasegawa, Mamoru] DNAVEC Corp, Tsukuba, Ibaraki 3002611, Japan. [Kouprina, Natalay; Larionov, Vladimir] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Oshimura, M (reprint author), Tottori Univ, Grad Sch Med Sci, Inst Regenerat Med & Biofunct, Dept Biomed Sci, 86 Nishi Cho, Yonago, Tottori 6838503, Japan. EM oshimura@med.tottori-u.ac.jp FU JST, CREST; 21st Century Center of Excellence (COE) program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, U.S.A. FX We thank Dr. Tetsuya Ohbayashi, Hiroyuki Kugoh, Masako Tada, Masaharu Hiratsuka, and Satoshi Abe at Tottori University for valuable discussions. This study was supported in part by JST, CREST (MO), and the 21st Century Center of Excellence (COE) program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MO), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, U.S.A. (V.L.). NR 38 TC 3 Z9 3 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2161-5063 J9 ACS SYNTH BIOL JI ACS Synth. Biol. PD FEB PY 2014 VL 3 IS 2 BP 83 EP 90 DI 10.1021/sb400166j PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AB6VH UT WOS:000331927100004 PM 25101815 ER PT J AU Luo, ZP Rajashankar, K Dauter, Z AF Luo, Zhipu Rajashankar, Kanagalaghatta Dauter, Zbigniew TI Weak data do not make a free lunch, only a cheap meal SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID X-RAY DATA; DATA QUALITY; RESOLUTION; CRYSTALLOGRAPHY; MODEL AB Four data sets were processed at resolutions significantly exceeding the criteria traditionally used for estimating the diffraction data resolution limit. The analysis of these data and the corresponding model-quality indicators suggests that the criteria of resolution limits widely adopted in the past may be somewhat conservative. Various parameters, such as R-merge and I/sigma(I), optical resolution and the correlation coefficients CC1/2 and CC*, can be used for judging the internal data quality, whereas the reliability factors R and R-free as well as the maximum-likelihood target values and real-space map correlation coefficients can be used to estimate the agreement between the data and the refined model. However, none of these criteria provide a reliable estimate of the data resolution cutoff limit. The analysis suggests that extension of the maximum resolution by about 0.2 angstrom beyond the currently adopted limit where the I/sigma(I) value drops to 2.0 does not degrade the quality of the refined structural models, but may sometimes be advantageous. Such an extension may be particularly beneficial for significantly anisotropic diffraction. Extension of the maximum resolution at the stage of data collection and structure refinement is cheap in terms of the required effort and is definitely more advisable than accepting a too conservative resolution cutoff, which is unfortunately quite frequent among the crystal structures deposited in the Protein Data Bank. C1 [Luo, Zhipu; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. [Rajashankar, Kanagalaghatta] Cornell Univ, NE CAT, Argonne Natl Lab, Argonne, IL 60439 USA. [Rajashankar, Kanagalaghatta] Cornell Univ, Dept Chem & Chem Biol, Argonne Natl Lab, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. EM dauter@anl.gov RI Luo, Zhipu/P-9168-2014 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001]; National Institute of General Medical Sciences of the National Institutes of Health [8 P41 GM103403-10]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, National Institutes of Health (contract No. HHSN261200800001). KRR is supported by a grant from the National Institute of General Medical Sciences (8 P41 GM103403-10) of the National Institutes of Health. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract No. W-31-109-Eng-38. NR 24 TC 10 Z9 10 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD FEB PY 2014 VL 70 BP 253 EP 260 DI 10.1107/S1399004713026680 PN 2 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AB1LY UT WOS:000331554500005 PM 24531460 ER PT J AU Sliwiak, J Jaskolski, M Dauter, Z McCoy, AJ Read, RJ AF Sliwiak, Joanna Jaskolski, Mariusz Dauter, Zbigniew McCoy, Airlie J. Read, Randy J. TI Likelihood-based molecular-replacement solution for a highly pathological crystal with tetartohedral twinning and sevenfold translational noncrystallographic symmetry SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID DIFFRACTION DATA; INTENSITY STATISTICS; X-RAY; REFINEMENT; SUPERSPACE; HYPERICIN; PROTEINS; SYSTEM AB Translational noncrystallographic symmetry (tNCS) is a pathology of protein crystals in which multiple copies of a molecule or assembly are found in similar orientations. Structure solution is problematic because this breaks the assumptions used in current likelihood-based methods. To cope with such cases, new likelihood approaches have been developed and implemented in Phaser to account for the statistical effects of tNCS in molecular replacement. Using these new approaches, it was possible to solve the crystal structure of a protein exhibiting an extreme form of this pathology with seven tetrameric assemblies arrayed along the c axis. To resolve space-group ambiguities caused by tetartohedral twinning, the structure was initially solved by placing 56 copies of the monomer in space group P1 and using the symmetry of the solution to define the true space group, C2. The resulting structure of Hyp-1, a pathogenesis-related class 10 (PR-10) protein from the medicinal herb St John's wort, reveals the binding modes of the fluorescent probe 8-anilino-1-naphthalene sulfonate (ANS), providing insight into the function of the protein in binding or storing hydrophobic ligands. C1 [Sliwiak, Joanna; Jaskolski, Mariusz] Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, PL-61704 Poznan, Poland. [Jaskolski, Mariusz] Adam Mickiewicz Univ, Fac Chem, Dept Crystallog, PL-60780 Poznan, Poland. [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Argonne Natl Lab, Argonne, IL 60439 USA. [McCoy, Airlie J.; Read, Randy J.] Univ Cambridge, Dept Haematol, Cambridge CB2 0XY, England. RP Jaskolski, M (reprint author), Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Noskowskiego 12-14, PL-61704 Poznan, Poland. EM mariuszj@amu.edu.pl; rjr27@cam.ac.uk RI Read, Randy/L-1418-2013 OI Read, Randy/0000-0001-8273-0047 FU European Union within the European Regional Developmental Fund; Polish Ministry of Science and Higher Education [NN 301 003739]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Wellcome Trust [082961/Z/07/Z] FX Financial support to MJ and JS was provided by the European Union within the European Regional Developmental Fund and by the Polish Ministry of Science and Higher Education (grant No. NN 301 003739). ZD was supported by funds from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. RJR was supported by a Principal Research Fellowship from the Wellcome Trust (grant No. 082961/Z/07/Z). NR 30 TC 5 Z9 5 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD FEB PY 2014 VL 70 BP 471 EP 480 DI 10.1107/S1399004713030319 PN 2 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AB1LY UT WOS:000331554500026 PM 24531481 ER PT J AU Shapiro, JM Oyen, ML AF Shapiro, Jenna M. Oyen, Michelle L. TI Viscoelastic analysis of single-component and composite PEG and alginate hydrogels SO ACTA MECHANICA SINICA LA English DT Article DE Hydrogel; Viscoelastic; Indentation; Nanoindentation; Composite ID MECHANICAL CHARACTERIZATION; INDENTATION; STIFFNESS; TISSUES; CELLS; BONE; GELS AB Hydrogels, three-dimensional hydrophilic polymer networks, are appealing candidate materials for studying the cellular microenvironment as their substantial water content helps to better mimic soft tissue. However, hydrogels can lack mechanical stiffness, strength, and toughness. Composite hydrogel systems have been shown to improve upon mechanical properties compared to their singlecomponent counterparts. Poly (ethylene glycol) dimethacrylate (PEGDMA) and alginate are polymers that have been used to form hydrogels for biological applications. Singlecomponent and composite PEGDMA and alginate systems were fabricated with a range of total polymer concentrations. Bulk gels were mechanically characterized using spherical indentation testing and a viscoelastic analysis framework. An increase in shear modulus with increasing polymer concentration was demonstrated for all systems. Alginate hydrogels were shown to have a smaller viscoelastic ratio than the PEGDMA gels, indicating more extensive relaxation over time. Composite alginate and PEGDMA hydrogels exhibited a combination of the mechanical properties of the constituents, as well as a qualitative increase in toughness. Additionally, multiple hydrogel systems were produced that had similar shear moduli, but different viscoelastic behaviors. Accurate measurement of the mechanical properties of hydrogels is necessary in order to determine what parameters are key in modeling the cellular microenvironment. C1 [Shapiro, Jenna M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Oyen, Michelle L.] Univ Cambridge, Dept Engn, Cambridge CB2 1PZ, England. RP Oyen, ML (reprint author), Univ Cambridge, Dept Engn, Cambridge CB2 1PZ, England. EM mlo29@cam.ac.uk OI Oyen, Michelle/0000-0002-3428-748X FU National Institutes of Health - University of Cambridge Scholars Program; laboratory of Dr. Constantine Stratakis at the National Institute of Child Health and Human Development at NIH FX The authors would like to thank Matteo Galli and Daniel Strange for writing the MATLAB script used in the viscoelastic analysis data. In addition, Jenna M. Shapiro acknowledges funding from the National Institutes of Health - University of Cambridge Scholars Program, and the laboratory of Dr. Constantine Stratakis at the National Institute of Child Health and Human Development at NIH. NR 29 TC 4 Z9 4 U1 5 U2 45 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0567-7718 EI 1614-3116 J9 ACTA MECH SINICA-PRC JI Acta Mech. Sin. PD FEB PY 2014 VL 30 IS 1 BP 7 EP 14 DI 10.1007/s10409-014-0025-x PG 8 WC Engineering, Mechanical; Mechanics SC Engineering; Mechanics GA AB7KC UT WOS:000331967600003 ER PT J AU Tam, J Godlewski, G Earley, BJ Zhou, L Jourdan, T Szanda, G Cinar, R Kunos, G AF Tam, Joseph Godlewski, Grzegorz Earley, Brian J. Zhou, Liang Jourdan, Tony Szanda, Gergoe Cinar, Resat Kunos, George TI Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE cannabinoid type 1 antagonism; insulin resistance; hepatic steatosis and fibrosis; fatty acid uptake ID ACTIVATED PROTEIN-KINASE; CARDIOMETABOLIC RISK-FACTORS; NONALCOHOLIC FATTY LIVER; DECREASED PLASMA ADIPONECTIN; INDUCED INSULIN-RESISTANCE; ADIPOSE-SPECIFIC PROTEIN; CB1 RECEPTOR; INVERSE AGONIST; BODY-WEIGHT; ANTAGONIST RIMONABANT AB The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(-/-)). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased beta-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin. C1 [Tam, Joseph; Godlewski, Grzegorz; Earley, Brian J.; Zhou, Liang; Jourdan, Tony; Szanda, Gergoe; Cinar, Resat; Kunos, George] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Tam, J (reprint author), NIAAA, NIH, 5625 Fishers Ln,MSC 9413, Bethesda, MD 20892 USA. EM tamy@mail.nih.gov OI CINAR, RESAT/0000-0002-8597-7253; Earley, Brian/0000-0002-6707-6785 FU National Institute on Alcohol Abuse and Alcoholism, NIH FX This work was supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism, NIH. NR 81 TC 10 Z9 10 U1 0 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD FEB PY 2014 VL 306 IS 4 BP E457 EP E468 DI 10.1152/ajpendo.00489.2013 PG 12 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA AB6KH UT WOS:000331896600011 PM 24381003 ER PT J AU Ohayon, J Finet, G Le Floc'h, S Cloutier, G Gharib, A Heroux, J Pettigrew, R AF Ohayon, Jacques Finet, Gerard Le Floc'h, Simon Cloutier, Guy Gharib, Ahmed M. Heroux, Julie Pettigrew, Roderic I. TI Biomechanics of Atherosclerotic Coronary Plaque: Site, Stability and In Vivo Elasticity Modeling SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Atherosclerotic plaque; Coronary artery disease; Arterial remodeling; Biomechanics wall stress and elastic modulus; Modeling; Young's modulus ID OPTICAL COHERENCE TOMOGRAPHY; 3-VESSEL INTRAVASCULAR ULTRASOUND; ACUTE MYOCARDIAL-INFARCTION; HUMAN CAROTID BIFURCATION; ENDOTHELIAL SHEAR-STRESS; THIN-CAP FIBROATHEROMA; VULNERABLE PLAQUE; PULSATILE FLOW; CIRCUMFERENTIAL STRESS; VASCULAR-RESPONSES AB Coronary atheroma develop in local sites that are widely variable among patients and are considerably variable in their vulnerability for rupture. This article summarizes studies conducted by our collaborative laboratories on predictive biomechanical modeling of coronary plaques. It aims to give insights into the role of biomechanics in the development and localization of atherosclerosis, the morphologic features that determine vulnerable plaque stability, and emerging in vivo imaging techniques that may detect and characterize vulnerable plaque. Composite biomechanical and hemodynamic factors that influence the actual site of development of plaques have been studied. Plaque vulnerability, in vivo, is more challenging to assess. Important steps have been made in defining the biomechanical factors that are predictive of plaque rupture and the likelihood of this occurring if characteristic features are known. A critical key in defining plaque vulnerability is the accurate quantification of both the morphology and the mechanical properties of the diseased arteries. Recently, an early IVUS based palpography technique developed to assess local strain, elasticity and mechanical instabilities has been successfully revisited and improved to account for complex plaque geometries. This is based on an initial best estimation of the plaque components' contours, allowing subsequent iteration for elastic modulus assessment as a basis for plaque stability determination. The improved method has also been preliminarily evaluated in patients with successful histologic correlation. Further clinical evaluation and refinement are on the horizon. C1 [Ohayon, Jacques] UJF, CNRS UMR 5525, Lab TIMC IMAG DyCTiM, In3S, Grenoble, France. [Ohayon, Jacques] Univ Savoie, Le Bourget Du Lac, France. [Finet, Gerard] Univ Lyon 1, INSERM Unit 886, Hosp Civils Lyon & Claude Bernard, Dept Hemodynam & Intervent Cardiol, Lyon, France. [Le Floc'h, Simon] Univ Montpellier 2, CNRS UMR 5508, Lab LMGC, Montpellier, France. [Cloutier, Guy] Univ Montreal, Hosp Res Ctr CRCHUM, Lab Biorheol & Med Ultrason, Montreal, PQ, Canada. [Gharib, Ahmed M.; Heroux, Julie; Pettigrew, Roderic I.] NIDDK, Lab Integrat Cardiovascular Imaging Sci, NIH, Bethesda, MD 20892 USA. [Pettigrew, Roderic I.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Pettigrew, R (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bldg 31,Room 1C14, Bethesda, MD 20892 USA. EM rpettigrew@nih.gov RI Ohayon, Jacques/M-6576-2014 FU National Institutes of Health (NIH); Region Rhone-Alpes; Agence Nationale de la Recherche (ANR), France (ATHE-BIOMECH) [06-BLANC-0263]; Natural Sciences and Engineering Research Council of Canada (NSERC) [323405-06]; Canadian Institutes of Health Research (CIHR) [CPG-80085]; ANR (MELANII) [09-BLANC-0423]; NSERC [STPGP-381136-09] FX The authors would like to thank Shadi Mamaghani, Ph.D. for her expert assistance in the review and editing of the manuscript. This research was supported in part by an appointment (J. Ohayon) to the Senior Fellow Program at the National Institutes of Health (NIH) 2006-2007. This program was administered by Oak Ridge Institute for Science and Education through an interagency agreement between the NIH and the U. S. Department of Energy. J. Ohayon, G. Cloutier and G. Finet were supported by grants from the Region Rhone-Alpes (2010-2013), the Agence Nationale de la Recherche (ANR), France (ATHE-BIOMECH project # 06-BLANC-0263), and by the collaborative health research joint program of the Natural Sciences and Engineering Research Council of Canada (NSERC # 323405-06) and Canadian Institutes of Health Research (CIHR # CPG-80085). This research is now supported by a joint international program of the ANR (MELANII project # 09-BLANC-0423) and NSERC strategic grant # STPGP-381136-09. NR 83 TC 8 Z9 9 U1 2 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD FEB PY 2014 VL 42 IS 2 SI SI BP 269 EP 279 DI 10.1007/s10439-013-0888-1 PG 11 WC Engineering, Biomedical SC Engineering GA AB7ND UT WOS:000331976300004 PM 24043605 ER PT J AU Harada, T Sano, K Sato, K Watanabe, R Yu, ZQ Hanaoka, H Nakajima, T Choyke, PL Ptaszek, M Kobayashi, H AF Harada, Toshiko Sano, Kohei Sato, Kazuhide Watanabe, Rira Yu, Zhanqian Hanaoka, Hirofumi Nakajima, Takahito Choyke, Peter L. Ptaszek, Marcin Kobayashi, Hisataka TI Activatable Organic Near-Infrared Fluorescent Probes Based on a Bacteriochlorin Platform: Synthesis and Multicolor in Vivo Imaging with a Single Excitation SO BIOCONJUGATE CHEMISTRY LA English DT Article ID OVARIAN-CANCER; SERUM-ALBUMIN; AGENT; CONJUGATE; PORPHYRIN; AVIDIN; CELLS AB Near infrared (NIR) fluorescent probes are ideal for in vivo imaging because they offer deeper tissue penetration and lower background autofluorescence. Although most fluorophores in this range are cyanine-based dyes, several new classes of fluorescent NIR probes have been developed. In this study, we developed organic bacteriochlorin derivatives, NMP4 and NMP5, which are excited with a single green light and emit different narrow, well-resolved bands in the NIR (peak of 739 and 770 nm for NMP4 and NMP5, respectively). When conjugated to galactosyl-human serum albumin (hGSA) or glucosyl-human serum albumin (glu-HSA), both targeting H-type lectins, including the beta-D-galactose receptor expressing on ovarian cancer, these agents become targeted, activatable, single excitation, multicolor NIR fluorescence probes. After conjugation to either glu-HSA or hGSA, substantial quenching of fluorescence occurs that is reversed after cell binding and internalization. In vitro studies showed higher cancer cell uptake with NMP4 or NMP5 conjugated to hGSA compared to the same conjugates with glu-HSA. In vivo single excitation two-color imaging was performed after intraperitoneal injection of these agents into mice with disseminated ovarian cancer. Excited with a single green light, distinct NIR emission spectra from each fluorophore were detected and could be distinguished with spectral unmixing. In vivo results using a red fluorescence protein (RFP) labeled tumor model of disseminated ovarian cancer demonstrated high sensitivity and specificity for all probes. The success of single excitation, 2-color NIR fluorescence imaging with a new class of bacteriochlorin-based activatable fluorophores, NMP4 and NMP5, paves the way for further exploration of noncyanine dye-based NIR fluorophores. C1 [Harada, Toshiko; Sano, Kohei; Sato, Kazuhide; Watanabe, Rira; Hanaoka, Hirofumi; Nakajima, Takahito; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Zhanqian; Ptaszek, Marcin] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; University of Maryland, Baltimore County FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. M.P. was supported by University of Maryland, Baltimore County (start-up funds and SRAIS Award). NR 34 TC 16 Z9 16 U1 9 U2 74 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD FEB PY 2014 VL 25 IS 2 BP 362 EP 369 DI 10.1021/bc4005238 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA AB4SH UT WOS:000331779700019 PM 24450401 ER PT J AU Tsai, HT Isaacs, C Fu, AZ Warren, JL Freedman, AN Barac, A Huang, CY Potosky, AL AF Tsai, H. -T. Isaacs, C. Fu, A. Z. Warren, J. L. Freedman, A. N. Barac, A. Huang, C. -Y. Potosky, A. L. TI Risk of cardiovascular adverse events from trastuzumab (Herceptin((R))) in elderly persons with breast cancer: a population-based study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Trastuzumab; Cardiomyopathy; Heart failure; Breast cancer; Risk; Adverse event ID HEART-FAILURE; CARDIOTOXICITY; TRIAL; INHIBITION; THERAPY AB Randomized controlled trials have reported a 4-5 times increased risk of heart failure (HF) in breast cancer patients receiving trastuzumab (Herceptin (A (R)) ) compared to patients who do not receive trastuzumab. However, data regarding the cardiac effects of trastuzumab on elderly patients treated in general practice remain very limited. Using the US surveillance, epidemiology, and end results (SEER)-Medicare database, we conducted a retrospective cohort study on the cardiac effects of trastuzumab use in all incident breast cancer patients diagnosed from 1998 to 2007 who were 66 years and older, had no prior recent claims for cardiomyopathy (CM) or HF, and were followed through 2009. We defined our outcome as the first CM/HF event after diagnosis. We performed Cox-proportional hazard models with propensity score adjustment to estimate CM/HF risk associated with trastuzumab use. A total of 6,829 out of 68,536 breast cancer patients (median age: 75) had an incident CM/HF event. Patients who received trastuzumab tended to be younger, non-white, diagnosed more recently, and had a stage IV diagnosis. Trastuzumab use was associated with an increased risk of CM/HF (HR = 2.08, 95 % CI 1.77-2.44, p < 0.001). The trastuzumab-associated CM/HF risk was stronger in patients who were younger (HR = 2.52 for 66-75 years and HR = 1.44 for 76 years and older, p < 0.001) and diagnosed in recent years (HR = 2.58 for 2006-2007 vs. 1.86 for 1998-2005, p = 0.01). The twofold risk of CM/HF associated with trastuzumab remained regardless of patients' diagnosis stage, presence of hypertension, cardiovascular comorbidities, or receipt of anthracyclines, taxanes, or radiation. Trastuzumab may double CM/HF risk among elderly breast cancer patients. Our findings reinforce the need to prevent and manage cardiac risk among elderly breast cancer patients receiving trastuzumab. C1 [Tsai, H. -T.; Fu, A. Z.; Potosky, A. L.] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Isaacs, C.] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Warren, J. L.; Freedman, A. N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Barac, A.] Medstar Washington Hosp Ctr, Div Cardiol, Washington, DC 20010 USA. [Huang, C. -Y.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Biostat & Bioinformat, Baltimore, MD 21287 USA. RP Tsai, HT (reprint author), Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. EM ht92@georgetown.edu OI Barac, Ana/0000-0002-9935-8904 FU National Cancer Institute at the National Institutes of Health [HHSN2612000900651P, P30CA051008]; Georgetown University Center for Clinical and Translational Science (GHUCCTS) Post-doctoral KL2 Award [5KL2TR000102-04]; Howard University Center for Clinical and Translational Science (GHUCCTS) Post-doctoral KL2 Award [5KL2TR000102-04] FX This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the applied research program, NCI; the office of research, development and information, CMS; information management services (IMS), Inc.; and the surveillance, epidemiology, and end results (SEER) Program tumor registries in the creation of the SEER-Medicare database. This work was supported by the National Cancer Institute at the National Institutes of Health [Grant numbers HHSN2612000900651P, P30CA051008]; and the Georgetown and Howard Universities Center for Clinical and Translational Science (GHUCCTS) Post-doctoral KL2 Award [5KL2TR000102-04 to A. B.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 20 TC 10 Z9 10 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD FEB PY 2014 VL 144 IS 1 BP 163 EP 170 DI 10.1007/s10549-014-2836-7 PG 8 WC Oncology SC Oncology GA AB2VD UT WOS:000331649300016 PM 24469642 ER PT J AU Jochems, C Tucker, JA Vergati, M Boyerinas, B Gulley, JL Schlom, J Tsang, KY AF Jochems, Caroline Tucker, Jo A. Vergati, Matteo Boyerinas, Benjamin Gulley, James L. Schlom, Jeffrey Tsang, Kwong-Yok TI Identification and characterization of agonist epitopes of the MUC1-C oncoprotein SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Vaccines; Oncogene; T cells; Agonist epitopes; MUC1-C ID MYELOGENOUS LEUKEMIA-CELLS; PROSTATE-SPECIFIC ANTIGEN; BREAST-CARCINOMA CELLS; GROWTH-FACTOR RECEPTOR; T-LYMPHOCYTE EPITOPE; HIGH-AVIDITY CTL; CANCER CELLS; LUNG-CANCER; MOLECULAR REQUIREMENTS; CYTOPLASMIC TAIL AB The MUC1 tumor-associated antigen is overexpressed in the majority of human carcinomas and several hematologic malignancies. Much attention has been paid to the hypoglycosylated variable number of tandem repeats (VNTR) region of the N-terminus of MUC1 as a vaccine target, and recombinant viral vector vaccines are also being evaluated that express the entire MUC1 transgene. While previous studies have described MUC1 as a tumor-associated tissue differentiation antigen, studies have now determined that the C-terminus of MUC1 (MUC1-C) is an oncoprotein, and its expression is an indication of poor prognosis in numerous tumor types. We report here the identification of nine potential CD8(+) cytotoxic T lymphocyte epitopes of MUC1, seven in the C-terminus and two in the VNTR region, and have identified enhancer agonist peptides for each of these epitopes. These epitopes span HLA-A2, HLA-A3, and HLA-A24 major histocompatibility complex (MHC) class I alleles, which encompass the majority of the population. The agonist peptides, compared to the native peptides, more efficiently (a) generate T-cell lines from the peripheral blood mononuclear cells of cancer patients, (b) enhance the production of IFN-gamma by peptide-activated human T cells, and (c) lyse human tumor cell targets in an MHC-restricted manner. The agonist epitopes described here can be incorporated into various vaccine platforms and for the ex vivo generation of human T cells. These studies provide the rationale for the T-cell-mediated targeting of the oncogenic MUC1-C, which has been shown to be an important factor in both drug resistance and poor prognosis for numerous tumor types. C1 [Jochems, Caroline; Tucker, Jo A.; Vergati, Matteo; Boyerinas, Benjamin; Gulley, James L.; Schlom, Jeffrey; Tsang, Kwong-Yok] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gulley, James L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Grant support was provided by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors thank Diane J. Poole for technical assistance and Debra Weingarten for editorial assistance in the preparation of this manuscript. NR 56 TC 13 Z9 13 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD FEB PY 2014 VL 63 IS 2 BP 161 EP 174 DI 10.1007/s00262-013-1494-7 PG 14 WC Oncology; Immunology SC Oncology; Immunology GA AB2OA UT WOS:000331630800007 PM 24233342 ER PT J AU Bowen, RAR Sattayapiwat, A Gounden, V Remaley, AT AF Bowen, Raffick A. R. Sattayapiwat, Annie Gounden, Verena Remaley, Alan T. TI Blood collection tube-related alterations in analyte concentrations in quality control material and serum specimens SO CLINICAL BIOCHEMISTRY LA English DT Article DE Blood collection tube; Quality control material; Thyroxine; Triiodothyronine ID TOTAL TRIIODOTHYRONINE; INTERFERENCE; MANAGEMENT; DEVICES AB Objectives: Several previous studies have described the effects of interfering substances on clinical assay results; however, the effects of exogenous substances, particularly additives from blood collection tubes on quality control (QC) specimens and serum specimens have not been well examined. This study examines the effects of blood-collection tube additives on total triiodothyronine (TT3), and thyroxine (TT4), cortisol, and routine clinical chemistry tests in QC and serum specimens from apparently healthy volunteers. Methods: QC and serum specimens were poured or collected into different blood collection tubes. TT3 and TT4, cortisol, and routine chemistry tests were analyzed from the different blood-collection tube types. Results: The findings of this study demonstrate statistically and/or clinically significant blood collection tube-related alterations in the TT3, TT4, and cortisol concentrations of QC specimens and TT4 concentrations from serum specimens. Conclusions: These findings have important implications for clinical laboratories, demonstrating that QC specimens should ideally, like patients' specimens, be poured into blood collection tubes. This strategy would reveal any adverse effects caused by blood collection tubes, which otherwise would not likely be detected by most routine QC practices. The results of this study also show the importance of producing blood collection tubes that contain additives that are truly inert and do not adversely affect clinical laboratory testing. (C) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Bowen, Raffick A. R.; Sattayapiwat, Annie] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Gounden, Verena; Remaley, Alan T.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Bowen, RAR (reprint author), 300 Pasteur Dr,Room H 1507B, Stanford, CA 94305 USA. EM rbowen@stanfordmed.org FU NIH Clinical Center FX The authors would like to thank Dr. Glen L. Hortin for his helpful comments of the manuscript. We also wish to thank Ms. Krista Tanquary for reviewing the parts of the manuscript prior to submission and Mr. Phil Cheng for the material management. Research by one of the authors (AR) was supported by intramural research funds from NIH Clinical Center. NR 24 TC 10 Z9 10 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD FEB PY 2014 VL 47 IS 3 BP 150 EP 157 DI 10.1016/j.clinbiochem.2013.11.003 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AB1NF UT WOS:000331558300002 PM 24240064 ER PT J AU Lee, MR Leggio, L AF Lee, Mary R. Leggio, Lorenzo TI Combined Pharmacotherapies for the Management of Alcoholism: Rationale and Evidence to Date SO CNS DRUGS LA English DT Article ID GAMMA-HYDROXYBUTYRIC ACID; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; PROOF-OF-CONCEPT; DOUBLE-BLIND; PREFERRING RATS; ETHANOL-CONSUMPTION; WITHDRAWAL SYNDROME; DEPENDENT PATIENTS; CLINICAL-DATA AB Pharmacotherapies for alcohol use disorders (AUDs) have limited efficacy. One approach to improving treatment outcomes for AUDs is to combine pharmacotherapies that have shown some efficacy as individual agents. The rationale for combining medications rests on the following principles: a combination of medications can target more than one neurotransmitter system that is dysfunctional in AUDs, can target different drinking behaviors (i.e., positive and negative reinforcement), can treat co-morbid psychiatric and medical disorders, and can minimize side effects, improving adherence to treatment by using lower doses of each drug in combination. Combined pharmacotherapy strategies may produce additive or even synergistic effects to decrease alcohol craving and consumption. Here, we reviewed the literature investigating the effect on alcohol-related outcomes of combinations of medications that have shown efficacy as single agents to reduce drinking in animal studies and clinical trials. We focused on 17 clinical studies investigating the combination of medications in AUDs, 11 of which were randomized, double-blind, and placebo-controlled. Ten of the 11 studies showed the combination to be superior to placebo, but only three showed an advantage of the combination compared with the single agent. Overall, these studies used diverse methodologies, assessments of severity, outcome measures, and adjunctive psychosocial treatments. Limitations of the current published studies and possible future directions for new combinations are discussed. C1 [Lee, Mary R.; Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Lee, Mary R.; Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, Lorenzo] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, 10 Ctr Dr 10CRC 15330 MSC 1108,Room 1-5429, Bethesda, MD 20892 USA. EM lorenzo.leggio@nih.gov RI Leggio, Lorenzo/M-2972-2016 FU Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA) FX The authors would like to thank Mrs. Karen Smith (National Institutes of Health Library) for bibliographic assistance. The work was supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA). The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 88 TC 5 Z9 5 U1 2 U2 10 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 1172-7047 EI 1179-1934 J9 CNS DRUGS JI CNS Drugs PD FEB PY 2014 VL 28 IS 2 BP 107 EP 119 DI 10.1007/s40263-013-0137-z PG 13 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AB3QT UT WOS:000331706000003 PM 24497006 ER PT J AU Heald, R Cohen-Fix, O AF Heald, Rebecca Cohen-Fix, Orna TI Morphology and function of membrane-bound organelles SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID TO-TUBULE TRANSFORMATION; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; CONTACT SITES; S. CEREVISIAE; ER; MITOCHONDRIA; PROTEINS; NETWORK; YEAST AB The cell interior is a busy and crowded place. A large fraction of the cell volume is taken up by organelles that come in a variety of shapes and sizes. These organelles are surrounded by membrane that not only acts as a diffusion barrier, but also provides each organelle with its unique morphology that contributes to its function, often in ways that are poorly understood. Here we discuss recent discoveries on the relationship between organelle structure and function. C1 [Heald, Rebecca] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Cohen-Fix, Orna] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Heald, R (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM bheald@berkeley.edu; ornac@helix.nih.gov OI Heald, Rebecca/0000-0001-6671-6528 FU NIH [R01 GM057839, GM098766]; NIDDK FX RH is supported by NIH: R01 GM057839 and GM098766. OCF is supported by intramural funding from NIDDK. NR 46 TC 5 Z9 5 U1 4 U2 16 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD FEB PY 2014 VL 26 BP 79 EP 86 DI 10.1016/j.ceb.2013.10.006 PG 8 WC Cell Biology SC Cell Biology GA AB5WW UT WOS:000331860400011 PM 24529249 ER PT J AU Klutstein, M Cooper, JP AF Klutstein, Michael Cooper, Julia Promisel TI The Chromosomal Courtship Dance - homolog pairing in early meiosis SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID OSCILLATORY NUCLEAR-MOVEMENT; EARLY MEIOTIC PROPHASE; YEAST SCHIZOSACCHAROMYCES-POMBE; DOUBLE-STRAND BREAKS; FISSION YEAST; SYNAPTONEMAL COMPLEX; ACHIASMATE SEGREGATION; DROSOPHILA OOCYTES; BOUQUET FORMATION; C. ELEGANS AB The intermingling of genomes that characterizes sexual reproduction requires haploid gametes in which parental homologs have recombined. For this, homologs must pair during meiosis. In a crowded nucleus where sequence homology is obscured by the enormous scale and packaging of the genome, partner alignment is no small task. Here we review the early stages of this process. Chromosomes first establish an initial docking site, usually at telomeres or centromeres. The acquisition of chromosome-specific patterns of binding factors facilitates homolog recognition. Chromosomes are then tethered to the nuclear envelope (NE) and subjected to nuclear movements that 'shake off' inappropriate contacts while consolidating homolog associations. Thereafter, homolog connections are stabilized by building the synaptonemal complex or its equivalent and creating genetic crossovers. Recent perspectives on the roles of these stages will be discussed. C1 [Klutstein, Michael; Cooper, Julia Promisel] Canc Res UK London Res Inst, NIH, London WC2A 3LY, England. [Klutstein, Michael; Cooper, Julia Promisel] NCI, NIH, Bethesda, MD 20892 USA. RP Cooper, JP (reprint author), Canc Res UK London Res Inst, NIH, London WC2A 3LY, England. EM julie.cooper@nih.gov FU Cancer Research UK; European Research Council; Marie Curie postdoctoral fellowship; National Institutes of Health FX We thank the Cooper lab for fruitful discussions, Alex Fennell for comments on the manuscript and Hani Ebrahimi for help with figure preparation. MK and JPC have been funded by Cancer Research UK, the European Research Council, a Marie Curie postdoctoral fellowship to MK, and the National Institutes of Health. NR 75 TC 14 Z9 14 U1 2 U2 16 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD FEB PY 2014 VL 26 BP 123 EP 131 DI 10.1016/j.ceb.2013.12.004 PG 9 WC Cell Biology SC Cell Biology GA AB5WW UT WOS:000331860400016 PM 24529254 ER PT J AU Moraitis, AG Martucci, VL Pacak, K AF Moraitis, Andreas G. Martucci, Victoria L. Pacak, Karel TI GENETICS, DIAGNOSIS, AND MANAGEMENT OF MEDULLARY THYROID CARCINOMA AND PHEOCHROMOCYTOMA/PARAGANGLIOMA SO ENDOCRINE PRACTICE LA English DT Review ID ENDOCRINE NEOPLASIA TYPE-2; POSITRON-EMISSION-TOMOGRAPHY; RET PROTOONCOGENE; METASTATIC PHEOCHROMOCYTOMA; BIOCHEMICAL-DIAGNOSIS; GERMLINE MUTATIONS; FOLLOW-UP; IN-111-PENTETREOTIDE SCINTIGRAPHY; MALIGNANT PHEOCHROMOCYTOMA; PLASMA METHOXYTYRAMINE AB Objective: Medullary thyroid carcinoma (MTC) and pheochromocytoma/paraganglioma (PHEO/PGL) are rare neuroendocrine tumors. Because of the increased metastatic rates in certain genetic backgrounds, early diagnosis and treatment are essential to improved patient outcomes. Our objective was to summarize recent findings related to the genetics, diagnosis, and management of MTC and PHEO/PGL. Methods: A literature review was performed. Results: MTC is primarily associated with mutations in the rearranged during transfection (RET) protooncogene. Determining the specific genetic mutation can guide patient management and screening. Early detection and appropriate surgical management of MTC is critical to prevent or limit metastatic spread, as treatment options for patients with metastatic disease are limited. PHEO/PGL also has a strong genetic component, with approximately 50% of cases linked to germline and somatic mutations in 15 genes. Although most PHEO/PGLs are benign, factors such as genetic background, size, tumor location, and high methoxytyramine levels are associated with higher rates of metastatic disease. The state-of-the-art diagnosis and localization of PHEO/PGLs is based on measurement of plasma metanephrines and methoxytyramine and functional imaging studies. For both PHEO/PGL and MTC, surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. Conclusion: As genetic testing becomes more widely available, the diagnosis of MTC and PHEO/PGL will be made earlier due to routine screening of at-risk patients. In addition, continued advances in basic science, diagnostic methods, and imaging techniques will improve understanding of the pathogenesis of these diseases and facilitate the introduction of novel treatment strategies for patients with metastatic disease. C1 [Moraitis, Andreas G.] Univ Michigan, Endocrine Oncol Branch, Ann Arbor, MI 48109 USA. [Martucci, Victoria L.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr MSC-1109, Bethesda, MD 20892 USA. EM karel.pacak@nih.gov NR 80 TC 5 Z9 5 U1 0 U2 5 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD FEB PY 2014 VL 20 IS 2 BP 176 EP 187 DI 10.4158/EP13268.RA PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB2IB UT WOS:000331615300014 PM 24449662 ER PT J AU Arguelles, S Camandola, S Cutler, RG Ayala, A Mattson, MP AF Argueelles, Sandro Camandola, Simonetta Cutler, Roy G. Ayala, Antonio Mattson, Mark P. TI Elongation factor 2 diphthamide is critical for translation of two IRES-dependent protein targets, XIAP and FGF2, under oxidative Stress conditions SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Eukaryotic elongation factor-2; Diphthamide; Lipid peroxidation; XIAP; FGF-2; Internal ribosomal entry site; Free radicals ID EUKARYOTIC ELONGATION-FACTOR-2; MEDIATED TRANSLATION; CELL-PROLIFERATION; ADP-RIBOSYLATION; MAMMALIAN-CELLS; KINASE; APOPTOSIS; DEATH; MTOR; PHOSPHORYLATION AB Elongation factor-2 (eEF2) catalyzes the movement of the ribosome along the mRNA. A single histidine residue in eEF2 (H715) is modified to form diphthamide. A role for eEF2 in the cellular stress response is highlighted by the fact that eEF2 is sensitive to oxidative stress and that it must be active to drive the synthesis of proteins that help cells to mitigate the adverse effects of oxidative stress. Many of these proteins are encoded by mRNAs containing a sequence called an "internal ribosomal entry site" (IRES). Under high oxidative stress conditions diphthamide-deficient cells were significantly more sensitive to cell death. These results suggest that diphthamide may play a role in protection against the degradation of eEF2. This protection is especially important in those situations in which eEF2 is necessary for the reprogramming of translation from global to IRES synthesis. Indeed, we found that the expression of X-linked inhibitor of apoptosis (XIAP) and fibroblast growth factor 2 (FGF2), two proteins synthesized from mRNAs with IRESs that promote cell survival, is deregulated in diphthamide-deficient cells. Our findings therefore suggest that eEF2 diphthamide controls the selective translation of IRES-dependent protein targets XIAP and FGF2, critical for cell survival under conditions of oxidative stress. Published by Elsevier Inc. C1 [Argueelles, Sandro; Camandola, Simonetta; Cutler, Roy G.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Argueelles, Sandro; Ayala, Antonio] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, E-41012 Seville, Spain. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, 5600 Nathan Shock Dr,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI IBIS, ENVEJECIMIENTO/O-9381-2015; OI Arguelles, Sandro/0000-0001-8450-3227 FU Ministerio de Educacion, Cultura y Deporte of Spain [EX2009-0918]; Ministerio de Ciencia e Innovacion [BFU 2010-20882]; Intramural Research Program of the National Institute on Aging FX We thank Stephen H. Leppla and Christopher Bachran of the Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, NIH, for providing wild-type and diphthamide-deficient Chinese hamster ovary cells and fusion protein (FP59). We thank Myriam Gorospe and Jennifer L. Martindale of the Laboratory of Molecular Biology and Immunology, NIH, for technical advice regarding protein synthesis assays. S.A.C. was supported by a Ministerio de Educacion, Cultura y Deporte of Spain postdoctoral fellowship (EX2009-0918)-A.A was supported by Ministerio de Ciencia e Innovacion BFU 2010-20882. This work was supported in part by the Intramural Research Program of the National Institute on Aging. NR 41 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB PY 2014 VL 67 BP 131 EP 138 DI 10.1016/j.freeradbiomed.2013.10.015 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AB5UM UT WOS:000331854200013 PM 24140707 ER PT J AU Kash, JC Xiao, YL Davis, AS Walters, KA Chertow, DS Easterbrook, JD Dunfee, RL Sandouk, A Jagger, BW Schwartzman, LM Kuestner, RE Wehr, NB Huffman, K Rosenthal, RA Ozinsky, A Levine, RL Doctrow, SR Taubenberger, JK AF Kash, John C. Xiao, Yongli Davis, A. Sally Walters, Kathie-Anne Chertow, Daniel S. Easterbrook, Judith D. Dunfee, Rebecca L. Sandouk, Aline Jagger, Brett W. Schwartzman, Louis M. Kuestner, Rolf E. Wehr, Nancy B. Huffman, Karl Rosenthal, Rosalind A. Ozinsky, Adrian Levine, Rodney L. Doctrow, Susan R. Taubenberger, Jeffery K. TI Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Influenza; Virus; Pathogenesis; Reactive oxygen species; Antioxidants; Immune response; Free radicals ID SUPEROXIDE DISMUTASE/CATALASE MIMETICS; SALEN-MANGANESE COMPLEXES; ANTIVIRAL CYTOKINE RESPONSES; BRAIN OXIDATIVE STRESS; NITRIC-OXIDE; RNA-SEQ; A VIRUS; RAPID SELECTION; IMMUNE-RESPONSE; AVIAN INFLUENZA AB The 1918 influenza pandemic caused over 40 million deaths worldwide, with 675,000 deaths in the United States alone. Studies in several experimental animal models showed that 1918 influenza virus infection resulted in severe lung pathology associated with dysregulated immune and cell death responses. To determine if reactive oxygen species produced by host inflammatory responses play a central role in promoting severity of lung pathology, we treated 1918 influenza virus-infected mice with the catalytic catalase/superoxide dismutase mimetic, salen-manganese complex EUK-207 beginning 3 days postinfection. Postexposure treatment of mice infected with a lethal dose of the 1918 influenza virus with EUK-207 resulted in significantly increased survival and reduced lung pathology without a reduction in viral titers. In vitro studies also showed that EUK-207 treatment did not affect 1918 influenza viral replication. Immunohistochemical analysis showed a reduction in the detection of the apoptosis marker cleaved caspase-3 and the oxidative stress marker 8-oxo-2'-deoxyguanosine in lungs of EUK-207-treated animals compared to vehicle controls. High-throughput sequencing and RNA expression microarray analysis revealed that treatment resulted in decreased expression of inflammatory response genes and increased lung metabolic and repair responses. These results directly demonstrate that 1918 influenza virus infection leads to an immunopathogenic immune response with excessive inflammatory and cell death responses that can be limited by treatment with the catalytic antioxidant EUK-207. Published by Elsevier Inc. C1 [Kash, John C.; Xiao, Yongli; Davis, A. Sally; Chertow, Daniel S.; Easterbrook, Judith D.; Dunfee, Rebecca L.; Sandouk, Aline; Jagger, Brett W.; Schwartzman, Louis M.; Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Walters, Kathie-Anne; Kuestner, Rolf E.; Ozinsky, Adrian] Inst Syst Biol, Seattle, WA 98109 USA. [Chertow, Daniel S.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Wehr, Nancy B.; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Huffman, Karl; Rosenthal, Rosalind A.; Doctrow, Susan R.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. RP Kash, JC (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM kashj@niaid.nih.gov RI Levine, Rodney/D-9885-2011; OI Davis, Anne/0000-0001-5711-3936 FU Intramural Research Programs of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Defense Threat Reduction Agency [HDTRA-1-08-C-0023]; [GM57770] FX This work was supported by the Intramural Research Programs of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and the National Heart, Lung, and Blood Institute. K.A.W., R.E.K., and A.O. were supported by Defense Threat Reduction Agency Contract HDTRA-1-08-C-0023. Development of EUK-207 was funded in part by GM57770 (S.R.D.). NR 75 TC 11 Z9 11 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB PY 2014 VL 67 BP 235 EP 247 DI 10.1016/j.freeradbiomed.2013.10.014 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AB5UM UT WOS:000331854200022 PM 24140866 ER PT J AU Wiggs, JL Pawlyk, B Connolly, E Adamian, M Miller, JW Pasquale, LR Haddadin, RI Grosskreutz, CL Rhee, DJ Li, T AF Wiggs, Janey L. Pawlyk, Basil Connolly, Edward Adamian, Michael Miller, Joan W. Pasquale, Louis R. Haddadin, Ramez I. Grosskreutz, Cynthia L. Rhee, Douglas J. Li, Tiansen TI Disruption of the Blood-Aqueous Barrier and Lens Abnormalities in Mice Lacking Lysyl Oxidase-Like 1 (LOXL1) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE exfoliation syndrome; LOXL1; glaucoma ID PSEUDOEXFOLIATION SYNDROME; EXFOLIATION GLAUCOMA; LAMINA-CRIBROSA; ELASTOSIS; PROTEIN; PHACOEMULSIFICATION; SYNDROME/GLAUCOMA; FIBRILLOPATHY; POPULATION; MICROSCOPY AB PURPOSE. Exfoliation syndrome (ES) is commonly associated with glaucoma, premature cataracts, and other ocular and systemic pathologies. LOXL1 gene variants are significantly associated with ES; however, the role of the protein in ES development remains unclear. The purpose of this study was to characterize the ocular phenotype in Loxl1(-/-) (null) mice. METHODS. Loxl1 null mice and strain-matched controls (C57BL) were evaluated by clinical and histologic analyses. RESULTS. Anterior segment histology showed a pronounced vesiculation of the anterior lens in the null mice. The lesions were subcapsular and in direct apposition with the posterior iris surface. Fluorescein angiography showed increased diffusion of fluorescein into the anterior chamber of the null mice compared with age-matched controls (P = 0.003, two-tailed, unequal variance t-test), suggesting compromise of the blood-aqueous barrier. Intraocular pressure measurements were within the normal range (16.5 +/- 2.0 mm Hg) in null mice up to 1 year of age. Immunohistochemistry showed decreased elastin in the iris and ciliary body in the null mouse compared with controls. CONCLUSIONS. Elimination of LOXL1 in mice impairs the blood-aqueous humor barrier in the ocular anterior segment and causes lens abnormalities consistent with cataract formation, but does not result in deposition of macromolecular material or glaucoma. These results show that mice lacking LOXL1 have some ES features but that complete disease manifestation requires other factors that could be genetic and/or environmental. C1 [Wiggs, Janey L.; Pawlyk, Basil; Connolly, Edward; Adamian, Michael; Miller, Joan W.; Pasquale, Louis R.; Haddadin, Ramez I.; Grosskreutz, Cynthia L.; Rhee, Douglas J.; Li, Tiansen] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Berman Gund & Angiogenesis Labs, Boston, MA USA. [Li, Tiansen] NEI, Bethesda, MD 20892 USA. RP Wiggs, JL (reprint author), 243 Charles St, Boston, MA 02114 USA. EM janey_wiggs@meei.harvard.edu; tiansen.li@nih.gov FU National Institutes of Health [R21EY019161, R01EY020928, P30EY014104]; Research to Prevent Blindness; Massachusetts Lions Eye Research Fund; Harvard Glaucoma Center of Excellence; Distinguished Ophthalmology Scholar award FX Supported by National Institutes of Health Grants R21EY019161 (TL), R01EY020928 (JLW), and P30EY014104; Research to Prevent Blindness; the Massachusetts Lions Eye Research Fund; the Harvard Glaucoma Center of Excellence; and a Distinguished Ophthalmology Scholar award (LRP). The authors alone are responsible for the content and writing of the paper. NR 46 TC 8 Z9 8 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2014 VL 55 IS 2 BP 856 EP 864 DI 10.1167/iovs.13-13033 PG 9 WC Ophthalmology SC Ophthalmology GA AB6IU UT WOS:000331891700029 PM 24425853 ER PT J AU Kay, P Yang, YC Hiscott, P Gray, D Maminishkis, A Paraoan, L AF Kay, Paul Yang, Yit C. Hiscott, Paul Gray, Donna Maminishkis, Arvydas Paraoan, Luminita TI Age-Related Changes of Cystatin C Expression and Polarized Secretion by Retinal Pigment Epithelium: Potential Age-Related Macular Degeneration Links SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE cystatin C; secretion; aging; retinal pigment epithelium ID GLYCATION END-PRODUCTS; BRUCHS MEMBRANE; GROWTH-FACTOR; EXTRACELLULAR-MATRIX; BARRIER DYSFUNCTION; ALZHEIMERS-DISEASE; G73A POLYMORPHISM; IN-VIVO; CELLS; PROTEIN AB PURPOSE. Cystatin C, a potent cysteine proteinase inhibitor, is abundantly secreted by the RPE and may contribute to regulating protein turnover in the Bruch's membrane (BrM). A cystatin C variant associated with increased risk of developing AMD and Alzheimer's disease (AD) presents reduced secretion levels from RPE. The purpose of this study was to analyze the effects of age and the accumulation of advanced glycation end-products (AGEs) on the expression and secretion of cystatin C by the RPE. METHODS. Confluent monolayers of human fetal RPE (hfRPE) cells were cultured using an in vitro model mimicking extracellular AGE accumulation. Cystatin C expression, secretion, and its polarity were analyzed following culture on AGE-containing BrM mimics (AGEd versus nonAGEd). Monolayer barrier properties were assessed by transepithelial resistance measurements. The relative level of cystatin C protein expression in human RPE in situ was assessed immunohistochemically in relation to age. RESULTS. Advanced glycation end product-exposed RPE monolayers presented significantly decreased cystatin C expression and secretion. Basolateral secretion was fully established by week 8 in non-AGEd conditions. In AGEd cultures, polarity of secretion was impaired despite maintenance of physiological barrier properties of the monolayer. In the macula region of RPE/choroid segments from human eyes, the level of cystatin C protein was reduced with increasing donor age. CONCLUSIONS. Exposure to AGEs reduces expression of cystatin C and affects its normal secretion in cultured RPE. Age-related changes of cystatin C in the RPE from the posterior pole may compromise its extracellular functions, potentially contributing to AMD pathogenesis. C1 [Kay, Paul; Hiscott, Paul; Gray, Donna; Paraoan, Luminita] Univ Liverpool, Dept Eye & Vis Sci, Inst Ageing & Chron Dis, Liverpool L69 3GA, Merseyside, England. [Yang, Yit C.] Royal Wolverhampton NHS Trust, Dept Ophthalmol, Wolverhampton, W Midlands, England. [Maminishkis, Arvydas] NEI, NIH, Bethesda, MD 20892 USA. RP Paraoan, L (reprint author), Univ Liverpool, Dept Eye & Vis Sci, Inst Ageing & Chron Dis, UCD Bldg,Daulby St, Liverpool L69 3GA, Merseyside, England. EM lparaoan@liv.ac.uk RI Paraoan, Luminita/K-1066-2016 OI Paraoan, Luminita/0000-0001-7568-7116 FU R & D Royal Wolverhampton NHS Trust; AgeUK FX Supported by a grant from R & D Royal Wolverhampton NHS Trust (LP). Work in Luminita Paraoan's lab is supported by AgeUK. NR 65 TC 1 Z9 1 U1 0 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2014 VL 55 IS 2 BP 926 EP 934 DI 10.1167/iovs.13-13239 PG 9 WC Ophthalmology SC Ophthalmology GA AB6IU UT WOS:000331891700037 PM 24458156 ER PT J AU Bharti, K Rao, M Hull, SC Stroncek, D Brooks, BP Feigal, E van Meurs, JC Huang, CA Miller, SS AF Bharti, Kapil Rao, Mahendra Hull, Sara Chandros Stroncek, David Brooks, Brian P. Feigal, Ellen van Meurs, Jan C. Huang, Christene A. Miller, Sheldon S. TI Developing Cellular Therapies for Retinal Degenerative Diseases SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE cell-based therapy; stem cells; age-related macular degeneration; retinitis pigmentosa ID PLURIPOTENT STEM-CELLS; INDUCED IMMUNE DEVIATION; PIGMENT EPITHELIUM; MACULAR DEGENERATION; SUBMACULAR SURGERY; INFORMED-CONSENT; ANTERIOR-CHAMBER; HUMANIZED MICE; SOMATIC-CELLS; CHOROID GRAFT AB Biomedical advances in vision research have been greatly facilitated by the clinical accessibility of the visual system, its ease of experimental manipulation, and its ability to be functionally monitored in real time with noninvasive imaging techniques at the level of single cells and with quantitative end-point measures. A recent example is the development of stem cell-based therapies for degenerative eye diseases including AMD. Two phase I clinical trials using embryonic stem cell-derived RPE are already underway and several others using both pluripotent and multipotent adult stem cells are in earlier stages of development. These clinical trials will use a variety of cell types, including embryonic or induced pluripotent stem cell-derived RPE, bone marrow- or umbilical cord-derived mesenchymal stem cells, fetal neural or retinal progenitor cells, and adult RPE stem cells-derived RPE. Although quite distinct, these approaches, share common principles, concerns and issues across the clinical development pipeline. These considerations were a central part of the discussions at a recent National Eye Institute meeting on the development of cellular therapies for retinal degenerative disease. At this meeting, emphasis was placed on the general value of identifying and sharing information in the so-called "precompetitive space.'' The utility of this behavior was described in terms of how it could allow us to remove road blocks in the clinical development pipeline, and more efficiently and economically move stem cell-based therapies for retinal degenerative diseases toward the clinic. Many of the ocular stem cell approaches we discuss are also being used more broadly, for nonocular conditions and therefore the model we develop here, using the precompetitive space, should benefit the entire scientific community. C1 [Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. [Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Hull, Sara Chandros] NHGRI, Bioeth Core, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Hull, Sara Chandros] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Stroncek, David] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Brooks, Brian P.] NEI, Unit Pediat Dev & Genet Ophthalmol, NIH, Bethesda, MD 20892 USA. [Feigal, Ellen] Calif Inst Regenerat Med, San Francisco, CA USA. [van Meurs, Jan C.] Rotterdam Univ Eye Hosp, Rotterdam, Netherlands. [Huang, Christene A.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Miller, Sheldon S.] NEI, Sect Epithelial & Retinal Physiol & Dis, NIH, Bethesda, MD 20892 USA. RP Bharti, K (reprint author), NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bldg 10,Room 10B10,10 Ctr Dr, Bethesda, MD 20892 USA. EM kapilbharti@nei.nih.gov; millers@nei.nih.gov FU Division of Intramural Research, National Eye Institute, National Institutes of Health; NIH Center for Regenerative Medicine FX Supported by the Division of Intramural Research, National Eye Institute, National Institutes of Health, and the NIH Center for Regenerative Medicine. NR 56 TC 25 Z9 28 U1 1 U2 21 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2014 VL 55 IS 2 BP 1191 EP 1201 DI 10.1167/iovs.13-13481 PG 11 WC Ophthalmology SC Ophthalmology GA AB6IU UT WOS:000331891700068 PM 24573369 ER PT J AU Drieling, RL Rosas, LG Ma, J Stafford, RS AF Drieling, Rebecca Lucia Rosas, Lisa Goldman Ma, Jun Stafford, Randall Scott TI Community Resource Utilization, Psychosocial Health, and Sociodemographic Factors Associated with Diet and Physical Activity among Low-Income Obese Latino Immigrants SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Latino; Obesity; Dietary habits; Physical activity ID RANDOMIZED CONTROLLED-TRIAL; BODY-MASS INDEX; ENVIRONMENTAL-INFLUENCES; CARDIOVASCULAR-DISEASE; UNITED-STATES; FOOD STAMPS; WEIGHT-LOSS; AMERICANS; INTERVENTIONS; DISPARITIES AB Low-socioeconomic-status (SES) Latinos are disproportionately represented among the. 78 million obese Americans. Tailored behavioral weight-loss interventions show promise, but there is limited adaptation to lower-SES Latino immigrants. This study provides guidance for tailoring obesity-reduction strategies for this population by evaluating food security, educational community resource utilization, education level, depression, sex, and length of US residence as predictors of diet and physical activity. The cross-sectional study used baseline data collected in July 2009 through September 2010 for a weight-loss trial among lower-SES obese (body mass index 30 to 55) Latino immigrants who were enrolled at a community health clinic (n=207). Physical activity was measured using 7-day pedometer recording. Dietary intake was measured using-an interviewer-administered food frequency questionnaire. Factors assessed by questionnaire included education community resource use (nutrition and physical activity classes), education level, US residence (years), food security, and depressive symptoms. Data were analyzed using multivariate-adjusted linear regression models. More than one third of participants were sedentary (<5,000 steps/day), and 41% had low fruit and vegetable intake (<5 servings/day). In multivariate-adjusted models, educational community resource use, male sex, less education, fewer depressive symptoms, and shorter US residence time were associated with more physical activity (all, P <= 0.05). Educational community resource use was positively associated with fruit and vegetable intake (P=0.05). Male sex was associated with more sweet-beverage intake (P=0.02) and fast-food intake (P=0.04). Fewer depressive symptoms were associated with lower sweet-beverage intake (P=0.05). In conclusion, obesity-reduction strategies among low-SES Latino immigrants might effectively emphasize educational community resource use and interventions tailored for psychosocial and sociodemographic characteristics. C1 [Drieling, Rebecca Lucia] NCI, Inst Biobehav Canc Prevent, Seattle, WA USA. [Drieling, Rebecca Lucia] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Drieling, Rebecca Lucia] Fred Hutchinson Canc Res Ctr, Div Prevent Hlth Studies, Seattle, WA 98104 USA. [Drieling, Rebecca Lucia; Rosas, Lisa Goldman] Stanford Univ, Stanford Prevent Res Ctr, Program Prevent Outcomes & Practices, Palo Alto, CA 94304 USA. [Ma, Jun] Palo Alto Med Fdn Res Inst, Palo Alto, CA USA. [Stafford, Randall Scott] Stanford Univ, Stanford Prevent Res Ctr, Palo Alto, CA 94304 USA. [Stafford, Randall Scott] Stanford Univ, Program Prevent Outcomes & Practices, Palo Alto, CA 94304 USA. RP Stafford, RS (reprint author), Stafford Prevent Res Ctr, 1265 Welch Rd, Stanford, CA 94305 USA. EM rstafford@stanford.edu FU National Institutes of Health/National Heart, Lung, and Blood Institute at Stanford University [HL089448]; National Cancer Institute Biobehavioral Cancer Prevention and Control Training Program at the University of Washington [R25CA092408] FX This study was funded by National Institutes of Health/National Heart, Lung, and Blood Institute Grant HL089448 at Stanford University and the National Cancer Institute Biobehavioral Cancer Prevention and Control Training Program (R25CA092408) at the University of Washington. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This trial is registered at Clinicaltrials.gov #NCT01242683 and has received appropriate Institutional Review Board approval. NR 45 TC 3 Z9 3 U1 6 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD FEB PY 2014 VL 114 IS 2 BP 257 EP 265 DI 10.1016/j.jand.2013.07.025 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AB5UB UT WOS:000331853100012 PM 24119533 ER PT J AU Piskorski, AM Amin, A Phornphutkul, C De la Monte, S Stopa, E Smith, ACM AF Piskorski, A. M. Amin, A. Phornphutkul, C. De la Monte, S. Stopa, E. Smith, A. C. M. TI Birt Hogg Dube Syndrome Manifestations in an Autopsy of a Patient with Smith-Magenis Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Brown Univ, Providence, RI 02912 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 22 BP 9A EP 9A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155800023 ER PT J AU Kohsaka, S Shukla, N Ameur, N Lim, D Viale, A Socci, N Qin, LX Sciot, R Bridge, J Singer, S Wexler, L Barr, FG Dogan, S Fletcher, JA Ladanyi, M AF Kohsaka, S. Shukla, N. Ameur, N. Lim, D. Viale, A. Socci, N. Qin, L-X Sciot, R. Bridge, J. Singer, S. Wexler, L. Barr, F. G. Dogan, S. Fletcher, J. A. Ladanyi, M. TI A Recurrent Point Mutation in MYOD1 Defines a Clinically Aggressive Subset of Embryonal Rhabdomyosarcoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Univ Nebraska Med Ctr, Omaha, NE USA. NCI, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 68 BP 20A EP 21A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155800069 ER PT J AU Solomon, DA Brohl, A Kim, JS Chang, W Song, Y Guerrero, JAL Machado, I Wang, Z Phillips, JJ Wai, DH Shahbazian, V Sorensen, P Horvai, AE Triche, TJ Miettinen, M Llombart-Bosch, A Waldman, T Khan, J AF Solomon, D. A. Brohl, A. Kim, J-S Chang, W. Song, Y. Guerrero, J. A. Lopez Machado, I. Wang, Z. Phillips, J. J. Wai, D. H. Shahbazian, V. Sorensen, P. Horvai, A. E. Triche, T. J. Miettinen, M. Llombart-Bosch, A. Waldman, T. Khan, J. TI Frequent Inactivating Mutations of the Cohesin Complex Gene STAG2 in Ewing's Sarcoma Associated with TP53 Mutations and Poor Outcome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Mt Sinai Sch Med, New York, NY USA. Georgetown Univ, Washington, DC USA. NCI, NIH, Gaithersburg, MD USA. Univ Valencia, Valencia, Spain. NCI, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Los Angeles, CA 90027 USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 104 BP 29A EP 29A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155800105 ER PT J AU Karakas, C McShane, LM Sahin, A Yi, M Trivedi, S Hunt, K Keyomarsi, K AF Karakas, C. McShane, L. M. Sahin, A. Yi, M. Trivedi, S. Hunt, K. Keyomarsi, K. TI Assessment of Discordances of HER2 Expression and Gene Amplification: 10% Versus 30% Cutoff? SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 227 BP 59A EP 59A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155800228 ER PT J AU Lara-Otero, K Macias, CG Sanz, J Merino, MJ AF Lara-Otero, K. Garcia Macias, C. Sanz, J. Merino, M. J. TI Male Breast Cancer, Is There a Correlation between Prognostic Factors and Molecular Analysis? SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. Univ Salamanca, E-37008 Salamanca, Spain. Hosp Clin Univ, Madrid, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 242 BP 62A EP 62A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155800243 ER PT J AU Otero, KL Maciass, CG Sanz, J Merino, MJ AF Otero, K. Lara Garcia Maciass, C. Sanz, J. Merino, M. J. TI Do Male and Female Breast Cancer Share mRNA Expression Patterns? Similarities and Differences SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. Univ Salamanca, E-37008 Salamanca, Spain. Hosp Clin Univ, Madrid, Spain. RI Sanz, Julian/G-5276-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 241 BP 62A EP 62A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155800242 ER PT J AU Farhat, N Tischler, A Powers, J Patricia, D Pacak, K AF Farhat, N. Tischler, A. Powers, J. Patricia, D. Pacak, K. TI A Previously Unrecognized Major Monocytic Component of Pheochromocytoma and Paraganglioma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Tufts Med Ctr, Boston, MA USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 615 BP 152A EP 153A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155800616 ER PT J AU Ghosh, A Lara-Otero, K Merino, MJ AF Ghosh, A. Lara-Otero, K. Merino, M. J. TI Does BAP1 Play an Important Role in Hereditary Kidney Cancers? SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Ghosh, A.; Lara-Otero, K.; Merino, M. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 948 BP 231A EP 231A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801166 ER PT J AU Giubellino, A Lara-Otero, K Martucci, V Huynh, T Agarwal, P Pacak, K Merino, MJ AF Giubellino, A. Lara-Otero, K. Martucci, V. Huynh, T. Agarwal, P. Pacak, K. Merino, M. J. TI Urinary Bladder Paragangliomas: How IHC Can Assist to Identity Patients with SDHB Mutations SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 950 BP 231A EP 231A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801168 ER PT J AU Otero, KL Linehan, MW Merino, MJ AF Otero, K. Lara Linehan, M. W. Merino, M. J. TI IHC Helps to Identified Renal Tumors Associated with HLRCC Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Otero, K. Lara; Linehan, M. W.; Merino, M. J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 998 BP 243A EP 243A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801216 ER PT J AU Li, A Ghosh, A Alimchandani, M Linehan, MW Merino, MJ AF Li, A. Ghosh, A. Alimchandani, M. Linehan, M. W. Merino, M. J. TI Chromophobe RCC with and without Sarcomatoid Differentiation: A Study of miRNAs in Tumor Heterogeneity and Metastasis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Li, A.; Ghosh, A.; Alimchandani, M.; Linehan, M. W.; Merino, M. J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1005 BP 244A EP 244A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801223 ER PT J AU Lee, S Sabourin, J Gage, J Franko, A Nation, J Duggan, MA AF Lee, S. Sabourin, J. Gage, J. Franko, A. Nation, J. Duggan, M. A. TI p16 and Ki67 Expression in Squamous Intraepithelial Lesions of the Uterine Cervix Which Cannot Be Qualified (SIL Q) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Calgary, Calgary, AB, Canada. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1205 BP 291A EP 292A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801423 ER PT J AU Lee, S Sabourin, J Gage, J Franko, A Nation, J Duggan, MA AF Lee, S. Sabourin, J. Gage, J. Franko, A. Nation, J. Duggan, M. A. TI Squamous Intraepithelial Lesions of the Uterine Cervix Which Cannot Be Qualified: SIL Q SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Calgary, Calgary, AB, Canada. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1208 BP 292A EP 292A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801426 ER PT J AU Merino, MJ Stratton, P Linehan, MN Lara-Otero, K AF Merino, M. J. Stratton, P. Linehan, M. N. Lara-Otero, K. TI Fumarate Hydratase Assist to Recognize Smooth Muscle Tumors Associated with Hereditary Leimyomatosis and Renal Cell Cancer (HLRCC) Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1224 BP 296A EP 296A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801442 ER PT J AU Thompson, LDR Chiosea, S McHugh, J Seethala, RR Miettinen, M Muller, S AF Thompson, L. D. R. Chiosea, S. McHugh, J. Seethala, R. R. Miettinen, M. Muller, S. TI Canalicular Adenoma: A Clinicopathologic and Immunohistochemical Analysis of 67 Cases SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 SCPMG, Woodland Hills, CA USA. UPMC Presbyterian Hosp, Pittsburgh, PA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NCI, Bethesda, MD 20892 USA. Emory Univ, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1360 BP 330A EP 330A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801578 ER PT J AU Alikhan, M Hu, Z Moroch, J Plonquet, A Jiang, L Gurbuxani, S Anastasi, J Bueso-Ramos, C Inamdar, K Menon, MP Nicolae, A Jaffe, ES Gaulard, P Venkataraman, G AF Alikhan, M. Hu, Z. Moroch, J. Plonquet, A. Jiang, L. Gurbuxani, S. Anastasi, J. Bueso-Ramos, C. Inamdar, K. Menon, M. P. Nicolae, A. Jaffe, E. S. Gaulard, P. Venkataraman, G. TI Follicular T Cell Lymphomas Frequently Display an aberrant CD3(-/) CD4(+) Population by Flow Cytometry: An Important Clue to the Diagnosis of a Hodgkin Lymphoma Mimic SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Chicago, Chicago, IL 60637 USA. Loyola Univ, Maywood, IL 60153 USA. Hop Henri Mondor, Paris, France. Mayo Clin, Jacksonville, FL 32224 USA. MD Anderson, Houston, TX USA. Henry Ford HS, Detroit, MI USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1373 BP 333A EP 333A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801591 ER PT J AU Calvo, KR Price, S Arthur, DC Rosenzweig, SD Braylan, RC Fleisher, TA Rao, KV AF Calvo, K. R. Price, S. Arthur, D. C. Rosenzweig, S. D. Braylan, R. C. Fleisher, T. A. Rao, K. V. TI Atypical Monocytosis in Patients with RAS-Associated Autoimmune Leukoproliferative Disorder (RALD): Overlapping Features with Juvenile Myelomonocytic Leukemia and Chronic Myelomonocytic Leukemia SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NIH CC, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1400 BP 340A EP 340A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801618 ER PT J AU Ganapathi, KA Ceribelli, M Evbuomwan, M Staudt, LM Pittaluga, S AF Ganapathi, K. A. Ceribelli, M. Evbuomwan, M. Staudt, L. M. Pittaluga, S. TI E2-2, a Novel Immunohistochemical Marker for Reactive and Neoplastic Plasmacytoid Dendritic Cells SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Ganapathi, K. A.; Ceribelli, M.; Evbuomwan, M.; Staudt, L. M.; Pittaluga, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1431 BP 347A EP 347A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801649 ER PT J AU Ganapathi, KA Townsley, DM Hsu, AP Zerbe, C Cueller-Rodriguez, J Hickstein, DD Young, NS Braylan, RC Holland, SM Calvo, KR AF Ganapathi, K. A. Townsley, D. M. Hsu, A. P. Zerbe, C. Cueller-Rodriguez, J. Hickstein, D. D. Young, N. S. Braylan, R. C. Holland, S. M. Calvo, K. R. TI Bone Marrow Morphologic and Flow Cytometric Features Assist in Differentiating GATA2 Mutation Associated-Hypocellular MDS from Aplastic Anemia SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1430 BP 347A EP 347A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155801648 ER PT J AU Nicolae, A Dunleavy, K Wilson, WH Raffeld, M Jaffe, ES Pittaluga, S AF Nicolae, A. Dunleavy, K. Wilson, W. H. Raffeld, M. Jaffe, E. S. Pittaluga, S. TI The Microenvironment in Mediastinal Gray Zone Lymphoma (MGZL) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Nicolae, A.; Dunleavy, K.; Wilson, W. H.; Raffeld, M.; Jaffe, E. S.; Pittaluga, S.] NCI, Bethesda, MD 20892 USA. RI Jaffe, Elaine/G-8984-2014 OI Jaffe, Elaine/0000-0003-4632-0301 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1505 BP 365A EP 365A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802061 ER PT J AU Xie, Y Pittaluga, S Smoot, E Fleisher, T Raffeld, M Jaffe, E Rao, K Maric, I AF Xie, Y. Pittaluga, S. Smoot, E. Fleisher, T. Raffeld, M. Jaffe, E. Rao, K. Maric, I. TI Spectrum of Non-Neoplastic Bone Marrow Pathology in Autoimmune Lymphoproliferative Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. NIH, CC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1584 BP 386A EP 386A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802140 ER PT J AU Yuan, J Wright, G Gascoyne, RD Connors, JM Rosenwald, A Weisenburger, DD Greiner, TC Smith, L Rimsza, LM Jaffe, ES Campo, E Martinez, A Delabie, J Braziel, RM Cook, JR Tubbs, RR Ott, G Vose, J Staudt, LM Chan, WC AF Yuan, J. Wright, G. Gascoyne, R. D. Connors, J. M. Rosenwald, A. Weisenburger, D. D. Greiner, T. C. Smith, L. Rimsza, L. M. Jaffe, E. S. Campo, E. Martinez, A. Delabie, J. Braziel, R. M. Cook, J. R. Tubbs, R. R. Ott, G. Vose, J. Staudt, L. M. Chan, W. C. TI Gene Expression Signature Helps to Identify Primary Mediastinal Large B-Cell Lymphoma at the Extra-Mediastinal Sites without Mediastinal Involvement SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Nebraska Med Ctr, LLMPP, Omaha, NE USA. NIH, LLMPP, Bethesda, MD USA. British Columbia Canc Agcy, LLMPP, Vancouver, BC, Canada. Univ Wurzburg, LLMPP, Wurzburg, Germany. City Hope Natl Med Ctr, LLMPP, Duarte, CA USA. Univ Arizona, LLMPP, Tucson, AZ 85721 USA. RI Jaffe, Elaine/G-8984-2014 OI Jaffe, Elaine/0000-0003-4632-0301 NR 0 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1590 BP 387A EP 387A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802146 ER PT J AU Aljinovic, N Cullinane, AR Gochuico, BR Gahl, WA Rosen, S AF Aljinovic, N. Cullinane, A. R. Gochuico, B. R. Gahl, W. A. Rosen, S. TI Pulmonary Fibrosis-Renal Lipofuscinosis ("Black Kidney"), a New Disorder with Histologic Features of Hermansky-Pudlak Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1657 BP 405A EP 405A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802213 ER PT J AU Kleiner, DE Brunt, EM Wilson, L Belt, PH Guy, CD Yeh, MM Kowdley, KV Sanyal, AJ Neuschwander-Tetri, BA AF Kleiner, D. E. Brunt, E. M. Wilson, L. Belt, P. H. Guy, C. D. Yeh, M. M. Kowdley, K. V. Sanyal, A. J. Neuschwander-Tetri, B. A. TI Fibrosis Progression in Adult Non-Alcoholic Fatty Liver Disease: Association with Severity of Histological Features SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Duke Univ, Durham, NC USA. Univ Washington, Seattle, WA 98195 USA. Virginia Mason Med Ctr, Seattle, WA 98101 USA. Virginia Commonwealth Univ, Richmond, VA USA. St Louis Univ, St Louis, MO 63103 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1731 BP 423A EP 423A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802287 ER PT J AU Makhlouf, HR Giblen, G Kleiner, DE Goodman, ZD AF Makhlouf, H. R. Giblen, G. Kleiner, D. E. Goodman, Z. D. TI Lack of Histological Significance of Antinuclear Antibodies in Patients with Nonalcoholic Fatty Liver Disease (NAFLD) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, NIH, Bethesda, MD 20892 USA. Mercy Med Ctr, Baltimore, MD USA. Inova Fairfax Hosp, Falls Church, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1742 BP 425A EP 425A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802298 ER PT J AU Paolino, RM Robinson, CL Summers, TA Hodson, DJ Staudt, LM AF Paolino, R. M. Robinson, C. L. Summers, T. A. Hodson, D. J. Staudt, L. M. TI Are BCL2 and MYC Alterations Sufficient to Drive Lymphomagenesis? SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 WRNMMC, Bethesda, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1914 BP 466A EP 466A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802470 ER PT J AU Rosenberg, AZ Blackler, AR Emmert-Buck, MR AF Rosenberg, A. Z. Blackler, A. R. Emmert-Buck, M. R. TI Collagen Expression Profiling of Normal and Diseased Human FFPE Tissues by Targeted Mass Spectrometry SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Rosenberg, A. Z.; Blackler, A. R.; Emmert-Buck, M. R.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 1915 BP 467A EP 467A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802471 ER PT J AU Aesif, SW Taylor, L Kuipers, I DePalma, L AF Aesif, S. W. Taylor, L. Kuipers, I. DePalma, L. TI In-Situ Redox Profiling of Diffuse Large B-Cell Lymphoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 George Washington Univ, Washington, DC USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 2116 BP 517A EP 517A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802672 ER PT J AU Robinson, CL Paolino, RM Summers, TA Hodson, DJ Staudt, LM AF Robinson, C. L. Paolino, R. M. Summers, T. A. Hodson, D. J. Staudt, L. M. TI Development of an In Vitro Model of Germinal Center Lymphomagenesis SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 WRNMMC, Bethesda, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2014 VL 94 SU 1 MA 2162 BP 529A EP 529A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AA5QX UT WOS:000331155802718 ER PT J AU Niemann, CU Polliack, A Hutchings, M AF Niemann, Carsten U. Polliack, Aaron Hutchings, Martin TI Suspected Richter transformation: positron emission tomography/computed tomography tells us who should have a biopsy and where SO LEUKEMIA & LYMPHOMA LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA C1 [Niemann, Carsten U.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Polliack, Aaron] Hebrew Univ Jerusalem, Sch Med, Hadassah Univ Hosp, Dept Hematol, IL-91010 Jerusalem, Israel. [Hutchings, Martin] Copenhagen Univ Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark. RP Hutchings, M (reprint author), Copenhagen Univ Hosp, Rigshosp, Dept Hematol, Bldg 4042, DK-2100 Copenhagen, Denmark. EM martin.hutchings@gmail.com RI Hutchings, Martin/B-6959-2012; Niemann, Carsten/P-3497-2015 OI Niemann, Carsten/0000-0001-9880-5242 NR 7 TC 1 Z9 1 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD FEB PY 2014 VL 55 IS 2 BP 233 EP 234 DI 10.3109/10428194.2013.820295 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 304FS UT WOS:000330733100002 PM 23915194 ER PT J AU Piskorski, AM Amin, A Phornphutkul, C De la Monte, S Stopa, E Smith, ACM AF Piskorski, A. M. Amin, A. Phornphutkul, C. De la Monte, S. Stopa, E. Smith, A. C. M. TI Birt Hogg Dube Syndrome Manifestations in an Autopsy of a Patient with Smith-Magenis Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Brown Univ, Providence, RI 02912 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 22 BP 9A EP 9A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502200023 ER PT J AU Kohsaka, S Shukla, N Ameur, N Lim, D Viale, A Socci, N Qin, LX Sciot, R Bridge, J Singer, S Wexler, L Barr, FG Dogan, S Fletcher, JA Ladanyi, M AF Kohsaka, S. Shukla, N. Ameur, N. Lim, D. Viale, A. Socci, N. Qin, L-X Sciot, R. Bridge, J. Singer, S. Wexler, L. Barr, F. G. Dogan, S. Fletcher, J. A. Ladanyi, M. TI A Recurrent Point Mutation in MYOD1 Defines a Clinically Aggressive Subset of Embryonal Rhabdomyosarcoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Univ Nebraska Med Ctr, Omaha, NE USA. NCI, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 68 BP 20A EP 21A PG 2 WC Pathology SC Pathology GA AB0SK UT WOS:000331502200069 ER PT J AU Solomon, DA Brohl, A Kim, JS Chang, W Song, Y Guerrero, JAL Machado, I Wang, Z Phillips, JJ Wai, DH Shahbazian, V Sorensen, P Horvai, AE Triche, TJ Miettinen, M Llombart-Bosch, A Waldman, T Khan, J AF Solomon, D. A. Brohl, A. Kim, J-S Chang, W. Song, Y. Lopez Guerrero, J. A. Machado, I. Wang, Z. Phillips, J. J. Wai, D. H. Shahbazian, V. Sorensen, P. Horvai, A. E. Triche, T. J. Miettinen, M. Llombart-Bosch, A. Waldman, T. Khan, J. TI Frequent Inactivating Mutations of the Cohesin Complex Gene STAG2 in Ewing's Sarcoma Associated with TP53 Mutations and Poor Outcome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Mt Sinai Sch Med, New York, NY USA. Georgetown Univ, Washington, DC USA. NCI, NIH, Gaithersburg, MD USA. Univ Valencia, Valencia, Spain. NCI, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Los Angeles, CA 90027 USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 104 BP 29A EP 29A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502200105 ER PT J AU Karakas, C McShane, LM Sahin, A Yi, M Trivedi, S Hunt, K Keyomarsi, K AF Karakas, C. McShane, L. M. Sahin, A. Yi, M. Trivedi, S. Hunt, K. Keyomarsi, K. TI Assessment of Discordances of HER2 Expression and Gene Amplification: 10% Versus 30% Cutoff? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 227 BP 59A EP 59A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502200228 ER PT J AU Otero, KL Maciass, CG Sanz, J Merino, MJ AF Lara Otero, K. Garcia Maciass, C. Sanz, J. Merino, M. J. TI Do Male and Female Breast Cancer Share mRNA Expression Patterns? Similarities and Differences SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. Univ Salamanca, E-37008 Salamanca, Spain. Hosp Clin Univ, Madrid, Spain. RI Sanz, Julian/G-5276-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 241 BP 62A EP 62A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502200242 ER PT J AU Lara-Otero, K Macias, CG Sanz, J Merino, MJ AF Lara-Otero, K. Garcia Macias, C. Sanz, J. Merino, M. J. TI Male Breast Cancer, Is There a Correlation between Prognostic Factors and Molecular Analysis? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. Univ Salamanca, E-37008 Salamanca, Spain. Hosp Clin Univ, Madrid, Spain. RI Sanz, Julian/G-5276-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 242 BP 62A EP 62A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502200243 ER PT J AU Farhat, N Tischler, A Powers, J Patricia, D Pacak, K AF Farhat, N. Tischler, A. Powers, J. Patricia, D. Pacak, K. TI A Previously Unrecognized Major Monocytic Component of Pheochromocytoma and Paraganglioma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Tufts Med Ctr, Boston, MA USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 615 BP 152A EP 153A PG 2 WC Pathology SC Pathology GA AB0SK UT WOS:000331502200614 ER PT J AU Ghosh, A Lara-Otero, K Merino, MJ AF Ghosh, A. Lara-Otero, K. Merino, M. J. TI Does BAP1 Play an Important Role in Hereditary Kidney Cancers? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Ghosh, A.; Lara-Otero, K.; Merino, M. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 948 BP 231A EP 231A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201263 ER PT J AU Giubellino, A Lara-Otero, K Martucci, V Huynh, T Agarwal, P Pacak, K Merino, MJ AF Giubellino, A. Lara-Otero, K. Martucci, V. Huynh, T. Agarwal, P. Pacak, K. Merino, M. J. TI Urinary Bladder Paragangliomas: How IHC Can Assist to Identify Patients with SDHB Mutations SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 950 BP 231A EP 231A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201265 ER PT J AU Otero, KL Linehan, MW Merino, MJ AF Otero, K. Lara Linehan, M. W. Merino, M. J. TI IHC Helps to Identified Renal Tumors Associated with HLRCC Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Otero, K. Lara; Linehan, M. W.; Merino, M. J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 998 BP 243A EP 243A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201313 ER PT J AU Li, A Ghosh, A Alimchandani, M Linehan, MW Merino, MJ AF Li, A. Ghosh, A. Alimchandani, M. Linehan, M. W. Merino, M. J. TI Chromophobe RCC with and without Sarcomatoid Differentiation: A Study of miRNAs in Tumor Heterogeneity and Metastasis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Li, A.; Ghosh, A.; Alimchandani, M.; Linehan, M. W.; Merino, M. J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1005 BP 244A EP 244A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201320 ER PT J AU Lee, S Sabourin, J Gage, J Franko, A Nation, J Duggan, MA AF Lee, S. Sabourin, J. Gage, J. Franko, A. Nation, J. Duggan, M. A. TI p16 and Ki67 Expression in Squamous Intraepithelial Lesions of the Uterine Cervix Which Cannot Be Qualified (SIL Q) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Calgary, Calgary, AB, Canada. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1205 BP 291A EP 292A PG 2 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201520 ER PT J AU Lee, S Sabourin, J Gage, J Franko, A Nation, J Duggan, MA AF Lee, S. Sabourin, J. Gage, J. Franko, A. Nation, J. Duggan, M. A. TI Squamous Intraepithelial Lesions of the Uterine Cervix Which Cannot Be Qualified: SIL Q SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Calgary, Calgary, AB, Canada. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1208 BP 292A EP 292A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201523 ER PT J AU Merino, MJ Stratton, P Linehan, MW Lara-Otero, K AF Merino, M. J. Stratton, P. Linehan, M. W. Lara-Otero, K. TI Fumarate Hydratase Assist to Recognize Smooth Muscle Tumors Associated with Hereditary Leimyomatosis and Renal Cell Cancer (HLRCC) Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1224 BP 296A EP 296A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201539 ER PT J AU Thompson, LDR Chiosea, S McHugh, J Seethala, RR Miettinen, M Muller, S AF Thompson, L. D. R. Chiosea, S. McHugh, J. Seethala, R. R. Miettinen, M. Muller, S. TI Canalicular Adenoma: A Clinicopathologic and Immunohistochemical Analysis of 67 Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 SCPMG, Woodland Hills, CA USA. UPMC Presbyterian Hosp, Pittsburgh, PA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NCI, Bethesda, MD 20892 USA. Emory Univ, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1360 BP 330A EP 330A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201675 ER PT J AU Alikhan, M Hu, Z Moroch, J Plonquet, A Jiang, L Gurbuxani, S Anastasi, J Bueso-Ramos, C Inamdar, K Menon, MP Nicolae, A Jaffe, ES Gaulard, P Venkataraman, G AF Alikhan, M. Hu, Z. Moroch, J. Plonquet, A. Jiang, L. Gurbuxani, S. Anastasi, J. Bueso-Ramos, C. Inamdar, K. Menon, M. P. Nicolae, A. Jaffe, E. S. Gaulard, P. Venkataraman, G. TI Follicular T Cell Lymphomas Frequently Display an aberrant CD3(-/) CD4(+) Population by Flow Cytometry: An Important Clue to the Diagnosis of a Hodgkin Lymphoma Mimic SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Chicago, Chicago, IL 60637 USA. Loyola Univ, Maywood, IL 60153 USA. Hop Henri Mondor, Paris, France. Mayo Clin, Jacksonville, FL 32224 USA. MD Anderson, Houston, TX USA. Henry Ford HS, Detroit, MI USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1373 BP 333A EP 333A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201688 ER PT J AU Calvo, KR Price, S Arthur, DC Rosenzweig, SD Braylan, RC Fleisher, TA Rao, KV AF Calvo, K. R. Price, S. Arthur, D. C. Rosenzweig, S. D. Braylan, R. C. Fleisher, T. A. Rao, K. V. TI Atypical Monocytosis in Patients with RAS-Associated Autoimmune Leukoproliferative Disorder (RALD): Overlapping Features with Juvenile Myelomonocytic Leukemia and Chronic Myelomonocytic Leukemia SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NIH CC, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1400 BP 340A EP 340A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201715 ER PT J AU Ganapathi, KA Ceribelli, M Evbuomwan, M Staudt, LM Pittaluga, S AF Ganapathi, K. A. Ceribelli, M. Evbuomwan, M. Staudt, L. M. Pittaluga, S. TI E2-2, a Novel Immunohistochemical Marker for Reactive and Neoplastic Plasmacytoid Dendritic Cells SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Ganapathi, K. A.; Ceribelli, M.; Evbuomwan, M.; Staudt, L. M.; Pittaluga, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1431 BP 347A EP 347A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201746 ER PT J AU Ganapathi, KA Townsley, DM Hsu, AP Zerbe, C Cueller-Rodriguez, J Hickstein, DD Young, NS Braylan, RC Holland, SM Calvo, KR AF Ganapathi, K. A. Townsley, D. M. Hsu, A. P. Zerbe, C. Cueller-Rodriguez, J. Hickstein, D. D. Young, N. S. Braylan, R. C. Holland, S. M. Calvo, K. R. TI Bone Marrow Morphologic and Flow Cytometric Features Assist in Differentiating GATA2 Mutation Associated-Hypocellular MDS from Aplastic Anemia SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1430 BP 347A EP 347A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502201745 ER PT J AU Nicolae, A Dunleavy, K Wilson, WH Raffeld, M Jaffe, ES Pittaluga, S AF Nicolae, A. Dunleavy, K. Wilson, W. H. Raffeld, M. Jaffe, E. S. Pittaluga, S. TI The Microenvironment in Mediastinal Gray Zone Lymphoma (MGZL) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Nicolae, A.; Dunleavy, K.; Wilson, W. H.; Raffeld, M.; Jaffe, E. S.; Pittaluga, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1505 BP 365A EP 365A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202061 ER PT J AU Xie, Y Pittaluga, S Smoot, E Fleisher, T Raffeld, M Jaffe, E Rao, K Maric, I AF Xie, Y. Pittaluga, S. Smoot, E. Fleisher, T. Raffeld, M. Jaffe, E. Rao, K. Maric, I. TI Spectrum of Non-Neoplastic Bone Marrow Pathology in Autoimmune Lymphoproliferative Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. NIH, CC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1584 BP 386A EP 386A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202140 ER PT J AU Yuan, J Wright, G Gascoyne, RD Connors, JM Rosenwald, A Weisenburger, DD Greiner, TC Smith, L Rimsza, LM Jaffe, ES Campo, E Martinez, A Delabie, J Braziel, RM Cook, JR Tubbs, RR Ott, G Vose, J Staudt, LM Chan, WC AF Yuan, J. Wright, G. Gascoyne, R. D. Connors, J. M. Rosenwald, A. Weisenburger, D. D. Greiner, T. C. Smith, L. Rimsza, L. M. Jaffe, E. S. Campo, E. Martinez, A. Delabie, J. Braziel, R. M. Cook, J. R. Tubbs, R. R. Ott, G. Vose, J. Staudt, L. M. Chan, W. C. TI Gene Expression Signature Helps to Identify Primary Mediastinal Large B-Cell Lymphoma at the Extra-Mediastinal Sites without Mediastinal Involvement SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Univ Nebraska Med Ctr, LLMPP, Omaha, NE USA. NIH, Bethesda, MD USA. British Columbia Canc Agcy, Vancouver, BC, Canada. Univ Wurzburg, Wurzburg, Germany. City Hope Natl Med Ctr, Duarte, CA USA. Univ Arizona, Tucson, AZ USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1590 BP 387A EP 387A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202146 ER PT J AU Aljinovic, N Cullinane, AR Gochuico, BR Gahl, WA Rosen, S AF Aljinovic, N. Cullinane, A. R. Gochuico, B. R. Gahl, W. A. Rosen, S. TI Pulmonary Fibrosis-Renal Lipofuscinosis ("Black Kidney"), a New Disorder with Histologic Features of Hermansky-Pudlak Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1657 BP 405A EP 405A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202213 ER PT J AU Kleiner, DE Brunt, EM Wilson, L Belt, PH Guy, CD Yeh, MM Kowdley, KV Sanyal, AJ Neuschwander-Tetri, BA AF Kleiner, D. E. Brunt, E. M. Wilson, L. Belt, P. H. Guy, C. D. Yeh, M. M. Kowdley, K. V. Sanyal, A. J. Neuschwander-Tetri, B. A. TI Fibrosis Progression in Adult Non-Alcoholic Fatty Liver Disease: Association with Severity of Histological Features SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Duke Univ, Durham, NC USA. Univ Washington, Seattle, WA 98195 USA. Virginia Mason Med Ctr, Seattle, WA 98101 USA. Virginia Commonwealth Univ, Richmond, VA USA. St Louis Univ, St Louis, MO 63103 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1731 BP 423A EP 423A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202287 ER PT J AU Makhlouf, HR Giblen, G Kleiner, DE Goodman, ZD AF Makhlouf, H. R. Giblen, G. Kleiner, D. E. Goodman, Z. D. TI Lack of Histological Significance of Antinuclear Antibodies in Patients with Nonalcoholic Fatty Liver Disease (NAFLD) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 NCI, NIH, Bethesda, MD 20892 USA. Mercy Med Ctr, Baltimore, MD USA. Inova Fairfax Hosp, Falls Church, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1742 BP 425A EP 425A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202298 ER PT J AU Paolino, RM Robinson, CL Summers, TA Hodson, DJ Staudt, LM AF Paolino, R. M. Robinson, C. L. Summers, T. A. Hodson, D. J. Staudt, L. M. TI Are BCL2 and MYC Alterations Sufficient to Drive Lymphomagenesis? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 WRNMMC, Bethesda, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1914 BP 466A EP 466A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202470 ER PT J AU Rosenberg, AZ Blackler, AR Emmert-Buck, MR AF Rosenberg, A. Z. Blackler, A. R. Emmert-Buck, M. R. TI Collagen Expression Profiling of Normal and Diseased Human FFPE Tissues by Targeted Mass Spectrometry SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 [Rosenberg, A. Z.; Blackler, A. R.; Emmert-Buck, M. R.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 1915 BP 467A EP 467A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202471 ER PT J AU Aesif, SW Taylor, L Kuipers, I DePalma, L AF Aesif, S. W. Taylor, L. Kuipers, I. DePalma, L. TI In-Situ Redox Profiling of Diffuse Large B-Cell Lymphoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 George Washington Univ, Washington, DC USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 2116 BP 517A EP 517A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202672 ER PT J AU Robinson, CL Paolino, RM Summers, TA Hodson, DJ Staudt, LM AF Robinson, C. L. Paolino, R. M. Summers, T. A. Hodson, D. J. Staudt, L. M. TI Development of an In Vitro Model of Germinal Center Lymphomagenesis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) CY MAR 01-07, 2014 CL San Diego, CA SP US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystems C1 WRNMMC, Bethesda, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2014 VL 27 SU 2 MA 2162 BP 529A EP 529A PG 1 WC Pathology SC Pathology GA AB0SK UT WOS:000331502202718 ER PT J AU Simons, SS Edwards, DP Kumar, R AF Simons, S. Stoney, Jr. Edwards, Dean P. Kumar, Raj TI Minireview: Dynamic Structures of Nuclear Hormone Receptors: New Promises and Challenges SO MOLECULAR ENDOCRINOLOGY LA English DT Review ID SMALL-MOLECULE INHIBITOR; HUMAN GLUCOCORTICOID-RECEPTOR; REGULATED GENE-EXPRESSION; HUMAN ESTROGEN-RECEPTOR; ACTIVATION FUNCTION 1; CANCER CELL-GROWTH; N-TERMINAL REGION; ANDROGEN RECEPTOR; DNA-BINDING; BREAST-CANCER AB Therapeutic targeting of nuclear receptors (NRs) is presently restricted due to 2 constraints: 1) a limited knowledge of the structural dynamics of intact receptor when complexed to DNA and coregulatory proteins; and 2) the inability to more selectively modulate NR actions at specific organ/gene targets. A major obstacle has been the current lack of understanding about the function and structure of the intrinsically disordered N-terminal domain that contains a major regulatory transcriptional activation function (AF1). Current studies of both mechanism of action and small molecule-selective receptor modulators for clinical uses target the structured pocket of the ligand-binding domain to modulate coregulatory protein interactions with the other activation function AF2. However, these approaches overlook AF1 activity. Recent studies have shown that highly flexible intrinsically disordered regions of transcription factors, including that of the N-terminal domain AF1 of NRs, not only are critical for several aspects of NR action but also can be exploited as drug targets, thereby opening unique opportunities for endocrine-based therapies. In this review article, we discuss the role of structural flexibilities in the allosteric modulation of NR activity and future perspectives for therapeutic interventions. C1 [Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. [Edwards, Dean P.] Baylor Coll Med, Dept Mol & Cellular Biol & Pathol & Immunol, Houston, TX 77030 USA. [Kumar, Raj] Commonwealth Med Coll, Dept Basic Sci, Scranton, PA 18510 USA. RP Kumar, R (reprint author), Commonwealth Med Coll, Dept Basic Sci, 525 Pine St, Scranton, PA 18509 USA. EM stoneys@helix.nih.gov; deane@bcm.edu; rkumar@tcmedc.org FU National Cancer Institute [CA046938]; National Institutes of Health (NIH) [DK049030]; Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by National Cancer Institute Grant CA046938 (to D. P. E.), National Institutes of Health (NIH) Grant DK049030 (to D. P. E.), and in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (to S.S.S.). NR 92 TC 14 Z9 14 U1 0 U2 25 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD FEB PY 2014 VL 28 IS 2 BP 173 EP 182 DI 10.1210/me.2013-1334 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB5AN UT WOS:000331801400003 PM 24284822 ER PT J AU Voss, TC Hager, GL AF Voss, Ty C. Hager, Gordon L. TI Dynamic regulation of transcriptional states by chromatin and transcription factors SO NATURE REVIEWS GENETICS LA English DT Review ID ESTROGEN-RECEPTOR-ALPHA; EUKARYOTIC GENE-EXPRESSION; SINGLE-MOLECULE TRACKING; GLUCOCORTICOID-RECEPTOR; LIVING CELLS; DNA-BINDING; IN-VIVO; EPIGENETIC SIGNATURES; BIOLOGICAL-SYSTEMS; PROTEIN DYNAMICS AB The interaction of regulatory proteins with the complex nucleoprotein structures that are found in mammalian cells involves chromatin reorganization at multiple levels. Mechanisms that support these transitions are complex on many timescales, which range from milliseconds to minutes or hours. In this Review, we discuss emerging concepts regarding the function of regulatory elements in living cells. We also explore the involvement of these dynamic and stochastic processes in the evolution of fluctuating transcriptional activity states that are now commonly reported in eukaryotic systems. C1 [Voss, Ty C.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, 41 Lib Dr, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov NR 124 TC 101 Z9 102 U1 5 U2 74 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD FEB PY 2014 VL 15 IS 2 BP 69 EP 81 DI 10.1038/nrg3623 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AB6JL UT WOS:000331894200007 PM 24342920 ER PT J AU McDannald, MA Jones, JL Takahashi, YK Schoenbaum, G AF McDannald, Michael A. Jones, Joshua L. Takahashi, Yuji K. Schoenbaum, Geoffrey TI Learning theory: A driving force in understanding orbitofrontal function SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Review DE Learning theory; Orbitofrontal; Reversal; Devaluation; Overexpectation; Sensory preconditioning; Blocking; Transfer ID PAVLOVIAN-INSTRUMENTAL TRANSFER; ORBITAL PREFRONTAL CORTEX; OUTCOME-SPECIFIC FORMS; VENTRAL TEGMENTAL AREA; REINFORCER DEVALUATION; UNCONDITIONED STIMULUS; NUCLEUS-ACCUMBENS; FRONTAL-CORTEX; RHESUS-MONKEYS; REWARD VALUE AB Since it was demonstrated the orbitofrontal cortex (OFC) is critical to reversal learning, there has been considerable interest in specifying its role in flexible, outcome-guided behavior. Behavioral paradigms from the learning theory tradition, such as outcome devaluation, blocking, Pavlovian to instrumental transfer, and overexpectation have been a driving force in this research. The use of these procedures has revealed OFC's unique role in forming and integrating information about specific features of events and outcomes to drive behavior and learning. These studies highlight the power and importance of learning theory principles in guiding neuroscience research. Published by Elsevier Inc. C1 [McDannald, Michael A.; Takahashi, Yuji K.; Schoenbaum, Geoffrey] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. [Jones, Joshua L.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP McDannald, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. EM michael.mcdannald@nih.gov; gscho002@gmail.com FU Intramural NIH HHS [Z99 DA999999, ZIA DA000587-01] NR 55 TC 21 Z9 21 U1 3 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 EI 1095-9564 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD FEB PY 2014 VL 108 SI SI BP 22 EP 27 DI 10.1016/j.nlm.2013.06.003 PG 6 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AB3GH UT WOS:000331678800004 PM 23770491 ER PT J AU Heymsfield, SB Avena, NM Baier, L Brantley, P Bray, GA Burnett, LC Butler, MG Driscoll, DJ Egli, D Elmquist, J Forster, JL Goldstone, AP Gourash, LM Greenway, FL Han, JC Kane, JG Leibel, RL Loos, RJF Scheimann, AO Roth, CL Seeley, RJ Sheffield, V Tauber, M Vaisse, C Wang, LH Waterland, RA Wevrick, R Yanovski, JA Zinn, AR AF Heymsfield, Steven B. Avena, Nicole M. Baier, Leslie Brantley, Phillip Bray, George A. Burnett, Lisa C. Butler, Merlin G. Driscoll, Daniel J. Egli, Dieter Elmquist, Joel Forster, Janice L. Goldstone, Anthony P. Gourash, Linda M. Greenway, Frank L. Han, Joan C. Kane, James G. Leibel, Rudolph L. Loos, Ruth J. F. Scheimann, Ann O. Roth, Christian L. Seeley, Randy J. Sheffield, Val Tauber, Maithe Vaisse, Christian Wang, Liheng Waterland, Robert A. Wevrick, Rachel Yanovski, Jack A. Zinn, Andrew R. TI Hyperphagia: Current Concepts and Future Directions Proceedings of the 2nd International Conference on Hyperphagia SO OBESITY LA English DT Article ID BARDET-BIEDL-SYNDROME; PRADER-WILLI-SYNDROME; BODY-MASS INDEX; GENOME-WIDE ASSOCIATION; FOOD ADDICTION; HYPOTHALAMIC OBESITY; BARIATRIC SURGERY; ENERGY-INTAKE; PIMA-INDIANS; PARAVENTRICULAR NUCLEUS AB Objective: Hyperphagia is a central feature of inherited disorders (e.g., Prader-Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. Design and Methods: International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates. Results: The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified. Conclusions: This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research. C1 [Heymsfield, Steven B.; Brantley, Phillip; Bray, George A.; Greenway, Frank L.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Avena, Nicole M.] Univ Florida, Coll Med, Dept Psychiat, Gainesville, FL USA. [Baier, Leslie] NIDDK, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Burnett, Lisa C.; Egli, Dieter; Leibel, Rudolph L.; Wang, Liheng] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Butler, Merlin G.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Driscoll, Daniel J.] Univ Florida, Coll Med, Dept Pediat, Div Genet & Metab, Gainesville, FL USA. [Egli, Dieter] New York Stem Cell Fdn, New York, NY USA. [Elmquist, Joel] UT Southwestern Med Ctr, Dallas, TX USA. [Forster, Janice L.; Gourash, Linda M.] Pittsburgh Partnership, Pittsburgh, PA USA. [Goldstone, Anthony P.] Imperial Coll London, MRC Clin Sci Ctr, Metab & Mol Imaging Grp, London, England. [Han, Joan C.; Yanovski, Jack A.] NICHHD, Sect Growth & Obes, NIH, Bethesda, MD 20892 USA. [Kane, James G.] Prader Willi Syndrome Assoc USA, Sarasota, FL USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY USA. [Scheimann, Ann O.] Johns Hopkins Sch Med, Div Pediat Gastroenterol Nutr & Hepatol, Baltimore, MD USA. [Roth, Christian L.] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA USA. [Seeley, Randy J.] Univ Cincinnati, Ctr Excellence Obes & Diabet, Cincinnati, OH USA. [Sheffield, Val] Univ Iowa, Coll Med, Iowa City, IA USA. [Tauber, Maithe] Hop Enfants, Dept Endocrinol, Toulouse, France. [Tauber, Maithe] Univ Toulouse 3, F-31062 Toulouse, France. [Vaisse, Christian] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Waterland, Robert A.] Baylor Coll Med, USDA, ARS Childrens Nutr Res Ctr, Dept Pediat & Mol & Human Genet, Houston, TX 77030 USA. [Wevrick, Rachel] Univ Alberta, Dept Med Genet, Edmonton, AB, Canada. [Zinn, Andrew R.] UT Southwestern Med Ctr, McDermott Ctr Human Growth & Dev, Dallas, TX USA. RP Heymsfield, SB (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. EM Steven.Heymsfield@pbrc.edu RI TAUBER, Maithe/K-7386-2014; OI Goldstone, Anthony/0000-0001-8179-7071; Yanovski, Jack/0000-0001-8542-1637 FU NIH [1K24 HD01361, 1K23 DK081203, R01DK53301, RL1DK081185, P01DK088761, DK079986, DK081185]; Department of Defense [W81XWH-08-1-0025]; NIH CTSA [1UL1RR029890]; Prader-Willi Syndrome Association; USPHS, Kildehoj-Santini, University of Florida Foundation [DA-03123]; NIDDK; NICHD; [1U54 RR019478] FX DJD: NIH 1K24 HD01361; NIH 1K23 DK081203; Department of Defense W81XWH-08-1-0025; 1U54 RR019478; NIH CTSA 1UL1RR029890; JE: NIH R01DK53301, NIH RL1DK081185, and NIH P01DK088761; RW: "Best Idea Grant for Hyperphagia Research" from the Prader-Willi Syndrome Association; AZ: Supported by NIH grants DK079986 and DK081185; NA: USPHS Grant DA-03123, Kildehoj-Santini, University of Florida Foundation; LB: This research was funded by the intramural program of NIDDK; JY: This research was funded by the intramural program of NICHD. NR 100 TC 8 Z9 8 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD FEB PY 2014 VL 22 SU 1 BP S1 EP S17 DI 10.1002/oby.20646 PG 17 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AB9JQ UT WOS:000332109300001 PM 24574081 ER PT J AU Yavuz, S Diker-Cohen, T Marx, SJ Simonds, WF Wermers, RA Collins, MT AF Yavuz, S. Diker-Cohen, T. Marx, S. J. Simonds, W. F. Wermers, R. A. Collins, M. T. TI DENOSUMAB-INDUCED PROLONGED HYPOCALCEMIA AND HYPOPHOSPHATEMIA IN THREE PATIENTS WITH SEVERE PRIMARY HYPERPARATHYROIDISM AND RENAL INSUFFICIENCY SO OSTEOPOROSIS INTERNATIONAL LA English DT Meeting Abstract CT International-Osteoporosis-Foundation (IOF) - International-Society-for-Clinical-Densitometry (ISCD) Skeletal Health Meeting CY FEB 20-22, 2014 CL Orlando, FL SP Int Osteoporosis Fdn, Int Soc Clin Densitometry C1 [Yavuz, S.; Diker-Cohen, T.; Marx, S. J.; Simonds, W. F.] NIH, Bethesda, MD 20892 USA. [Wermers, R. A.] Mayo Clin, Div Endocrinol, Dept Med, Coll Med, Rochester, MN USA. [Collins, M. T.] NIDCR, Skeletal Clin Studies Unit, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD FEB PY 2014 VL 25 SU 1 BP S63 EP S63 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3ML UT WOS:000331694800101 ER PT J AU Jenkins, RA AF Jenkins, Richard A. TI Supplemental Issue on Does Early Intervention Prevent Health-Risking Sexual Behaviors Related to HIV/AIDS: Commentary on Effects SO PREVENTION SCIENCE LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; PSYCHIATRIC-DISORDERS; INFECTION; PREVALENCE; PREGNANCY; MEN; AGE C1 NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Jenkins, RA (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, NIH, 6001 Execut Blvd,MSC9589 Room 5185, Bethesda, MD 20892 USA. EM jenkinsri@mail.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 21 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD FEB PY 2014 VL 15 SU 1 BP S84 EP S86 DI 10.1007/s11121-013-0422-6 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AB7NO UT WOS:000331977500010 PM 23881420 ER PT J AU Reider, EE Robertson, EB Sims, BE AF Reider, Eve E. Robertson, Elizabeth B. Sims, Belinda E. TI Does Early Intervention Prevent Health-Risking Sexual Behaviors Related to HIV/AIDS? SO PREVENTION SCIENCE LA English DT Editorial Material ID ADOLESCENTS; UNIVERSAL; OUTCOMES; YOUTH; MODEL C1 [Reider, Eve E.; Robertson, Elizabeth B.; Sims, Belinda E.] NIDA, PRB, DESPR, Bethesda, MD 20892 USA. RP Reider, EE (reprint author), NIDA, PRB, DESPR, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM ereider@mail.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 29 TC 1 Z9 1 U1 1 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD FEB PY 2014 VL 15 SU 1 BP S1 EP S5 DI 10.1007/s11121-013-0455-x PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AB7NO UT WOS:000331977500001 PM 24464321 ER PT J AU Wang, MY Jiang, LQ Monticone, RE Lakatta, EG AF Wang, Mingyi Jiang, Liqun Monticone, Robert E. Lakatta, Edward G. TI Proinflammation: the key to arterial aging SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review DE proinflammation; angiotensin II; central arterial aging; hypertension; atherosclerosis ID SMOOTH-MUSCLE-CELLS; VASCULAR ENDOTHELIAL DYSFUNCTION; PRIMATE MACACA-MULATTA; NF-KAPPA-B; ANGIOTENSIN-II; OXIDATIVE STRESS; CELLULAR SENESCENCE; MATRIX METALLOPROTEINASE-2; AEROBIC EXERCISE; HEART-DISEASE AB Arterial aging is the major contributing factor to increases in the incidence and prevalence of cardiovascular disease, due mainly to the presence of chronic, low-grade, 'sterile' arterial inflammation. Inflammatory signaling driven by the angiotensin II cascade perpetrates adverse age-associated arterial structural and functional remodeling. The aged artery is characterized by endothelial disruption, enhanced vascular smooth muscle cell (VMSC) migration and proliferation, extracellular matrix (ECM) deposition, elastin fracture, and matrix calcification/amyloidosis/glycation. Importantly, the molecular mechanisms of arterial aging are also relevant to the pathogenesis of hypertension and atherosclerosis. Age-associated arterial proinflammation is to some extent mutable, and interventions to suppress or delay it may have the potential to ameliorate or retard age-associated arterial diseases. C1 [Wang, Mingyi; Jiang, Liqun; Monticone, Robert E.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Wang, MY (reprint author), NIA, Lab Cardiovasc Sci, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mingyiw@gre.nia.nih.gov; lakattae@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 77 TC 42 Z9 43 U1 3 U2 24 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 FEB PY 2014 VL 25 IS 2 BP 72 EP 79 DI 10.1016/j.tem.2013.10.002 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3HA UT WOS:000331680700003 PM 24365513 ER PT J AU Marosi, K Mattson, MP AF Marosi, Krisztina Mattson, Mark P. TI BDNF mediates adaptive brain and body responses to energetic challenges SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review DE Alzheimer's disease; BDNF; diabetes; exercise; glucocorticoid; insulin resistance; learning and memory; obesity ID NEUROTROPHIC FACTOR BDNF; CORTICAL-NEURONS; DIABETIC MICE; ENVIRONMENTAL ENRICHMENT; DOPAMINERGIC-NEURONS; SYNAPTIC PLASTICITY; CALORIE RESTRICTION; DIETARY RESTRICTION; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE AB Emerging findings suggest that brain-derived neurotrophic factor (BDNF) serves widespread roles in regulating energy homeostasis by controlling patterns of feeding and physical activity, and by modulating glucose metabolism in peripheral tissues. BDNF mediates the beneficial effects of energetic challenges such as vigorous exercise and fasting on cognition, mood, cardiovascular function, and on peripheral metabolism. By stimulating glucose transport and mitochondria! biogenesis BDNF bolsters cellular bioenergetics and protects neurons against injury and disease. By acting in the brain and periphery, BDNF increases insulin sensitivity and parasympathetic tone. Genetic factors, a 'couch potato' lifestyle, and chronic stress impair BDNF signaling, and this may contribute to the pathogenesis of metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes, and neurological disorders. C1 [Marosi, Krisztina; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov FU National Institute on Aging FX This work was supported by the intramural research program of the National Institute on Aging. We thank KC (Kristen) Alexander for preparing the illustrations for Figures 1 and 2. NR 97 TC 60 Z9 61 U1 9 U2 57 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 FEB PY 2014 VL 25 IS 2 BP 89 EP 98 DI 10.1016/j.tem.2013.10.006 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3HA UT WOS:000331680700005 PM 24361004 ER PT J AU Pollock, JD Wu, DY Satterlee, JS AF Pollock, Jonathan D. Wu, Da-Yu Satterlee, John S. TI Molecular neuroanatomy: a generation of progress SO TRENDS IN NEUROSCIENCES LA English DT Review ID TRANSLATIONAL PROFILING APPROACH; SUBTYPE-SPECIFIC GENES; NEURONAL CELL-TYPES; BRAIN ACTIVITY MAP; NERVOUS-SYSTEM; NEURAL CIRCUITS; MOUSE-BRAIN; IN-VIVO; FLUORESCENT PROTEIN; REMOTE-CONTROL AB The neuroscience research landscape has changed dramatically over the past decade. Specifically, an impressive array of new tools and technologies have been generated, including but not limited to: brain gene expression atlases, genetically encoded proteins to monitor and. manipulate neuronal activity, and new methods for imaging and mapping circuits. However, despite these technological advances, several significant challenges must be overcome to enable a better understanding of brain function and to develop cell type-targeted therapeutics to treat brain disorders. This review provides an overview of some of the tools and technologies currently being used to advance the field of molecular neuroanatomy, and also discusses emerging technologies that may enable neuroscientists to address these crucial scientific challenges over the coming decade. C1 [Pollock, Jonathan D.; Wu, Da-Yu; Satterlee, John S.] NIDA, Div Basic Neurobiol & Behav Res, Genet & Mol Neurobiol Res Branch, NIH, Rockville, MD 20850 USA. RP Pollock, JD (reprint author), NIDA, Div Basic Neurobiol & Behav Res, Genet & Mol Neurobiol Res Branch, NIH, 6001 Execut Blvd, Rockville, MD 20850 USA. EM jpollock@mail.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 153 TC 11 Z9 11 U1 1 U2 33 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD FEB PY 2014 VL 37 IS 2 BP 106 EP 123 DI 10.1016/j.tins.2013.11.001 PG 18 WC Neurosciences SC Neurosciences & Neurology GA AB3JO UT WOS:000331687300006 PM 24388609 ER PT J AU Cranston, RD Hoesley, C Carballo-Dieguez, A Hendrix, CW Husnik, M Levy, L Hall, W Soto-Torres, L Nel, AM AF Cranston, Ross D. Hoesley, Craig Carballo-Dieguez, Alex Hendrix, Craig W. Husnik, Marla Levy, Lisa Hall, Wayne Soto-Torres, Lydia Nel, Annalene M. TI A Randomized Male Tolerance Study of Dapivirine Gel Following Multiple Topical Penile Exposures (MTN 012/IPM 010) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HIV-NEGATIVE WOMEN; VAGINAL MICROBICIDE GEL; UNIVERSAL PLACEBO GEL; TENOFOVIR GEL; SAFETY; ACCEPTABILITY; HEALTHY; PHARMACOKINETICS; MEN AB Dapivirine (DPV) is a nonnucleoside reverse transcriptase inhibitor with a favorable safety profile following vaginal application. A penile tolerance study was conducted prior to further development of DPV as a candidate vaginal microbicide. Twenty-four circumcised and 24 uncircumcised (N=48) healthy HIV-negative male participants aged 18 years or older were randomized 2:1:1 to apply DPV 0.05% gel, matched placebo gel, or universal placebo gel, respectively, to their penis once daily for 7 sequential days. The safety, acceptability, and pharmacokinetic profile of DPV 0.05% gel were assessed by the presence of Grade 2 or higher genitourinary adverse events (AEs) and systemic AEs, a behavioral questionnaire, and pharmacokinetic plasma blood draw, respectively, at the final clinic visit (FCV). There were no Grade 2 genitourinary AEs in 47 participants completing the FCV. One participant in the DPV arm failed to attend the FCV. There were 13 AEs reported; all were Grade 1 except one Grade 2 corneal laceration unrelated to study product. Participants liked the gel to a moderate extent, yet 72% reported they would be very likely to use a gel like the one they used in the study every time they have intercourse. DPV was detectable in plasma in all 23 DPV arm study participants at the FCV. On average, the circumcised participants' DPV concentrations were 54% of those in uncircumcised participants (p=0.07). Topical seven-day penile application of DPV 0.05% gel was locally and systemically safe, was acceptable to male participants, and resulted in systemic exposure to the drug. C1 [Cranston, Ross D.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Hoesley, Craig] Univ Alabama Birmingham, Birmingham, AL USA. [Carballo-Dieguez, Alex] New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. [Hendrix, Craig W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Husnik, Marla] Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. [Levy, Lisa] Family Hlth Int 360, Res Triangle Pk, NC USA. [Hall, Wayne] Microbicide Trials Network, Pittsburgh, PA USA. [Soto-Torres, Lydia] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Nel, Annalene M.] Int Partnership Microbicides, Silver Spring, MD USA. RP Cranston, RD (reprint author), 3520 Fifth Ave,Suite 510, Pittsburgh, PA 15213 USA. EM rdc27@pitt.edu RI Hendrix, Craig/G-4182-2014; OI Hendrix, Craig/0000-0002-5696-8665; Cranston, Ross/0000-0002-2687-6217 FU National Institutes of Health [5U01AI068633, UM1AI068615] FX The study team gratefully acknowledges the participants of MTN 012/IPM 010, the International Partnership for Microbicides for providing the study product, and both Rebecca Giguere, MPH, and Curtis Dolezal, PhD, for their work on the behavioral data analysis. Funding was provided by the National Institutes of Health Grants 5U01AI068633 and UM1AI068615. Presented in abstract: Microbicides 2012, abstract number 542, April 15-18 2012, Sydney, Australia. NR 11 TC 4 Z9 4 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD FEB 1 PY 2014 VL 30 IS 2 BP 184 EP 189 DI 10.1089/aid.2013.0170 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AA6NI UT WOS:000331214600012 PM 24070431 ER PT J AU Nash, TE Bartelt, LA Korpe, PS Lopes, B Houpt, ER AF Nash, Theodore E. Bartelt, Luther A. Korpe, Poonum S. Lopes, Beatriz Houpt, Eric R. TI Case Report: Calcified Neurocysticercus, Perilesional Edema, and Histologic Inflammation SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID COLLOID CYST; CYSTICERCI; SEIZURES; LESIONS; MIMICKING AB Here, we present the second report of the histopathology of a Taenia solium calcification giving rise to perilesional edema. This has important implications, because if perilesional edema lesions are inflammatory in character, immunosuppressive or anti-inflammatory medications, not just antiepileptic drugs alone, may be useful to prevent or treat recurring episodes in such patients. C1 [Nash, Theodore E.] Parasit Dis Lab, NIH, Bethesda, MD USA. [Bartelt, Luther A.; Houpt, Eric R.] Univ Virginia, Charlottesville, VA USA. [Korpe, Poonum S.] Univ Virginia, Dept Med, Charlottesville, VA USA. RP Houpt, ER (reprint author), MR6 1716, Charlottesville, VA 22908 USA. EM tnash@niaid.nih.gov; lab2za@virginia.edu; psk9p@virginia.edu; MSL2E@virginia.edu; erh6k@virginia.edu FU Intramural National Institutes of Allergy and Infectious diseases at the National Institutes of Health FX The support for this study was in part received from the Intramural National Institutes of Allergy and Infectious diseases at the National Institutes of Health. NR 20 TC 10 Z9 10 U1 1 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2014 VL 90 IS 2 BP 318 EP 321 DI 10.4269/ajtmh.13-0589 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AA3RC UT WOS:000331009000026 PM 24394477 ER PT J AU Lemaitre, M Watier, L Briand, V Garcia, A Le Hesran, JY Cot, M AF Lemaitre, Magali Watier, Laurence Briand, Valerie Garcia, Andre Le Hesran, Jean Yves Cot, Michel TI Coinfection with Plasmodium falciparum and Schistosoma haematobium: Additional Evidence of the Protective Effect of Schistosomiasis on Malaria in Senegalese Children SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID ASCARIS-LUMBRICOIDES; INFLAMMATORY MARKERS; ANTIBODY-RESPONSES; MANSONI INFECTION; IMMUNE-RESPONSES; RANDOMIZED-TRIAL; MALIAN CHILDREN; SUSCEPTIBILITY; WORMS; MICE AB Parasitic infections are associated with high morbidity and mortality in developing countries. Several studies focused on the influence of helminth infections on malaria but the nature of the biological interaction is under debate. Our objective was to undertake a study to explore the influence of the measure of excreted egg load caused by Schistosoma haematobium on Plasmodium falciparum parasite densities. Ten measures of malaria parasite density and two measures of schistosomiasis egg urinary excretion over a 2-year follow-up period on 178 Senegalese children were considered. A linear mixed-effect model was developed to take data dependence into account. This work showed that children with a light S. haematobium infection (1-9 eggs/mL of urine) presented lower P. falciparum parasite densities than children not infected by S. haematobium (P < 0.04). Possible changes caused by parasite coinfections should be considered in the anti-helminth treatment of children and in malaria vaccination development. C1 [Lemaitre, Magali; Briand, Valerie; Garcia, Andre; Le Hesran, Jean Yves; Cot, Michel] Univ Paris 05, Fac Pharm, Inst Rech Dev, Unite Rech Mere & Enfant Face Infect, Paris 06, France. [Watier, Laurence] Univ Versailles St Quentin, Fac Med Paris Ile France Ouest, Versailles, France. RP Lemaitre, M (reprint author), Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. EM maglemaitre@gmail.com; laurence.watier@rpc.aphp.fr; valerie.briand@gmail.com; re.garcia@ird.sn; jean-yves.lehesran@ird.fr; michel.cot@ird.fr RI Watier, Laurence/K-8213-2013; Garcia, Andre/S-2959-2016 OI Watier, Laurence/0000-0002-4057-1102; Garcia, Andre/0000-0002-1808-472X FU French Ministry of Research and Technology (Pal+ program) FX This work was supported by a grant from the French Ministry of Research and Technology (Pal+ program). NR 30 TC 12 Z9 13 U1 1 U2 18 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2014 VL 90 IS 2 BP 329 EP 334 DI 10.4269/ajtmh.12-0431 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AA3RC UT WOS:000331009000028 PM 24323515 ER PT J AU Jackson, SN Baldwin, K Muller, L Womack, VM Schultz, JA Balaban, C Woods, AS AF Jackson, Shelley N. Baldwin, Kathrine Muller, Ludovic Womack, Virginia M. Schultz, J. Albert Balaban, Carey Woods, Amina S. TI Imaging of lipids in rat heart by MALDI-MS with silver nanoparticles SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE MALDI; Mass spectrometry imaging; Lipids; Silver nanoparticles ID DESORPTION/IONIZATION MASS-SPECTROMETRY; ION MOBILITY-TOFMS; BRAIN-TISSUE; MATRIX DEPOSITION; SMALL MOLECULES; SECTIONS; PHOSPHOLIPIDS; IONIZATION; MODEL AB Lipids are a major component of heart tissue and perform several important functions such as energy storage, signaling, and as building blocks of biological membranes. The heart lipidome is quite diverse consisting of glycerophospholipids such as phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidylinositols (PIs), phosphatidylglycerols (PGs), cardiolipins (CLs), and glycerolipids, mainly triacylglycerols (TAGs). In this study, mass spectrometry imaging (MSI) enabled by matrix implantation of ionized silver nanoparticles (AgNP) was used to map several classes of lipids in heart tissue. The use of AgNP matrix implantation was motivated by our previous work showing that implantation doses of only 10(14)/cm(2) of 2 nm gold nanoparticulates into the first 10 nm of the near surface of the tissue enabled detection of most brain lipids (including neutral lipid species such as cerebrosides) more efficiently than traditional organic MALDI matrices. Herein, a similar implantation of 500 eV AgNP- across the entire heart tissue section results in a quick, reproducible, solvent-free, uniform matrix concentration of 6 nm AgNP residing near the tissue surface. MALDI-MSI analysis of either positive or negative ions produce high-quality images of several heart lipid species. In negative ion mode, 24 lipid species [16 PEs, 4 PIs, 1 PG, 1 CL, 2 sphingomyelins (SMs)] were imaged. Positive ion images were also obtained from 29 lipid species (10 PCs, 5 PEs, 5 SMs, 9 TAGs) with the TAG species being heavily concentrated in vascular regions of the heart. C1 [Jackson, Shelley N.; Baldwin, Kathrine; Muller, Ludovic; Womack, Virginia M.; Woods, Amina S.] NIDA IRP, Struct Biol Unit, NIH, Baltimore, MD 21224 USA. [Muller, Ludovic; Womack, Virginia M.; Balaban, Carey] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Schultz, J. Albert] Ionwerks Inc, Houston, TX 77002 USA. RP Woods, AS (reprint author), NIDA IRP, Struct Biol Unit, NIH, 333 Cassell Dr,Room 1120, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov OI Balaban, Carey/0000-0002-3570-3844 FU Intramural Research Program of the National Institute on Drug Abuse, NIH; ARRA through NIDA phase II SBIR grant [1RC3DA031431-01] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. The authors acknowledge Dr. Mari Prieto and Thermo Fisher Corporation for technical and instrumentation advices. Ionwerks and the University of Pittsburgh gratefully acknowledge ARRA support through NIDA phase II SBIR grant 1RC3DA031431-01. NR 39 TC 31 Z9 31 U1 5 U2 81 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD FEB PY 2014 VL 406 IS 5 BP 1377 EP 1386 DI 10.1007/s00216-013-7525-6 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AA3PL UT WOS:000331004700011 PM 24309627 ER PT J AU Bereszczak, JZ Havlik, M Weiss, VU Marchetti-Deschmann, M van Duijn, E Watts, NR Wingfield, PT Allmaier, G Steven, AC Heck, AJR AF Bereszczak, Jessica Z. Havlik, Marlene Weiss, Victor U. Marchetti-Deschmann, Martina van Duijn, Esther Watts, Norman R. Wingfield, Paul T. Allmaier, Guenter Steven, Alasdair C. Heck, Albert J. R. TI Sizing up large protein complexes by electrospray ionisation-based electrophoretic mobility and native mass spectrometry: morphology selective binding of Fabs to hepatitis B virus capsids SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Native MS; GEMMA; Hepatitis B; Virus-antibody complexes; Quasi-equivalence; Immune complex ID OF-FLIGHT INSTRUMENT; CORE ANTIGEN; ION MOBILITY; MONOCLONAL-ANTIBODIES; MOLECULAR ANALYZER; ASSEMBLIES; STABILITY; PARTICLES; EPITOPE; CRYOMICROSCOPY AB The capsid of hepatitis B virus (HBV) is a major viral antigen and important diagnostic indicator. HBV capsids have prominent protrusions ('spikes') on their surface and are unique in having either T = 3 or T = 4 icosahedral symmetry. Mouse monoclonal and also human polyclonal antibodies bind either near the spike apices (historically the 'alpha-determinant') or in the 'floor' regions between them (the 'beta-determinant'). Native mass spectrometry (MS) and gas-phase electrophoretic mobility molecular analysis (GEMMA) were used to monitor the titration of HBV capsids with the antigen-binding domain (Fab) of mAb 3120, which has long defined the beta-determinant. Both methods readily distinguished Fab binding to the two capsid morphologies and could provide accurate masses and dimensions for these large immune complexes, which range up to similar to 8 MDa. As such, native MS and GEMMA provide valuable alternatives to a more time-consuming cryo-electron microscopy analysis for preliminary characterisation of virus-antibody complexes. C1 [Bereszczak, Jessica Z.; Heck, Albert J. R.] Univ Utrecht, Bijvoet Ctr Biomol Res, NL-3584 CH Utrecht, Netherlands. [Bereszczak, Jessica Z.; Heck, Albert J. R.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, NL-3584 CH Utrecht, Netherlands. [Havlik, Marlene; Weiss, Victor U.; Marchetti-Deschmann, Martina; Allmaier, Guenter] Vienna Univ Technol, Inst Chem Technol & Analyt, A-1060 Vienna, Austria. [Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Watts, Norman R.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [van Duijn, Esther] TNO, NL-3700 AJ Zeist, Netherlands. RP Heck, AJR (reprint author), Univ Utrecht, Bijvoet Ctr Biomol Res, Padualaan 8, NL-3584 CH Utrecht, Netherlands. EM a.j.r.heck@uu.nl RI Heck, Albert/D-7098-2011; OI Heck, Albert/0000-0002-2405-4404; Marchetti-Deschmann, Martina/0000-0002-8060-7851 FU Netherlands Organization for Scientific Research (NWO); ALW-ECHO [819.02.10]; Netherlands Proteomics Centre, embedded in the Netherlands Genomics Initiative; Austrian Science Foundation [TRP 29-N20]; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health FX This work was supported by the Netherlands Organization for Scientific Research (NWO) with ALW-ECHO (819.02.10) to AJRH. We thank the Netherlands Proteomics Centre, embedded in the Netherlands Genomics Initiative, for financial support. Financial support for the GEMMA experiments was provided by the Austrian Science Foundation (TRP 29-N20) to GA. Additional support was provided by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health. NR 55 TC 5 Z9 5 U1 2 U2 25 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD FEB PY 2014 VL 406 IS 5 BP 1437 EP 1446 DI 10.1007/s00216-013-7548-z PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AA3PL UT WOS:000331004700016 PM 24357008 ER PT J AU Tokar, EJ Kojima, C Waalkes, MP AF Tokar, Erik J. Kojima, Chikara Waalkes, Michael P. TI Methylarsonous acid causes oxidative DNA damage in cells independent of the ability to biomethylate inorganic arsenic SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Arsenic; Cancer; Malignant transformation; Oxidative DNA damage ID INDUCED MALIGNANT-TRANSFORMATION; CANCER STEM-CELLS; EPITHELIAL-CELLS; MULTIDRUG-RESISTANCE; GENE-EXPRESSION; FREE-RADICALS; CD1 MICE; EXPOSURE; TRIVALENT; STRESS AB Inorganic arsenic (iAs) and its toxic methylated metabolite, methylarsonous acid (MMA(III)), both have carcinogenic potential. Prior study shows iAs-induced malignant transformation in both arsenic methylation-proficient (liver) and methylation-deficient (prostate) cells, but only methylation-proficient cells show oxidative DNA damage (ODD) during this transformation. To further define whether arsenic methylation is necessary for transformation or ODD induction, here we chronically exposed these same liver or prostate cell lines to MMA(III) (0.25-1.0 mu M) and tested for acquired malignant phenotype. Various metrics of oncogenic transformation were periodically assessed along with ODD during chronic MMA(III) exposure. Methylation-deficient and methylation-proficient cells both acquired a cancer phenotype with MMA(III) exposure at about 20 weeks, based on increased matrix metalloproteinase secretion, colony formation, and invasion. In contrast, prior work showed iAs-induced transformation took longer in biomethylation-deficient cells (similar to 30 weeks) than in biomethylation-proficient cells (similar to 18 weeks). In the present study, MMA(III) caused similar peak ODD levels at similar concentrations and at similar exposure times (18-22 weeks) in both cell types. At the approximate peak of ODD production, both cell types showed similar alterations in arsenic and oxidative stress adaptation factors (i.e., ABCC1, ABCC2, GST-pi, SOD-1). Thus, MMA(III) causes oncogenic transformation associated with ODD in methylation-deficient cells, indicating that further methylation is not required to induce ODD. Together, these results show that MMA(III) and iAs cause an acquired malignant phenotype in methylation-deficient cells, yet iAs does not induce ODD. This indicates iAs likely has both genotoxic and non-genotoxic mechanisms dictated by the target cell's ability to methylate arsenic. C1 [Tokar, Erik J.; Kojima, Chikara; Waalkes, Michael P.] NIEHS, Div Natl Toxicol Program, Natl Toxicol Program NTP Lab, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Div Natl Toxicol Program, Natl Toxicol Program NTP Lab, 111 Alexander Dr,MD E1-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102925-01, ZIA ES102925-02, ZIA ES102925-03, ZIA ES102925-04] NR 58 TC 7 Z9 7 U1 0 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD FEB PY 2014 VL 88 IS 2 BP 249 EP 261 DI 10.1007/s00204-013-1141-2 PG 13 WC Toxicology SC Toxicology GA AA2YF UT WOS:000330959400007 PM 24091636 ER PT J AU Xu, Y Tokar, EJ Waalkes, MP AF Xu, Yuanyuan Tokar, Erik J. Waalkes, Michael P. TI Arsenic-induced cancer cell phenotype in human breast epithelia is estrogen receptor-independent but involves aromatase activation SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Arsenic; Aromatase; Breast cancer; Estrogen; Stem cells ID STEM-CELLS; IN-UTERO; ALPHA EXPRESSION; EXPOSURE; MICE; CARCINOGENESIS; HYPERPLASIA; TRANSITIONS; METALS; LEADS AB Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies. Therefore, we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor (ER)-negative breast epithelial cell line, MCF-10A. Cells were chronically exposed to a low-level arsenite (500 nM) for up to 24 weeks. Markers of cancer cell phenotype and the expression of critical genes relevant to breast cancer or stem cells (SCs) were examined. After 24 weeks, chronic arsenic-exposed breast epithelial (CABE) cells showed increases in secreted MMP activity, colony formation, invasion, and proliferation rate, indicating an acquired cancer cell phenotype. These CABE cells presented with basal-like breast cancer characteristics, including ER-alpha, HER-2, and progesterone receptor negativity, and overexpression of K5 and p63. Putative CD44(+)/CD24(-/low) breast SCs were increased to 80 % over control in CABE cells. CABE cells also formed multilayer cell mounds, indicative of loss of contact inhibition. These mounds showed high levels of K5 and p63, indicating the potential presence of cancer stem cells (CSCs). Epithelial-to-mesenchymal transition occurred during arsenic exposure. Overexpression of aromatase, a key rate-limiting enzyme in estrogen synthesis, occurred with arsenic starting early on in exposure. Levels of 17 beta-estradiol increased in CABE cells and their conditioned medium. The aromatase inhibitor letrozole abolished arsenic-induced increases in 17 beta-estradiol production and reversed cancer cell phenotype. Thus, chronic arsenic exposure drives human breast epithelia into a cancer cell phenotype with an apparent overabundance of putative CSCs. Arsenic appears to transform breast epithelia through overexpression of aromatase, thereby activating oncogenic processes independent of ER. C1 [Xu, Yuanyuan; Tokar, Erik J.; Waalkes, Michael P.] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102925-02, ZIA ES102925-01, ZIA ES102925-03, ZIA ES102925-04] NR 46 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD FEB PY 2014 VL 88 IS 2 BP 263 EP 274 DI 10.1007/s00204-013-1131-4 PG 12 WC Toxicology SC Toxicology GA AA2YF UT WOS:000330959400008 PM 24068038 ER PT J AU Kanbe, H Kamijo, Y Nakajima, T Tanaka, N Sugiyama, E Wang, LX Fang, ZZ Hara, A Gonzalez, FJ Aoyama, T AF Kanbe, Hiroki Kamijo, Yuji Nakajima, Takero Tanaka, Naoki Sugiyama, Eiko Wang, Lixuan Fang, Zhong-Ze Hara, Atsushi Gonzalez, Frank J. Aoyama, Toshifumi TI Chronic ethanol consumption decreases serum sulfatide levels by suppressing hepatic cerebroside sulfotransferase expression in mice SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Ethanol; Sulfatide; Cardiovascular disease; Cerebroside sulfotransferase; Oxidative stress; Tissue factor ID ACTIVATED-RECEPTOR-ALPHA; AMINO-ACID-SEQUENCE; OXIDATIVE STRESS; PPAR-ALPHA; ALCOHOL-CONSUMPTION; NONALCOHOLIC STEATOHEPATITIS; DISTINCT SPECIFICITIES; TRANSCRIPTION FACTOR; TISSUE FACTOR; GENE-PRODUCT AB Epidemiological studies demonstrate a possible relationship between chronic ethanol drinking and thrombotic diseases, such as myocardial infarction and stroke. However, the precise mechanism for this association remains unclear. Sulfatides are endogenous glycosphingolipids composed of ceramide, galactose, and sulfate, known to have anti-thrombotic properties. Low (0.5 g/kg/day), middle (1.5 g/kg/day), and high (3.0 g/kg/day) doses of ethanol were administered for 21 days intraperitoneally to female wild-type mice, and serum/liver sulfatide levels were measured. No significant changes in cholesterol and triglycerides were seen in serum and liver by ethanol treatment. However, serum/liver sulfatide levels were significantly decreased by middle- and high-dose ethanol treatment, likely due to downregulation of hepatic cerebroside sulfotransferase (CST) levels. Marked decreases in the expression of catalase and superoxide dismutases and ensuing increases in lipid peroxides were also observed in the livers of mice with middle- and high-dose ethanol treatment, suggesting the association between the suppression of hepatic CST expression and enhancement of oxidative stress. Furthermore, serum levels of tissue factor, a typical pro-coagulant molecule, were significantly increased in the mice with middle- and high-dose ethanol treatment showing decreases in serum sulfatide levels. Collectively, these results demonstrate that chronic ethanol consumption reduces serum sulfatide levels by increasing oxidative stress and decreasing the expression of CST in the liver. These findings could provide a mechanism by which chronic ethanol drinking increases thrombotic events. C1 [Kanbe, Hiroki; Kamijo, Yuji; Nakajima, Takero; Tanaka, Naoki; Sugiyama, Eiko; Hara, Atsushi; Aoyama, Toshifumi] Shinshu Univ, Inst Aging & Adaptat, Dept Metab Regulat, Grad Sch Med, Matsumoto, Nagano 3908621, Japan. [Kanbe, Hiroki] Kissei Pharmaceut Co Ltd, Basic Discovery Res R&D, Hotaka, Azumino 3998304, Japan. [Kamijo, Yuji] Shinshu Univ, Dept Nephrol, Sch Med, Matsumoto, Nagano 3908621, Japan. [Tanaka, Naoki; Fang, Zhong-Ze; Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20852 USA. [Sugiyama, Eiko] Nagano Prefectural Coll, Dept Nutr Sci, Nagano 3808525, Japan. [Wang, Lixuan] Hebei Med Univ, Dept Histol & Embryol, Shijiazhuang 050017, Peoples R China. RP Tanaka, N (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20852 USA. EM tanakan@mail.nih.gov NR 52 TC 6 Z9 6 U1 0 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD FEB PY 2014 VL 88 IS 2 BP 367 EP 379 DI 10.1007/s00204-013-1132-3 PG 13 WC Toxicology SC Toxicology GA AA2YF UT WOS:000330959400018 PM 24065054 ER PT J AU Hourigan, CS McCarthy, P de Lima, M AF Hourigan, Christopher S. McCarthy, Philip de Lima, Marcos TI Back to the Future! The Evolving Role of Maintenance Therapy after Hematopoietic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE Immune system; Leukemia; Lymphoma; Residual disease; Hematology malignancy ID MINIMAL RESIDUAL DISEASE; ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; 2ND INTERNATIONAL WORKSHOP; DIAGNOSED MULTIPLE-MYELOMA; ACUTE MYELOGENOUS LEUKEMIA; PROGRESSION-FREE SURVIVAL; RANDOMIZED PHASE-3 TRIAL AB Relapse is a devastating event for patients with hematologic cancers treated with hematopoietic stem cell transplantation. In most situations, relapse treatment options are limited. Maintenance therapy offers the possibility of delaying or avoiding disease recurrence, but its role remains unclear in most conditions that we treat with transplantation. Here, Dr. Hourigan presents an overview of minimal residual disease (MRD) measurement in hematologic malignancies and the applicability of MRD-based post-transplantation interventions. Dr. McCarthy reviews current knowledge of maintenance therapy in the autologous transplantation context, with emphasis on immunologic interventions and immune modulation strategies designed to prevent relapse. Dr. de Lima discusses current lines of investigation in disease recurrence prevention after allogeneic transplantation, focusing on acute myeloid leukemia and myelodysplastic syndrome. (C) 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Hourigan, Christopher S.] NHLBI, Hematol Branch, Myeloid Malignancies Sect, Bethesda, MD 20892 USA. [McCarthy, Philip] Roswell Pk Canc Inst, Blood & Marrow Transplant Program, Buffalo, NY 14263 USA. [de Lima, Marcos] Case Western Reserve Univ, Univ Hosp, Case Med Ctr, Seidman Canc Ctr, Cleveland, OH 44106 USA. RP de Lima, M (reprint author), Case Western Reserve Univ, Univ Hosp, Case Med Ctr, 11100 Euclid Ave,LKS 5079, Cleveland, OH 44106 USA. EM marcos.delima@uhhospitals.org RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU Intramural Research Program of the NIH, National Heart, Lung and Blood Institute FX Financial disclosure: This research was supported by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. Any views expressed here represent personal opinion and do not necessarily reflect those of the United States Department of Health and Human Services, or the United States federal government. (C.S.H). NR 108 TC 20 Z9 20 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 BP 154 EP 163 DI 10.1016/j.bbmt.2013.11.017 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QS UT WOS:000331155300004 PM 24291784 ER PT J AU Jain, NA Pophali, PA Klotz, JK Ito, S Koklanaris, E Chawla, K Hourigan, CS Gormley, N Savani, BN Barrett, AJ Battiwalla, M AF Jain, Natasha A. Pophali, Priyanka A. Klotz, Jeffrey K. Ito, Sawa Koklanaris, Eleftheria Chawla, Kamna Hourigan, Christopher S. Gormley, Nicole Savani, Bipin N. Barrett, Austin John Battiwalla, Minoo TI Repair of Impaired Pulmonary Function Is Possible in Very-Long-Term Allogeneic Stem Cell Transplantation Survivors SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Pulmonary complications; HSCT; BMT; Allogeneic; Stem cell transplant; Lung shielding; Total body irradiation; Pulmonary function; DLCO; Adjusted DLCO; Long-term survivor ID BONE-MARROW-TRANSPLANTATION; TOTAL-BODY IRRADIATION; VERSUS-HOST-DISEASE; LUNG-FUNCTION; FUNCTION ABNORMALITIES; FUNCTION TESTS; COMPLICATIONS; MORTALITY; CHILDREN; PREVENTION AB Both early- and late-onset noninfectious pulmonary injury are important contributors to the nonrelapse mortality seen after allogeneic stem cell transplantation (allo-SCT), particularly in subjects conditioned with high-dose total body irradiation (TBI). To characterize the kinetics of recovery from pulmonary injury in long-term survivors, we collected data on 138 subjects who survived >3 years (median survival, 10.2 years) after predominantly TBI-based allo-SCT from their HLA-matched siblings. Baseline pulmonary function tests served as the reference for subsequent measurements at 3, 5, 10, and 15 years for each survivor. The only parameter showing a clinically and statistically significant decline post-transplant was adjusted diffusion capacity of lung for carbon monoxide (DLCO), which reached a nadir at 5 years but surprisingly normalized at the 10-year mark. Multivariable modeling identified chronic graft-versus-host disease (P < .02) and abnormal baseline-adjusted DLCO (P < .03) as the only significant factors associated with the decline in adjusted DLCO at 5 years but excluded smoking, conditioning intensity, baseline C-reactive protein level, TBI dose to the lungs, disease, and demographic variables. In conclusion, pulmonary injury as monitored by the adjusted DLCO continues to deteriorate in the first 5 years after allo-SCT but recovers at 10 years. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Jain, Natasha A.; Pophali, Priyanka A.; Klotz, Jeffrey K.; Ito, Sawa; Koklanaris, Eleftheria; Chawla, Kamna; Hourigan, Christopher S.; Gormley, Nicole; Barrett, Austin John; Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Nashville, TN 37235 USA. RP Battiwalla, M (reprint author), Rm 5-3581,10 CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Pophali, Priyanka/P-8646-2016; Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU intramural research program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX Financial disclosure: Supported by the intramural research program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 24 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 BP 209 EP 213 DI 10.1016/j.bbmt.2013.10.025 PG 5 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QS UT WOS:000331155300011 PM 24188917 ER PT J AU Buxbaum, NP Farthing, DE Treadwell, S Bare, C Kapoor, V Telford, W Gress, R AF Buxbaum, Nataliya Prokopenko Farthing, Donald Eugene Treadwell, Shirin Bare, Catherine Kapoor, Veena Telford, William Gress, Ronald TI In Vivo T Regulatory Cell Kinetics Are Altered in a Pre-Clinical Model of Chronic Graft-Versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Buxbaum, Nataliya Prokopenko; Farthing, Donald Eugene; Bare, Catherine; Kapoor, Veena; Telford, William] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Treadwell, Shirin] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Gress, Ronald] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 45 BP S50 EP S51 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400050 ER PT J AU Gadalla, S Wang, T Haagenson, M Spellman, SR Lee, SJ Williams, KM Wong, JY De Vivo, I Savage, SA AF Gadalla, Shahinaz Wang, Tao Haagenson, Michael Spellman, Stephen R. Lee, Stephanie J. Williams, Kirsten M. Wong, Jason Y. De Vivo, Immaculata Savage, Sharon A. TI Donor Telomere Length Predicts Recipient Survival after Allogeneic Hematopoietic Cell Transplantation in Patients with Bone Marrow Failure Syndromes SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Gadalla, Shahinaz] NCI, Clin Genet Branch, Rockville, MD USA. [Wang, Tao] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Wang, Tao] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Haagenson, Michael] CIBMTR, Minneapolis, MN USA. [Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, CIBMTR, Seattle, WA 98104 USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Williams, Kirsten M.] NCI, NIH, Bethesda, MD 20892 USA. [Wong, Jason Y.; De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 16 BP S33 EP S34 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400021 ER PT J AU Hakim, F Jin, P Memon, S Yan, XY Imanguli, M Baird, K Cowen, EW Stroncek, DE Gress, R Pavletic, SZ AF Hakim, Fran Jin, Ping Memon, Sarfraz Yan, Xiao-Yi Imanguli, Matin Baird, Kristin Cowen, Edward W. Stroncek, David E. Gress, Ronald Pavletic, Steven Z. TI Elevated Expression of Interferon-Induced Genes and Damage Associated Molecular Pattern Receptor Genes in Chronic Graft Versus Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Hakim, Fran; Gress, Ronald; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Jin, Ping; Stroncek, David E.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Memon, Sarfraz; Yan, Xiao-Yi; Imanguli, Matin] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Baird, Kristin] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 349 BP S226 EP S226 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400354 ER PT J AU Halverson, D Rowley, S Hansen, B Schuver, BB Mossoba, M Steinberg, S Hakim, F Kurlander, R Gea-Banacloche, J Sportes, C Hardy, N Hickstein, D Pavletic, SZ Khuu, H Castiello, L Sabatino, M Stroncek, DF Levine, B June, CH Donato, ML Goy, A Korngold, R Pecora, A Bishop, MR Gress, R Fowler, D AF Halverson, David Rowley, Scott Hansen, Brenna Schuver, Bazetta Blacklock Mossoba, Miriam Steinberg, Seth Hakim, Fran Kurlander, Roger Gea-Banacloche, Juan Sportes, Claude Hardy, Nancy Hickstein, Dennis Pavletic, Steven Z. Khuu, Hanh Castiello, Luciano Sabatino, Marianna Stroncek, David F. Levine, Bruce June, Carl H. Donato, Michele L. Goy, Andre Korngold, Robert Pecora, Andrew Bishop, Michael R. Gress, Ronald Fowler, Daniel TI T-Rapa6 and T-Rapa12 Cells Differentially Mediate Acute Gvhd after Low-Intensity Allogeneic HCT SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Halverson, David; Hansen, Brenna; Schuver, Bazetta Blacklock; Hakim, Fran; Gea-Banacloche, Juan; Hickstein, Dennis; Pavletic, Steven Z.; Gress, Ronald; Fowler, Daniel] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Rowley, Scott; Donato, Michele L.; Goy, Andre; Korngold, Robert; Pecora, Andrew] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Mossoba, Miriam] NCI, ETIB, Bethesda, MD 20892 USA. [Steinberg, Seth] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Kurlander, Roger] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Sportes, Claude] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. [Hardy, Nancy] NCI, Bethesda, MD 20892 USA. [Khuu, Hanh; Castiello, Luciano; Sabatino, Marianna] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Stroncek, David F.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Levine, Bruce; June, Carl H.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Bishop, Michael R.] Univ Chicago, Chicago, IL 60637 USA. RI Castiello, Luciano/K-8616-2016 OI Castiello, Luciano/0000-0001-7146-3158 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 177 BP S130 EP S131 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400182 ER PT J AU Hanley, PJ Nikiforow, S Melenhorst, J Scheinberg, P Savoldo, B Dotti, G Rooney, CM Heslop, HE Shpall, EJ Barrett, AJ Bollard, CM AF Hanley, Patrick J. Nikiforow, Sarah Melenhorst, Jan Scheinberg, Phillip Savoldo, Barbara Dotti, Gianpietro Rooney, Cliona M. Heslop, Helen E. Shpall, Elizabeth J. Barrett, A. John Bollard, Catherine M. TI Extending the Option of CMV-Specific T Cells from the CMV-Seronegative Donor SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Hanley, Patrick J.; Bollard, Catherine M.] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA. [Nikiforow, Sarah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Melenhorst, Jan] NHLBI, NIH, Bethesda, MD 20892 USA. [Scheinberg, Phillip] Hosp Beneficencia Portuguesa Sao Paulo, Antonio Ermirio de Moraes Oncol Ctr, Sao Paulo, Brazil. [Savoldo, Barbara; Rooney, Cliona M.] Texas Childrens Hosp, Houston, TX 77030 USA. [Dotti, Gianpietro; Bollard, Catherine M.] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Rooney, Cliona M.] Houston Methodist Hosp, Baylor Coll Med, Dept Mol Virol & Microbiol, Ctr Cell & Gene Therapy,Dept Pediat, Houston, TX USA. [Heslop, Helen E.] Methodist Hosp, Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Shpall, Elizabeth J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Barrett, A. John] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 178 BP S131 EP S131 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400183 ER PT J AU Holter-Chakrabarty, JL Zhang, MJ Zhu, XC Akpek, G Aljurf, MD Artz, AS Baron, F Borden, AM Bredeson, CN Dvorak, CC Epstein, RB Lazarus, HM Olsson, R Pierson, N Selby, GB Williams, KM Cooke, KR Pasquini, MC McCarthy, PL AF Holter-Chakrabarty, Jennifer L. Zhang, Mei-Jie Zhu, Xiaochun Akpek, Goergun Aljurf, Mahmoud D. Artz, Andrew S. Baron, Frederic Borden, Amber M. Bredeson, Christopher N. Dvorak, Christopher C. Epstein, Robert B. Lazarus, Hillard M. Olsson, Richard Pierson, Namali Selby, George B. Williams, Kirsten M. Cooke, Kenneth R. Pasquini, Marcelo C. McCarthy, Philip L. TI Sequence of Cyclophosphamide (Cy) and Total Body Irradiation (TBI) Prior to Hematopoietic Cell Transplant (HCT) for Patients with Acute Leukemia: Impact upon Complications and Patient Outcome SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Holter-Chakrabarty, Jennifer L.; Borden, Amber M.; Epstein, Robert B.; Pierson, Namali; Selby, George B.] Univ Oklahoma, Oklahoma City, OK USA. [Zhang, Mei-Jie] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Zhu, Xiaochun] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Akpek, Goergun] Banner MD Anderson Canc Ctr, Gilbert, AZ USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. [Artz, Andrew S.] Univ Chicago Hosp, Chicago, IL 60637 USA. [Baron, Frederic] Univ Liege, GIGA I3, Liege, Belgium. [Bredeson, Christopher N.] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Dvorak, Christopher C.] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Olsson, Richard] Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Williams, Kirsten M.] NCI, NIH, Bethesda, MD 20892 USA. [Cooke, Kenneth R.] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. [Pasquini, Marcelo C.] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [McCarthy, Philip L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 13 BP S31 EP S32 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400018 ER PT J AU Im, A Mitchell, S Steinberg, S Curtis, L Berger, A Baird, K Kuzmina, Z Zhang, D Cole, K Avila, D Taylor, T Baruffaldi, JL Pavletic, SZ AF Im, Annie Mitchell, Sandra Steinberg, Seth Curtis, Lauren Berger, Ann Baird, Kristin Kuzmina, Zoya Zhang, Dan Cole, Kristen Avila, Daniele Taylor, Tiffani Baruffaldi, Judy L. Pavletic, Steven Z. TI Factors Associated with Fatigue in Chronic Graft-Versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Im, Annie] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Mitchell, Sandra] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Steinberg, Seth; Zhang, Dan] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Curtis, Lauren; Kuzmina, Zoya; Cole, Kristen; Avila, Daniele; Taylor, Tiffani; Baruffaldi, Judy L.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Berger, Ann] NCI, NIH, Bethesda, MD 20892 USA. [Baird, Kristin] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 206 BP S148 EP S148 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400211 ER PT J AU Jagasia, MH Chai, XY Pidala, J Inamoto, Y Arora, M Cutler, CS Flowers, MED Johnston, L Pavletic, SZ Lee, SJ AF Jagasia, Madan H. Chai, Xiaoyu Pidala, Joseph Inamoto, Yoshihiro Arora, Mukta Cutler, Corey S. Flowers, Mary E. D. Johnston, Laura Pavletic, Steven Z. Lee, Stephanie J. TI Ocular Gvhd: Epidemiology, Risk Factors and Impact on Quality of Life-a Chronic Gvhd Consortium Study SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Jagasia, Madan H.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Chai, Xiaoyu] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Pidala, Joseph] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Inamoto, Yoshihiro; Flowers, Mary E. D.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Arora, Mukta] Univ Minnesota, Minneapolis, MN USA. [Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Johnston, Laura] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 418 BP S269 EP S269 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400423 ER PT J AU Jain, NA Ito, S Muranski, P Lu, K Haggerty, J Ramos, C Cook, L Hourigan, CS Childs, R Battiwalla, M Barrett, AJ AF Jain, Natasha A. Ito, Sawa Muranski, Pawel Lu, Kit Haggerty, Jan Ramos, Catalina Cook, Lisa Hourigan, Christopher S. Childs, Richard Battiwalla, Minoo Barrett, A. John TI The Clinical and Financial Cost of Preemptive Management of CMV Disease - Implications for Immunotherapy SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Jain, Natasha A.; Ito, Sawa; Muranski, Pawel; Lu, Kit; Haggerty, Jan; Ramos, Catalina; Cook, Lisa; Hourigan, Christopher S.; Childs, Richard; Battiwalla, Minoo; Barrett, A. John] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 172 BP S128 EP S128 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400177 ER PT J AU Kuzmina, Z Rose, JJ Baird, K Naik, HB Cowen, EW Pavletic, SZ Hakim, F AF Kuzmina, Zoya Rose, Jeremy J. Baird, Kristin Naik, Haley Bharat Cowen, Edward W. Pavletic, Steven Z. Hakim, Fran TI Regulatory B Cells Deficiency in Sclerotic-Type Cutaneous Chronic Graft-Versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Kuzmina, Zoya; Rose, Jeremy J.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Baird, Kristin] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Naik, Haley Bharat; Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Pavletic, Steven Z.; Hakim, Fran] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 423 BP S273 EP S273 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400428 ER PT J AU Kuzmina, Z Joe, GO Baird, K Cowen, EW Naik, HB Steinberg, S Comis, L Baruffaldi, JL Avila, D Taylor, T Cole, K Mitchell, S Pavletic, SZ AF Kuzmina, Zoya Joe, Galen O. Baird, Kristin Cowen, Edward W. Naik, Haley Bharat Steinberg, Seth Comis, Leora Baruffaldi, Judy L. Avila, Daniele Taylor, Tiffani Cole, Kristen Mitchell, Sandra Pavletic, Steven Z. TI Prevalence of Joint Deficit Among Chronic Gvhd Patients Who Do Not Manifest Cutaneous or Fascial Sclerosis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Kuzmina, Zoya] NCI, Graft versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Joe, Galen O.; Comis, Leora] NIH, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Baird, Kristin] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.; Naik, Haley Bharat] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Baruffaldi, Judy L.; Avila, Daniele; Taylor, Tiffani; Cole, Kristen] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Mitchell, Sandra] NIH, Outcomes Res Branch, Rockville, MD USA. [Mitchell, Sandra] NIH, Div Canc Control & Populat Sci, Rockville, MD USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 422 BP S272 EP S273 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400427 ER PT J AU Pai, SY Logan, BR Griffith, LM Buckley, RH Parrott, RE Dvorak, CC Kapoor, N Hanson, IC Filipovich, A Jyonouchi, S Small, T Burroughs, L Haight, AE Pulsipher, MA Chan, KW Fuleihan, R Haddad, E Loechelt, B Aquino, V Gillio, AP Davis, JH Knutsen, A Smith, A Moore, TB Schroeder, M Goldman, F Connelly, JA Porteus, MH Xiang, Q Shearer, W Fleisher, T Kohn, DB Puck, J Notarangelo, LD Cowan, MJ O'Reilly, R AF Pai, Sung-Yun Logan, Brent R. Griffith, Linda M. Buckley, Rebecca H. Parrott, Roberta E. Dvorak, Christopher C. Kapoor, Neena Hanson, Imelda C. Filipovich, Alexandra Jyonouchi, Soma Small, Trudy Burroughs, Lauri Haight, Ann E. Pulsipher, Michael A. Chan, Ka Wah Fuleihan, Ramsay Haddad, Elie Loechelt, Brett Aquino, Victor Gillio, Alfred P. Davis, Jeffrey H. Knutsen, Alan Smith, Angela Moore, Theodore B. Schroeder, Marlis Goldman, Frederick Connelly, James A. Porteus, Matthew H. Xiang, Qun Shearer, William Fleisher, Thomas Kohn, Donald B. Puck, Jennifer Notarangelo, Luigi D. Cowan, Morton J. O'Reilly, Richard TI Retrospective Study of 240 Patients with Severe Combined Immunodeficiency Transplanted from 2000-2009: A Report from the Primary Immune Deficiency Treatment Consortium of North America SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Pai, Sung-Yun] Boston Childrens Hosp, Boston, MA USA. [Logan, Brent R.; Xiang, Qun] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Griffith, Linda M.] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Buckley, Rebecca H.; Parrott, Roberta E.] Duke Univ, Med Ctr, Durham, NC USA. [Dvorak, Christopher C.] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Kapoor, Neena] Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90027 USA. [Hanson, Imelda C.; Shearer, William] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Filipovich, Alexandra] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Jyonouchi, Soma] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Small, Trudy] Mem Sloan Kettering Canc Ctr, Dept Pediat, Pediat Bone Marrow Transplant Serv, New York, NY 10021 USA. [Burroughs, Lauri] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Haight, Ann E.] Emory Childrens Healthcare Atlanta, Aflac Canc Ctr, Atlanta, GA USA. [Haight, Ann E.] Emory Childrens Healthcare Atlanta, Blood Disorders Serv, Atlanta, GA USA. [Pulsipher, Michael A.] Univ Utah, Sch Med, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Chan, Ka Wah] Texas Transplant Inst, San Antonio, TX USA. [Fuleihan, Ramsay] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Haddad, Elie] Ste Justine Hosp, Montreal, PQ, Canada. [Loechelt, Brett] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Aquino, Victor] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Gillio, Alfred P.] HUMC, Hackensack, NJ USA. [Davis, Jeffrey H.] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Knutsen, Alan] Cardinal Glennon Childrens Med Ctr, St Louis, MO USA. [Smith, Angela] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Moore, Theodore B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Schroeder, Marlis] CancerCare Manitoba, Pediat BMT Program, Winnipeg, MB, Canada. [Goldman, Frederick] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Connelly, James A.] Univ Michigan, Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Porteus, Matthew H.] Stanford Univ, Palo Alto, CA 94304 USA. [Fleisher, Thomas] NIH, Host Def Lab, Bethesda, MD 20892 USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Puck, Jennifer; Cowan, Morton J.] UCSF Benioff Childrens Hosp, San Francisco, CA USA. [Puck, Jennifer; Cowan, Morton J.] UCSF Benioff Childrens Hosp, Blood & Marrow Transplant Div, San Francisco, CA USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Primary Immunodeficiencies, Boston, MA USA. [O'Reilly, Richard] Mem Sloan Kettering Canc Ctr, Dept Pediat, Bone Marrow Transplant Serv, New York, NY 10021 USA. RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 4 BP S24 EP S25 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400009 ER PT J AU Preussler, JM Majhail, NS Mau, LW Carr, DW Bevans, M Clancy, E Messner, C Parran, L Pederson, K Ferguson, SS Vaughan, W Walters, K Murphy, E Denzen, E AF Preussler, Jaime M. Majhail, Navneet S. Mau, Lih-Wen Carr, Diane W. Bevans, Margaret Clancy, Emilie Messner, Carolyn Parran, Leslie Pederson, Kate Ferguson, Stacy Stickney Vaughan, William Walters, Kent Murphy, Elizabeth Denzen, Ellen TI Housing and Caregiver Challenges for Hematopoietic Cell Transplant Recipients and Their Potential Solutions: Results from a Mixed-Method Study SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Preussler, Jaime M.] Be The Match, Natl Marrow Donor Program, Patient & Hlth Profess Serv, Minneapolis, MN USA. [Majhail, Navneet S.] Cleveland Clin Fdn, Blood & Manow Transplant Program, Cleveland, OH 44195 USA. [Majhail, Navneet S.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Mau, Lih-Wen; Clancy, Emilie] Natl Marrow Donor Program, Minneapolis, MN USA. [Carr, Diane W.; Pederson, Kate; Ferguson, Stacy Stickney; Denzen, Ellen] Natl Marrow Donor Program, Patient & Hlth Profess Serv, Minneapolis, MN USA. [Bevans, Margaret] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Messner, Carolyn] Canc Care Inc, New York, NY USA. [Parran, Leslie] Univ Minnesota, Med Ctr, BMT, Minneapolis, MN 55455 USA. [Vaughan, William] Univ Alabama Birmingham, Bone Marrow Transplantat & Cell Therapy Program, Birmingham, AL USA. [Walters, Kent] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Murphy, Elizabeth] Natl Marrow Donor Program, Patient Serv, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 165 BP S124 EP S124 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400170 ER PT J AU Pulsipher, MA Chitphakdithai, P Logan, BR Switzer, GE Tomblyn, MR Rizzo, JD Anderlini, P Leitman, SF Varni, JW Hays, A Kobusingye, H Miller, JP Drexler, RJ King, R Horowitz, MM Confer, DL Navarro, WH AF Pulsipher, Michael A. Chitphakdithai, Pintip Logan, Brent R. Switzer, Galen E. Tomblyn, Marcie R. Rizzo, J. Douglas Anderlini, Paolo Leitman, Susan F. Varni, James W. Hays, Amy Kobusingye, Hati Miller, John P. Drexler, Rebecca J. King, Roberta Horowitz, Mary M. Confer, Dennis L. Navarro, Willis H. TI Related PBSC Donors Age > 60 Have High Rates of Baseline and Donation-Related Pain and Slow Recovery: First Report from the Related Donor Safety Study (RDSafe) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Pulsipher, Michael A.] Univ Utah, Sch Med, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Chitphakdithai, Pintip; Drexler, Rebecca J.; Confer, Dennis L.; Navarro, Willis H.] Natl Marrow Donor Program, CIBMTR, Minneapolis, MN USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Switzer, Galen E.] Univ Pittsburgh, Pittsburgh, PA USA. [Tomblyn, Marcie R.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Rizzo, J. Douglas] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Leitman, Susan F.] Natl Heart & Lung Inst, NIH, Bethesda, MD USA. [Varni, James W.] Texas A&M Univ, College Stn, TX USA. [Kobusingye, Hati; King, Roberta] CIBMTR, Minneapolis, MN USA. [Miller, John P.] Natl Marrow Donor Program, Minneapolis, MN USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 30 BP S41 EP S42 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400035 ER PT J AU Williams, KM Agwu, AG Chen, M Ahn, KW Szabolcs, P Boeckh, MJ Auletta, JJ Tomblyn, MR AF Williams, Kirsten M. Agwu, Allison G. Chen, Min Ahn, Kwang Woo Szabolcs, Paul Boeckh, Michael J. Auletta, Jeffery J. Tomblyn, Marcie R. TI Cibmtr Retrospective Analysis Reveals Incidence, Mortality, and Timing of Pneumocystis Jiroveci Pneumonia (PCP) after Hematopoietic Stem Cell Transplantation (HSCT) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 26-MAR 02, 2014 CL Grapevine, TX C1 [Williams, Kirsten M.] NCI, NIH, Bethesda, MD 20892 USA. [Williams, Kirsten M.] George Washington Univ, Med Ctr, Childrens Natl Med Ctr, Washington, DC 20037 USA. [Agwu, Allison G.] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. [Chen, Min] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Szabolcs, Paul] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Boeckh, Michael J.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Auletta, Jeffery J.] Nationwide Childrens Hosp, Columbus, OH USA. [Tomblyn, Marcie R.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2014 VL 20 IS 2 SU 1 MA 108 BP S94 EP S94 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AA5QT UT WOS:000331155400113 ER PT J AU Jayes, FL Burns, KA Rodriguez, KF Kissling, GE Korach, KS AF Jayes, Friederike L. Burns, Katherine A. Rodriguez, Karina F. Kissling, Grace E. Korach, Kenneth S. TI The Naturally Occurring Luteinizing Hormone Surge Is Diminished in Mice Lacking Estrogen Receptor Beta in the Ovary SO BIOLOGY OF REPRODUCTION LA English DT Article ID ALPHA ER-ALPHA; REPRODUCTIVE PHENOTYPES; NULL MICE; FEEDBACK-REGULATION; POSITIVE FEEDBACK; LIGHT-INTENSITY; KNOCKOUT MOUSE; IN-VIVO; GONADOTROPIN; PROGESTERONE AB Female ESR2-null mice (betaERKO) display defects in ovarian function and are subfertile. Follicular maturation is impaired and explains smaller litters, but betaERKO also produce fewer litters, which may be partially due to inadequate ovulatory signals. To test this, the amplitude and timing of the naturally occurring luteinizing hormone (LH) surge was measured in individual intact betaERKO and wild-type (WT) mice. Vaginal cytology was evaluated daily, and blood samples were taken from mice in proestrus. The amplitude of the LH surge was severely blunted in betaERKO mice compared to WT, but pituitary LH levels revealed no differences. The betaERKO mice did not produce a preovulatory estradiol surge. To determine if the smaller LH surges and the reduced number of litters in betaERKO were due to the lack of ESR2 in the hypothalamic-pituitary axis or due to the absence of ESR2 in the ovary, ovaries were transplanted from WT into betaERKO mice and vice versa. The size of the LH surge was reduced only in mice lacking ESR2 within the ovary, and these mice had fewer litters. Fertility and size of the LH surge were rescued in betaERKO mice receiving a WT ovary. These data provide the first experimental evidence that the LH surge is impaired in betaERKO females and may contribute to their reduced fertility. ESR2 is not necessary within the pituitary and hypothalamus for the generation of a normal LH surge and for normal fertility, but ESR2 is essential within the ovary to provide proper signals. C1 [Jayes, Friederike L.; Burns, Katherine A.; Rodriguez, Karina F.; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Jayes, Friederike L.] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, LRDT, NIH, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM Korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Division of Intramural Research of the National Institute of Environmental Health Sciences [Z01 ES70065] FX Supported by the Division of Intramural Research of the National Institute of Environmental Health Sciences through Z01 ES70065 to K. S. K. Presented in part at the 39th Annual Meeting of the Society for the Study of Reproduction, 20 July-1 August 2006, Omaha, NE; the 41st Annual Meeting of the Society for the Study of Reproduction, 1730 May 2008, Kailua-Kona, Hawaii; and the Reproductive Tract Biology Gordon Conference, 3-8 August 2008, Andover, NH. NR 48 TC 4 Z9 4 U1 1 U2 3 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD FEB PY 2014 VL 90 IS 2 AR 24 DI 10.1095/biolreprod.113.113316 PG 9 WC Reproductive Biology SC Reproductive Biology GA AA7IZ UT WOS:000331272300003 PM 24337314 ER PT J AU Bobick, BE Alexander, PG Tuan, RS AF Bobick, Brent E. Alexander, Peter G. Tuan, Rocky S. TI High efficiency transfection of embryonic limb mesenchyme with plasmid DNA using square wave pulse electroporation and sucrose buffer SO BIOTECHNIQUES LA English DT Article DE transfection protocol; square wave pulse electroporation; sucrose buffer; cell suspension; embryonic limb mesenchyme; micromass culture; chondrogenesis ID MICROMASS CULTURES; CHONDROGENESIS; CELLS; ANHYDROBIOSIS; SIGNALS AB Micromass cultures of primary embryonic limb mesenchyme are a valuable model system for studying cartilage formation in vitro. However, high efficiency introduction of plasrnid DNA into this hard-to-transfect cell type typically results in considerable cell death and significantly impeded chondrogenesis when the cells are subsequently plated in high density micromass. Here, we describe a novel method in which square wave pulse electroporation of chick embryo wing bud mesenchyme suspended in protective sucrose buffer results in high efficiency transfection without substantially affecting micromass culture cell viability or chondrogenic differentiation potential. Furthermore, we show that this protocol can be employed, along with effector gene expression vectors, to generate observable changes in the amount of cartilage tissue formed in micromass, unlike lower efficiency, higher cytotoxicity techniques that require co-transfection of reporter plasmids to monitor changes in the extent of chondrogenesis and correct for differences in cell viability. C1 [Bobick, Brent E.; Alexander, Peter G.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Alexander, Peter G.; Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15261 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15261 USA. EM rst13@pitt.edu FU Natural Sciences and Engineering Research Council of Canada; Intramural Research Program of the National Institutes of Health [ZO1 AR41131]; Commonwealth of Pennsylvania Department of Health FX The authors thank Mr. Jim Simone (Flow Cytometry Section, NIAMS) and Dr. Farida Djouad (Cartilage Biology and Orthopaedics Branch, NIAMS) for assistance with FACS analysis. Dr. Brent Bobick was supported by a postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada. This research was supported by the Intramural Research Program of the National Institutes of Health (ZO1 AR41131) and funding from the Commonwealth of Pennsylvania Department of Health. This paper is subject to the NIH Public Access Policy. NR 20 TC 1 Z9 1 U1 1 U2 6 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 EI 1940-9818 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 2014 VL 56 IS 2 BP 85 EP 89 DI 10.2144/000114136 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB0OK UT WOS:000331491800006 PM 24502798 ER PT J AU Johnson, TV DeKorver, NW Levasseur, VA Osborne, A Tassoni, A Lorber, B Heller, JP Villasmil, R Bull, ND Martin, KR Tomarev, SI AF Johnson, Thomas V. DeKorver, Nicholas W. Levasseur, Victoria A. Osborne, Andrew Tassoni, Alessia Lorber, Barbara Heller, Janosch P. Villasmil, Rafael Bull, Natalie D. Martin, Keith R. Tomarev, Stanislav I. TI Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome SO BRAIN LA English DT Article DE mesenchymal stem cell; retinal ganglion cell; neuroprotection; glaucoma; platelet derived growth factor ID OPTIC-NERVE; EXPERIMENTAL GLAUCOMA; SIGNALING PATHWAYS; STROMAL CELLS; RAT EYES; B-CHAIN; TRANSPLANTATION; MODEL; PDGF; SURVIVAL AB The development of neuroprotective strategies to attenuate retinal ganglion cell death could lead to novel therapies for chronic optic neuropathies such as glaucoma. Intravitreal transplantation of mesenchymal stem cells slows retinal ganglion cell death in models of optic nerve injury, but the mechanism of action remains unclear. Here we characterized the neuroprotective effects of mesenchymal stem cells and mesenchymal stem cell-derived factors in organotypic retinal explant culture and an in vivo model of ocular hypertensive glaucoma. Co-culture of rat and human bone marrow-derived mesenchymal stem cells with retinal explants increased retinal ganglion cell survival, after 7 days ex vivo, by similar to 2-fold and was associated with reduced apoptosis and increased nerve fibre layer and inner plexiform layer thicknesses. These effects were not demonstrated by co-culture with human or mouse fibroblasts. Conditioned media from mesenchymal stem cells conferred neuroprotection, suggesting that the neuroprotection is mediated, at least partly, by secreted factors. We compared the concentrations of 29 factors in human mesenchymal stem cell and fibroblast conditioned media, and identified 11 enriched in the mesenchymal stem cell secretome. Treatment of retinal explants with a cocktail of these factors conferred retinal ganglion cell neuroprotection, with factors from the platelet-derived growth factor family being the most potent. Blockade of platelet-derived growth factor signalling with neutralizing antibody or with small molecule inhibitors of platelet-derived growth factor receptor kinase or downstream phosphatidylinositol 3 kinase eliminated retinal ganglion cell neuroprotection conferred by mesenchymal stem cell co-culture. Intravitreal injection of platelet-derived growth factor -AA or -AB led to profound optic nerve neuroprotection in vivo following experimental induction of elevated intraocular pressure. These data demonstrate that mesenchymal stem cells secrete a number of neuroprotective proteins and suggest that platelet-derived growth factor secretion in particular may play an important role in mesenchymal stem cell-mediated retinal ganglion cell neuroprotection. Furthermore, platelet-derived growth factor may represent an independent target for achieving retinal ganglion cell neuroprotection. C1 [Johnson, Thomas V.; DeKorver, Nicholas W.; Levasseur, Victoria A.; Tomarev, Stanislav I.] NEI, Sect Retinal Gangl Cell Biol, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Johnson, Thomas V.; Osborne, Andrew; Tassoni, Alessia; Lorber, Barbara; Heller, Janosch P.; Bull, Natalie D.; Martin, Keith R.] Univ Cambridge, John van Geest Ctr Brain Repair, Dept Ophthalmol, NIHR Biomed Res Ctr, Cambridge CB2 0PY, England. [Johnson, Thomas V.; Osborne, Andrew; Tassoni, Alessia; Lorber, Barbara; Heller, Janosch P.; Bull, Natalie D.; Martin, Keith R.] Univ Cambridge, Wellcome Trust MRC Cambridge Stem Cell Inst, Cambridge CB2 0PY, England. [Johnson, Thomas V.] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. [Villasmil, Rafael] NEI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20814 USA. RP Johnson, TV (reprint author), Johns Hopkins Sch Med, 1830 Monument St,Suite 2-300, Baltimore, MD 21205 USA. EM tvjohnson@jhmi.edu; krgm2@cam.ac.uk; tomarevs@nei.nih.gov RI Johnson, Thomas/C-9351-2011 OI Johnson, Thomas/0000-0002-5372-5457 FU National Institutes of Health OxCam Scholarship; Johns Hopkins Medical Scientist Training Program; Fight for Sight (UK); Prevention of Blindness Society of Metropolitan Washington; Cambridge Eye Trust; Jukes Glaucoma Research Fund; National Eye Institute Intramural Research Program FX T.V.J. was supported by a National Institutes of Health OxCam Scholarship and the Johns Hopkins Medical Scientist Training Program. N.D.B. and K.R.M. were supported by a grant from Fight for Sight (UK). This work was also funded by a grant from the Prevention of Blindness Society of Metropolitan Washington, the Cambridge Eye Trust, The Jukes Glaucoma Research Fund, and the National Eye Institute Intramural Research Program. NR 49 TC 34 Z9 36 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD FEB PY 2014 VL 137 BP 503 EP 519 DI 10.1093/brain/awt292 PN 2 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AA7QB UT WOS:000331290900018 PM 24176979 ER PT J AU Jeong, W Rapisarda, A Park, SR Kinders, RJ Chen, A Melillo, G Turkbey, B Steinberg, SM Choyke, P Doroshow, JH Kummar, S AF Jeong, Woondong Rapisarda, Annamaria Park, Sook Ryun Kinders, Robert J. Chen, Alice Melillo, Giovanni Turkbey, Baris Steinberg, Seth M. Choyke, Peter Doroshow, James H. Kummar, Shivaani TI Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1 alpha), in patients with refractory solid tumors SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Synthetic locked nucleic acid (LNA) oligodeoxynucleotide; Pharmacodynamics-driven trials; Antiangiogenesis; HIF mRNA ID CANCER-THERAPY; OVEREXPRESSION; FACTOR-1-ALPHA; GROWTH; RNA AB Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor tissues to oxygen deprivation. HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many genes necessary for survival. EZN-2968 is an antisense oligodeoxynucleotide that specifically targets HIF-1 alpha, one of the subunits of HIF-1. We conducted a trial of EZN-2968 in patients with refractory solid tumors to evaluate antitumor response and to measure modulation of HIF-1 alpha mRNA and protein levels as well as HIF-1 target genes. Adult patients with refractory advanced solid tumors were administered EZN-2968 as a 2-h IV infusion at a dose of 18 mg/kg once a week for three consecutive weeks followed by 3-week off; in a 6-week cycle. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were performed at baseline and after the third dose. Ten patients were enrolled, of whom all were evaluable for response; one patient with a duodenal neuroendocrine tumor had prolonged stabilization of disease (24 weeks). Reduction in HIF-1 alpha mRNA levels compared to baseline was demonstrated in 4 of 6 patients with paired tumor biopsies. Reductions in levels of HIF-1 alpha protein and mRNA levels of some target genes were observed in two patients. Quantitative analysis of DCE-MRI from two patients revealed changes in K (trans) and k (ep). The trial was closed prematurely when the sponsor suspended development of this agent. This trial provides preliminary proof of concept for modulation of HIF-1 alpha mRNA and protein expression and target genes in tumor biopsies following the administration of EZN-2968. C1 [Jeong, Woondong; Park, Sook Ryun; Chen, Alice; Doroshow, James H.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Rapisarda, Annamaria; Kinders, Robert J.; Melillo, Giovanni] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Turkbey, Baris; Steinberg, Seth M.; Choyke, Peter; Doroshow, James H.; Kummar, Shivaani] 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 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Drs. Yvonne, A. Evrard, and Andrea Voth for editorial assistance. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 20 TC 22 Z9 22 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2014 VL 73 IS 2 BP 343 EP 348 DI 10.1007/s00280-013-2362-z PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AA6IQ UT WOS:000331202400015 PM 24292632 ER PT J AU Yao, PL Gonzalez, FJ Peters, JM AF Yao, Pei-Li Gonzalez, Frank J. Peters, Jeffrey M. TI Targeting Estrogen Receptor-beta for the Prevention of Nonmelanoma Skin Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID EXPRESSION; LEUKOCYTES; SEQUENCE; AGONISTS; LIGANDS; DISEASE; DESIGN; MODELS AB The potential for targeting estrogen receptor (ER)-beta in various cancer models has been gaining considerable attention in recent years. In this issue of the journal, Chaudhary and colleagues demonstrate markedly decreased ultraviolet B (UVB)-induced skin cancer in a mouse model using a highly specific ER-beta agonist, ERB-041. The mechanisms that underlie this strong inhibitory effect are mediated by inhibition of proinflammatory signaling and epithelial-mesenchymal transition (EMT). The changes in EMT were due in part to modulation of WNT/beta-catenin signaling. Collectively, the results from these studies provide important new insights into the mechanisms by which the ER-beta agonist ERB-041 inhibits UVB-induced skin cancer and opens the door for future studies that could examine combinatorial approaches for UVB-dependent skin cancer chemoprevention. (C) 2014 AACR. C1 [Yao, Pei-Li; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Yao, Pei-Li; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, Life Sci Bldg, University Pk, PA 16802 USA. EM jmp21@psu.edu FU NCI NIH HHS [R01 CA124533, R01 CA140369] NR 21 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2014 VL 7 IS 2 BP 182 EP 185 DI 10.1158/1940-6207.CAPR-13-0409 PG 4 WC Oncology SC Oncology GA AA5FW UT WOS:000331122500002 PM 24464730 ER PT J AU Chaudhary, SC Singh, T Talwelkar, SS Srivastava, RK Arumugam, A Weng, ZP Elmets, CA Afaq, F Kopelovich, L Athar, M AF Chaudhary, Sandeep C. Singh, Tripti Talwelkar, Sarang S. Srivastava, Ritesh K. Arumugam, Aadithya Weng, Zhiping Elmets, Craig A. Afaq, Farrukh Kopelovich, Levy Athar, Mohammad TI Erb-041, an Estrogen Receptor-beta Agonist, Inhibits Skin Photocarcinogenesis in SKH-1 Hairless Mice by Downregulating the WNT Signaling Pathway SO CANCER PREVENTION RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; EPITHELIAL-MESENCHYMAL TRANSITION; XENOGRAFT MURINE MODEL; NF-KAPPA-B; TARGETING MTOR; ER-BETA; CANCER; INFLAMMATION; EXPRESSION; BASAL AB Estrogen receptors (ER), including ER-alpha and ER-beta, are known to regulate multiple biologic responses in various cell types. The expression of ER-beta is lost in various cancers. ER-beta agonists were shown to modulate inflammation, cancer cell proliferation, and differentiation. Here, we investigated the cancer chemopreventive properties of Erb-041, an ER-beta agonist, using a model of UVB-induced photocarcinogenesis in SKH-1 mice. Erb-041 significantly reduced UVB-induced carcinogenesis. Tumor numbers and volume were reduced by 60% and 84%, respectively, in the Erb-041-treated group as compared with UVB (alone) control. This inhibition in tumorigenesis was accompanied by the decrease in proliferating cell nuclear antigen (PCNA), cyclin D1, VEGF, and CD31, and an increase in apoptosis. The lost ER-beta expression in squamous cell carcinomas (SCC) was significantly recovered by Erb-041 treatment. In addition, the UVB-induced inflammatory responses were remarkably reduced. Myeloperoxidase activity, levels of cytokines (interleukin (IL)-1 beta, IL-6, and IL-10), and expression of p-ERK (extracellular signal-regulated kinase) 1/2, p-p38, p-I kappa B, iNOS, COX-2, and nuclear NF-kappa Bp65 were diminished. The number of tumor-associated inflammatory cells (GR-1(+)/CD11b(+) and F4/80(+)) was also decreased. Tumors excised from Erb-041-treated animal were less invasive and showed reduced epithelial-mesenchymal transition (EMT). The enhanced expression of E-cadherin with the concomitantly reduced expression of N-cadherin, Snail, Slug, and Twist characterized these lesions. The WNT/beta-catenin signaling pathway, which underlies pathogenesis of skin cancer, was found to be downregulated by Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory proteins were noticed following treatment of tumor cells with a WNT signaling inhibitor XAV939. Our results show that Erb-041 is a potent skin cancer chemopreventive agent that acts by dampening the WNT/beta-catenin signaling pathway. (C)2013 AACR. C1 [Chaudhary, Sandeep C.; Singh, Tripti; Talwelkar, Sarang S.; Srivastava, Ritesh K.; Arumugam, Aadithya; Weng, Zhiping; Elmets, Craig A.; Afaq, Farrukh; Athar, Mohammad] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Athar, M (reprint author), Univ Alabama Birmingham, Dept Dermatol, 1530 3rd Ave South,VH 509, Birmingham, AL 35294 USA. EM mathar@uab.edu RI Talwelkar, Sarang/C-8925-2015; OI Srivastava, Rakesh/0000-0003-3112-4252; Srivastava, Rakesh/0000-0002-0065-4069 FU National Cancer Institute [NIH/NCI N01-CN-43300 274, R01 CA138998] FX This study was supported by grants NIH/NCI N01-CN-43300 274 and R01 CA138998 from National Cancer Institute (to M. Athar). NR 47 TC 9 Z9 10 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2014 VL 7 IS 2 BP 186 EP 198 DI 10.1158/1940-6207.CAPR-13-0276 PG 13 WC Oncology SC Oncology GA AA5FW UT WOS:000331122500003 PM 24217507 ER PT J AU Kim, MS Kim, JE Lim, DY Huang, ZN Chen, HY Langfald, A Lubet, RA Grubbs, CJ Dong, ZG Bode, AM AF Kim, Mi-Sung Kim, Jong-Eun Lim, Do Young Huang, Zunnan Chen, Hanyong Langfald, Alyssa Lubet, Ronald A. Grubbs, Clinton J. Dong, Zigang Bode, Ann M. TI Naproxen Induces Cell-Cycle Arrest and Apoptosis in Human Urinary Bladder Cancer Cell Lines and Chemically Induced Cancers by Targeting PI3K SO CANCER PREVENTION RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CANINE MODEL; INHIBITION; CARCINOMA; PATHWAY; PROLIFERATION; 3-KINASE/AKT; MODULATION; EXPRESSION; PIROXICAM AB Naproxen [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid] is a potent nonsteroidal anti-inflammatory drug that inhibits both COX-1 and COX-2 and is widely used as an over-the-counter medication. Naproxen exhibits analgesic, antipyretic, and anti-inflammatory activities. Naproxen, as well as other nonsteroidal anti-inflammatory drug, has been reported to be effective in the prevention of urinary bladder cancer in rodents. However, potential targets other than the COX isozymes have not been reported. We examined potential additional targets in urinary bladder cancer cells and in rat bladder cancers. Computer kinase profiling results suggested that phosphoinositide 3-kinase (PI3K) is a potential target for naproxen. In vitro kinase assay data revealed that naproxen interacts with PI3K and inhibits its kinase activity. Pull-down binding assay data confirmed that PI3K directly binds with naproxen in vitro and ex vivo. Western blot data showed that naproxen decreased phosphorylation of Akt, and subsequently decreased Akt signaling in UM-UC-5 and UM-UC-14 urinary bladder cancer cells. Furthermore, naproxen suppressed anchorage-independent cell growth and decreased cell viability by targeting PI3K in both cell lines. Naproxen caused an accumulation of cells at the G(1) phase mediated through cyclin-dependent kinase 4, cyclin D1, and p21. Moreover, naproxen induced significant apoptosis, accompanied with increased levels of cleaved caspase-3, caspase-7, and PARP in both cell types. Naproxen-induced cell death was mainly because of apoptosis in which a prominent downregulation of Bcl-2 and upregulation of Bax were involved. Naproxen also caused apoptosis and inhibited Akt phosphorylation in rat urinary bladder cancers induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine. (C)2013 AACR. C1 [Kim, Mi-Sung; Kim, Jong-Eun; Lim, Do Young; Huang, Zunnan; Chen, Hanyong; Langfald, Alyssa; Dong, Zigang; Bode, Ann M.] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lubet, Ronald A.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Grubbs, Clinton J.] Univ Alabama Birmingham, Birmingham, AL USA. RP Bode, AM (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM ambode@hi.umn.edu RI kim, jong-eun/B-3550-2017 OI kim, jong-eun/0000-0002-5030-6126 FU The Hormel Foundation; National Institutes of Health [HHSN-261200433009C, NO1-CN-55006-72] FX This work was supported by The Hormel Foundation and National Institutes of Health Contract HHSN-261200433009C and NO1-CN-55006-72. NR 34 TC 6 Z9 7 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2014 VL 7 IS 2 BP 236 EP 245 DI 10.1158/1940-6207.CAPR-13-0288 PG 10 WC Oncology SC Oncology GA AA5FW UT WOS:000331122500008 PM 24327721 ER PT J AU Nicastro, HL Grubbs, CJ Juliana, MM Bode, AM Kim, MS Lu, Y You, M Milne, GL Boring, D Steele, VE Lubet, RA AF Nicastro, Holly L. Grubbs, Clinton J. Juliana, M. Margaret Bode, Ann M. Kim, Mi-Sung Lu, Yan You, Ming Milne, Ginger L. Boring, Daniel Steele, Vernon E. Lubet, Ronald A. TI Preventive Effects of NSAIDs, NO-NSAIDs, and NSAIDs Plus Difluoromethylornithine in a Chemically Induced Urinary Bladder Cancer Model SO CANCER PREVENTION RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SPORADIC COLORECTAL ADENOMAS; CYCLOOXYGENASE-2 INHIBITOR; CHEMOPREVENTIVE EFFICACY; ANIMAL-MODELS; DOUBLE-BLIND; RAT COLON; CELECOXIB; CARCINOGENESIS; MODULATION AB Urinary bladder cancer prevention studies were performed with the nonsteroidal anti-inflammatory drugs (NSAID) naproxen (a standard NSAID with a good cardiovascular profile), sulindac, and their nitric oxide (NO) derivatives. In addition, the effects of the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), alone or combined with a suboptimal dose of naproxen or sulindac was examined. Agents were evaluated at their human equivalent doses (HED), as well as at lower doses. In the hydroxybutyl(butyl) nitrosamine (OH-BBN) model of urinary bladder cancer, naproxen (400 or 75 ppm) and sulindac (400 ppm) reduced the incidence of large bladder cancers by 82%, 68%, and 44%, respectively, when the agents were initially given 3 months after the final dose of the carcinogen; microscopic cancers already existed. NO-naproxen was highly effective, whereas NO-sulindac was inactive. To further compare naproxen and NO-naproxen, we examined their effects on gene expression in rat livers following a 7-day exposure. Limited, but similar, gene expression changes in the liver were induced by both agents, implying that the primary effects of both are mediated by the parent NSAID. When agents were initiated 2 weeks after the last administration of OH-BBN, DFMO at 1,000 ppm had limited activity, a low dose of naproxen (75 ppm) and sulindac (150 ppm) were highly and marginally effective. Combining DFMO with suboptimal doses of naproxen had minimal effects, whereas the combination of DMFO and sulindac was more active than either agent alone. Thus, naproxen and NO-naproxen were highly effective, whereas sulindac was moderately effective in the OH-BBN model at their HEDs. (C)2013 AACR. C1 [Nicastro, Holly L.] NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Bethesda, MD 20852 USA. [Boring, Daniel; Steele, Vernon E.; Lubet, Ronald A.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20852 USA. [Grubbs, Clinton J.; Juliana, M. Margaret] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Grubbs, Clinton J.; Juliana, M. Margaret] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA. [Bode, Ann M.; Kim, Mi-Sung] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lu, Yan; You, Ming] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [Milne, Ginger L.] Vanderbilt Univ Sch Med, Div Clin Pharmacol, Eicosanoid Core Lab, Nashville, TN USA. RP Lubet, RA (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20852 USA. EM lubetr@mail.nih.gov RI Milne, Ginger/D-7648-2014 OI Milne, Ginger/0000-0003-3890-151X FU NCI [HHSN261200433001C] FX The work is supported by NCI contracts number HHSN261200433001C and HHSN261200433001C to C. Grubbs. NR 31 TC 4 Z9 4 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2014 VL 7 IS 2 BP 246 EP 254 DI 10.1158/1940-6207.CAPR-13-0164 PG 9 WC Oncology SC Oncology GA AA5FW UT WOS:000331122500009 PM 24346344 ER PT J AU Charbonneau, B Block, MS Bamlet, WR Vierkant, RA Kalli, KR Fogarty, Z Rider, DN Sellers, TA Tworoger, SS Poole, E Risch, HA Salvesen, HB Kiemeney, LA Baglietto, L Giles, GG Severi, G Trabert, B Wentzensen, N Chenevix-Trench, G Whittemore, AS Sieh, W Chang-Claude, J Bandera, EV Orlow, I Terry, K Goodman, MT Thompson, PJ Cook, LS Rossing, MA Ness, RB Narod, SA Kupryjanczyk, J Lu, KR Butzow, R Dork, T Pejovic, T Campbell, I Le, ND Bunker, CH Bogdanova, N Runnebaum, IB Eccles, D Paul, J Wu, ANH Gayther, SA Hogdall, E Heitz, F Kaye, SB Karlan, BY Anton-Culver, H Gronwald, J Hogdall, CK Lambrechts, D Fasching, PA Menon, U Schildkraut, J Pearce, CL Levine, DA Kjaer, SK Cramer, D Flanagan, JM Phelan, CM Brown, R Massuger, LFAG Song, HL Doherty, JA Krakstad, C Liang, D Odunsi, K Berchuck, A Jensen, A Lubinski, J Nevanlinna, H Bean, YT Lurie, G Ziogas, A Walsh, C Despierre, E Brinton, L Hein, A Rudolph, A Dansonka-Mieszkowska, A Olson, SH Harter, P Tyrer, J Vitonis, AF Brooks-Wilson, A Aben, KK Pike, MC Ramus, SJ Wik, E Cybulski, C Lin, J Sucheston, L Edwards, R McGuire, V Lester, J du Bois, A Lundvall, L Wang-Gohrke, S Szafron, LM Lambrechts, S Yang, H Beckmann, MW Pelttari, LM Van Altena, AM van den Berg, D Halle, MK Gentry-Maharaj, A Schwaab, I Chandran, U Menkiszak, J Ekici, AB Wilkens, LR Leminen, A Modugno, F Friel, G Rothstein, JH Vergote, I Garcia-Closas, M Hildebrandt, MAT Sobiczewski, P Kelemen, LE Pharoah, PDP Moysich, K Knutson, KL Cunningham, JM Fridley, BL Goode, EL AF Charbonneau, Bridget Block, Matthew S. Bamlet, William R. Vierkant, Robert A. Kalli, Kimberly R. Fogarty, Zachary Rider, David N. Sellers, Thomas A. Tworoger, Shelley S. Poole, Elizabeth Risch, Harvey A. Salvesen, Helga B. Kiemeney, Lambertus A. Baglietto, Laura Giles, Graham G. Severi, Gianluca Trabert, Britton Wentzensen, Nicolas Chenevix-Trench, Georgia Whittemore, Alice S. Sieh, Weiva Chang-Claude, Jenny Bandera, Elisa V. Orlow, Irene Terry, Kathryn Goodman, Marc T. Thompson, Pamela J. Cook, Linda S. Rossing, Mary Anne Ness, Roberta B. Narod, Steven A. Kupryjanczyk, Jolanta Lu, Karen Butzow, Ralf Doerk, Thilo Pejovic, Tanja Campbell, Ian Le, Nhu D. Bunker, Clareann H. Bogdanova, Natalia Runnebaum, Ingo B. Eccles, Diana Paul, James Wu, Anna H. Gayther, Simon A. Hogdall, Estrid Heitz, Florian Kaye, Stanley B. Karlan, Beth Y. Anton-Culver, Hoda Gronwald, Jacek Hogdall, Claus K. Lambrechts, Diether Fasching, Peter A. Menon, Usha Schildkraut, Joellen Pearce, Celeste Leigh Levine, Douglas A. Kjaer, Susanne Kruger Cramer, Daniel Flanagan, James M. Phelan, Catherine M. Brown, Robert Massuger, Leon F. A. G. Song, Honglin Doherty, Jennifer A. Krakstad, Camilla Liang, Dong Odunsi, Kunle Berchuck, Andrew Jensen, Allan Lubinski, Jan Nevanlinna, Heli Bean, Yukie T. Lurie, Galina Ziogas, Argyrios Walsh, Christine Despierre, Evelyn Brinton, Louise Hein, Alexander Rudolph, Anja Dansonka-Mieszkowska, Agnieszka Olson, Sara H. Harter, Philipp Tyrer, Jonathan Vitonis, Allison F. Brooks-Wilson, Angela Aben, Katja K. Pike, Malcolm C. Ramus, Susan J. Wik, Elisabeth Cybulski, Cezary Lin, Jie Sucheston, Lara Edwards, Robert McGuire, Valerie Lester, Jenny du Bois, Andreas Lundvall, Lene Wang-Gohrke, Shan Szafron, Lukasz M. Lambrechts, Sandrina Yang, Hannah Beckmann, Matthias W. Pelttari, Liisa M. Van Altena, Anne M. van den Berg, David Halle, Mari K. Gentry-Maharaj, Aleksandra Schwaab, Ira Chandran, Urmila Menkiszak, Janusz Ekici, Arif B. Wilkens, Lynne R. Leminen, Arto Modugno, Francesmary Friel, Grace Rothstein, Joseph H. Vergote, Ignace Garcia-Closas, Montserrat Hildebrandt, Michelle A. T. Sobiczewski, Piotr Kelemen, Linda E. Pharoah, Paul D. P. Moysich, Kirsten Knutson, Keith L. Cunningham, Julie M. Fridley, Brooke L. Goode, Ellen L. CA AOCS-ACS Grp TI Risk of Ovarian Cancer and the NF-kappa B Pathway: Genetic Association with IL1A and TNFSF10 SO CANCER RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SINGLE-NUCLEOTIDE POLYMORPHISMS; PELVIC-INFLAMMATORY-DISEASE; GENOME-WIDE ASSOCIATION; ORAL-CONTRACEPTIVES; REPRODUCTIVE FACTORS; EPITHELIAL-CELLS; ACTIVATION; POPULATION; APOPTOSIS AB A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1 alpha (IL1A) is both regulated by and able to activate NF-kappa B, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 x 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. C1 [Charbonneau, Bridget; Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. [Block, Matthew S.; Kalli, Kimberly R.] Mayo Clin, Dept Med Oncol, Rochester, MN 55905 USA. [Bamlet, William R.; Vierkant, Robert A.; Fogarty, Zachary; Rider, David N.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Knutson, Keith L.] Mayo Clin, Dept Hlth Sci Res, Dept Immunol, Rochester, MN 55905 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN 55905 USA. [Sellers, Thomas A.; Phelan, Catherine M.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL 33682 USA. [Tworoger, Shelley S.; Poole, Elizabeth] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Terry, Kathryn; Cramer, Daniel; Vitonis, Allison F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Tworoger, Shelley S.; Poole, Elizabeth; Terry, Kathryn; Cramer, Daniel] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Salvesen, Helga B.; Krakstad, Camilla; Wik, Elisabeth; Halle, Mari K.] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Salvesen, Helga B.; Krakstad, Camilla; Halle, Mari K.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Wik, Elisabeth] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Kiemeney, Lambertus A.; Aben, Katja K.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Massuger, Leon F. A. G.; Van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.; Aben, Katja K.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Campbell, Ian] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Campbell, Ian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. Peter MacCallum Canc Inst, Melbourne, Vic 3000, Australia. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic, Australia. [Chenevix-Trench, Georgia; AOCS-ACS Grp] Queensland Inst Med Res, Canc Div, Herston, Qld 4006, Australia. [Trabert, Britton; Wentzensen, Nicolas; Brinton, Louise; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Whittemore, Alice S.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Palo Alto, CA 94304 USA. [Goodman, Marc T.; Thompson, Pamela J.] Samuel Oschin Comprehens Canc Inst, Los Angeles, CA USA. [Karlan, Beth Y.; Walsh, Christine; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Wu, Anna H.; Gayther, Simon A.; Pearce, Celeste Leigh; Pike, Malcolm C.; Ramus, Susan J.; van den Berg, David] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Doerk, Thilo; Bogdanova, Natalia] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Runnebaum, Ingo B.] Univ Jena, Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Heitz, Florian; Harter, Philipp; du Bois, Andreas] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Heitz, Florian; Harter, Philipp; du Bois, Andreas] Kliniken Essen Mitte, Evang Huyssens Stiftung, Knappschaft GmbH, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.] Univ Hosp Erlangen, Ctr Comprehens Canc, Dept Gynecol & Obstet, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Bandera, Elisa V.; Chandran, Urmila] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Orlow, Irene; Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Odunsi, Kunle; Pike, Malcolm C.; Sucheston, Lara; Friel, Grace; Moysich, Kirsten] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Lin, Jie; Hildebrandt, Michelle A. T.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Le, Nhu D.] BC Canc Agcy, Vancouver, BC, Canada. [Brooks-Wilson, Angela] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet & Oncol, Calgary, AB, Canada. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Szafron, Lukasz M.] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol, Warsaw, Poland. [Sobiczewski, Piotr] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Gynecol Oncol, Warsaw, Poland. [Gronwald, Jacek; Lubinski, Jan; Cybulski, Cezary] Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Clin Gynaecol Surg & Oncol, Szczecin, Poland. [Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Leminen, Arto] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. [Pejovic, Tanja; Bean, Yukie T.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja; Bean, Yukie T.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Bunker, Clareann H.; Modugno, Francesmary] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Edwards, Robert; Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert; Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Edwards, Robert; Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, Southampton SO9 5NH, Hants, England. [Paul, James] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Kaye, Stanley B.] Inst Canc Res, Div Clin Studies, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Royal Marsden Hosp, Sutton, Surrey, England. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Gynaecol Canc Res Ctr, London, England. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, London, England. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Dept Womens Canc, London, England. [Flanagan, James M.; Brown, Robert] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London, England. [Song, Honglin; Tyrer, Jonathan; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Hogdall, Estrid; Kjaer, Susanne Kruger; Jensen, Allan] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Hogdall, Claus K.; Kjaer, Susanne Kruger; Lundvall, Lene] Rigshosp, Dept Obstet & Gynecol, Juliane Marie Ctr, DK-2100 Copenhagen, Denmark. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Louvain, Belgium. [Lambrechts, Diether] Univ Louvain, Dept Oncol, Lab Translat Genet, Louvain, Belgium. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Univ Hosp Leuven, Leuven Canc Inst, Dept Obstet & Gynecol, Div Gynecol Oncol, Louvain, Belgium. [Schildkraut, Joellen] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Schildkraut, Joellen] Duke Canc Inst, Cancer Prevent Detect & Control Res Program, Durham, NC USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Epidemiol & Biostat Sect, Lebanon, NH USA. [Lurie, Galina; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. RP Goode, EL (reprint author), Mayo Clin, Coll Med, Dept Hlth Sci Res, 200 First St SW,Charlton 6, Rochester, MN 55905 USA. EM egoode@mayo.edu RI Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Menkiszak, Janusz/I-4036-2014; Gronwald, Jacek/A-4576-2017; salvesen, Helga/C-1187-2017; Whittemore, Alice/F-9925-2014; Brooks-Wilson, Angela/E-9399-2012; Brinton, Louise/G-7486-2015; van Altena, Anne/B-9824-2016; Dork, Thilo/J-8620-2012; Trabert, Britton/F-8051-2015; Hein, Alexander/F-6999-2010; Bandera, Elisa/M-4169-2014; Massuger, Leon/H-8072-2014; Kiemeney, Lambertus/D-3357-2009; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015 OI Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Gronwald, Jacek/0000-0002-3643-2871; salvesen, Helga/0000-0002-4438-8831; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; Brooks-Wilson, Angela/0000-0003-1009-6408; Brinton, Louise/0000-0003-3853-8562; Hein, Alexander/0000-0003-2601-3398; Bandera, Elisa/0000-0002-8789-2755; Kiemeney, Lambertus/0000-0002-2368-1326; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650 FU European Community [223175, HEALTH-F2-2009-223175; COGS]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689]; NIH [CA128978]; Post-Cancer GWAS initiative [1 U19 CA 148537]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; Kathryn Sladek Smith [PPD/RPCI.07]; US National Cancer Institute GAME-ON Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113]; Deutsche Krebshilfe; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; Canadian Institutes of Health Research New Investigator award [MSH-87734]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; American Cancer Society [CRTG-00-196-01-CCE]; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Canadian Institutes for Health Research [MOP-86727]; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Celma Mastry Ovarian Cancer Foundation the Danish Cancer Society [94-222-52]; ELAN Funds of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Sigrid Juselius Foundation; Imperial Experimental Cancer Research Centre [C1312/A15589]; Nationaal Kankerplan of Belgium; L & S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; U.S. Army Medical Research and Materiel Command [W81XWH-07-1-0449]; U.S. National Cancer Institute [K07-CA80668, K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966]; Intramural research funds; NIH/National Center for Research Resources/General Clinical Research Center [MO1-RR000056]; U.S. Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669]; National Health and Medical Research Council of Australia [199600, 400281, 209057, 251533, 396414, 504715]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttembergthrough Medical Faculty of the University of Ulm [P.685]; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College London Hospital; Royal Marsden Hospital; WorkSafeBC; Helse Vest; Norwegian Cancer Society; Research Council of Norway (HBS/NOR); [R25 CA92049] FX Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692), the NIH (CA128978) and Post-Cancer GWAS initiative (No. 1 U19 CA 148537-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.; The OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of the data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available at http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113.; B. Charbonneau is supported by R25 CA92049. G. Chenevix-Trench and P.A. Fasching are supported by the Deutsche Krebshilfe. B.Y. Karlan holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). L.E. Kelemen is supported by a Canadian Institutes of Health Research New Investigator award (MSH-87734).; Funding of the constituent studies was provided by the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation the Danish Cancer Society (94-222-52); ELAN Funds of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Sigrid Juselius Foundation; Imperial Experimental Cancer Research Centre (C1312/A15589); the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the U.S. Army Medical Research and Materiel Command (W81XWH-07-1-0449); the U.S. National Cancer Institute (K07-CA80668, K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, and Intramural research funds); NIH/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056; the U.S. Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669); the National Health and Medical Research Council of Australia (199600, 400281, 209057, 251533, 396414, 504715); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttembergthrough Medical Faculty of the University of Ulm (P.685); the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College London Hospital and the Royal Marsden Hospital; WorkSafeBC; Helse Vest, The Norwegian Cancer Society, The Research Council of Norway (HBS/NOR). NR 58 TC 15 Z9 15 U1 0 U2 20 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2014 VL 74 IS 3 BP 852 EP 861 DI 10.1158/0008-5472.CAN-13-1051 PG 10 WC Oncology SC Oncology GA AA4NX UT WOS:000331073900022 PM 24272484 ER PT J AU Deroo, LA Bolick, SCE Xu, ZL Umbach, DM Shore, D Weinberg, CR Sandler, DP Taylor, JA AF DeRoo, Lisa A. Bolick, Sophia C. E. Xu, Zongli Umbach, David M. Shore, David Weinberg, Clarice R. Sandler, Dale P. Taylor, Jack A. TI Global DNA methylation and one-carbon metabolism gene polymorphisms and the risk of breast cancer in the Sister Study SO CARCINOGENESIS LA English DT Article ID METHYLENETETRAHYDROFOLATE REDUCTASE; LINE-1 METHYLATION; COMMON MUTATION; WIDE ASSOCIATION; NORMAL-TISSUES; BLOOD; HYPOMETHYLATION; COHORT; LEVEL; TUMOR AB Global decrease in DNA methylation is a common feature of cancer and is associated with genomic and chromosomal instability. Retrospective casecontrol studies have reported that cancer patients have lower global methylation levels in blood DNA than do controls. We used prospectively collected samples and a casecohort study design to examine global DNA methylation and incident breast cancer in 294 cases and a sample of 646 non-cases in the Sister Study, a study of 50 884 women aged 3574 years who had not been diagnosed with breast cancer at the time of blood draw. Global methylation in DNA from peripheral blood was assessed by pyrosequencing of the LINE-1 repetitive element. Quartiles of LINE-1 methylation levels were associated with the risk of breast cancer in a dose-dependent fashion (P, trend 0.002), with an increased risk observed among women in the lowest quartile compared with those in the highest quartile (hazard ratio 1.75; 95% confidence interval 1.19, 2.59). We also examined 22 polymorphisms in 10 one-carbon metabolism genes in relation to both LINE-1 methylation levels and breast cancer. We found three single-nucleotide polymorphisms in those genes associated with LINE-1 methylation: SLC19A1 (rs1051266); MTRR (rs10380) and MTHFR (rs1537514), one of which was also associated with breast cancer risk: MTHFR (rs1537514). PON1 (rs757158) was associated with breast cancer but not methylation. C1 [DeRoo, Lisa A.; Xu, Zongli; Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [DeRoo, Lisa A.] Univ Bergen, Dept Global Publ Hlth & Primary Care, NO-5020 Bergen, Norway. [Bolick, Sophia C. E.; Taylor, Jack A.] NIEHS, Lab Mol Carcinogenesis, Res Triangle Pk, NC 27709 USA. [Umbach, David M.; Weinberg, Clarice R.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Shore, David] Westat Corp, Res Triangle Pk, NC 27703 USA. RP Taylor, JA (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES044005, Z01 ES049033] FX Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES044005, Z01 ES049033). NR 50 TC 18 Z9 18 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2014 VL 35 IS 2 BP 333 EP 338 DI 10.1093/carcin/bgt342 PG 6 WC Oncology SC Oncology GA AA7IX UT WOS:000331272100010 PM 24130171 ER PT J AU Dallal, CM Tice, JA Buist, DS Bauer, DC Lacey, JV Cauley, JA Hue, TF LaCroix, A Falk, RT Pfeiffer, RM Fuhrman, BJ Veenstra, TD Xu, X Brinton, LA AF Dallal, Cher M. Tice, Jeffrey A. Buist, Diana S. M. Bauer, Douglas C. Lacey, James V., Jr. Cauley, Jane A. Hue, Trisha F. LaCroix, Andrea Falk, Roni T. Pfeiffer, Ruth M. Fuhrman, Barbara J. Veenstra, Timothy D. Xu, Xia Brinton, Louise A. CA B-FIT Res Grp TI Estrogen metabolism and breast cancer risk among postmenopausal women: a casecohort study within B similar to FIT SO CARCINOGENESIS LA English DT Article ID FRACTURE INTERVENTION TRIAL; ENDOGENOUS ESTRADIOL METABOLITES; VERTEBRAL FRACTURES; RANDOMIZED-TRIAL; BONE-DENSITY; CELLS; ALENDRONATE; QUINONES; SERUM; 16-ALPHA-HYDROXYESTRONE AB Although elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a casecohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 199293, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EMs were measured by liquid chromatographytandem mass spectrometry. EMs (quintiles, Q) were analyzed individually, as metabolic pathways (C-2, -4 or -16) and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HRQ5vsQ1 1.86; 95% CI: 1.192.90; P trend 0.04). An elevated ratio of the 2-hydroxylation pathway (HRQ5vsQ1 0.69; 95% CI: 0.461.05; P trend 0.01) and 4-hydroxylation pathway (HRQ5vsQ1 0.61; 95% CI: 0.400.93; P trend 0.004) to parent estrogens (estradiol and estrone) was inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HRQ5vsQ1 0.60; 95% CI: 0.400.90; P trend 0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis. C1 [Dallal, Cher M.; Falk, Roni T.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Dallal, Cher M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Tice, Jeffrey A.; Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Buist, Diana S. M.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Lacey, James V., Jr.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Hue, Trisha F.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [LaCroix, Andrea] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fuhrman, Barbara J.] Univ Arkansas Med Sci, Coll Publ Hlth, Dept Epidemiol, Little Rock, AR 72205 USA. [Veenstra, Timothy D.; Xu, Xia] SAIC Frederick Inc, Adv Technol Program, Lab Prote & Analyt Technol, Adv Technol Program,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Dallal, CM (reprint author), Univ Maryland, Sch Publ Hlth, Dept Epidemiol & Biostat, College Pk, MD 20742 USA. EM cdallal@umd.edu RI Brinton, Louise/G-7486-2015; Cauley, Jane/N-4836-2015; OI Brinton, Louise/0000-0003-3853-8562; Cauley, Jane/0000-0003-0752-4408; Fuhrman, Barbara/0000-0002-1777-9888 FU Merck Research Laboratories; National Cancer Institute, National Institutes of Health [N02-CP-01019] FX Merck Research Laboratories (to the original FIT study); National Cancer Institute, National Institutes of Health (contract no. N02-CP-01019 to B similar to FIT. NR 38 TC 31 Z9 31 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2014 VL 35 IS 2 BP 346 EP 355 DI 10.1093/carcin/bgt367 PG 10 WC Oncology SC Oncology GA AA7IX UT WOS:000331272100012 PM 24213602 ER PT J AU Xu, ZL Taylor, JA AF Xu, Zongli Taylor, Jack A. TI Genome-wide age-related DNA methylation changes in blood and other tissues relate to histone modification, expression and cancer SO CARCINOGENESIS LA English DT Article ID EMBRYONIC STEM-CELLS; CHROMATIN STATE; HUMAN BRAIN; HYPERMETHYLATION; GENES; PLURIPOTENT; POLYCOMB; MARKS; RISK; MAPS AB Epigenetic marks are extensively altered in cancer but may also change in normal tissues with age, which is the primary risk factor for most cancers. We conducted an epigenome-wide study to identify age-related methylation sites and examine their relationship to cancer and other underlying epigenetic marks. We analyzed 1006 blood DNA samples of women aged 3576 years from the Sister Study and found that 7694 (28%) of the 27 578 CpGs assayed were associated with age (false discovery rate, q < 0.05). Using independent data sets, we confirmed 749 high-confidence age-related CpG (arCpGs) sites in normal blood. Based on The Cancer Genome Atlas data, we show that these age-related changes are largely concordant in a broad variety of normal tissues and that a significantly higher (7191%, P < 10(74)) than expected proportion of increasingly methylated arCpGs (IM-arCpGs) were overmethylated in a wide variety of tumor types. IM-arCpGs sites occurred almost exclusively at CpG islands and were disproportionately marked with the repressive H3K27me3 histone modification (P < 1 10(50)). Genes containing these IM-arCpG sites were highly enriched for developmental and signaling pathways (P < 10(10)). Our findings suggest that as cells acquire methylation at age-related sites, they have a lower threshold for malignant transformation that may explain in part the increase in cancer incidence with age. C1 [Xu, Zongli; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Taylor, Jack A.] NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Taylor, JA (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [Z01 ES044005, Z01 ES044032, Z01 ES049033] FX The Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences (Z01 ES044005, Z01 ES044032, Z01 ES049033). NR 35 TC 40 Z9 45 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2014 VL 35 IS 2 BP 356 EP 364 DI 10.1093/carcin/bgt391 PG 9 WC Oncology SC Oncology GA AA7IX UT WOS:000331272100013 PM 24287154 ER PT J AU Jun, DY Taub, D Chrest, FJ Kim, YH AF Jun, Do Youn Taub, Dennis Chrest, Francis J. Kim, Young Ho TI Requirement of the expression of 3-phosphoglycerate dehydrogenase for traversing S phase in murine T lymphocytes following immobilized anti-CD3 activation SO CELLULAR IMMUNOLOGY LA English DT Article DE L-Serine biosynthesis; The phosphorylated pathway; PHGDH; T cell activation; IL-2R signaling; S phase; Antisense oligonucleotide ID BLOOD-BRAIN-BARRIER; CELL-ACTIVATION; SERINE BIOSYNTHESIS; NUCLEOTIDE-SEQUENCE; IL-2 RECEPTOR; FUNCTIONAL-ANALYSIS; GENE-EXPRESSION; CYCLOSPORINE-A; METABOLISM; INTERLEUKIN-2-RECEPTOR AB Murine resting (G(0)) T lymphocytes contained no detectable mRNA of 3-phosphoglycerate dehydrogenase (PHGDH) catalyzing the first step in the phosphorylated pathway of L-serine biosynthesis. Immobilized anti-CD3 activation of G(0) T cells expressed the PHGDH mRNA in G(1) with a maximum level in S phase. G(0) T cells activated with either immobilized anti-CD3 plus CsA or PBu2, which failed to drive the activated T cells to enter S phase, did not express the PHGDH mRNA unless exogenous rIL-2 was added. Blocking of IL-2R signaling by adding anti-IL-2 and anti-IL-2R alpha resulted in no expression of the PHGDH mRNA during immobilized anti-CD3 activation of G(0) T cells. Deprivation of L-serine from culture medium or addition of antisense PHGDH oligonucleotide significantly reduced [H-3]TdR incorporation of activated T cells. These results indicate that the PHGDH gene expression, dictated by IL-2R signaling, is a crucial event for DNA synthesis during S phase of activated T cells. (C) 2013 Elsevier Inc. All rights reserved. C1 [Jun, Do Youn; Kim, Young Ho] Kyungpook Natl Univ, Immunobiol Lab, Sch Life Sci & Biotechnol, Coll Nat Sci, Taegu 702701, South Korea. [Taub, Dennis; Chrest, Francis J.] NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Kim, YH (reprint author), Kyungpook Natl Univ, Immunobiol Lab, Sch Life Sci & Biotechnol, Coll Nat Sci, Taegu 702701, South Korea. EM ykim@knu.ac.kr FU Ministry of Health and Welfare, Korea [02-PJ1-PG3-20908-0036]; Korean Research Foundation [KRF-2003-005-J00103]; National Research Foundation of Korea; Korean government [NRF-353-2009-2-F00021]; Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by a Grant (02-PJ1-PG3-20908-0036) from the Ministry of Health and Welfare, Korea, and a Grant (KRF-2003-005-J00103) from the Korean Research Foundation, the National Research Foundation of Korea Grant funded by the Korean government (NRF-353-2009-2-F00021), and in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 41 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 EI 1090-2163 J9 CELL IMMUNOL JI Cell. Immunol. PD FEB PY 2014 VL 287 IS 2 BP 78 EP 85 DI 10.1016/j.cellimm.2013.12.003 PG 8 WC Cell Biology; Immunology SC Cell Biology; Immunology GA AB0LJ UT WOS:000331483200003 ER PT J AU Xiao, H Lin, XL Chowell, G Huang, CR Gao, LD Chen, BY Wang, Z Zhou, L He, XG Liu, HN Zhang, XX Yang, HS AF Xiao, Hong Lin, Xiaoling Chowell, Gerardo Huang, Cunrui Gao, Lidong Chen, Biyun Wang, Zheng Zhou, Liang He, Xinguang Liu, Haining Zhang, Xixing Yang, Huisuo TI Urban structure and the risk of influenza A (H1N1) outbreaks in municipal districts SO CHINESE SCIENCE BULLETIN LA English DT Article DE Influenza A (H1N1); Spatial risk factors; Spatial-temporal K functions; Proximity model; Logistic regression ID TRANSMISSION DYNAMICS; URBANIZATION; SPREAD; VIRUS; INFECTION; PATTERNS; HEALTH; CHINA AB Changsha was one of the most affected areas during the 2009 A (H1N1) influenza pandemic in China. Here, we analyze the spatial-temporal dynamics of the 2009 pandemic across Changsha municipal districts, evaluate the relationship between case incidence and the local urban spatial structure and predict high-risk areas of influenza A (H1N1). We obtained epidemiological data on all cases of influenza A (H1N1) reported across municipal districts in Changsha during period May 2009-December 2010 and data on population density and basic geographic characteristics for 239 primary schools, 97 middle schools, 347 universities, 96 malls and markets, 674 business districts and 121 hospitals. Spatial-temporal K functions, proximity models and logistic regression were used to analyze the spatial distribution pattern of influenza A (H1N1) incidence and the association between influenza A (H1N1) cases and spatial risk factors and predict the infection risks. We found that the 2009 influenza A (H1N1) was driven by a transmission wave from the center of the study area to surrounding areas and reported cases increased significantly after September 2009. We also found that the distribution of influenza A (H1N1) cases was associated with population density and the presence of nearest public places, especially universities (OR = 10.166). The final predictive risk map based on the multivariate logistic analysis showed high-risk areas concentrated in the center areas of the study area associated with high population density. Our findings support the identification of spatial risk factors and high-risk areas to guide the prioritization of preventive and mitigation efforts against future influenza pandemics. C1 [Xiao, Hong; Lin, Xiaoling; Zhou, Liang; He, Xinguang; Liu, Haining] Hunan Normal Univ, Coll Resources & Environm Sci, Changsha 410081, Hunan, Peoples R China. [Chowell, Gerardo] Arizona State Univ, Math Computat & Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Huang, Cunrui] Griffith Univ, Ctr Environm & Populat Hlth, Sch Environm, Brisbane, Qld 4111, Australia. [Gao, Lidong; Chen, Biyun] Hunan Prov Ctr Dis Control & Prevent, Changsha 410002, Hunan, Peoples R China. [Wang, Zheng] Capital Med Univ, Dept Resp & Crit Care Med, Beijing Inst Resp Med, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China. [Zhang, Xixing] Changsha Municipal Ctr Dis Prevent & Control, Changsha 410001, Hunan, Peoples R China. [Yang, Huisuo] Beijing Mil Reg, Ctr Dis Control & Prevent, Beijing 100042, Peoples R China. RP Xiao, H (reprint author), Hunan Normal Univ, Coll Resources & Environm Sci, Changsha 410081, Hunan, Peoples R China. EM xiaohong.hnnu@gmail.com FU Key Discipline Construction Project in Hunan Province [2008001]; National Natural Science Foundation of China; Scientific Research Fund of Hunan Provincial Education Department [13A051] FX We wish to express our thanks to the anonymous referees for their helpful comments on an earlier draft of this article. This work was supported by the Key Discipline Construction Project in Hunan Province (2008001), the National Natural Science Foundation of China and the Scientific Research Fund of Hunan Provincial Education Department (13A051). NR 31 TC 1 Z9 1 U1 2 U2 18 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1001-6538 EI 1861-9541 J9 CHINESE SCI BULL JI Chin. Sci. Bull. PD FEB PY 2014 VL 59 IS 5-6 BP 554 EP 562 DI 10.1007/s11434-013-0084-6 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB1OW UT WOS:000331563100014 ER PT J AU Coury, DL Swedo, SE Thurm, AE Miller, DT Veenstra-VanderWeele, JM Carbone, PS Taylor, JL AF Coury, Daniel L. Swedo, Susan E. Thurm, Audrey E. Miller, David T. Veenstra-VanderWeele, Jeremy M. Carbone, Paul S. Taylor, Julie Lounds TI Treating the Whole Person With Autism: The Proceedings of the Autism Speaks National Autism Conference SO CURRENT PROBLEMS IN PEDIATRIC AND ADOLESCENT HEALTH CARE LA English DT Article ID PERVASIVE DEVELOPMENTAL DISORDERS; HEALTH-CARE NEEDS; RANDOMIZED CLINICAL-TRIAL; DSM-5 FIELD TRIALS; DE-NOVO MUTATIONS; SPECTRUM DISORDERS; YOUNG-ADULTS; CHILDRENS HEALTH; UNITED-STATES; MEDICAL HOME AB The identification of autism spectrum disorders has increased dramatically over the past decade, with the latest estimates indicating prevalence as high as 1 in 54 boys. There is greater awareness of medical conditions that co-occur with autism and expansion of treatment options. Closer scrutiny has led to refinement of the diagnostic criteria, and there have been advances in genetics examining potential causal factors. Transition to adulthood is an area of growing concern, and professionals and families require guidance on this issue. This article summarizes the proceedings of the Autism Speaks conference on Treating the Whole Person with Autism: Care across the Lifespan. The conference was organized with the intent of providing a forum for both families and professionals to learn about the most current research in the field. Dr. Sue Swedo provides important background information regarding the changes in the diagnostic criteria for autism spectrum disorders. She particularly deals with the concerns of individuals and families that their autism diagnosis may change. Recommendations for genetic testing and its interpretation are provided by Dr. David Miller. His discussion helps make sense of the utility of genetic testing for ASD, along with demonstration of the complexity of determining which genetic factors are doing what and through which pathways. Dr. Jeremy Veenstra-Vander-Weele provides useful background information on how medicines are initially identified and for what purpose and goes on to describe the present and future treatments in pharmacology. Medical issues are addressed by Dr. Paul Carbone, especially the coordination of comprehensive services through the medical home model of care. Dr. Julie Lounds Taylor concludes with guidance on preparation for adulthood, a topic of great importance to families as their child matures and for the professionals who will help guide this transition. C1 [Coury, Daniel L.] Nationwide Childrens Hosp, Dept Pediat, Columbus, OH 43205 USA. [Coury, Daniel L.] Ohio State Univ, Columbus, OH 43210 USA. [Swedo, Susan E.; Thurm, Audrey E.] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Miller, David T.] Boston Childrens Hosp, Div Genet, Boston, MA USA. [Veenstra-VanderWeele, Jeremy M.] Vanderbilt Kennedy Ctr Res Human Dev, Treatment & Res Inst Autism Spectrum Disorder, Nashville, TN USA. [Carbone, Paul S.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Taylor, Julie Lounds] Vanderbilt Univ, Dept Pediat, Nashville, TN USA. [Taylor, Julie Lounds] Vanderbilt Univ, Dept Special Educ, Nashville, TN 37235 USA. RP Coury, DL (reprint author), Nationwide Childrens Hosp, Dept Pediat, Columbus, OH 43205 USA. RI Coury, Daniel/E-2925-2011; Veenstra-VanderWeele, Jeremy/K-1935-2015 OI Veenstra-VanderWeele, Jeremy/0000-0002-6349-1076 FU Autism Speaks; SynapDx; Novartis; Roche Pharmaceuticals; Seaside Therapeutics; Forest; Sunovion; U.S. Department of Health and Human Services [UA3 MC 11054]; Health Resources and Services Administration; Maternal and Child Health Research Program FX Dr. Coury has received research funding from Autism Speaks and SynapDx. Dr. Miller has served on the Scientific Advisory Board, Integragen, Inc., as a Consultant to SynapDx, Inc., Roche NimbleGen, Inc., and Correlagen Diagnostics, Inc.; and as a Consultant and Medical Director to Claritas Genomics, Inc. Dr. Veenstra-Vander Weele has received research funding from Novartis, Roche Pharmaceuticals, Seaside Therapeutics, Forest, Sunovion, and SynapDx, and has served on advisory boards for Novartis and Roche Pharmaceuticals. Dr. Carbone has received grant funding from Autism Speaks. Drs. Swedo, Thurm, and Taylor have no financial relationships to disclose with respect to this article.; Received funding from Autism Speaks and from cooperative agreement UA3 MC 11054 from the U.S. Department of Health and Human Services, Health Resources and Services Administration, and Maternal and Child Health Research Program. NR 117 TC 5 Z9 5 U1 5 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-5442 EI 1538-3199 J9 CURR PROB PEDIATR AD JI Curr. Probl. Pediatr. Adolesc. Health Care PD FEB PY 2014 VL 44 IS 2 BP 26 EP 47 DI 10.1016/j.cppeds.2013.12.002 PG 22 WC Pediatrics SC Pediatrics GA AB2BM UT WOS:000331598000002 PM 24491508 ER PT J AU Hilliard, ME Perlus, JG Clark, LM Haynie, DL Plotnick, LP Guttmann-Bauman, I Iannotti, RJ AF Hilliard, Marisa E. Perlus, Jessamyn G. Clark, Loretta M. Haynie, Denise L. Plotnick, Leslie P. Guttmann-Bauman, Ines Iannotti, Ronald J. TI Perspectives From Before and After the Pediatric to Adult Care Transition: A Mixed-Methods Study in Type 1 Diabetes SO DIABETES CARE LA English DT Article ID YOUNG-ADULTS; HEALTH-CARE; GLYCEMIC CONTROL; SELF-MANAGEMENT; EMERGING ADULTS; ADOLESCENTS; SERVICES; PROGRAM AB OBJECTIVEAmong the many milestones of adolescence and young adulthood, transferring from pediatric to adult care is a significant transition for those with type 1 diabetes. The aim of this study was to understand the concerns, expectations, preferences, and experiences of pretransition adolescents and parents and posttransition young adults.RESEARCH DESIGN AND METHODSParticipants completed questionnaires and responded to open-ended qualitative questions regarding self-management, self-efficacy, and their expectations and experiences with pediatric and adult care providers across the transition process.RESULTSAt a mean age of 16.1 years, most pretransition adolescents had not yet discussed transferring care with their parents or doctors. Although many posttransition young adults reported positive, supportive interactions, several described challenges locating or establishing a relationship with an adult diabetes care provider. Qualitative themes emerged related to the anticipated timing of transfer, early preparation for transition, the desire for developmentally appropriate interactions with providers, the maintenance of family and social support, and strategies for coordinating care between pediatric and adult care providers.CONCLUSIONSStandardizing transition preparation programs in pediatric care and introducing transition-oriented clinics for late adolescents and young adults prior to adult care may help address patients' preferences and common transfer-related challenges. C1 [Hilliard, Marisa E.; Plotnick, Leslie P.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Perlus, Jessamyn G.; Haynie, Denise L.; Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Clark, Loretta M.; Guttmann-Bauman, Ines] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Iannotti, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM ronald.iannotti@umb.edu OI Hilliard, Marisa/0000-0002-8813-629X; Haynie, Denise/0000-0002-8270-6079 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 36 TC 22 Z9 22 U1 4 U2 18 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2014 VL 37 IS 2 BP 346 EP 354 DI 10.2337/dc13-1346 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA4NM UT WOS:000331072800020 PM 24089544 ER PT J AU Pettitt, DJ Talton, J Dabelea, D Divers, J Imperatore, G Lawrence, JM Liese, AD Linder, B Mayer-Davis, EJ Pihoker, C Saydah, SH Standiford, DA Hamman, RF AF Pettitt, David J. Talton, Jennifer Dabelea, Dana Divers, Jasmin Imperatore, Giuseppina Lawrence, Jean M. Liese, Angela D. Linder, Barbara Mayer-Davis, Elizabeth J. Pihoker, Catherine Saydah, Sharon H. Standiford, Debra A. Hamman, Richard F. CA SEARCH Diabet Youth Study Grp TI Prevalence of Diabetes in US Youth in 2009: The SEARCH for Diabetes in Youth Study SO DIABETES CARE LA English DT Article ID RISK-FACTORS; TYPE-2; CHILDREN; MELLITUS; AMERICAN; CHILDHOOD; CANADA; COHORT; ADOLESCENTS; REGISTRY AB OBJECTIVETo estimate the prevalence of diabetes in U.S. youth aged <20 years in 2009 and to estimate the total number of youth with diabetes in the U.S. by age, race/ethnicity, and diabetes type.RESEARCH DESIGN AND METHODSTo address one of its primary aims, the SEARCH for Diabetes in Youth Study identified youth aged <20 years on 31 December 2009 with physician-diagnosed diabetes in selected areas of Colorado, Ohio, South Carolina, and Washington, among health plan members of Kaiser Permanente Southern California and among American Indians living on reservations in Arizona and New Mexico. Diabetes was classified as type 1, type 2, or other. Race/ethnicity was by self-report.RESULTSFrom a population of 3,458,974 youth aged <20 years, 7,695 youth with diabetes were identified (2.22/1,000): 6,668 with type 1 diabetes (1.93/1,000), 837 with type 2 diabetes (0.24/1,000), and 190 (0.05/1,000) with other diabetes types. Prevalence increased with age, was slightly higher in females than males, and was most prevalent in non-Hispanic White and least prevalent in Asian/Pacific Islanders, with Native American and black youth having the highest prevalence of type 2 diabetes. An estimated 191,986 U.S. youth aged <20 years have diabetes; 166,984 type 1 diabetes, 20,262 type 2 diabetes, and 4,740 other types.CONCLUSIONSDiabetes, one of the leading chronic diseases in childhood, affects >190,000 (1 of 433) youth aged <20 years in the U.S., with racial and ethnic disparities seen in diabetes prevalence, overall and by diabetes type. C1 [Pettitt, David J.] Sansum Diabet Res Inst, Santa Barbara, CA 93105 USA. [Talton, Jennifer; Divers, Jasmin] Wake Forest Sch Med, Winston Salem, NC USA. [Dabelea, Dana; Hamman, Richard F.] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Imperatore, Giuseppina; Saydah, Sharon H.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Lawrence, Jean M.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Liese, Angela D.] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Linder, Barbara] NIDDK, NIH, Bethesda, MD 20892 USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Pihoker, Catherine] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Standiford, Debra A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RP Pettitt, DJ (reprint author), Sansum Diabet Res Inst, Santa Barbara, CA 93105 USA. EM dpettitt@sansum.org FU Centers for Disease Control and Prevention [00097, DP-05-069, DP-10-001]; National Institute of Diabetes and Digestive and Kidney Diseases; Kaiser Permanente Southern California [U48/CCU919219, U01DP000246, U18DP002714]; University of Colorado Denver [U48/CCU819241-3, U01DP000247, U18DP000247-06A1]; Children's Hospital Medical Center (Cincinnati) [U48/CCU519239, U01DP000248, 1U18DP002709]; University of North Carolina at Chapel Hill [U48/CCU419249, U01DP000254, U18DP002708-01]; University of Washington School of Medicine [U58/CCU019235-4, U01DP000244, U18DP002710-01]; Wake Forest University School of Medicine [U48/CCU919219, U01DP000250, 200-2010-35171] FX The SEARCH for Diabetes in Youth Study is funded by the Centers for Disease Control and Prevention (PA numbers 00097, DP-05-069, and DP-10-001) and is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Site contract numbers: Kaiser Permanente Southern California (U48/CCU919219, U01DP000246, and U18DP002714), University of Colorado Denver (U48/CCU819241-3, U01DP000247, and U18DP000247-06A1), Children's Hospital Medical Center (Cincinnati) (U48/CCU519239, U01DP000248, and 1U18DP002709), University of North Carolina at Chapel Hill (U48/CCU419249, U01DP000254, and U18DP002708-01), University of Washington School of Medicine (U58/CCU019235-4, U01DP000244, and U18DP002710-01), and Wake Forest University School of Medicine (U48/CCU919219, U01DP000250, and 200-2010-35171). NR 39 TC 82 Z9 84 U1 2 U2 19 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2014 VL 37 IS 2 BP 402 EP 408 DI 10.2337/dc13-1838 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA4NM UT WOS:000331072800027 PM 24041677 ER PT J AU Hruby, A Meigs, JB O'Donnell, CJ Jacques, PF McKeown, NM AF Hruby, Adela Meigs, James B. O'Donnell, Christopher J. Jacques, Paul F. McKeown, Nicola M. TI Higher Magnesium Intake Reduces Risk of Impaired Glucose and Insulin Metabolism and Progression From Prediabetes to Diabetes in Middle-Aged Americans SO DIABETES CARE LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; BETA-CELL FUNCTION; DOUBLE-BLIND; CARDIOVASCULAR-DISEASE; NONDIABETIC SUBJECTS; PROSPECTIVE COHORT; DIETARY MAGNESIUM; RANDOMIZED-TRIAL; RESISTANCE; SENSITIVITY AB OBJECTIVETo assess 7-year associations between magnesium intake and incident prediabetes and/or insulin resistance (IR), and progression from these states to type 2 diabetes.RESEARCH DESIGN AND METHODSIn 2,582 community-dwelling participants 26-81 years old at baseline, magnesium intake and risk of incident metabolic impairment, defined as impaired fasting glucose (FG) (5.6 to <7.0 mmol/L), impaired glucose tolerance (2-h postload glucose 7.8 to <11.1 mmol/L), IR, or hyperinsulinemia (90th percentile of homeostasis model assessment of IR or fasting insulin, respectively), was estimated among those with normal baseline status, and risk of incident diabetes was estimated among those with baseline metabolic impairment. In participants without incident diabetes, we examined magnesium intake in relation to 7-year changes in fasting and postload glucose and insulin, IR, and insulin sensitivity.RESULTSAfter adjusting for age, sex, and energy intake, compared with those with the lowest magnesium intake, those with the highest intake had 37% lower risk of incident metabolic impairment (P trend = 0.02), and in those with baseline metabolic impairment, higher intake was associated with 32% lower risk of incident diabetes (P trend = 0.05). In the combined population, the risk in those with the highest intake was 53% (P trend = 0.0004) of those with the lowest intake. Adjusting for risk factors and dietary fiber attenuated associations in the baseline normal population but did not substantially affect associations in the metabolically impaired. Higher magnesium intake tended to associate with lower follow-up FG and IR, but not fasting insulin, postload values, or insulin sensitivity.CONCLUSIONSMagnesium intake may be particularly beneficial in offsetting risk of developing diabetes among those at high risk. Magnesium's long-term associations with non-steady-state (dynamic) measures deserve further research. C1 [Hruby, Adela; Jacques, Paul F.; McKeown, Nicola M.] Tufts Univ, Jean Mayer US Dept Agr, Nutr Epidemiol Program, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] MGH, Dept Med, Div Cardiovasc, Boston, MA USA. RP McKeown, NM (reprint author), Tufts Univ, Jean Mayer US Dept Agr, Nutr Epidemiol Program, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu FU National Heart, Lung, and Blood Institute's FHS [N01-HC-25195]; U.S. Department of Agriculture [58-1950-0-014]; [K24-DK-080140] FX At the time of writing, A.H. was an American Heart Association Predoctoral Fellow. This work was also supported by the National Heart, Lung, and Blood Institute's FHS (Contract N01-HC-25195) and the U.S. Department of Agriculture (Agreement 58-1950-0-014). J.B.M. is supported by K24-DK-080140. NR 41 TC 19 Z9 19 U1 1 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2014 VL 37 IS 2 BP 419 EP 427 DI 10.2337/dc13-1397 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA4NM UT WOS:000331072800029 PM 24089547 ER PT J AU Buschur, E Sarma, AV Pietropaolo, M Dunn, RL Braffett, BH Cleary, PA Cowie, C Larkin, ME Wessells, H Nathan, DM Kim, C AF Buschur, Elizabeth Sarma, Aruna V. Pietropaolo, Massimo Dunn, Rodney L. Braffett, Barbara H. Cleary, Patricia A. Cowie, Catherine Larkin, Mary E. Wessells, Hunter Nathan, David M. Kim, Catherine CA DCCT EDIC Res Grp TI Self-Reported Autoimmune Disease by Sex in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study SO DIABETES CARE LA English DT Letter C1 [Buschur, Elizabeth; Pietropaolo, Massimo] Univ Michigan, Dept Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Sarma, Aruna V.; Dunn, Rodney L.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Braffett, Barbara H.; Cleary, Patricia A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Cowie, Catherine] NIDDK, Bethesda, MD 20892 USA. [Larkin, Mary E.; Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [Wessells, Hunter] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Kim, Catherine] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Kim, Catherine] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. RP Kim, C (reprint author), Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. EM cathkim@umich.edu FU NIDDK NIH HHS [U01-DK-094157, K23 DK071552, P30 DK017047, P30 DK020572, R01 DK083297, R01 DK083927, U01 DK094157, U01 DK094176, U01-DK-094176] NR 4 TC 3 Z9 3 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2014 VL 37 IS 2 BP E28 EP E29 DI 10.2337/dc13-1890 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA4NM UT WOS:000331072800004 PM 24459159 ER PT J AU Knowler, WC Ackermann, RT AF Knowler, William C. Ackermann, Ronald T. TI Preventing Diabetes in American Indian Communities. Diabetes Care 2013;36:1820-1822 RESPONSE SO DIABETES CARE LA English DT Letter C1 [Knowler, William C.] NIDDK, NIH, Phoenix, AZ USA. [Ackermann, Ronald T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Knowler, WC (reprint author), NIDDK, NIH, Phoenix, AZ USA. EM knowler@nih.gov FU NCATS NIH HHS [UL1 TR000150]; NCCDPHP CDC HHS [U58 DP002718]; NIDDK NIH HHS [R18 DK079855] NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2014 VL 37 IS 2 BP E37 EP E37 DI 10.2337/dc13-2282 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA4NM UT WOS:000331072800010 PM 24459165 ER PT J AU Crowley, NA Cody, PA Davis, MI Lovinger, DM Mateo, Y AF Crowley, Nicole A. Cody, Patrick A. Davis, Margaret I. Lovinger, David M. Mateo, Yolanda TI Chronic methylphenidate exposure during adolescence reduces striatal synaptic responses to ethanol SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article ID DOPAMINE TRANSPORTER; DORSAL STRIATUM; ORAL METHYLPHENIDATE; COLLEGE-STUDENTS; PRESCRIPTION STIMULANTS; PARKINSONS-DISEASE; SUBSTANCE-ABUSE; GENE-REGULATION; PLASTICITY; COCAINE C1 [Crowley, Nicole A.; Cody, Patrick A.; Davis, Margaret I.; Lovinger, David M.; Mateo, Yolanda] NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, NIH, Rockville, MD 20852 USA. RP Mateo, Y (reprint author), NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM mateoy@mail.nih.gov OI Davis, Margaret/0000-0002-0489-8351 FU Intramural NIH HHS [ZIA AA000407-12] NR 56 TC 2 Z9 2 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD FEB PY 2014 VL 39 IS 4 BP 548 EP 556 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AA8IF UT WOS:000331338500003 PM 24236977 ER PT J AU Murase, S McKay, RD AF Murase, Sachiko McKay, Ronald D. TI Neuronal activity-dependent STAT3 localization to nucleus is dependent on Tyr-705 and Ser-727 phosphorylation in rat hippocampal neurons SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article ID TRANSCRIPTION 3 STAT3; ACTIVATED PROTEIN-KINASE; SIGNAL TRANSDUCER; SERINE PHOSPHORYLATION; TYROSINE PHOSPHORYLATION; EXTRACELLULAR-MATRIX; NEWBORN HIPPOCAMPUS; SYNAPTIC PLASTICITY; JAK/STAT PATHWAY; SURVIVAL C1 [Murase, Sachiko; McKay, Ronald D.] NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [McKay, Ronald D.] Lieber Inst Brain Dev, Baltimore, MD USA. RP Murase, S (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM sachikom@ninds.nih.gov FU NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. NR 44 TC 5 Z9 5 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD FEB PY 2014 VL 39 IS 4 BP 557 EP 565 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AA8IF UT WOS:000331338500004 PM 24199834 ER PT J AU Perez-Aso, M Fernandez, P Mediero, A Chan, ES Cronstein, BN AF Perez-Aso, Miguel Fernandez, Patricia Mediero, Aranzazu Chan, Edwin S. Cronstein, Bruce N. TI Adenosine 2A receptor promotes collagen production by human fibroblasts via pathways involving cyclic AMP and AKT but independent of Smad2/3 SO FASEB JOURNAL LA English DT Article DE fibrosis; intracellular signaling ID HUMAN DERMAL FIBROBLASTS; PROTEIN-KINASE-A; TGF-BETA; MATRIX METALLOPROTEINASE-1; PHARMACOLOGICAL BLOCKADE; SIGNALING PATHWAY; PROSTAGLANDIN E-2; DOWN-REGULATION; A(2A) RECEPTOR; MURINE MODEL AB Activation of adenosine A2A receptor (A(2A)R) promotes fibrosis and collagen synthesis. However, the underlying mechanism is still unclear, not least because cAMP, its principal effector, has been found to inhibit TGF1-induced collagen synthesis. Here, we show that in primary normal human dermal fibroblasts, A(2A)R stimulation with CGS21680 elicits a modest cAMP increase (150 +/- 12% of control; EC50 54.8 nM), which stimulates collagen1 (Col1) and collagen3 (Col3), but maximal cAMP resulting from direct activation of adenylyl cyclase by forskolin (15,689 +/- 7038% of control; EC50 360.7 nM) inhibits Col1 and increases Col3. Similar to Col1 expression, fibroblast proliferation increased following physiological cAMP increases by CGS21680 but was inhibited by cAMP increases beyond the physiological range by forskolin. The A(2A)R-mediated increase of Col1 and Col3 was mediated by AKT, while Col3, but not Col1, expression was dependent on p38 and repressed by ERK. TGF1 induced phosphorylation of Smad2/3 and increased Col3 expression, which was prevented by Smad3 depletion. In contrast, CGS21680 did not activate Smad2/3, and Smad2/3 knockdown did not prevent CGS21680-induced Col1 or Col3 increases. Our results indicate that cAMP is a concentration-dependent switch for collagen production via noncanonical, AKT-dependent, Smad2/3-independent signaling. These observations explain the paradoxical effects of cAMP on collagen expression.Perez-Aso, M., Fernandez, P., Mediero, A., Chan, E. S., and Cronstein, B. N. Adenosine 2A receptor promotes collagen production by human fibroblasts via pathways involving cyclic AMP and AKT but independent of Smad2/3. C1 [Perez-Aso, Miguel; Mediero, Aranzazu; Chan, Edwin S.; Cronstein, Bruce N.] NYU, Sch Med, Dept Med, New York, NY 10016 USA. [Fernandez, Patricia] NCI, NIH, Bethesda, MD 20892 USA. RP Cronstein, BN (reprint author), NYU, Sch Med, Dept Med, 550 First Ave, New York, NY 10016 USA. EM bruce.cronstein@nyumc.org FU U.S. National Institutes of Health (NIH) [AR56672, AR54897]; New York University (NYU)-Health and Hospitals Corporation Clinical and Translational Science Institute [UL1RR029893]; NYU Cancer Institute (Center Support grant); NIH/National Cancer Institute [5 P30CA16087-31] FX This work was supported by grants from the U.S. National Institutes of Health (NIH; AR56672 and AR54897), the New York University (NYU)-Health and Hospitals Corporation Clinical and Translational Science Institute (UL1RR029893), the NYU Cancer Institute (Center Support grant), and the NIH/National Cancer Institute (5 P30CA16087-31). NR 49 TC 13 Z9 13 U1 1 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD FEB PY 2014 VL 28 IS 2 BP 802 EP 812 DI 10.1096/fj.13-241646 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AA4NG UT WOS:000331072200027 PM 24200882 ER PT J AU Uchida, N Weitzel, RP Evans, ME Green, R Bonifacino, AC Krouse, AE Metzger, ME Hsieh, MM Donahue, RE Tisdale, JF AF Uchida, N. Weitzel, R. P. Evans, M. E. Green, R. Bonifacino, A. C. Krouse, A. E. Metzger, M. E. Hsieh, M. M. Donahue, R. E. Tisdale, J. F. TI Evaluation of engraftment and immunological tolerance after reduced intensity conditioning in a rhesus hematopoietic stem cell gene therapy model SO GENE THERAPY LA English DT Article DE lentiviral vector; CD34(+) cells; large animal model; hematopoietic stem cell transplantation; lymphocyte infusion ID LENTIVIRAL VECTOR; T-LYMPHOCYTES; EFFICIENT TRANSDUCTION; REPOPULATING CELLS; PROGENITOR CELLS; IN-VIVO; IMMUNODEFICIENCY; TRANSPLANTATION; DISEASE; ACTIVATION AB Reduced intensity conditioning (RIC) is desirable for hematopoietic stem cell (HSC) targeted gene therapy; however, RIC may be insufficient for efficient engraftment and inducing immunological tolerance to transgenes. We previously established long-term gene marking in our rhesus macaque autologous HSC transplantation model following 10 Gy total body irradiation (TBI). In this study, we evaluated RIC transplantation with 4 Gy TBI in two rhesus macaques that received equal parts of CD34(+) cells transduced with green fluorescent protein (GFP)-expressing lentiviral vector and empty vector not expressing transgenes. In both animals, equivalently low gene marking between GFP and empty vectors was observed 6 months post-transplantation, even with efficient transduction of CD34(+) cells in vitro. Autologous lymphocyte infusion with GFP marking resulted in an increase of gene marking in lymphocytes in a control animal with GFP tolerance, but not in the two RIC-transplanted animals. In vitro assays revealed strong cellular and humoral immune responses to GFP protein in the two RIC-transplanted animals, but this was not observed in controls. In summary, 4 Gy TBI is insufficient to permit engraftment of genetically modified HSCs and induce immunological tolerance to transgenes. Our findings should help in the design of conditioning regimens in gene therapy trials. C1 [Uchida, N.; Weitzel, R. P.; Evans, M. E.; Green, R.; Hsieh, M. M.; Tisdale, J. F.] NIDDK, NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bonifacino, A. C.; Krouse, A. E.; Metzger, M. E.; Donahue, R. E.] NHLBI, Hematol Branch, NIH, Rockville, MD USA. RP Tisdale, JF (reprint author), NIH, Mol & Clin Hematol Branch, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). We thank the animal care staff and technicians at 5 Research Court for their excellent care and handling of the animals. We would also like to thank William DeGraff and Dr Jim Mitchell of the Radiation Biology Branch, National Cancer Institute (NCI) for the use of the Eldorado Cobalt-60 irradiator. NR 35 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD FEB PY 2014 VL 21 IS 2 BP 148 EP 157 DI 10.1038/gt.2013.67 PG 10 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 AA6OM UT WOS:000331217700005 PM 24257347 ER PT J AU Jaeger, S Karargyris, A Candemir, S Folio, L Siegelman, J Callaghan, F Xue, ZY Palaniappan, K Singh, RK Antani, S Thoma, G Wang, YX Lu, PX McDonald, CJ AF Jaeger, Stefan Karargyris, Alexandros Candemir, Sema Folio, Les Siegelman, Jenifer Callaghan, Fiona Xue, Zhiyun Palaniappan, Kannappan Singh, Rahul K. Antani, Sameer Thoma, George Wang, Yi-Xiang Lu, Pu-Xuan McDonald, Clement J. TI Automatic Tuberculosis Screening Using Chest Radiographs SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Computer-aided detection and diagnosis; lung; pattern recognition and classification; segmentation; tuberculosis (TB); X-ray imaging ID COMPUTER-AIDED DIAGNOSIS; INFECTIOUS PULMONARY TUBERCULOSIS; LOCAL BINARY PATTERNS; TEXTURE CLASSIFICATION; LUNG NODULES; GRAPH CUTS; SEGMENTATION; SHAPE; RECOGNITION; INFORMATION AB Tuberculosis is a major health threat in many regions of the world. Opportunistic infections in immunocompromised HIV/AIDS patients and multi-drug-resistant bacterial strains have exacerbated the problem, while diagnosing tuberculosis still remains a challenge. When left undiagnosed and thus untreated, mortality rates of patients with tuberculosis are high. Standard diagnostics still rely on methods developed in the last century. They are slow and often unreliable. In an effort to reduce the burden of the disease, this paper presents our automated approach for detecting tuberculosis in conventional posteroanterior chest radiographs. We first extract the lung region using a graph cut segmentation method. For this lung region, we compute a set of texture and shape features, which enable the X-rays to be classified as normal or abnormal using a binary classifier. We measure the performance of our system on two datasets: a set collected by the tuberculosis control program of our local county's health department in the United States, and a set collected by Shenzhen Hospital, China. The proposed computer-aided diagnostic system for TB screening, which is ready for field deployment, achieves a performance that approaches the performance of human experts. We achieve an area under the ROC curve (AUC) of 87% (78.3% accuracy) for the first set, and an AUC of 90% (84% accuracy) for the second set. For the first set, we compare our system performance with the performance of radiologists. When trying not to miss any positive cases, radiologists achieve an accuracy of about 82% on this set, and their false positive rate is about half of our system's rate. C1 [Jaeger, Stefan; Karargyris, Alexandros; Candemir, Sema; Callaghan, Fiona; Xue, Zhiyun; Antani, Sameer; Thoma, George; McDonald, Clement J.] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. [Folio, Les] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Siegelman, Jenifer] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Siegelman, Jenifer] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Palaniappan, Kannappan; Singh, Rahul K.] Univ Missouri, Dept Comp Sci, Columbia, MO 65211 USA. [Wang, Yi-Xiang] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Imaging & Intervent Radiol, Shatin, Hong Kong, Peoples R China. [Lu, Pu-Xuan] Guangdong Med Coll, Shenzhen Peoples Hosp 3, Dept Radiol, Shenzhen 518020, Peoples R China. RP Jaeger, S (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. EM stefan.jaeger@nih.gov; alexandros.karargyris@nih.gov; sema.candemir@nih.gov; les.folio@nih.gov; jen.siegelman@gmail.com; fiona.callaghan@nih.gov; zhiyun.xue@nih.gov; palaniappank@missouri.edu; rksc82@mail.missouri.edu; sameer.antani@nih.gov; george.thoma@nih.gov; yixiang_wang@cuhk.edu.hk; lupuxuan@126.com; clement.mcdonald@nih.gov RI Wang , Yi Xiang /I-5952-2016; OI siegelman, jenifer/0000-0002-9835-7790; Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC); National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) [R33-EB00573] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), in part by the National Library of Medicine (NLM), and in part by the Lister Hill National Center for Biomedical Communications (LHNCBC). The work of K. Palaniappan was supported by the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) under Award R33-EB00573. NR 73 TC 20 Z9 20 U1 5 U2 20 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD FEB PY 2014 VL 33 IS 2 BP 233 EP 245 DI 10.1109/TMI.2013.2284099 PG 13 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA AA7SU UT WOS:000331298000003 PM 24108713 ER PT J AU Candemir, S Jaeger, S Palaniappan, K Musco, JP Singh, RK Xue, ZY Karargyris, A Antani, S Thoma, G McDonald, CJ AF Candemir, Sema Jaeger, Stefan Palaniappan, Kannappan Musco, Jonathan P. Singh, Rahul K. Xue, Zhiyun Karargyris, Alexandros Antani, Sameer Thoma, George McDonald, Clement J. TI Lung Segmentation in Chest Radiographs Using Anatomical Atlases With Nonrigid Registration SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Chest X-ray imaging; computer-aided detection; image registration; image segmentation; tuberculosis (TB) ID CONTEXTUAL PIXEL CLASSIFICATION; GRAPH CUTS; IMAGE SEGMENTATION; COMPUTER-ANALYSIS; SHAPE; RETRIEVAL; OPTIMIZATION; INFORMATION; REGULARIZATION; RECOGNITION AB The National Library of Medicine (NLM) is developing a digital chest X-ray (CXR) screening system for deployment in resource constrained communities and developing countries worldwide with a focus on early detection of tuberculosis. A critical component in the computer-aided diagnosis of digital CXRs is the automatic detection of the lung regions. In this paper, we present a nonrigid registration-driven robust lung segmentation method using image retrieval-based patient specific adaptive lung models that detects lung boundaries, surpassing state-of-the-art performance. The method consists of three main stages: 1) a content-based image retrieval approach for identifying training images (with masks) most similar to the patient CXR using a partial Radon transform and Bhattacharyya shape similarity measure, 2) creating the initial patient-specific anatomical model of lung shape using SIFT-flow for deformable registration of training masks to the patient CXR, and 3) extracting refined lung boundaries using a graph cuts optimization approach with a customized energy function. Our average accuracy of 95.4% on the public JSRT database is the highest among published results. A similar degree of accuracy of 94.1% and 91.7% on two new CXR datasets from Montgomery County, MD, USA, and India, respectively, demonstrates the robustness of our lung segmentation approach. C1 [Candemir, Sema; Jaeger, Stefan; Xue, Zhiyun; Karargyris, Alexandros; Antani, Sameer; Thoma, George; McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, Bethesda, MD 20894 USA. [Palaniappan, Kannappan; Singh, Rahul K.] Univ Missouri Columbia, Dept Comp Sci, Columbia, MO 65211 USA. [Musco, Jonathan P.] Univ Missouri Columbia, Sch Med, Dept Radiol, Columbia, MO 65212 USA. RP Candemir, S (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, Bethesda, MD 20894 USA. EM sema.candemir@nih.gov; stefan.jaeger@nih.gov; pal@missouri.edu; muscoj@health.missouri.edu; rksc82@mail.missouri.edu; zhiyun.xue@nih.gov; alexandros.karargyris@nih.gov; sameer.antani@nih.gov; george.thoma@nih.gov; clement.mcdonald@nih.gov OI Antani, Sameer/0000-0002-0040-1387 FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC); U.S. NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) [R33-EB00573] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC). The work of K. Palaniappan was supported by the U.S. NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB) under Award R33-EB00573. The views and opinions of authors expressed in this paper do not necessarily state or reflect those of the United States Government or any agency thereof, and they may not be used for advertising or product endorsement purposes. Asterisk indicates corresponding author. NR 68 TC 18 Z9 19 U1 2 U2 17 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD FEB PY 2014 VL 33 IS 2 BP 577 EP 590 DI 10.1109/TMI.2013.2290491 PG 14 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA AA7SU UT WOS:000331298000029 PM 24239990 ER PT J AU Lee, P Werner, CD Kebebew, E Celi, FS AF Lee, P. Werner, C. D. Kebebew, E. Celi, F. S. TI Functional thermogenic beige adipogenesis is inducible in human neck fat SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE fibroblast growth factor 21; FGF21; brown adipose tissue; beige adipose tissue; brite adipose tissue; adipokine; infrared thermography ID BROWN ADIPOSE-TISSUE; ADULT HUMANS; COLD-EXPOSURE; ADAPTIVE THERMOGENESIS; MESSENGER-RNA; BETA-KLOTHO; ADIPOCYTES; WHITE; GROWTH; FGF21 AB BACKGROUND: Recent studies suggest human neck brown adipose tissue (BAT) to consist of 'brown adipocyte (BA)-like' or beige adipocytes. However, little is known about their thermogenic function. Within the beige adipocyte transcriptome, fibroblast growth factor-21 (FGF21) is a gene whose protein product acts as an adipokine, regulating cold-induced thermogenesis in animals. Here, we explored (i) the adipogenic potential, thermogenic function and FGF21 secretory capacity of beige adipocytes derived from human neck fat and (ii) the role of FGF21 in modulating adipose bioenergetics. METHODS: Progenitors isolated from human cervical fat were differentiated into adipocytes with either a BA-like or white adipocyte (WA) phenotype. FGF21 secretion was measured by enzyme-linked immuosorbent assay. Real-time PCR/western blotting was used to determine cellular mRNA/protein levels. Extracellular flux bioanalyzer was used to quantify adipocyte oxygen consumption and fatty acid oxidation. Adipocyte heat production was measured by infrared thermography. RESULTS: Under hormonal manipulation, primary human neck pre-adipocytes differentiated into adipocytes with either BA-like or WA phenotypes, on gene/protein and functional levels. BA-like cells expressed beige but not classic BA markers. During BA differentiation, FGF21 gene expression and secretion were increased, and were augmented following norepinephrine exposure (a cold mimic in vitro). Differentiated WA expressed beta-klotho, a critical co-factor mediating FGF21 action. Treatment of WA with FGF21-induced UCP1 expression and increased oxygen consumption, respiratory uncoupling, norepinephrine-mediated thermogenesis, fatty acid oxidation and heat production, thus recapitulating the association between cold-induced FGF21 secretion and cold-induced thermogenesis in vivo. CONCLUSION: Beige adipocytes are thermogenic in humans. FGF21 is a beige adipokine capable of promoting a brown fat-like thermogenic program in WAs. SIGNIFICANCE: This study provides first evidence of inducible functional thermogenic beige adipogenesis in human neck fat. FGF21 holds promise as a cold-induced beige adipokine with metabolic benefits of therapeutic relevance through browning of white adipose tissue. C1 [Lee, P.; Werner, C. D.; Celi, F. S.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Kebebew, E.] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Lee, P (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bldg 10,CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM pcylee@gmail.com FU Australian NHMRC; RACP Foundation Diabetes Australia Fellowship; Bushell Travelling Fellowship; Intramural Research Program of NIDDK [Z01-DK047057-02, Z01-DK071044] FX We thank Dr Michael Sack and Dr Jie Liu from National Heart, Lung and Blood Institute, for advice on Seahorse bioanalyzer operations, and Dr Douglas Forrest, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, for helpful discussion and critical appraisal on the manuscript. Paul Lee is supported by the Australian NHMRC Early Career Fellowship, the RACP Foundation Diabetes Australia Fellowship, and the Bushell Travelling Fellowship. This study was supported by the Intramural Research Program of NIDDK: programs Z01-DK047057-02 and Z01-DK071044. NR 30 TC 65 Z9 67 U1 4 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2014 VL 38 IS 2 BP 170 EP 176 DI 10.1038/ijo.2013.82 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AA9HL UT WOS:000331404300002 PM 23736373 ER PT J AU Weise, CM Hohenadel, MG Krakoff, J Votruba, SB AF Weise, C. M. Hohenadel, M. G. Krakoff, J. Votruba, S. B. TI Body composition and energy expenditure predict ad-libitum food and macronutrient intake in humans SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE body composition; fat-free mass; fat mass; food intake; macronutrient intake ID RESTING METABOLIC-RATE; FAT-FREE MASS; US ADULTS; MEAL SIZE; OBESITY; LEPTIN; APPETITE; NEUROENDOCRINE; PREVALENCE; DISEASE AB BACKGROUND: Obesity is the result of chronic positive energy balance. The mechanisms underlying the regulation of energy homeostasis and food intake are not understood. Despite large increases in fat mass (FM), recent evidence indicates that fat-free mass (FFM) rather than FM is positively associated with intake in humans. METHODS: In 184 humans (73 females/111 males; age 34.5 +/- 8.8 years; percentage body fat: 31.6 +/- 8.1%), we investigated the relationship of FFM index (FFMI, kg m(-2)), FM index (FMI, kg m(-2)); and 24-h energy expenditure (EE, n = 127) with ad-libitum food intake using a 3-day vending machine paradigm. Mean daily calories (CAL) and macronutrient intake (PRO, CHO, FAT) were determined and used to calculate the relative caloric contribution of each (%PRO, %CHO, %FAT) and percent of caloric intake over weight maintaining energy needs (%WMENs). RESULTS: FFMI was positively associated with CAL (P=0.0001), PRO (P = 0.0001), CHO (P = 0.0075) and FAT (P<0.0001). This remained significant after adjusting for FMI. Total EE predicted CAL and macronutrient intake (all P<0.0001). FMI was positively associated with CAL (P = 0.019), PRO (P = 0.025) and FAT (P = 0.0008). In models with both FFMI and FMI, FMI was negatively associated with CAL (P = 0.019) and PRO (P = 0.033). Both FFMI and FMI were negatively associated with %CHO and positively associated with %FAT (all P<0.001). EE and FFMI (adjusted for FMI) were positively (EE P = 0.0085; FFMI P = 0.0018) and FMI negatively (P = 0.0018; adjusted for FFMI) associated with %WMEN. CONCLUSION: Food and macronutrient intake are predicted by FFMI and to a lesser degree by FMI. FFM and FM may have opposing effects on energy homeostasis. C1 [Weise, C. M.] Univ Leipzig, Neurol Klin & Poliklin, D-04109 Leipzig, Germany. [Hohenadel, M. G.; Krakoff, J.; Votruba, S. B.] NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, Phoenix, AZ 85016 USA. RP Votruba, SB (reprint author), NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, 4212N 16th St, Phoenix, AZ 85016 USA. EM votrubas@mail.nih.gov FU Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 29 TC 16 Z9 17 U1 0 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2014 VL 38 IS 2 BP 243 EP 251 DI 10.1038/ijo.2013.85 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AA9HL UT WOS:000331404300012 PM 23736368 ER PT J AU Wang, H Troy, LM Rogers, GT Fox, CS McKeown, NM Meigs, JB Jacques, PF AF Wang, H. Troy, L. M. Rogers, G. T. Fox, C. S. McKeown, N. M. Meigs, J. B. Jacques, P. F. TI Longitudinal association between dairy consumption and changes of body weight and waist circumference: the Framingham Heart Study SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE dairy; weight; waist circumference; longitudinal; milk; yogurt ID FOOD FREQUENCY QUESTIONNAIRE; INSULIN-RESISTANCE; CARDIOVASCULAR RISK; METABOLIC SYNDROME; PROSPECTIVE COHORT; CLINICAL-TRIALS; OBESITY; ADULTS; DIET; MANAGEMENT AB BACKGROUND: Dairy foods are nutrient dense and may be protective against long-term weight gain. OBJECTIVE: We aimed to examine the longitudinal association between dairy consumption and annualized changes in weight and waist circumference (WC) in adults. METHODS: Members of the Framingham Heart Study Offspring Cohort who participated in the fifth through eighth study examinations (1991-2008) were included in these analyses (3440 participants with 11 683 observations). At each exam, dietary intake was assessed by a validated food frequency questionnaire, and weight and WC were assessed following standardized procedures. Repeated measures models were used for the longitudinal analyses of annualized weight and waist circumference changes, adjusting for time-varying or invariant covariates. RESULTS: On average, participants gained weight and WC during follow-up. Dairy intake increased across exams. After adjusting for demographic and lifestyle factors (including diet quality), participants who consumed >= 3 servings per day of total dairy had 0.10 kg (+/- 0.04) smaller annualized increment of weight (P-trend = 0.04) than those consuming <1 serving per day. Higher total dairy intake was also marginally associated with less WC gain (P-trend = 0.05). Similarly, participants who consumed >= 3 servings per week of yogurt had a 0.10 kg (+/- 0.04) and 0.13 cm (+/- 0.05) smaller annualized increment of weight (P-trend = 0.03) and WC (P-trend = 0.008) than those consuming <1 serving per week, respectively. Skim/ low-fat milk, cheese, total high-fat or total low-fat dairy intake were not associated with long-term change in weight or WC. CONCLUSION: Further longitudinal and interventional studies are warranted to confirm the beneficial role of increasing total dairy and yogurt intake, as part of a healthy and calorie-balanced dietary pattern, in the long-term prevention of gain in weight and WC. C1 [Wang, H.; Troy, L. M.; Rogers, G. T.; McKeown, N. M.; Jacques, P. F.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Epidemiol Program, Boston, MA 02111 USA. [Troy, L. M.] Univ Massachusetts, Dept Nutr, Chenoweth Lab, Amherst, MA 01003 USA. [Troy, L. M.; McKeown, N. M.; Jacques, P. F.] Tufts Univ, Gerald J & Dorothy R Friedman Sch Nutr Sci & Poli, Boston, MA 02111 USA. [Fox, C. S.] Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, Framingham, MA USA. [Meigs, J. B.] Massachusetts Gen Hosp, Dept Med, Gen Internal Med Unit, Boston, MA 02114 USA. RP Jacques, PF (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM Paul.jacques@tufts.edu FU National Heart, Lung and Blood Institute of the National Institute of Health [NO1-HC-25195]; US Department of Agriculture [58-1950-7-707]; Dannon Company, Inc.; General Mills Bell Institute of Health and Nutrition FX We thank Kara A Livingston, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, for the help with data set management. This work was supported by the National Heart, Lung and Blood Institute of the National Institute of Health (contract number: NO1-HC-25195), US Department of Agriculture Agreement 58-1950-7-707 and research grants from The Dannon Company, Inc., and General Mills Bell Institute of Health and Nutrition. NR 53 TC 36 Z9 37 U1 4 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2014 VL 38 IS 2 BP 299 EP 305 DI 10.1038/ijo.2013.78 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AA9HL UT WOS:000331404300020 PM 23736371 ER PT J AU Chew, EY Clemons, TE SanGiovanni, JP Danis, RP Ferris, FL Elman, MJ Antoszyk, AN Ruby, AJ Orth, D Bressler, SB Fish, GE Hubbard, GB Klein, ML Chandra, SR Blodi, BA Domalpally, A Friberg, T Wong, WT Rosenfeld, PJ Agron, E Toth, CA Bernstein, PS Sperduto, RD AF Chew, Emily Y. Clemons, Traci E. SanGiovanni, John Paul Danis, Ronald P. Ferris, Frederick L. Elman, Michael J. Antoszyk, Andrew N. Ruby, Alan J. Orth, David Bressler, Susan B. Fish, Gary E. Hubbard, George Baker Klein, Michael L. Chandra, Suresh R. Blodi, Barbara A. Domalpally, Amitha Friberg, Thomas Wong, Wai T. Rosenfeld, Philip J. Agron, Elvira Toth, Cynthia A. Bernstein, Paul S. Sperduto, Robert D. CA AREDS2 Res Grp Authors Writing Tea TI Secondary Analyses of the Effects of Lutein/Zeaxanthin on Age-Related Macular Degeneration Progression AREDS2 Report No. 3 SO JAMA OPHTHALMOLOGY LA English DT Article ID LONG-TERM INCIDENCE; BLUE MOUNTAINS EYE; FATTY-ACID INTAKE; BETA-CAROTENE; VITAMIN-C; CIGARETTE-SMOKING; FISH CONSUMPTION; CLINICAL-TRIAL; UNITED-STATES; RISK-FACTORS AB IMPORTANCE The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURES Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. C1 [Chew, Emily Y.] NIH, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. [Clemons, Traci E.; SanGiovanni, John Paul] EMMES Corp, Rockville, MD USA. [SanGiovanni, John Paul] NEI, Clin Trials Branch, Bethesda, MD 20892 USA. [Danis, Ronald P.] Univ Wisconsin Madison, Dept Ophthalmol, Bethesda, MD USA. [Ferris, Frederick L.; Agron, Elvira] NEI, Bethesda, MD 20892 USA. [Elman, Michael J.] Elman Retina Grp, Baltimore, MD USA. [Antoszyk, Andrew N.] Charlotte Eye Ear Nose & Throat, Charlotte, NC USA. [Ruby, Alan J.] William Beaumont Hosp, Associated Retinal Consultants, Royal Oak, MI 48072 USA. [Orth, David] Ingalls Mem Hosp, Harvey, IL USA. [Bressler, Susan B.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21287 USA. [Fish, Gary E.] Texas Retina Associates, Dallas, TX USA. [Hubbard, George Baker] Emory Univ, Atlanta, GA 30322 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Dept Ophthalmol, Portland, OR USA. [Chandra, Suresh R.; Blodi, Barbara A.; Domalpally, Amitha] Univ Wisconsin Madison, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Blodi, Barbara A.] Univ Wisconsin Madison, Fundus Photograph Reading Ctr, Madison, WI USA. [Friberg, Thomas] Univ Pittsburgh, Sch Med, Dept Ophthalmol, Pittsburgh, PA 15261 USA. [Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Rosenfeld, Philip J.] Bascom Palmer Eye Inst, Dept Ophthalmol, Miami, FL 33136 USA. [Toth, Cynthia A.] Duke Univ, Med Ctr, Durham, NC USA. [Bernstein, Paul S.] Univ Utah, Hlth Sci Ctr, Moran Eye Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT USA. RP Chew, EY (reprint author), NIH, Div Epidemiol & Clin Res, 10 Ctr Dr,MSC1204,Bldg 10-CRC,Room 3-2531, Bethesda, MD 20892 USA. EM echew@nei.nih.gov RI Domalpally, Amitha/B-2367-2015; Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute/National Institutes of Health (NEI/NIH), Department of Health and Human Services, Bethesda, Maryland [HHS-N-260-2005-00007-C, N01-EY-5-0007]; NIH institute Office of Dietary Supplements; NIH institute National Center for Complementary and Alternative Medicine; NIH institute National Institute on Aging; NIH institute National Heart, Lung and Blood Institute; NIH institute National Institute of Neurological Disorders and Stroke FX This study was supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health (NEI/NIH), Department of Health and Human Services, Bethesda, Maryland (contract No. HHS-N-260-2005-00007-C and ADB contract No. N01-EY-5-0007). Funds were contributed to these contracts by the following NIH institutes: Office of Dietary Supplements, National Center for Complementary and Alternative Medicine, National Institute on Aging, National Heart, Lung and Blood Institute, and National Institute of Neurological Disorders and Stroke. The study medications and raw materials were provided by Alcon, Bausch and Lomb, DSM, and Pfizer. NR 36 TC 56 Z9 57 U1 6 U2 26 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD FEB PY 2014 VL 132 IS 2 BP 142 EP 149 DI 10.1001/jamaophthalmol.2013.7376 PG 8 WC Ophthalmology SC Ophthalmology GA AA8TJ UT WOS:000331367600003 ER PT J AU Pappas, A Kendrick, DE Shankaran, S Stoll, BJ Bell, EF Laptook, AR Walsh, MC Das, A Hale, EC Newman, NS Higgins, RD AF Pappas, Athina Kendrick, Douglas E. Shankaran, Seetha Stoll, Barbara J. Bell, Edward F. Laptook, Abbott R. Walsh, Michele C. Das, Abhik Hale, Ellen C. Newman, Nancy S. Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Chorioamnionitis and Early Childhood Outcomes Among Extremely Low-Gestational-Age Neonates SO JAMA PEDIATRICS LA English DT Article ID EXTREMELY PRETERM INFANTS; BIRTH-WEIGHT INFANTS; CEREBRAL-PALSY; HISTOLOGIC CHORIOAMNIONITIS; ISCHEMIC TOLERANCE; RESEARCH NETWORK; IMPACT; TERM; INFECTION; PREGNANCY AB IMPORTANCE Chorioamnionitis is strongly linked to preterm birth and neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral, and neurodevelopmental outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18- to 22-month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates. OBJECTIVE To compare the neonatal and neurodevelopmental outcomes of 3 groups of extremely low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis. DESIGN, SETTING, AND PARTICIPANTS Longitudinal observational study at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Two thousand three hundred ninety extremely preterm infants born at less than 27 weeks' gestational age (GA) between January 1, 2006, and December 31, 2008, with placental histopathology and 18 to 22 months' corrected age follow-up data were eligible. MAIN EXPOSURE Chorioamnionitis. MAIN OUTCOMES AND MEASURES Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant and Toddler Development, Third Edition), and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth. RESULTS Neonates exposed to chorioamnionitis had a lower GA and higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of GA in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological plus clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (adjusted odds ratio [OR], 2.38 [95% CI, 1.32 to 4.28] without GA; adjusted OR, 2.00 [95% CI, 1.10 to 3.64] with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological plus clinical chorioamnionitis (adjusted OR, 0.68 [95% CI, 0.52 to 0.89] without GA; adjusted OR, 0.66 [95% CI, 0.49 to 0.89] with GA as a covariate). Risk of behavioral problems did not differ statistically between groups. CONCLUSIONS AND RELEVANCE Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants. C1 [Pappas, Athina; Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Kendrick, Douglas E.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Stoll, Barbara J.; Bell, Edward F.; Walsh, Michele C.] Emory Univ, Sch Med, Dept Pediat, Childrens Healthcare Atlanta, Atlanta, GA USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Laptook, Abbott R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Newman, Nancy S.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Pappas, A (reprint author), Wayne State Univ, Childrens Hosp Michigan, Sch Med, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM apappas@med.wayne.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Center for Research Resources; National Center for Advancing Translational Sciences FX The National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Research Resources, and National Center for Advancing Translational Sciences provided grant support for the NRN Generic Database and Follow-up studies. NR 47 TC 36 Z9 38 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD FEB PY 2014 VL 168 IS 2 BP 137 EP 147 DI 10.1001/jamapediatrics.2013.4248 PG 11 WC Pediatrics SC Pediatrics GA AA8TD UT WOS:000331366900011 PM 24378638 ER PT J AU Lewis, A Hayashi, T Su, TP Betenbaugh, MJ AF Lewis, Abasha Hayashi, Teruo Su, Tsung-Ping Betenbaugh, Michael J. TI Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Review DE Calcium signaling; Apoptosis; Bcl-2; Mitochondria-associated ER membrane (MAM); Bioenergetics; ER; Mitochondria; Inositol 1,4,5-trisphosphate receptor (IP3R) ID APOPTOSIS-INDUCED CHANNEL; PERMEABILITY TRANSITION PORE; DEPENDENT ANION CHANNEL; HAMSTER OVARY CELLS; CYTOCHROME-C RELEASE; ENDOPLASMIC-RETICULUM; MITOCHONDRIAL APOPTOSIS; INOSITOL 1,4,5-TRISPHOSPHATE; LACTATE PRODUCTION; MAMMALIAN-CELLS AB Bcl-2 family proteins, known for their apoptosis functioning at the mitochondria, have been shown to localize to other cellular compartments to mediate calcium (Ca2+) signals. Since the proper supply of Ca2+ in cells serves as an important mechanism for cellular survival and bioenergetics, we propose an integrating role for Bcl-2 family proteins in modulating Ca2+ signaling. The endoplasmic reticulum (ER) is the main Ca2+ storage for the cell and Bcl-2 family proteins competitively regulate its Ca2+ concentration. Bcl-2 family proteins also regulate the flux of Ca2+ from the ER by physically interacting with inositol 1,4,5-trisphosphate receptors (IP(3)Rs) to mediate their opening. Type 1 IP(3)Rs reside at the bulk ER to coordinate cytosolic Ca2+ signals, while type 3 IP(3)Rs reside at mitochondria-associated ER membrane (MAM) to facilitate mitochondrial Ca2+ uptake. In healthy cells, mitochondrial Ca2+ drives pyruvate into the citric acid (TCA) cycle to facilitate ATP production, while a continuous accumulation of Ca2+ can trigger the release of cytochrome c, thus initiating apoptosis. Since multiple organelles and Bcl-2 family proteins are involved in Ca2+ signaling, we aim to clarify the role that Bcl-2 family proteins play in facilitating Ca2+ signaling and how mitochondrial Ca2+ is relevant in both bioenergetics and apoptosis. We also explore how these insights could be useful in controlling bioenergetics in apoptosis-resistant cell lines. C1 [Lewis, Abasha; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA. [Lewis, Abasha; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, IRP, NIH,DHHS, Baltimore, MD USA. [Hayashi, Teruo] Seiwakai Nishikawa Hosp, Hamada, Shimane, Japan. RP Lewis, A (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, 3400 North Charles St, Baltimore, MD USA. EM anlewis@jhu.edu FU Intramural Research Program of the National Institute on Drug Abuse; National Institutes of Health; Department of Health and Human Services FX This work is supported in part by the Intramural Research Program of the National Institute on Drug Abuse, the National Institutes of Health and the Department of Health and Human Services. NR 119 TC 10 Z9 11 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0145-479X EI 1573-6881 J9 J BIOENERG BIOMEMBR JI J. Bioenerg. Biomembr. PD FEB PY 2014 VL 46 IS 1 BP 1 EP 15 DI 10.1007/s10863-013-9527-7 PG 15 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA AA8VR UT WOS:000331373600001 PM 24078116 ER PT J AU Roger, JE Hiriyanna, A Gotoh, N Hao, H Cheng, DF Ratnapriya, R Kautzmann, MAI Chang, B Swaroop, A AF Roger, Jerome E. Hiriyanna, Avinash Gotoh, Norimoto Hao, Hong Cheng, Debbie F. Ratnapriya, Rinki Kautzmann, Marie-Audrey I. Chang, Bo Swaroop, Anand TI OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PHOTORECEPTOR-SPECIFIC EXPRESSION; TRANSCRIPTION FACTOR CRX; LEUCINE-ZIPPER NRL; HOMEOBOX GENE; CELL FATE; RETINITIS-PIGMENTOSA; STAT3 ACTIVATION; PRECURSOR CELLS; DEFICIENT MICE; MOUSE RETINA AB Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx (Crx(RiP)). We determined that CrxRiP is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the CrxRiP phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in CrxRiP retinas. Expression of NRL partially restored rod development in Crx(RiP/+) mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in CrxRiP mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design. C1 [Roger, Jerome E.; Hiriyanna, Avinash; Gotoh, Norimoto; Hao, Hong; Cheng, Debbie F.; Ratnapriya, Rinki; Kautzmann, Marie-Audrey I.; Swaroop, Anand] NEI, N NRL, NIH, Bethesda, MD 20892 USA. [Chang, Bo] Jackson Lab, Bar Harbor, ME 04609 USA. RP Swaroop, A (reprint author), NEI, N NRL, NIH, MSC0610,6 Ctr Dr, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Roger, Jerome/0000-0002-5061-230X; Swaroop, Anand/0000-0002-1975-1141 FU Intramural Research Program of the National Eye Institute [EY000450, EY000473, EY000474, EY019943] FX We are grateful to Jung-Woong Kim for expression profiles from flow-sorted photoreceptors and Rivka Rachel, Matthew Brooks, and Harsha Rajasimha for advice and assistance. We also thank Peter Colosi, Zhijian Wu, and Suja Hiriyanna for help with the AAV experiment. This research was supported by Intramural Research Program (EY000450, EY000473, EY000474) and EY019943 of the National Eye Institute. NR 60 TC 21 Z9 21 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2014 VL 124 IS 2 BP 631 EP 643 DI 10.1172/JCI72722 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AA9KV UT WOS:000331413300023 PM 24382353 ER PT J AU Kim, JH Thimmulappa, RK Kumar, V Cui, WC Kumar, S Kombairaju, P Zhang, H Margolick, J Matsui, W Macvittie, T Malhotra, SV Biswal, S AF Kim, Jung-Hyun Thimmulappa, Rajesh K. Kumar, Vineet Cui, Wanchang Kumar, Sarvesh Kombairaju, Ponvijay Zhang, Hao Margolick, Joseph Matsui, William Macvittie, Thomas Malhotra, Sanjay V. Biswal, Shyam TI NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TRANSCRIPTION FACTOR NRF2; INDUCED INFLAMMATORY RESPONSE; SMOKE-INDUCED EMPHYSEMA; NONHUMAN PRIMATE MODEL; MESENCHYMAL STEM-CELLS; SELF-RENEWAL; ANTIOXIDANT RESPONSE; OXIDATIVE STRESS; BONE-MARROW; IN-VIVO AB A nuclear disaster may result in exposure to potentially lethal doses of ionizing radiation (IR). Hematopoietic acute radiation syndrome (H-ARS) is characterized by severe myelosuppression, which increases the risk of infection, bleeding, and mortality. Here, we determined that activation of nuclear factor erythroid-2-related factor 2 (NRF2) signaling enhances hematopoietic stem progenitor cell (HSPC) function and mitigates IR-induced myelosuppression and mortality. Augmenting NRF2 signaling in mice, either by genetic deletion of the NRF2 inhibitor Keap1 or by pharmacological NRF2 activation with 2-trifluoromethyl-2'-methoxychalone (TMC), enhanced hematopoietic reconstitution following bone marrow transplantation (BMT). Strikingly, even 24 hours after lethal IR exposure, oral administration of TMC mitigated myelosuppression and mortality in mice. Furthermore, TMC administration to irradiated transgenic Notch reporter mice revealed activation of Notch signaling in HSPCs and enhanced HSPC expansion by increasing Jagged1 expression in BM stromal cells. Administration of a Notch inhibitor ablated the effects of TMC on hematopoietic reconstitution. Taken together, we identified a mechanism by which NRF2-mediated Notch signaling improves HSPC function and myelosuppression following IR exposure. Our data indicate that targeting this pathway may provide a countermeasure against the damaging effects of IR exposure. C1 [Kim, Jung-Hyun; Thimmulappa, Rajesh K.; Kumar, Sarvesh; Kombairaju, Ponvijay; Biswal, Shyam] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Kumar, Vineet; Malhotra, Sanjay V.] Leidos Biomed Res Inc, Lab Synthet Chem, Frederick Natl Lab Canc Res, Frederick, MD USA. [Cui, Wanchang; Macvittie, Thomas] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Zhang, Hao; Margolick, Joseph] Johns Hopkins Bloomberg Sch Publ Heath, Dept Microbiol & Mol Immunol, Baltimore, MD USA. [Matsui, William] Sidney Kimmel Comprehens Canc Ctr, Sch Med, Dept Oncol, Baltimore, MD USA. RP Biswal, S (reprint author), 615 N Wolfe St,Room E7624, Baltimore, MD 21205 USA. EM rthimmul@jhsph.edu; malhotrasa@mail.nih.gov; sbiswal@jhsph.edu OI Matsui, William/0000-0002-3088-0964 FU NIH [R33AI080541, U01AI107361, R01 CA140492]; Flight Attendant Medical Research Institute; NCI [P50 CA058184]; National Institute on Environmental Health Sciences [P50ES015903, ES03819, U01HL105569, P50HL107169, P01ES018176]; NCI, NIH [HHSN261200800001E] FX We acknowledge the help of the Mouse Phenotyping Core, the Department of Molecular and Comparative Pathobiology, and the Flow Cytometry Core of Johns Hopkins University. We thank Michael B. Sporn (Dartmouth Medical School) for providing CDDO-Me. We wish to thank Steven Ahn (Johns Hopkins University Bloomberg School of Public Health) for editing the manuscript and Il MM (Johns Hopkins University School of Medicine) for helpful discussions. We also thank G. Xin (Johns Hopkins University Bloomberg School of Public Health) for timely help with the mice studies and T. Kensler (Johns Hopkins University) and M. Yamamoto (Tohoku University, Aoba-ku, Sendai, Japan) for providing Nrf2-/- mice. Finally, we thank Nicholas Gaiano (Johns Hopkins University) for the Notch reporter mice. This work was supported by NIH grants R33AI080541, U01AI107361, and R01 CA140492 (to S. Biswal); a grant from the Flight Attendant Medical Research Institute (to S. Biswal and R.K. Thimmulappa); a NCI lung spore grant P50 CA058184 (to S. Biswal); and by National Institute on Environmental Health Sciences grants P50ES015903, ES03819, U01HL105569, P50HL107169, and P01ES018176. V. Kumar and S.V. Malhotra would like to acknowledge support from the NCI, NIH, under contract no. HHSN261200800001E. NR 73 TC 31 Z9 32 U1 0 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2014 VL 124 IS 2 BP 730 EP 741 DI 10.1172/JCI70812 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AA9KV UT WOS:000331413300032 PM 24463449 ER PT J AU Hsiao, CP Moore, IM Insel, KC Merkle, CJ AF Hsiao, Chao-Pin Moore, Ida M. (Ki) Insel, Kathleen C. Merkle, Carrie J. TI Symptom self-management strategies in patients with non-metastatic prostate cancer SO JOURNAL OF CLINICAL NURSING LA English DT Article DE prostate cancer; self-management; strategy; symptom distress; symptom management; symptoms ID RADICAL RETROPUBIC PROSTATECTOMY; SEXUAL FUNCTION; OUTCOMES; RADIOTHERAPY; RADIATION; URINARY AB Aims and objectivesTo explore the association between symptoms, symptom distress and symptom self-management and to identify effective strategies of symptom self-management in men with non-metastatic prostate cancer following radical prostatectomy or radiation therapy. BackgroundMen receiving treatments for localised prostate cancer experience symptoms of urinary incontinence, urinary obstruction/irritation, bowel difficulties and sexual dysfunction. Understanding patients' symptom experiences and identifying strategies that they use to manage these symptoms are imperative for symptom management planning. DesignA descriptive, cross-sectional study was conducted with a sample of 53 men, who were within threemonths of the initiation of their treatment. MethodsThe Symptom Indexes and the Strategy and Effectiveness of Symptom Self-Management questionnaires were used to measure symptoms, symptom distress and symptom self-management. Descriptive statistics, t-tests, correlations and multiple regressions were used to analyse the data. ResultsSymptoms were significantly correlated with symptom-related distress (r=067, p<001). Frequency of symptoms was significantly associated with symptom self-management strategies for urinary (=050, p<001), bowel (=071, p<001) and sexual problems (=028, p=005). The most effective strategies were as follows: pads and doing Kegel exercise for managing urinary problems, rest and endurance for bowel symptoms, and expressing feelings and finding alternative ways to express affection for management of sexual dysfunction. ConclusionsAssessing symptom self-management among men with newly diagnosed prostate cancer can help healthcare providers develop strategies that will enhance health-related quality of life. Relevance to clinical practiceResults provide information on effective strategies that patients with prostate cancer found to reduce their symptoms. The strategies used provide a foundation for developing and testing interventions for personalised symptom management. C1 [Hsiao, Chao-Pin] NINR, NIH, Bethesda, MD 20892 USA. [Moore, Ida M. (Ki); Insel, Kathleen C.; Merkle, Carrie J.] Univ Arizona, Coll Nursing, Tucson, AZ 85721 USA. RP Hsiao, CP (reprint author), NINR, NIH, 10 Ctr Dr,CRC 2-1339, Bethesda, MD 20892 USA. EM hsiaoc@mail.nih.gov FU Beta Mu Chapter of Sigma Theta Tau International Honor Society of Nursing; Young Investigator Award funds from Yuma Friends of Arizona Health Sciences Center FX This study was supported by the Beta Mu Chapter of Sigma Theta Tau International Honor Society of Nursing and the Young Investigator Award funds from Yuma Friends of Arizona Health Sciences Center. The authors would like to thank Dr. Joan Austin and Brigit Sullivan, Biomedical Librarian, National Institutes of Health (NIH) Library Writing Center, for editing assistance. NR 30 TC 4 Z9 5 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1067 EI 1365-2702 J9 J CLIN NURS JI J. Clin. Nurs. PD FEB PY 2014 VL 23 IS 3-4 BP 440 EP 449 DI 10.1111/jocn.12178 PG 10 WC Nursing SC Nursing GA AA6IS UT WOS:000331202600015 PM 23551614 ER PT J AU Al-huniti, MH Lu, SY Pike, VW Lepore, SD AF Al-huniti, Mohammed H. Lu, Shuiyu Pike, Victor W. Lepore, Salvatore D. TI Enhanced nucleophilic fluorination and radiofluorination of organosilanes appended with potassium-chelating leaving groups SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE Chelating leaving group; Fluoroorganosilane; Fluorine-18; Fluorination; Radiofluorination ID BUILDING-BLOCKS; PEPTIDES; PET; COMPOUND AB Here we aimed to explore the feasibility of enhancing the fluorination of organosilanes by appending potassium-chelating groups to the substrates. For this purpose, eight organosilanes were prepared in which a linear or cyclic leaving group, with putative potassium-chelating ability, was attached covalently to a congested silicon atom via an ether linkage to serve as a potential nucleophilic assisting leaving group (NALG). Organosilicon-NALGs with expected strong potassium-chelating capability enhanced reactions with potassium fluoride in acetonitrile to produce organofluorosilanes without any need to separately add phase transfer reagent. Similar rate enhancements were also observed with cyclotron-produced [F-18]fluoride ion (t(1/2) = 109.7 min, beta(+) = 97%) in the presence of potassium carbonate in MeCN-0.5% H2O. This study found that metal-chelating NALG units can accelerate fluorination and radiofluorination reactions at sterically crowded silicon atoms. (C) 2013 Elsevier B.V. All rights reserved. C1 [Al-huniti, Mohammed H.; Lepore, Salvatore D.] Florida Atlantic Univ, Dept Chem, Boca Raton, FL 33431 USA. [Lu, Shuiyu; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov; slepore@fau.edu OI Lu, Shuiyu/0000-0003-0310-4318 FU National Institute of Mental Health [MH087932]; National Institutes of Health (NIMH) FX This work was supported by a grant from the National Institute of Mental Health (MH087932). We also acknowledge the National Science Foundation Division of Undergraduate Education (NSF-0311369) for the 400 MHz NMR used in this study. SL and VWP were supported by the Intramural Research Program of the National Institutes of Health (NIMH). The authors are grateful to the NIH Clinical PET Center for the cyclotron production of fluorine-18. NR 30 TC 7 Z9 7 U1 3 U2 19 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 EI 1873-3328 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD FEB PY 2014 VL 158 BP 48 EP + DI 10.1016/j.jfluchem.2013.12.005 PG 5 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA AB0LG UT WOS:000331482900009 PM 24653526 ER PT J AU Chen, C Weider, K Konopka, K Danis, M AF Chen, Candice Weider, Katie Konopka, Kristen Danis, Marion TI Incorporation of Socioeconomic Status Indicators into Policies for the Meaningful Use of Electronic Health Records SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Editorial Material ID SUBJECTIVE SOCIAL-STATUS; CORONARY-HEART-DISEASE; INDIVIDUAL-LEVEL; MORTALITY; EDUCATION; INCOME; INEQUALITIES; DISPARITIES; QUESTIONS; RISK AB Socioeconomic status (SES) has an important effect on health. Individuals with lower SES experience more chronic disease, are less likely to receive preventive care, and have shorter life expectancies. As the Affordable Care Act is implemented and increasing numbers of previously uninsured people gain access to health care, the imperative to recognize patients' SES and develop health initiatives that account for the social determinants of health increases. Health care providers across the nation are adopting electronic health records (EHRs). Policies such as Meaningful Use offer opportunities systematically to incorporate the collection of standardized SES indicators into EHRs in ways that improve health, increase the understanding of the relationship between SES and health, and inform future policies. This paper examines the use of SES indicators in research, national surveys, and federal programs and finds adding an income question is the most feasible and optimal SES indicator for the inclusion in EHRs. C1 [Chen, Candice] George Washington Univ, Dept Hlth Policy, SPHHS, Washington, DC 20037 USA. [Weider, Katie; Konopka, Kristen; Danis, Marion] NIH, Sect Eth & Hlth Policy, Dept Bioeth, Bethesda, MD USA. [Weider, Katie; Konopka, Kristen; Danis, Marion] NIH, Ctr Clin, Bethesda, MD USA. RP Chen, C (reprint author), George Washington Univ, Dept Hlth Policy, 2121 K St NW,Suite 210, Washington, DC 20037 USA. EM cpchen@gwu.edu FU NIMHD NIH HHS [K22 MD006135] NR 46 TC 0 Z9 0 U1 1 U2 7 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2014 VL 25 IS 1 BP 1 EP 16 PG 16 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AA9NH UT WOS:000331419700008 PM 24509007 ER PT J AU Georgiev, IS Rudicell, RS Saunders, KO Shi, W Kirys, T McKee, K O'Dell, S Chuang, GY Yang, ZY Ofek, G Connors, M Mascola, JR Nabel, GJ Kwong, PD AF Georgiev, Ivelin S. Rudicell, Rebecca S. Saunders, Kevin O. Shi, Wei Kirys, Tatsiana McKee, Krisha O'Dell, Sijy Chuang, Gwo-Yu Yang, Zhi-Yong Ofek, Gilad Connors, Mark Mascola, John R. Nabel, Gary J. Kwong, Peter D. TI Antibodies VRC01 and 10E8 Neutralize HIV-1 with High Breadth and Potency Even with Ig-Framework Regions Substantially Reverted to Germline SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MONOCLONAL-ANTIBODIES; SOMATIC MUTATIONS; BROAD; DESIGN; VIRUS; INDIVIDUALS; PROTECTION; REVEAL; TARGET AB Abs capable of effectively neutralizing HIV-1 generally exhibit very high levels of somatic hypermutation, both in their CDR and framework-variable regions. In many cases, full reversion of the Ab-framework mutations back to germline results in substantial to complete loss of HIV-1-neutralizing activity. However, it has been unclear whether all or most of the observed framework mutations would be necessary or whether a small subset of these mutations might be sufficient for broad and potent neutralization. To address this issue and to explore the dependence of neutralization activity on the level of somatic hypermutation in the Ab framework, we applied a computationally guided framework-reversion procedure to two broadly neutralizing anti-HIV-1 Abs, VRC01 and 10E8, which target two different HIV-1 sites of vulnerability. Ab variants in which up to 78% (38 of 49 for VRC01) and 89% (31 of 35 for 10E8) of framework mutations were reverted to germline retained breadth and potency within 3-fold of the mature Abs when evaluated on a panel of 21 diverse viral strains. Further, a VRC01 variant with an similar to 50% framework-reverted L chain showed a 2-fold improvement in potency over the mature Ab. Our results indicate that only a small number of Ab-framework mutations may be sufficient for high breadth and potency of HIV-1 neutralization by Abs VRC01 and 10E8. Partial framework revertants of HIV-1 broadly neutralizing Abs may present advantages over their highly mutated counterparts as Ab therapeutics and as targets for immunogen design. C1 [Georgiev, Ivelin S.; Rudicell, Rebecca S.; Saunders, Kevin O.; Shi, Wei; Kirys, Tatsiana; McKee, Krisha; O'Dell, Sijy; Chuang, Gwo-Yu; Yang, Zhi-Yong; Ofek, Gilad; Connors, Mark; Mascola, John R.; Nabel, Gary J.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 4508, Bethesda, MD 20892 USA. EM pdkwong@nih.gov FU Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases; Office of AIDS Research, National Institutes of Health FX This work was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and the Office of AIDS Research, National Institutes of Health. NR 37 TC 30 Z9 30 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2014 VL 192 IS 3 BP 1100 EP 1106 DI 10.4049/jimmunol.1302515 PG 7 WC Immunology SC Immunology GA AA7FZ UT WOS:000331264200030 PM 24391217 ER PT J AU Strech, D Danis, M AF Strech, Daniel Danis, Marion TI How can bedside rationing be justified despite coexisting inefficiency? The need for 'benchmarks of efficiency' SO JOURNAL OF MEDICAL ETHICS LA English DT Article DE Allocation of Health Care Resources ID HEALTH-CARE; PHYSICIANS; PROFESSIONALISM; RESPONSIBILITY; PERCEPTIONS; BENEFITS; CANCER AB Imperfect efficiency in healthcare delivery is sometimes given as a justification for refusing to ration or even discuss how to pursue fair rationing. This paper aims to clarify the relationship between inefficiency and rationing, and the conditions under which bedside rationing can be justified despite coexisting inefficiency. This paper first clarifies several assumptions that underlie the classification of a clinical practice as being inefficient. We then suggest that rationing is difficult to justify in circumstances where the rationing agent is or should be aware of and contributes to clinical inefficiency. We further explain the different ethical implications of this suggestion for rationing decisions made by clinicians. We argue that rationing is more legitimate when sufficient efforts are undertaken to decrease inefficiency in parallel with efforts to pursue unavoidable but fair rationing. While the qualifier sufficient' is crucial here, we explain why sufficient efforts' should be translated into benchmarks of efficiency' that address specific healthcare activities where clinical inefficiency can be decreased. Referring to recent consensus papers, we consider some examples of specific clinical situations where improving clinical inefficiency has been recommended and consider how benchmarks for efficiency might apply. These benchmarks should state explicitly how much inefficiency shall be reduced in a reasonable time range and why these efforts are sufficient'. Possible strategies for adherence to benchmarks are offered to address the possibility of non-compliance. C1 [Strech, Daniel] Hannover Med Sch, Inst Hist Eth & Philosophy Med, D-30625 Hannover, Germany. [Strech, Daniel] Univ Zurich, Inst Biomed Eth, Zurich, Switzerland. [Danis, Marion] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Strech, D (reprint author), Hannover Med Sch, Inst Hist Eth & Philosophy Med, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM strech.daniel@mh-hannover.de OI Strech, Daniel/0000-0002-9153-079X FU intramural program at the National Institutes of Health FX This work was in part funded by the intramural program at the National Institutes of Health. NR 44 TC 4 Z9 4 U1 2 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD FEB PY 2014 VL 40 IS 2 BP 89 EP 93 DI 10.1136/medethics-2012-100769 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AA5ZA UT WOS:000331177200007 PM 23258082 ER PT J AU Wertheimer, A AF Wertheimer, Alan TI Non-completion and informed consent SO JOURNAL OF MEDICAL ETHICS LA English DT Article DE Informed Consent; Research Ethics; Clinical Ethics AB There is a good deal of biomedical research that does not produce scientifically useful data because it fails to recruit a sufficient number of subjects. This fact is typically not disclosed to prospective subjects. In general, the guidance about consent concerns the information required to make intelligent self-interested decisions and ignores some of the information required for intelligent altruistic decisions. Bioethics has worried about the therapeutic misconception', but has ignored the completion misconception'. This article argues that, other things being equal, prospective subjects should be informed about the possibility of non-completion as part of the standard consent process if (1) it is or should be anticipatable that there is a non-trivial possibility of non-completion and (2) that information is likely to be relevant to a prospective subject's decision to consent. The article then considers several objections to the argument, including the objection that disclosing non-completion information would make recruitment even more difficult. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 02892 USA. RP Wertheimer, A (reprint author), NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 02892 USA. EM wertheimera@cc.nih.gov NR 9 TC 3 Z9 3 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD FEB PY 2014 VL 40 IS 2 BP 127 EP 130 DI 10.1136/medethics-2012-101108 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AA5ZA UT WOS:000331177200016 PM 23371314 ER PT J AU Gharwan, H Groninger, H AF Gharwan, Helen Groninger, Hunter TI Targeted Cancer Therapies Part 1 #276 SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID TYROSINE KINASE INHIBITORS; FOCUS; DRUGS C1 [Groninger, Hunter] NIH, Pain & Palliat Care Serv, Bethesda, MD 20892 USA. RP Groninger, H (reprint author), NIH, Pain & Palliat Care Serv, Clin Res Ctr Bldg 10,Room 2-1733,10 Ctr Dr, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov NR 10 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 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD FEB 1 PY 2014 VL 17 IS 2 BP 236 EP 240 DI 10.1089/jpm.2013.9452 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AA6TG UT WOS:000331230400020 PM 24438132 ER PT J AU Shi, TJ Gao, YQ Quek, SI Fillmore, TL Nicora, CD Su, D Zhao, R Kagan, J Srivastava, S Rodland, KD Liu, T Smith, RD Chan, DW Camp, DG Liu, AY Qian, WJ AF Shi, Tujin Gao, Yuqian Quek, Sue Ing Fillmore, Thomas L. Nicora, Carrie D. Su, Dian Zhao, Rui Kagan, Jacob Srivastava, Sudhir Rodland, Karin D. Liu, Tao Smith, Richard D. Chan, Daniel W. Camp, David G., II Liu, Alvin Y. Qian, Wei-Jun TI A Highly Sensitive Targeted Mass Spectrometric Assay for Quantification of AGR2 Protein in Human Urine and Serum SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE AGR2; PSA; prostate cancer; PRISM-SRM; human urine; human serum ID ANTERIOR GRADIENT 2; PROSTATE-CANCER; IMMUNOAFFINITY DEPLETION; OVARIAN-CANCER; GENE AGR2; PROTEOMICS; PLASMA; ADENOCARCINOMA; EXPRESSION; DIAGNOSIS AB Anterior gradient 2 (AGR2) is a secreted, cancer-associated protein in many types of epithelial cancer cells. We developed a highly sensitive targeted mass spectrometric assay for quantification of AGR2 in urine and serum. Digested peptides from clinical samples were processed by PRISM (high pressure and high resolution separations coupled with intelligent selection and multiplexing), which incorporates high pH reversed-phase liquid chromatography (LC) separations to fractionate and select target fractions for follow-on LC-selected reaction monitoring (LC-SRM) analyses. The PRISM-SRM assay for AGR2 showed a reproducibility of <10% CV and limit of quantification (LOQ) values of similar to 130 pg/mL in serum and similar to 10 pg per 100 mu g of total protein mass in urine, respectively. A good correlation (R-2 = 0.91) was observed for the measurable AGR2 concentrations in urine between SRM and enzyme-linked immunosorbent assay (ELISA). On the basis of an initial cohort of 37 subjects, urinary AGR2/PSA concentration ratios showed a significant difference (P = 0.026) between noncancer and cancer. Large clinical cohort studies are needed for the validation of AGR2 as a useful diagnostic biomarker for prostate cancer. Our work validated the approach of identifying candidate secreted protein biomarkers through genomics and measurement by targeted proteomics, especially for proteins where no immunoassays are available. C1 [Shi, Tujin; Gao, Yuqian; Nicora, Carrie D.; Su, Dian; Rodland, Karin D.; Liu, Tao; Smith, Richard D.; Camp, David G., II; Qian, Wei-Jun] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Fillmore, Thomas L.; Zhao, Rui] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Quek, Sue Ing; Liu, Alvin Y.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Quek, Sue Ing; Liu, Alvin Y.] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. [Kagan, Jacob; Srivastava, Sudhir] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Chan, Daniel W.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21231 USA. RP Liu, AY (reprint author), Univ Washington, Dept Urol, Seattle, WA 98195 USA. EM aliu@u.washington.edu; weijun.qian@pnnl.gov RI Smith, Richard/J-3664-2012; Shi, Tujin/O-1789-2014 OI Smith, Richard/0000-0002-2381-2349; FU NIH Grant [U01CA111244]; NIH Director's New Innovator Award Program [DP2OD006668]; NCI Early Detection Research Network from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC) [Y01-CN-05013-29, U24-CA-16001901]; DOE [DE-AC05-76RL0 1830]; [P41GM103493] FX We thank Drs. Robin Leach and Ian Thompson at the University of Texas Health Science Center at San Antonio for providing some of the clinical urine samples. Portions of the research were supported by NIH Grant U01CA111244, NIH Director's New Innovator Award Program DP2OD006668, NCI Early Detection Research Network Interagency Agreement Y01-CN-05013-29, U24-CA-16001901 from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC), and P41GM103493. The experimental work described herein was performed in the Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, a national scientific user facility sponsored by the DOE under Contract DE-AC05-76RL0 1830. NR 37 TC 26 Z9 26 U1 2 U2 20 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 FEB PY 2014 VL 13 IS 2 BP 875 EP 882 DI 10.1021/pr400912c PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AA5UC UT WOS:000331164100047 PM 24251762 ER PT J AU Sen, A Marsche, G Freudenberger, P Schallert, M Toeglhofer, AM Nagl, C Schmidt, R Launer, LJ Schmidt, H AF Sen, Abhijit Marsche, Gunther Freudenberger, Paul Schallert, Michael Toeglhofer, Anna M. Nagl, Christoph Schmidt, Reinhold Launer, Lenore J. Schmidt, Helena TI Association Between Higher Plasma Lutein, Zeaxanthin, and Vitamin C Concentrations and Longer Telomere Length: Results of the Austrian Stroke Prevention Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE telomere length; vitamin C; lutein zeaxanthin; aging; antioxidants; oxidative stress ID WHITE-MATTER HYPERINTENSITIES; OXIDATION PROTEIN PRODUCTS; NITRIC-OXIDE; DNA-DAMAGE; IN-VIVO; STRESS; DISEASE; WOMEN; CANCER; CELLS AB ObjectivesTo examine the association between plasma concentrations of antioxidative micronutrients and leukocyte telomere length (LTL) in elderly adults. DesignCross-sectional cohort study. SettingAustrian Stroke Prevention Study, a population-based cohort study on brain aging. ParticipantsIndividuals with a mean age of 667 (n=786; 58% female). MeasurementsConcentrations of vitamin C, lutein, zeaxanthin, -cryptoxanthin, canthaxanthin, lycopene, - and -tocopherol, - and -carotene, and retinol in plasma, advanced oxidation protein products as a measure of oxidative stress in serum, and LTL were measured. Vitamins and carotenoids were measured using high-performance liquid chromatography, advanced oxidation protein products using spectrophotometry, and telomere length using quantitative real-time polymerase chain reaction. ResultsMultiple linear regression analyses with adjustment for age and sex demonstrated that higher lutein, zeaxanthin, and vitamin C concentrations were strongly associated with longer telomere length. The associations were independent of body mass index, maximum oxygen uptake, and vascular risk factors and were not mediated by advanced oxidation protein products content. ConclusionThis study provides first evidence that higher lutein, zeaxanthin, and vitamin C concentrations in plasma are associated with longer LTL in normal elderly persons and suggest a protective role of these vitamins in telomere maintenance. C1 [Sen, Abhijit; Freudenberger, Paul; Toeglhofer, Anna M.; Nagl, Christoph; Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, Res Unit Genet Epidemiol, A-8010 Graz, Austria. [Marsche, Gunther] Med Univ Graz, Inst Expt & Clin Pharmacol, A-8010 Graz, Austria. [Schallert, Michael; Schmidt, Reinhold; Schmidt, Helena] Med Univ Graz, Dept Neurol, A-8010 Graz, Austria. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Schmidt, H (reprint author), Med Univ Graz, Inst Mol Biol & Biochem, Harrachgasse 21, A-8010 Graz, Austria. EM helena.schmidt@medunigraz.at OI Marsche, Gunther/0000-0002-2422-5381 FU PhD Program Neurosciences of the Medical University of Graz; Oesterreichische Nationalbank (Anniversary Fund) [15435]; Austrian Science Fund [P20545-B05, P22976-B18, P13180]; Intramural Research Program, National Institute on Aging, National Institutes of Health FX The study was funded by the PhD Program Neurosciences of the Medical University of Graz, by funds from the Oesterreichische Nationalbank (Anniversary Fund, project 15435), and by Austrian Science Fund grants P20545-B05 to Helena Schmidt, P22976-B18 to Gunther Marsche, and P13180 to Reinhold Schmidt. Lenore J. Launer is supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 51 TC 6 Z9 6 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2014 VL 62 IS 2 BP 222 EP 229 DI 10.1111/jgs.12644 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AA6KL UT WOS:000331207100002 PM 24428184 ER PT J AU Moore, AZ Caturegli, G Metter, EJ Makrogiannis, S Resnick, SM Harris, TB Ferrucci, L AF Moore, Ann Zenobia Caturegli, Giorgio Metter, E. Jeffrey Makrogiannis, Sokratis Resnick, Susan M. Harris, Tamara B. Ferrucci, Luigi TI Difference in Muscle Quality over the Adult Life Span and Biological Correlates in the Baltimore Longitudinal Study of Aging SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE muscle quality; muscle strength; muscle area ID AGE-RELATED-CHANGES; BODY-COMPOSITION; SKELETAL-MUSCLE; ELDERLY-MEN; PHYSICAL FUNCTION; OLDER-ADULTS; DOUBLE-BLIND; STRENGTH; WOMEN; MASS AB ObjectivesTo examine differences in a proxy measure of muscle quality across the adult life span and explore potential mechanisms of muscle quality change through identification of cross-sectional correlates of muscle quality. DesignCross-sectional study. SettingBaltimore Longitudinal Study of Aging. ParticipantsSeven hundred eighty-six individuals with a mean age of 66.3 (range 26-96) (N=786). A sensitivity analysis was conducted in a subset of participants matched according to sex, muscle mass, and body size. MeasurementsMuscle quality was operationalized as the ratio of knee-extension strength (isokinetic dynamometry) to thigh muscle cross-sectional area (computed tomography). Differences in muscle strength, muscle area, and muscle quality ratio with age were evaluated, and the association between the muscle quality ratio and measures reflecting domains of cognitive function, motor control, peripheral nerve function, adiposity, glucose homeostasis, and inflammation were assessed through multivariate regression analyses. ResultsA linear relationship between age and muscle quality ratio was observed, suggesting a gradual decline in muscle quality over the adult life course. Associations were observed between muscle quality ratio and measures of adiposity, as well as peroneal nerve motor conduction velocity, finger tapping speed, and memory performance (P<.01). The association between muscle quality ratio and nerve conduction velocity was maintained after adjustment for anthropometric measurements (P<.05). ConclusionMuscle quality declines progressively with age over the adult life span and is affected by obesity and neurological factors. Studies are needed to clarify the mechanisms of these associations and their implications for functional outcomes. C1 [Moore, Ann Zenobia; Caturegli, Giorgio; Metter, E. Jeffrey; Makrogiannis, Sokratis; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Moore, AZ (reprint author), Harbor Hosp, NIA, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. EM mooreaz@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 43 TC 29 Z9 29 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2014 VL 62 IS 2 BP 230 EP 236 DI 10.1111/jgs.12653 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AA6KL UT WOS:000331207100003 PM 24438020 ER PT J AU Simonsick, EM Schrack, JA Glynn, NW Ferrucci, L AF Simonsick, Eleanor M. Schrack, Jennifer A. Glynn, Nancy W. Ferrucci, Luigi TI Assessing Fatigability in Mobility-Intact Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE fatigue; fatigability; performance measures; validation; mobility ID DISTANCE CORRIDOR WALK; FATIGUE; LIMITATION; DISABILITY; MORTALITY; ASSOCIATION; SEVERITY; EXERTION; FITNESS AB ObjectivesTo evaluate the criterion validity of two measures of fatigability, defined as performance deterioration or perceived effort to perform a standardized task. DesignCross-sectional analysis of data from the Baltimore Longitudinal Study of Aging (BLSA). SettingNational Institute on Aging, Intramural Research Program, Clinical Research Unit, Baltimore, Maryland. ParticipantsSix hundred five men (53.7%) and women aged 65 to 97 participating in the BLSA and eligible for endurance walk testing without a walking aid. MeasurementsFatigability was assessed using completion status and lap times from a 400-m walk performed as quickly as possible and perceived exertion rating using the Borg scale (range 6-20) after 5minutes of treadmill walking at 1.5miles per hour (0.67m/s). Criterion measures included self-report of tiredness, level of weakness and energy in past month, and walking ability and objective measures of usual and fast gait speed, time to complete 10 chair stands, and grip strength. Covariates included age, race, sex, obesity, smoking status, and walking activity. ResultsOf mobility-intact older persons, 23% exhibited performance deterioration (slowed or stopped) during the 400-m walk, and one-third reported more than very light exertion after a 5-minute slow walk. Slowing was strongly associated with self-reported fatigue and walking ability but weakly associated with performance-based mobility measures. High perceived exertion was associated with tiredness, weakness, and reported and observed mobility deficits. ConclusionSlowing down may have low sensitivity for identifying fatigability in older persons, but ascertaining perceived exertion during a defined workload shows promise. In seemingly healthy, motivated individuals, fatigue and fatigability were common and may affect socially meaningful mobility behaviors. Assessment of fatigability in well-elderly examinations may help identify threats to independent functioning earlier in the decline process. C1 [Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore, MD 21225 USA. [Schrack, Jennifer A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Glynn, Nancy W.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. RP Simonsick, EM (reprint author), NIA, 3001 S Hanover St, Baltimore, MD 21225 USA. EM simonsickel@mail.nih.gov OI Glynn, Nancy/0000-0003-2265-0162 FU Intramural Research Program, National Institute on Aging FX Funding received from the Intramural Research Program, National Institute on Aging. NR 23 TC 22 Z9 22 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2014 VL 62 IS 2 BP 347 EP 351 DI 10.1111/jgs.12638 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AA6KL UT WOS:000331207100020 PM 24417536 ER PT J AU Mahar, JE Donker, NC Bok, K Talbo, GH Green, KY Kirkwood, CD AF Mahar, Jackie E. Donker, Nicole C. Bok, Karin Talbo, Gert H. Green, Kim Y. Kirkwood, Carl D. TI Identification and Characterization of Antibody-Binding Epitopes on the Norovirus GII.3 Capsid SO JOURNAL OF VIROLOGY LA English DT Article ID NORWALK-LIKE VIRUSES; BLOOD GROUP ANTIGENS; MONOCLONAL-ANTIBODIES; IMMUNE-RESPONSES; GENETIC-ANALYSIS; STRUCTURAL BASIS; GENOGROUP-I; PROTEIN; EVOLUTION; VACCINE AB Genotype II.3 (GII.3) noroviruses are a major cause of sporadic gastroenteritis, particularly in children. The greater incidence of GII.3 noroviruses in the pediatric population compared to the adult demographic suggests development of herd immunity to this genotype, possibly as a consequence of limited evolution of immune epitopes. This study aimed to identify and characterize immune epitopes on the GII.3 capsid protein and to determine the level of immune cross-reactivity within the genotype. A panel of seven GII.3 virus-like particles (VLPs), representing norovirus strains isolated during 1975 to 2008, was tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with human sera and a rabbit anti-GII.3 strain-specific polyclonal serum generated against the 2008 GII.3 VLP. Immunoprecipitation of protease-digested GII.3 VLPs and sequencing of bound peptides via mass spectrometry were used to locate epitopes on the capsid. Two epitopes were investigated further using Mimotopes technology. Serum binding studies demonstrated complete intragenotype GII.3 cross-reactivity using both human and rabbit serum. Six immunoreactive regions containing epitopes were located on the GII.3 capsid protein, two within each capsid domain. Epitopes in the S and P1 domains were highly conserved within GII.3 noroviruses. P2 domain epitopes were variable and contained evolutionarily important residues and histo-blood group antigen (HBGA) binding residues. In conclusion, anti-GII.3 antibody-binding epitopes are highly cross-reactive and mostly conserved within GII.3 strains. This may account for the limited GII.3 prevalence in adults and suggests that a GII.3 strain may be a valuable inclusion in a multivalent pediatric targeted VLP vaccine. Exploration of norovirus immune epitopes is vital for effective vaccine design. IMPORTANCE This study represents an important contribution to the understanding of norovirus immunology in a pediatric genotype. The high cross-reactivity and conservation of GII.3 epitopes suggest development of herd immunity against GII.3 and indicate that a GII.3 strain would be a valuable inclusion in a pediatric targeted multivalent vaccine. Immunological understanding of pediatric norovirus strains is important since norovirus vaccines will likely target high-risk groups such as the pediatric population. C1 [Mahar, Jackie E.; Donker, Nicole C.; Kirkwood, Carl D.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Enter Virus Grp, Parkville, Vic 3052, Australia. [Mahar, Jackie E.; Donker, Nicole C.; Kirkwood, Carl D.] La Trobe Univ, Dept Microbiol, Bundoora, Vic 3083, Australia. [Bok, Karin; Green, Kim Y.] NIAID, Infect Dis Lab, Caliciviruses Sect, NIH,DHHS, Bethesda, MD 20892 USA. [Talbo, Gert H.] La Trobe Univ, Dept Biochem, Bundoora, Vic 3083, Australia. RP Mahar, JE (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Enter Virus Grp, Flemington Rd, Parkville, Vic 3052, Australia. EM jemahar@students.latrobe.edu.au; carl.kirkwood@mcri.edu.au FU Victorian Government; NIH, NIAID; Australian Postgraduate Award; National Health and Medical Research Council of Australia [607347] FX This study was supported by the Victorian Government's Operational Infrastructure Support Program and the Intramural Research Program of the NIH, NIAID.; J. E. Mahar was supported by an Australian Postgraduate Award, and C. D. Kirkwood was supported by a Research Fellowship from the National Health and Medical Research Council of Australia (607347). NR 60 TC 1 Z9 2 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2014 VL 88 IS 4 BP 1942 EP 1952 DI 10.1128/JVI.02992-13 PG 11 WC Virology SC Virology GA AA5HA UT WOS:000331125500009 PM 24284328 ER PT J AU Edwards, D Fukumoto, R de Castro-Amarante, MF Alcantara, LC Galvao-Castro, B Parks, RW Pise-Masison, C Franchini, G AF Edwards, Dustin Fukumoto, Risaku de Castro-Amarante, Maria Fernanda Alcantara Junior, Luiz Carlos Galvao-Castro, Bernardo Parks, Robyn Washington Pise-Masison, Cynthia Franchini, Genoveffa TI Palmitoylation and p8-Mediated Human T-Cell Leukemia Virus Type 1 Transmission SO JOURNAL OF VIROLOGY LA English DT Article ID P12(I) PROTEIN; NUCLEAR FACTOR; SIGNAL-TRANSDUCTION; ACTIVATION; EXPRESSION; MYELOPATHY; RECEPTOR; HTLV-1; FAMILY; LINES AB The orf-I gene of human T-cell leukemia type 1 (HTLV-1) encodes p8 and p12 and has a conserved cysteine at position 39. p8 and p12 form disulfide-linked dimers, and only the monomeric forms of p8 and p12 are palmitoylated. Mutation of cysteine 39 to alanine (C39A) abrogated dimerization and palmitoylation of both proteins. However, the ability of p8 to localize to the cell surface and to increase cell adhesion and viral transmission was not affected by the C39A mutation. C1 [Edwards, Dustin; Fukumoto, Risaku; de Castro-Amarante, Maria Fernanda; Alcantara Junior, Luiz Carlos; Parks, Robyn Washington; Pise-Masison, Cynthia; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Alcantara Junior, Luiz Carlos; Galvao-Castro, Bernardo] Fundacao Oswaldo Cruz, Goncalo Moniz Res Ctr, Salvador, BA, Brazil. [Galvao-Castro, Bernardo] Bahia Fdn Sci Dev, Bahia Sch Med & Publ Hlth, Salvador, BA, Brazil. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov NR 20 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2014 VL 88 IS 4 BP 2319 EP 2322 DI 10.1128/JVI.03444-13 PG 4 WC Virology SC Virology GA AA5HA UT WOS:000331125500041 PM 24284316 ER PT J AU Jensen, SMR Ruscetti, FW Rein, A Bertolette, DC Saucedo, CJ O'Keefe, BR Jones, KS AF Jensen, Stig M. R. Ruscetti, Francis W. Rein, Alan Bertolette, Daniel C. Saucedo, Carrie J. O'Keefe, Barry R. Jones, Kathryn S. TI Differential Inhibitory Effects of Cyanovirin-N, Griffithsin, and Scytovirin on Entry Mediated by Envelopes of Gammaretroviruses and Deltaretroviruses SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VESICULAR STOMATITIS-VIRUS; FELINE LEUKEMIA VIRUSES; ANTI-HIV PROTEIN; PLANT-LECTINS; INACTIVATING PROTEIN; POTENT; TRANSMISSION; BINDING; GLYCOPROTEINS AB The antiviral lectins griffithsin (GRFT), cyanovirin-N (CV-N), and scytovirin (SVN), which inhibit several enveloped viruses, including lentiviruses, were examined for their ability to inhibit entry mediated by Env proteins of delta-and gammaretroviruses. The glycoproteins from human T-cell leukemia virus type 1 (HTLV-1) were resistant to the antiviral effects of all three lectins. For gammaretroviruses, CV-N inhibited entry mediated by some but not all of the envelopes examined, whereas GRFT and SVN displayed only little or no effect. C1 [Jensen, Stig M. R.; Ruscetti, Francis W.; Bertolette, Daniel C.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Rein, Alan] NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. [O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Saucedo, Carrie J.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Mol Targets Lab, Frederick, MD USA. [Jones, Kathryn S.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Basic Res Program, Frederick, MD USA. RP Jones, KS (reprint author), Howard Community Coll, Div Sci Engn & Technol, Columbia, MD 21044 USA. EM kjones@howardcc.edu FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. NR 48 TC 2 Z9 2 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2014 VL 88 IS 4 BP 2327 EP 2332 DI 10.1128/JVI.02553-13 PG 6 WC Virology SC Virology GA AA5HA UT WOS:000331125500043 PM 24284326 ER PT J AU Wu, SH Shu, XO Chow, WH Xiang, YB Zhang, XL Li, HL Cai, QY Milne, G Ji, BT Cai, H Rothman, N Gao, YT Zheng, W Yang, G AF Wu, Sheng Hui Shu, Xiao Ou Chow, Wong-Ho Xiang, Yong-Bing Zhang, Xianglan Li, Hong-Lan Cai, Qiuyin Milne, Ginger Ji, Bu-Tian Cai, Hui Rothman, Nathaniel Gao, Yu-Tang Zheng, Wei Yang, Gong TI Nonexercise Physical Activity and Inflammatory and Oxidative Stress Markers in Women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID CHINESE WOMEN; ENERGY-EXPENDITURE; CYTOKINE RESPONSE; EXERCISE; MORTALITY; SHANGHAI; HUMANS; HEALTH; DISEASE; REPRODUCIBILITY AB Background: Leisure time exercise has been linked to lower circulating levels of inflammatory markers. Few studies have examined the association of nonexercise physical activity with markers of inflammation and oxidative stress. Methods: This cross-sectional analysis included 1005 Chinese women aged 40-70 years. Usual physical activity was assessed through in-person interviews using a validated physical activity questionnaire. Plasma proinflammatory cytokines and urinary F-2-isoprostanes were measured. Multivariable linear models were used to evaluate the association of inflammatory and oxidative stress markers with nonexercise physical activity and its major components. Results: Nonexercise physical activity accounted for 93.8% of overall physical activity energy expenditure. Levels of nonexercise physical activity were inversely associated with circulating concentrations of interleukin (IL)-6 (P-trend=0.004), IL-1 (P-trend=0.03) and tumor necrosis factor-alpha (TNF-) (P-trend=0.01). Multivariable-adjusted concentrations of these cytokines were 28.2% for IL-6, 22.1% for IL-1, and 15.9% for TNF- lower in the highest quartile of nonexercise physical activity compared with the lowest quartile. Similar inverse associations were found for two major components of nonexercise physical activity, walking and biking for transportation, and household activity. No significant associations were observed between nonexercise physical activity and oxidative stress markers. Conclusion: Daily nonexercise physical activity is associated with lower levels of systemic inflammation. This finding may have important public health implications because this type of activity is the main contributor to overall physical activity among middle-aged and elderly women. C1 [Wu, Sheng Hui; Shu, Xiao Ou; Zhang, Xianglan; Cai, Qiuyin; Cai, Hui; Zheng, Wei; Yang, Gong] Vanderbilt Univ Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37203 USA. [Chow, Wong-Ho; Ji, Bu-Tian; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Xiang, Yong-Bing; Li, Hong-Lan; Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Milne, Ginger] Vanderbilt Univ Sch Med, Dept Med, Div Clin Pharmacol, Nashville, TN 37203 USA. RP Yang, G (reprint author), Vanderbilt Univ Sch Med, Dept Med, Div Epidemiol, 2525 West End Ave,Suite 600 IMPH, Nashville, TN 37203 USA. EM Gong.Yang@Vanderbilt.edu RI Milne, Ginger/D-7648-2014 OI Milne, Ginger/0000-0003-3890-151X FU U.S. Public Health Service; National Institutes of Health [R01CA122364, R37CA070867, R01HL095931, N02 CP1101066] FX We are grateful to the participants and research staff of the Shanghai Women's Health Study for their contributions to the study. We thank Bethanie Rammer and Jacqueline Stern for their assistance in editing and preparing the manuscript. We also thank Regina Courtney and Rodica Cal-Chris for sample preparation. This study was, in part, supported by U.S. Public Health Service grants and contracts from the National Institutes of Health, including R01CA122364 (to G. Y.), R37CA070867 (to W. Z.), R01HL095931 (to X. L. Z.), and N02 CP1101066 (to X. O. S.). NR 43 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD FEB 1 PY 2014 VL 23 IS 2 BP 159 EP 167 DI 10.1089/jwh.2013.4456 PG 9 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 AA7HC UT WOS:000331267300009 PM 24168102 ER PT J AU Kobilo, T Guerrieri, D Zhang, YQ Collica, SC Becker, KG van Praag, H AF Kobilo, Tali Guerrieri, Davide Zhang, Yongqing Collica, Sarah C. Becker, Kevin G. van Praag, Henriette TI AMPK agonist AICAR improves cognition and motor coordination in young and aged mice SO LEARNING & MEMORY LA English DT Article ID ACTIVATED PROTEIN-KINASE; SKELETAL-MUSCLE; MITOCHONDRIAL BIOGENESIS; HIPPOCAMPAL NEUROGENESIS; GENE-EXPRESSION; SPATIAL MEMORY; EXERCISE; COMPLEX; DISEASE; GLUCOSE AB Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced spatial memory function, and endurance. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young (4- to 6-wk-old) transgenic mice with muscle-specific mutated AMPK alpha 2-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3-14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice. In the AMPK-DN mice, the compound did not enhance behavior, providing support for a muscle-mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus, genes relevant to neuronal development and plasticity were enriched. Altogether, endurance-related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions. C1 [Kobilo, Tali; Guerrieri, Davide; Collica, Sarah C.; van Praag, Henriette] NIA, NIH, Neuroplast & Behav Unit, Lab Neurosciences, Baltimore, MD 21224 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, NIH, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, NIH, Neuroplast & Behav Unit, Lab Neurosciences, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015; Meijer, Anna/K-5118-2016; OI van Praag, Henriette/0000-0002-5727-434X; Becker, Kevin/0000-0002-6794-6656 FU NIH, National Institute on Aging (NIA) FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging (NIA). We thank Chunyan Yuan for assistance with initial experiments and William H. Wood III for assistance with the microarray analysis. NR 67 TC 16 Z9 16 U1 1 U2 6 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 EI 1549-5485 J9 LEARN MEMORY JI Learn. Mem. PD FEB PY 2014 VL 21 IS 2 BP 119 EP 126 DI 10.1101/lm.033332.113 PG 8 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AA9EG UT WOS:000331396000008 PM 24443745 ER PT J AU Patel, B Kang, Y Cui, K Litt, M Riberio, MSJ Deng, C Salz, T Casada, S Fu, X Qiu, Y Zhao, K Huang, S AF Patel, B. Kang, Y. Cui, K. Litt, M. Riberio, M. S. J. Deng, C. Salz, T. Casada, S. Fu, X. Qiu, Y. Zhao, K. Huang, S. TI Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia SO LEUKEMIA LA English DT Article DE TAL1/SCL oncogene; chromatin loops; CTCF insulator; T-cell leukemia; epigenetic regulation ID CHROMOSOME CONFORMATION CAPTURE; BETA-GLOBIN LOCUS; PEDIATRIC-ONCOLOGY-GROUP; VERTEBRATE SCL LOCI; C-MAF; TRANSCRIPTION FACTOR; GENE-EXPRESSION; HUMAN GENOME; HEMATOPOIETIC LINEAGES; HISTONE MODIFICATIONS AB Long-range chromatin interactions control metazoan gene transcription. However, the involvement of intra-and interchromosomal interactions in development and oncogenesis remains unclear. TAL1/SCL is a critical transcription factor required for the development of all hematopoietic lineages; yet, aberrant TAL1 transcription often occurs in T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that oncogenic TAL1 expression is regulated by different intra-and interchromosomal loops in normal hematopoietic and leukemic cells, respectively. These intra-and interchromosomal loops alter the cell-type-specific enhancers that interact with the TAL1 promoter. We show that human SET1 (hSET1)-mediated H3K4 methylations promote a long-range chromatin loop, which brings the +51 enhancer in close proximity to TAL1 promoter 1 in erythroid cells. The CCCTC-binding factor (CTCF) facilitates this long-range enhancer/promoter interaction of the TAL1 locus in erythroid cells while blocking the same enhancer/promoter interaction of the TAL1 locus in human T-cell leukemia. In human T-ALL, a T-cell-specific transcription factor c-Mafmediated interchromosomal interaction brings the TAL1 promoter into close proximity with a T-cell-specific regulatory element located on chromosome 16, activating aberrant TAL1 oncogene expression. Thus, our study reveals a novel molecular mechanism involving changes in three-dimensional chromatin interactions that activate the TAL1 oncogene in human T-cell leukemia. C1 [Patel, B.; Kang, Y.; Riberio, M. S. J.; Deng, C.; Salz, T.; Huang, S.] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Kang, Y.; Fu, X.] Jilin Univ, Coll Life Sci, Changchun 130023, Peoples R China. [Cui, K.; Zhao, K.] NHLBI, Ctr Syst Biol, NIH, Bethesda, MD 20892 USA. [Litt, M.; Casada, S.] Ball State Univ, Med Educ Ctr, Muncie, IN 47306 USA. [Qiu, Y.] Univ Florida, Coll Med, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Qiu, Y.; Huang, S.] Univ Florida, Coll Med, Shands Canc Ctr, Gainesville, FL 32610 USA. RP Huang, S (reprint author), Univ Florida, Coll Med, Dept Biochem & Mol Biol, POB 103633,2033 Mowry Rd, Gainesville, FL 32610 USA. EM sumingh@ufl.edu FU National Institute of Health (SH) [R01HL090589, R01HL091929, R01HL091929-01A1S1, R01HL095674, 5T32CA009126-35]; Intramural Research programs; National Heart Lung Blood Institute; National Institute of Health FX We are grateful to members of the Huang laboratory for their suggestions and comments. We thank Drs Christopher Cogle and Zhixiong Xu for generously providing T-ALL samples and for their advice on the 4C assay. This work was supported by grants from the National Institute of Health (SH, R01HL090589, R01HL091929 and R01HL091929-01A1S1-the ARRA Administrative supplement; YQ, R01HL095674; BP, 5T32CA009126-35). KZ is supported by the Intramural Research programs, the National Heart Lung Blood Institute, and the National Institute of Health. NR 60 TC 20 Z9 22 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD FEB PY 2014 VL 28 IS 2 BP 349 EP 361 DI 10.1038/leu.2013.158 PG 13 WC Oncology; Hematology SC Oncology; Hematology GA AA6QV UT WOS:000331223900014 PM 23698277 ER PT J AU Bhutani, M Turkbey, B Tan, E Kemp, TJ Pinto, LA Berg, AR Korde, N Minter, AR Weiss, BM Mena, E Lindenberg, L Aras, O Purdue, MP Hofmann, JN Steinberg, SM Calvo, KR Choyke, PL Maric, I Kurdziel, K Landgren, O AF Bhutani, M. Turkbey, B. Tan, E. Kemp, T. J. Pinto, L. A. Berg, A. R. Korde, N. Minter, A. R. Weiss, B. M. Mena, E. Lindenberg, L. Aras, O. Purdue, M. P. Hofmann, J. N. Steinberg, S. M. Calvo, K. R. Choyke, P. L. Maric, I. Kurdziel, K. Landgren, O. TI Bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial SO LEUKEMIA LA English DT Letter ID MULTIPLE-MYELOMA; CYTOKINES; THALIDOMIDE; PROGRESSION; PARAMETERS; SURVIVAL; MRI C1 [Bhutani, M.; Tan, E.; Berg, A. R.; Korde, N.; Minter, A. R.; Weiss, B. M.; Landgren, O.] NCI, Multiple Myeloma Sect, CCR, NIH, Bethesda, MD 20892 USA. [Turkbey, B.; Mena, E.; Lindenberg, L.; Aras, O.; Choyke, P. L.; Kurdziel, K.] NCI, Mol Imaging Program, CCR, NIH, Bethesda, MD 20892 USA. [Kemp, T. J.; Pinto, L. A.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. [Purdue, M. P.; Hofmann, J. N.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Steinberg, S. M.] NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. [Calvo, K. R.; Maric, I.] NIH, Hematol Sect, CCR, DLM, Bethesda, MD 20892 USA. RP Bhutani, M (reprint author), NCI, Multiple Myeloma Sect, CCR, NIH, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Calvo, Katherine/0000-0002-0771-4191 FU Intramural NIH HHS NR 15 TC 14 Z9 14 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD FEB PY 2014 VL 28 IS 2 BP 413 EP 416 DI 10.1038/leu.2013.268 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA AA6QV UT WOS:000331223900023 PM 24045500 ER PT J AU Murase, S AF Murase, Sachiko TI A New Model for Developmental Neuronal Death and Excitatory/Inhibitory Balance in Hippocampus SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Developmental neuronal death; Hippocampus; GABA; E/I balance; Neurotrophin; STAT3 ID NERVE GROWTH-FACTOR; INTEGRIN-LINKED KINASE; OCCURRING CELL-DEATH; NEUROTROPHIC FACTOR; SIGNAL TRANSDUCER; SERINE PHOSPHORYLATION; PROTEIN-KINASE; TRANSCRIPTION FACTOR; SYMPATHETIC NEURONS; TYROSINE PHOSPHORYLATION AB The nervous system develops through a program that produces neurons in excess and then eliminates approximately half during a period of naturally occurring death. Neuronal activity has been shown to promote the survival of neurons during this period by stimulating the production and release of neurotrophins. In the peripheral nervous system (PNS), neurons depends on neurotrophins that activate survival pathways, which explains how the size of target cells influences number of neurons that innervate them (neurotrophin hypothesis). However, in the central nervous system (CNS), the role of neurotrophins has not been clear. Contrary to the neurotrophin hypothesis, a recent study shows that, in neonatal hippocampus, neurotrophins cannot promote survival without spontaneous network activity: Neurotrophins recruit neurons into spontaneously active networks, and this activity determines which neurons survive. By placing neurotrophin upstream of activity in the survival signaling pathway, these new results change our understanding of how neurotrophins promote survival. Spontaneous, synchronized network activity begins to spread through both principle neurons and interneurons in the hippocampus as they enter the death period. At this stage, neurotransmission mediated by gamma-aminobutyric acid (GABA) is excitatory and drives the spontaneous activity. An important recent observation is that neurotrophins preferentially recruit GABAergic neurons into spontaneously active networks; thus, neurotrophins select for survival only those neurons joined to active networks with strong GABAergic inputs, which would later become inhibitory. A proper excitatory/inhibitory (E/I) balance is critical for normal adult brain function. This balance may be especially important in the hippocampus where impairments in E/I balance are associated with pathologies including epilepsy. Here, I discuss the molecular mechanisms for survival in neonatal neurons, how these mechanisms change during development, and how they may be linked to degenerative diseases. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Murase, S (reprint author), NINDS, Mol Biol Lab, NIH, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM sachikom@ninds.nih.gov FU NINDS/NIH FX I thank Dr. Chris McBain for critical reading. This work was supported by the Intramural Research Program of NINDS/NIH. NR 120 TC 1 Z9 1 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD FEB PY 2014 VL 49 IS 1 BP 316 EP 325 DI 10.1007/s12035-013-8521-8 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AA4EC UT WOS:000331046800026 PM 23943504 ER PT J AU Zhang, Y McClellan, M Efros, L Shi, D Bielekova, B Tang, MT Vexler, V Sheridan, JP AF Zhang, Y. McClellan, M. Efros, L. Shi, D. Bielekova, B. Tang, M. T. Vexler, V. Sheridan, J. P. TI Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Daclizumab; multiple sclerosis; trogocytosis; CD25; Treg; HLA-DR; regulatory T cell ID MULTIPLE-SCLEROSIS; NK CELLS; IL-2; ACTIVATION; EXPRESSION; RECEPTORS; RITUXIMAB; THERAPY; SERUM AB Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4(+) T cells and FoxP3(+) Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling. C1 [Zhang, Y.; McClellan, M.; Efros, L.; Shi, D.; Tang, M. T.; Vexler, V.; Sheridan, J. P.] AbbVie Biotherapeut Corp, Redwood City, CA 94063 USA. [Bielekova, B.] NINDS, NIH, Bethesda, MD 20892 USA. RP Sheridan, JP (reprint author), AbbVie Biotherapeut Corp, Translat Med, 1500 Seaport Blvd, Redwood City, CA 94063 USA. EM james.sheridan@abbvie.com FU NINDS/NIH FX Participation of Dr Bielekova in this work was supported by the intramural research program of the NINDS/NIH. NR 23 TC 9 Z9 9 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD FEB PY 2014 VL 20 IS 2 BP 156 EP 164 DI 10.1177/1352458513494488 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AA6RV UT WOS:000331226600008 PM 23846354 ER PT J AU McMahon, GM O'Seaghdha, CM Hwang, SJ Meigs, JB Fox, CS AF McMahon, Gearoid M. O'Seaghdha, Conall M. Hwang, Shih-Jen Meigs, James B. Fox, Caroline S. TI The association of a single-nucleotide polymorphism in CUBN and the risk of albuminuria and cardiovascular disease SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE epidemiology ID RENAL PROXIMAL TUBULE; DIABETIC-NEPHROPATHY; UNMODIFIED ALBUMIN; CUBILIN; KIDNEY; PROTEINURIA; HEART; MICROALBUMINURIA; CELLS; EXCRETION AB Background. Albuminuria is an important risk factor for cardiovascular disease (CVD). We have previously identified a missense single-nucleotide polymorphism (rs1801239) in the CUBN gene that is associated with albuminuria. Whether albuminuria is associated with CVD in the presence of the CUBN mutation is unknown. Methods. We analyzed participants from the Framingham Heart Study (n = 6399, mean age 47 years, 53.4% women) who underwent genotyping of rs1801239. Cox proportional hazards models were used to test the association between microalbuminuria [UACR >= 17 mg/g (men) and >= 25 mg/g (women)] and incident CVD stratified by the presence or absence of the CUBN risk allele. We tested whether the association between microalbuminuria and CVD was altered by the presence of the risk allele with interaction testing. Results. Overall, 21.1% of participants carried the risk allele. As expected, carriers of the risk (C) allele had a higher prevalence of microalbuminuria (10.7 versus 8.9%, P = 0.04). During a mean follow-up of 10.4 years, 5.6% (n = 346) of participants experienced a CVD event. Microalbuminuria was associated with an increased risk of CVD [hazards ratio (HR) 1.46, 95% confidence interval (CI) 1.14-1.88]. When stratified by risk allele carrier status, the HR for CVD was 1.95 (95% CI 1.15-3.29) among those with compared to 1.33 (95% CI 1.00-1.76) among those without the risk allele. There was no interaction between microalbuminuria and rs1801239 on CVD (P-interaction = 0.49). Conclusions. MA is associated with CVD irrespective of the presence of the CUBN risk allele. These results challenge the concept that albuminuria in the setting of this mutation is benign. C1 [McMahon, Gearoid M.; O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [McMahon, Gearoid M.; O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [McMahon, Gearoid M.; Fox, Caroline S.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [McMahon, Gearoid M.; Meigs, James B.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [O'Seaghdha, Conall M.] Beaumont Hosp, Div Nephrol & Transplantat, Dublin 9, Ireland. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI McMahon, Gearoid/0000-0002-7723-2198 FU [N01-HC-25195]; [K24 DK080140] FX The Framingham Heart Study of the National Heart, Lung and Blood Institute is supported by contract N01-HC-25195. J.B.M. is supported by K24 DK080140. NR 38 TC 3 Z9 3 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD FEB PY 2014 VL 29 IS 2 BP 342 EP 347 DI 10.1093/ndt/gft386 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA AA9HJ UT WOS:000331404100017 PM 24052458 ER PT J AU Lima, BR Mandelcorn, ED Bakshi, N Nussenblatt, RB Sen, HN AF Lima, Breno R. Mandelcorn, Efrem D. Bakshi, Nupura Nussenblatt, Robert B. Sen, H. Nida TI Syphilitic Outer Retinopathy SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE AZOOR; outer retinopathy; syphilis AB Purpose: To present ocular syphilis masquerading as an outer retinopathy. Methods: Retrospective case series, including 2 patients with features of acute zonal occult outer retinopathy (AZOOR) complex diseases. Results: Laboratory results confirmed the diagnosis of syphilis in the 2 cases. Therapy with intravenous penicillin led to an improvement in symptoms, visual acuity, and ancillary testing. Conclusions: The protean ophthalmic presentations of syphilis are well known. However, AZOOR-like presentation has not been described previously. This atypical outer retinopathy should alert physicians to keep syphilis in the differential diagnosis of any inflammatory disorder. C1 [Lima, Breno R.; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. [Mandelcorn, Efrem D.; Bakshi, Nupura] Univ Toronto, Dept Ophthalmol & Vis Sci, Toronto, ON, Canada. RP Sen, HN (reprint author), NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 8 TC 5 Z9 5 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0927-3948 EI 1744-5078 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD FEB PY 2014 VL 22 IS 1 BP 4 EP 8 DI 10.3109/09273948.2013.841960 PG 5 WC Ophthalmology SC Ophthalmology GA AA7PW UT WOS:000331290400003 PM 24171649 ER PT J AU Siberry, GK Cohen, RA Harris, DR Cruz, MLS Oliveira, R Peixoto, MF Cervi, MC Hazra, R Pinto, JA AF Siberry, George K. Cohen, Rachel A. Harris, D. Robert Santos Cruz, Maria Leticia Oliveira, Ricardo Peixoto, Mario F. Cervi, Maria Celia Hazra, Rohan Pinto, Jorge A. CA NISDI PL Protocol TI Prevalence and Predictors of Elevated Aspartate Aminotransferase-to-Platelet Ratio Index in Latin American Perinatally HIV-infected Children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE aspartate aminotransferase-to-platelet ratio index; HIV-1; perinatal HIV infection; Latin America ID HEPATITIS-C VIRUS; LIVER FIBROSIS; ANTIRETROVIRAL THERAPY; NONINVASIVE INDEX; MARKERS; SEROPREVALENCE; COINFECTION; PERFORMANCE; MORTALITY; DISEASE AB Background: Chronic liver disease has emerged as an important problem in adults with longstanding HIV infection, but data are lacking for children. We characterized elevated aspartate aminotransferase-to-platelet ratio index (APRI), a marker of possible liver fibrosis, in perinatally HIV-infected children. Methods: The National Institute of Child Health and Human Development International Site Development Initiative enrolled HIV-infected children (ages 0.1-20.1 years) from 5 Latin American countries in an observational cohort from 2002 to 2009. Twice yearly visits included medical history, physical examination and laboratory evaluations. The prevalence (95% confidence interval) of APRI > 1.5 was calculated, and associations with demographic, HIV-related and liver-related variables were investigated in bivariate analyses. Results: APRI was available for 1012 of 1032 children. APRI was >1.5 in 32 (3.2%, 95% confidence interval: 2.2%-4.4%) including 2 of 4 participants with hepatitis B virus infection. Factors significantly associated with APRI > 1.5 (P < 0.01 compared with APRI 1.5) included country, younger age, past or current hepatitis B virus, higher alanine aminotransferase, lower total cholesterol, higher log(10) current viral load, lower current CD4 count, lower nadir CD4 count, use of hepatotoxic nonantiretroviral (ARV) medications and no prior ARV use. Rates of APRI > 1.5 varied significantly by current ARV regimen (P = 0.0002), from 8.0% for no ARV to 3.2% for non-protease inhibitor regimens to 1.5% for protease inhibitor-based regimens. Conclusions: Elevated APRI occurred in approximately 3% of perinatally HIV-infected children. Protease inhibitor-based ARVs appeared protective whereas inadequate HIV control appeared to increase risk of elevated APRI. Additional investigations are needed to better assess potential subclinical, chronic liver disease in HIV-infected children. C1 [Siberry, George K.; Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediatric Infect Dis Branch, NIH, Bethesda, MD 20892 USA. [Cohen, Rachel A.; Harris, D. Robert] Westat Corp, Rockville, MD USA. [Oliveira, Ricardo] Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira, Rio De Janeiro, Brazil. [Peixoto, Mario F.] Femina Hosp, Vert Transmiss Unit, Porto Alegre, RS, Brazil. [Cervi, Maria Celia] Univ Sao Paulo, Dept Pediat, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, Brazil. [Pinto, Jorge A.] Univ Fed Minas Gerais, Dept Pediat, Belo Horizonte, MG, Brazil. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediatric Infect Dis Branch, NIH, 6100 Executive Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health, NICHD [N01-HD-3-3345]; NICHD [HHSN267200800001C, N01-HD-8-0001] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health, NICHD Contract # N01-HD-3-3345 (2002-2007) and by NICHD Contract # HHSN267200800001C (NICHD Control #: N01-HD-8-0001) (2007-2012). The authors have no other funding or conflicts of interest to disclose. NR 29 TC 6 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2014 VL 33 IS 2 BP 177 EP 182 DI 10.1097/INF.0b013e3182a01dfb PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA AA5KZ UT WOS:000331139100020 PM 23799515 ER PT J AU Waxman, R Fenton, MC Skodol, AE Grant, BF Hasin, D AF Waxman, Rachel Fenton, Miriam C. Skodol, Andrew E. Grant, Bridget F. Hasin, Deborah TI Childhood maltreatment and personality disorders in the USA: Specificity of effects and the impact of gender SO PERSONALITY AND MENTAL HEALTH LA English DT Article ID PSYCHIATRIC DIAGNOSTIC MODULES; NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; ALCOHOL-USE-DISORDER; IV AUDADIS-IV; UNITED-STATES; SUBSTANCE USE; ABUSE; RELIABILITY; CHILDREN AB Childhood maltreatment increases the risk for adult personality disorders (PDs), but several PDs or maltreatment types co-occur. Specificity of maltreatment-personality associations is poorly understood. Using a representative US population sample, we identified specific associations between maltreatment types (sexual, physical and emotional abuse and physical and emotional neglect) and PDs after controlling for basic demographics, parental psychopathology, co-occurring maltreatment types and comorbid PD. We then examined interactions of gender and maltreatment in predicting PDs. Each maltreatment type significantly predicted three-four PDs. Borderline and schizotypal PDs were most strongly predicted by sexual abuse, antisocial by physical abuse and avoidant and schizoid by emotional neglect. Specific vulnerabilities differ by gender; maltreated boys may respond with attention seeking and girls with social withdrawal. Findings highlight the importance of evaluating all forms of maltreatment even when they co-occur and can inform development of interventions to prevent personality pathology in at-risk children. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Waxman, Rachel; Fenton, Miriam C.; Hasin, Deborah] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Fenton, Miriam C.; Hasin, Deborah] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Skodol, Andrew E.; Hasin, Deborah] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA. [Skodol, Andrew E.] Univ Arizona, Coll Med, Phoenix, AZ 85004 USA. [Grant, Bridget F.] NIAAA, Rockville, MD 20849 USA. RP Hasin, D (reprint author), Columbia Univ, Dept Psychiat, Coll Phys & Surg, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu FU Intramural NIH HHS; NIAAA NIH HHS [K05 AA014223, K05AA014223, U01 AA018111, U01AA018111] NR 36 TC 14 Z9 14 U1 8 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8621 EI 1932-863X J9 PERSONAL MENT HEALTH JI Personal. Ment. Health PD FEB PY 2014 VL 8 IS 1 BP 30 EP 41 DI 10.1002/pmh.1239 PG 12 WC Psychiatry; Psychology, Social SC Psychiatry; Psychology GA AA9YY UT WOS:000331450200004 PM 24532553 ER PT J AU Kaszynski, K Kallis, DL Karnik, N Soller, M Hunter, S Haapanen, R Blair, J Steiner, H AF Kaszynski, Katie Kallis, Diana L. Karnik, Niranjan Soller, Marie Hunter, Scott Haapanen, Rudy Blair, James Steiner, Hans TI Incarcerated youth with personality disorders: Prevalence, comorbidity and convergent validity SO PERSONALITY AND MENTAL HEALTH LA English DT Article ID PSYCHIATRIC-DISORDERS; JUVENILE-DELINQUENTS; CONDUCT DISORDER; ADOLESCENTS; IMPULSIVITY; RECIDIVISM; CHILDREN; TRAITS; MALES AB Objective The aims of this study were to examine the prevalence and comorbidities of personality disorders among incarcerated juveniles and to investigate the validity of these results. Method A sample of 790 incarcerated youth (650 boys and 140 girls; mean age = 16.8 years) completed an assessment of Axis II diagnoses (Structured Interview for DSM-IV Personality). Subjects also completed secondary questionnaires assessing anger-irritability (Youth Self-Report (YSR)), aggression (YSR), delinquency (Massachusetts Youth Screening Instrument-2), and distress and restraint (Weinberger Adjustment Inventory). Results Personality disorders can be found among incarcerated youth at high rates. Many meet the criteria for more than one personality disorder. Those with personality disorders have significant elevations of anger-irritability, aggression, delinquency, and distress and reduced restraint compared with incarcerated youth without a personality disorder. Conclusions Results indicate that personality disorders can be found in incarcerated youth at high rates. These findings further our understanding of chronic psychiatric illness and possibly criminal recidivism in this at-risk population. Addition of personality measures in the assessment of delinquents may assist in the development of more effective interventions. Furthermore, the supportive convergent validity of these findings in a population younger than 18 years may indicate a need to reassess the current rationale for the diagnosis of Axis II disorders. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Kaszynski, Katie] IIT, Chicago, IL 60616 USA. [Karnik, Niranjan; Hunter, Scott] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Kaszynski, Katie; Kallis, Diana L.] Wright State Univ, Dept Psychiat, Fairborn, OH USA. [Soller, Marie] Wildwood Psychiat Resource Ctr, Beaverton, OR USA. [Haapanen, Rudy] Univ Calif Davis, Ctr Publ Policy Res, Davis, CA 95616 USA. [Blair, James] NIMH, Unit Affect Cognit Neurosci, Bethesda, MD 20892 USA. [Steiner, Hans] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Karnik, N (reprint author), Univ Chicago, Dept Psychiat & Behav Sci, Chicago, IL 60637 USA. EM nkarnik@bsd.uchicago.edu RI Hunter, Scott/S-7866-2016; OI Hunter, Scott/0000-0001-7434-2327; Karnik, Niranjan/0000-0001-7650-3008 NR 36 TC 6 Z9 6 U1 4 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8621 EI 1932-863X J9 PERSONAL MENT HEALTH JI Personal. Ment. Health PD FEB PY 2014 VL 8 IS 1 BP 42 EP 51 DI 10.1002/pmh.1241 PG 10 WC Psychiatry; Psychology, Social SC Psychiatry; Psychology GA AA9YY UT WOS:000331450200005 PM 24532554 ER PT J AU Boyette, LB Creasey, OA Guzik, L Lozito, T Tuan, RS AF Boyette, Lisa B. Creasey, Olivia A. Guzik, Lynda Lozito, Thomas Tuan, Rocky S. TI Human Bone Marrow-Derived Mesenchymal Stem Cells Display Enhanced Clonogenicity but Impaired Differentiation With Hypoxic Preconditioning SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Mesenchymal stem cells; Hypoxia; Colony-forming units assay; Chondrogenesis; Osteogenesis; Adipogenesis ID REDUCED OXYGEN-TENSION; WNT SIGNALING PATHWAYS; BETA-CATENIN; OSTEOGENIC DIFFERENTIATION; STROMAL CELLS; IN-VITRO; PROGENITOR CELLS; CHONDROGENIC DIFFERENTIATION; CHONDROCYTE DIFFERENTIATION; CULTURE-CONDITIONS AB Stem cells are promising candidate cells for regenerative applications because they possess high proliferative capacity and the potential to differentiate into other cell types. Mesenchymal stem cells (MSCs) are easily sourced but do not retain their proliferative and multilineage differentiative capabilities after prolonged ex vivo propagation. We investigated the use of hypoxia as a preconditioning agent and in differentiating cultures to enhance MSC function. Culture in 5% ambient O-2 consistently enhanced clonogenic potential of primary MSCs from all donors tested. We determined that enhanced clonogenicity was attributable to increased proliferation, increased vascular endothelial growth factor secretion, and increased matrix turnover. Hypoxia did not impact the incidence of cell death. Application of hypoxia to osteogenic cultures resulted in enhanced total mineral deposition, although this effect was detected only in MSCs preconditioned in normoxic conditions. Osteogenesis-associated genes were upregulated in hypoxia, and alkaline phosphatase activity was enhanced. Adipogenic differentiation was inhibited by exposure to hypoxia during differentiation. Chondrogenesis in three-dimensional pellet cultures was inhibited by preconditioning with hypoxia. However, in cultures expanded under normoxia, hypoxia applied during subsequent pellet culture enhanced chondrogenesis. Whereas hypoxic preconditioning appears to be an excellent way to expand a highly clonogenic progenitor pool, our findings suggest that it may blunt the differentiation potential of MSCs, compromising their utility for regenerative tissue engineering. Exposure to hypoxia during differentiation (post-normoxic expansion), however, appears to result in a greater quantity of functional osteoblasts and chondrocytes and ultimately a larger quantity of high-quality differentiated tissue. C1 [Boyette, Lisa B.; Lozito, Thomas; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Boyette, Lisa B.; Creasey, Olivia A.; Lozito, Thomas; Tuan, Rocky S.] Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Pittsburgh, PA 15219 USA. [Boyette, Lisa B.; Guzik, Lynda; Lozito, Thomas; Tuan, Rocky S.] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15219 USA. [Creasey, Olivia A.; Tuan, Rocky S.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15219 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU National Institutes of Health [Z01AR41131]; Commonwealth of Pennsylvania Department of Health [SAP4100050913] FX We thank the Flow Cytometry Facility at the McGowan Institute for Regenerative Medicine, Dr. Juan Taboas for discussion and comments regarding this study, Jian Tan for assistance isolating MSCs, and Dr. Paul Manner (University of Washington) for providing human tissues. This work was supported in part by the Intramural Research Program of the National Institutes of Health (Z01AR41131) and the Commonwealth of Pennsylvania Department of Health (SAP4100050913). NR 96 TC 23 Z9 25 U1 1 U2 11 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD FEB PY 2014 VL 3 IS 2 BP 241 EP 254 DI 10.5966/sctm.2013-0079 PG 14 WC Cell & Tissue Engineering SC Cell Biology GA AB0SG UT WOS:000331501800018 PM 24436440 ER PT J AU Sosa, JA Elisei, R Jarzab, B Balkissoon, J Lu, SP Bal, C Marur, S Gramza, A Ben Yosef, R Gitlitz, B Haugen, BR Ondrey, F Lu, C Karandikar, SM Khuri, F Licitra, L Remick, SC AF Sosa, Julie A. Elisei, Rossella Jarzab, Barbara Balkissoon, Jai Lu, Shiao-ping Bal, Chandrasekhar Marur, Shanthi Gramza, Ann Ben Yosef, Rami Gitlitz, Barbara Haugen, Bryan R. Ondrey, Frank Lu, Charles Karandikar, S. M. Khuri, Fadlo Licitra, Lisa Remick, Scot C. TI Randomized Safety and Efficacy Study of Fosbretabulin with Paclitaxel/Carboplatin Against Anaplastic Thyroid Carcinoma SO THYROID LA English DT Article ID COMBRETASTATIN A4 PHOSPHATE; PHASE-I TRIAL; VASCULAR-TARGETING AGENT; A-4 PHOSPHATE; COMBINATION CHEMOTHERAPY; NATURAL PRODUCT; ADVANCED CANCER; SOLID TUMORS; CARBOPLATIN; DOXORUBICIN AB Background: Anaplastic thyroid cancer (ATC), a rare highly vascularized tumor, has a dismal outcome. We conducted an open-label study of doublet carboplatin/paclitaxel chemotherapy with or without fosbretabulin in patients with ATC. Methods: Patients were randomly assigned in a 2:1 ratio to 6 cycles of paclitaxel 200mg/m(2) followed by carboplatin AUC 6 on day 1 every 3 weeks (CP), or these drugs were given on day 2 after fosbretabulin 60mg/m(2) (CP/fosbretabulin) on days 1, 8 and 15. After 6 cycles, patients on the fosbretabulin arm without progression could continue to receive fosbretabulin on days 1 and 8 of a 3-week schedule until progression. The primary end point was overall survival (OS). Results: Eighty patients were assigned (planned, 180) when enrollment was stopped due to rarity of disease and very low accrual. Median OS was 5.2 months [95% confidence interval (CI) 3.1, 9.0] for the CP/fosbretabulin arm (n=55; hazard ratio 0.73 [95% CI 0.44, 1.21]) and 4.0 months [95% CI 2.8, 6.2] for the CP arm (n=25; p=0.22 [log rank test]). One-year survival for CP/fosbretabulin versus CP was 26% versus 9%, respectively. There was no significant difference in progression-free survival between the two arms. Grade 1-2 hypertension and grade 3-4 neutropenia were more common with CP/fosbretabulin. There were no significant adverse cardiovascular side effects. Conclusions: Although the study did not meet statistical significance in improvement in OS with the addition of fosbretabulin to carboplatin/paclitaxel, it represents the largest prospective randomized trial ever conducted in ATC. The regimen is well tolerated, with AEs and deaths primarily related to ATC and disease progression. C1 [Sosa, Julie A.] Duke Univ, Sch Med, Dept Surg, Durham, NC 27710 USA. [Elisei, Rossella] Univ Pisa, Dept Endocrinol & Metab, Pisa, Italy. [Jarzab, Barbara] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Nucl Med & Endocrine Oncol, Gliwice, Poland. [Balkissoon, Jai] Oxigene Inc, Dept Clin Dev, San Francisco, CA USA. [Lu, Shiao-ping] Oxigene Inc, Dept Biostat, San Francisco, CA USA. [Bal, Chandrasekhar] All India Inst Med Sci, Dept Nucl Med, New Delhi, India. [Marur, Shanthi] Johns Hopkins Univ, Ctr Oncol, Baltimore, MD 21205 USA. [Gramza, Ann] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Ben Yosef, Rami] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Oncol, IL-69978 Tel Aviv, Israel. [Gitlitz, Barbara] Univ So Calif, Norris Comprehens Canc Ctr, Dept Oncol, Los Angeles, CA USA. [Haugen, Bryan R.] Univ Colorado, Dept Med, Div Endocrinol Diabet & Metab, Aurora, CO USA. [Ondrey, Frank] Univ Minnesota, Dept Otolaryngol Head & Neck Surg, Minneapolis, MN USA. [Lu, Charles] Univ Texas MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX 77030 USA. [Karandikar, S. M.] Ruby Hall Clin, Dept Oncol, Pune, Maharashtra, India. [Khuri, Fadlo] Emory Univ, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Licitra, Lisa] Natl Inst Study & Care Tumors, Dept Med Oncol, Milan, Italy. [Remick, Scot C.] W Virginia Univ, Sch Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. RP Sosa, JA (reprint author), Duke Univ, Med Ctr 2945, Dept Surg, Sect Endocrine Surg, Durham, NC 27710 USA. EM julie.sosa@duke.edu RI Licitra, Lisa/C-6271-2017 OI Licitra, Lisa/0000-0003-0623-4118 FU Oxigene, Inc. FX This work was supported by Oxigene, Inc. NR 34 TC 38 Z9 39 U1 3 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB 1 PY 2014 VL 24 IS 2 BP 232 EP 240 DI 10.1089/thy.2013.0078 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA6YX UT WOS:000331245300007 PM 23721245 ER PT J AU Kim, WG Zhao, L Kim, DW Willingham, MC Cheng, SY AF Kim, Won Gu Zhao, Li Kim, Dong Wook Willingham, Mark C. Cheng, Sheue-yann TI Inhibition of Tumorigenesis by the Thyroid Hormone Receptor beta in Xenograft Models SO THYROID LA English DT Article ID REDUCES TUMOR-GROWTH; CLEAR-CELL CARCINOMA; MOUSE MODEL; NUCLEAR RECEPTORS; PITUITARY-TUMOR; BREAST-CANCER; IN-VIVO; TR-BETA; EXPRESSION; GENE AB Background: Previous studies showed a close association between several types of human cancers and somatic mutations of thyroid hormone receptor (TR) and reduced expression of TR due to epigenetic inactivation and/or deletion of the THRB gene. These observations suggest that TR could act as a tumor suppressor in carcinogenesis. However, the mechanisms by which TR could function to inhibit tumorigenesis are less well understood. Methods: We used the human follicular thyroid cancer cell lines (FTC-133 and FTC-236 cells) to elucidate how functional expression of the THRB gene could affect tumorigenesis. We stably expressed the THRB gene in FTC cells and evaluated the effects of the expressed TR on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. Results: Expression of TR in FTC-133 cells, as compared with control FTC cells without TR, reduced cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT-mTOR-p70 S6K pathway. TR expression in FTC-133 and FTC-236 led to less tumor growth in xenograft models. Importantly, new vessel formation was significantly suppressed in tumors induced by FTC cells expressing TR compared with control FTC cells without TR. The decrease in vessel formation was mediated by the downregulation of vascular endothelial growth factor in FTC cells expressing TR. Conclusions: These findings indicate that TR acts as a tumor suppressor through downregulation of the AKT-mTOR-p70 S6K pathway and decreased vascular endothelial growth factor expression in FTC cells. The present results raise the possibility that TR could be considered as a potential therapeutic target for thyroid cancer. C1 [Kim, Won Gu; Zhao, Li; Kim, Dong Wook; Willingham, Mark C.; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Gene Regulat Sect, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov OI Kim, Won Gu/0000-0002-8404-7759 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 40 TC 10 Z9 12 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB 1 PY 2014 VL 24 IS 2 BP 260 EP 269 DI 10.1089/thy.2013.0054 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA6YX UT WOS:000331245300011 PM 23731250 ER PT J AU Wark, L Danescu, A Natarajan, S Zhu, XG Cheng, SY Hombach-Klonisch, S Mai, S Klonisch, T AF Wark, Landon Danescu, Adrian Natarajan, Suchitra Zhu, Xuguang Cheng, Sheue-yann Hombach-Klonisch, Sabine Mai, Sabine Klonisch, Thomas TI Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer SO THYROID LA English DT Article ID HORMONE-BETA-RECEPTOR; MOUSE MODEL; CHROMOSOMAL REARRANGEMENTS; FLUORESCENCE MICROSCOPY; TARGETED MUTATION; INTERPHASE NUCLEI; COWDEN-DISEASE; IN-SITU; CARCINOMA; CELLS AB Background: Over the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world. However, the genomic mechanisms impacting thyroid carcinogenesis remain elusive. Methods: We employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (Thrb(PV/PV)) in the thyroid receptor 1 (TR1) and applied quantitative three-dimensional (3D) telomere analysis to determine 3D telomeric profiles in Thrb(PV/PV), Thrb(PV/+), and Thrb(+/+) mouse thyrocytes before and after histological presentation of FTC. Results: Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloView image analysis, we found altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1 month of age, Thrb(PV/PV) mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of Thrb(PV/PV) thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in Thrb(PV/PV) mice well before the presentation of histological signs of thyroid carcinoma. Conclusions: We identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma. C1 [Wark, Landon; Danescu, Adrian; Natarajan, Suchitra; Hombach-Klonisch, Sabine; Mai, Sabine; Klonisch, Thomas] Univ Manitoba, Dept Human Anat & Cell Sci, Fac Med, Winnipeg, MB R3E 0J9, Canada. [Hombach-Klonisch, Sabine] Univ Manitoba, Dept Obstet Gynecol & Reprod Med, Fac Med, Winnipeg, MB R3E 0J9, Canada. [Mai, Sabine] Univ Manitoba, Dept Physiol, Fac Med, Winnipeg, MB R3E 0J9, Canada. [Klonisch, Thomas] Univ Manitoba, Dept Med Microbiol & Infect Dis, Fac Med, Winnipeg, MB R3E 0J9, Canada. [Klonisch, Thomas] Univ Manitoba, Dept Surg, Fac Med, Winnipeg, MB R3E 0J9, Canada. [Wark, Landon; Mai, Sabine] Manitoba Inst Cell Biol, Genom Ctr Canc Res & Diag, Winnipeg, MB R3E 0V9, Canada. [Zhu, Xuguang; Cheng, Sheue-yann] NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Klonisch, T (reprint author), Univ Manitoba, Dept Human Anat & Cell Sci, Fac Med, 130 Basic Med Sci,130-745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada. EM thomas.klonisch@med.umanitoba.ca RI Mai, Sabine/E-5667-2017 OI Mai, Sabine/0000-0002-5797-2201 FU Natural Sciences and Engineering Council of Canada (NSERC); Manitoba Institute of Child Health (MICH); Department of Surgery Research Fund at the Faculty of Medicine, University of Manitoba; Manitoba Health Research Council (MHRC); Canadian Institutes of Health Research (CIHR) FX S.H.K. and T.K. are both grateful for financial support from the Natural Sciences and Engineering Council of Canada (NSERC), the Manitoba Institute of Child Health (MICH), and the Department of Surgery Research Fund at the Faculty of Medicine, University of Manitoba. L. W. is the recipient of a Manitoba Health Research Council (MHRC) fellowship and S.M. is supported by the Canadian Institutes of Health Research (CIHR). The authors thank Ms. Mary Cheang for statistical analysis of the data. NR 63 TC 3 Z9 3 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB 1 PY 2014 VL 24 IS 2 BP 296 EP 304 DI 10.1089/thy.2013.0118 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA6YX UT WOS:000331245300015 PM 23819464 ER PT J AU Eliades, M El-Maouche, D Choudhary, C Zinsmeister, B Burman, KD AF Eliades, Myrto El-Maouche, Diala Choudhary, Chitra Zinsmeister, Bruce Burman, Kenneth D. TI Takotsubo Cardiomyopathy Associated with Thyrotoxicosis: A Case Report and Review of the Literature SO THYROID LA English DT Article ID TAKO-TSUBO CARDIOMYOPATHY; LEFT-VENTRICULAR DYSFUNCTION; ANGIOTENSIN-CONVERTING ENZYME; EMOTIONAL-STRESS; THYROID-HORMONE; GRAVES-DISEASE; HYPERTHYROIDISM; HYPOTHYROIDISM; CATECHOLAMINES; MECHANISMS AB Background: Takotsubo or stress-induced cardiomyopathy is a form of reversible cardiomyopathy commonly associated with emotional or physical stress. Thyrotoxicosis has been identified as a rare cause of Takotsubo cardiomyopathy, with only 12 cases reported in the literature. Here, we report a case of thyroid storm presenting with Takotsubo cardiomyopathy in the setting of Graves' disease. Patient Findings: A 71-year-old woman presented with abdominal pain, vomiting, confusion, and history of weight loss. She was initially diagnosed and treated for diabetic ketoacidosis at another hospital and was transferred to our hospital one day after initial presentation because of concern for acute coronary syndrome. A diagnosis of Takotsubo cardiomyopathy was made on the basis of cardiac catheterization. At that time, she was diagnosed and treated for thyroid storm. Follow-up 7 weeks later revealed improvement of her cardiac function and near-normalization of thyroid hormone levels. Summary: In this patient, who presented with symptoms of heart failure, acute coronary syndrome was initially considered, but the diagnosis of Takotsubo cardiomyopathy associated with thyroid storm was ultimately made based on cardiac catheterization and laboratory investigation. Conclusions: Thyrotoxicosis is associated with adverse disturbances in the cardiovascular system. Takotsubo cardiomyopathy could be a presenting manifestation of thyroid storm, perhaps related to excess catecholamine levels or sensitivity. C1 [Zinsmeister, Bruce; Burman, Kenneth D.] Medstar Washington Hosp Ctr, Endocrinol Sect, Washington, DC 20010 USA. [Zinsmeister, Bruce; Burman, Kenneth D.] Medstar Washington Hosp Ctr, Cardiol Sect, Washington, DC 20010 USA. [Eliades, Myrto; Choudhary, Chitra; Zinsmeister, Bruce; Burman, Kenneth D.] Medstar Washington Hosp Ctr, Dept Internal Med, Washington, DC 20010 USA. [El-Maouche, Diala] NIDDK, NIH, Bethesda, MD 20892 USA. RP Eliades, M (reprint author), Medstar Washington Hosp Ctr, Dept Internal Med, 110 Irving St NW,Suite 2A-50, Washington, DC 20010 USA. EM eliadesm@yahoo.com OI El-Maouche, Diala/0000-0002-0936-2249 NR 51 TC 8 Z9 8 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB 1 PY 2014 VL 24 IS 2 BP 383 EP 389 DI 10.1089/thy.2012.0384 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA6YX UT WOS:000331245300025 PM 23560557 ER PT J AU Strickler, HD Martinson, J Desai, S Xie, XH Burk, RD Anastos, K Massad, LS Minkoff, H Xue, XN D'Souza, G Levine, AM Colie, C Watts, DH Palefsky, JM Landay, A AF Strickler, Howard D. Martinson, Jeffrey Desai, Seema Xie, Xianhong Burk, Robert D. Anastos, Kathryn Massad, L. Stewart Minkoff, Howard Xue, Xiaonan D'Souza, Gypsyamber Levine, Alexandra M. Colie, Christine Watts, D. Heather Palefsky, Joel M. Landay, Alan TI The Relation of Plasmacytoid Dendritic Cells (pDCs) and Regulatory T-Cells (Tregs) with HPV Persistence in HIV-Infected and HIV-Uninfected Women SO VIRAL IMMUNOLOGY LA English DT Article ID INTERFERON-PRODUCING CELLS; ACTIVE ANTIRETROVIRAL THERAPY; VIRUS-POSITIVE WOMEN; HUMAN-PAPILLOMAVIRUS; IMMUNE-RESPONSES; NATURAL-HISTORY; NEOPLASIA; CYTOKINES; INNATE AB Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted. C1 [Strickler, Howard D.; Xie, Xianhong; Burk, Robert D.; Anastos, Kathryn; Xue, Xiaonan] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Martinson, Jeffrey; Desai, Seema; Landay, Alan] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Massad, L. Stewart] Washington Univ, Sch Med, Dept Obstet Gynecol, St Louis, MO USA. [Minkoff, Howard] Maimonides Hosp, Dept Obstet Gynecol, Brooklyn, NY 11219 USA. [D'Souza, Gypsyamber] Johns Hopkins Sch Publ Hlth, Dept Epidmiol, Baltimore, MD USA. [Levine, Alexandra M.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Colie, Christine] Georgetown Univ, Med Ctr, Dept Obstet Gynecol, Washington, DC 20007 USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Pediat, Bethesda, MD USA. [Palefsky, Joel M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Strickler, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Belfer Bldg 1308B,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM howard.strickler@einstein.yu.edu FU National Institute of Allergy and Infectious Diseases [U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, U01-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health & Human Development [U01-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131]; Einstein-Montefiore Center for AIDS Research [P30-AI-51519]; Institute for Clinical and Translational Research [UL1 RR025750] FX Major support for this study, including HPV DNA testing, was provided through R01-CA-085178 (Howard Strickler). Data in this article were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, and U01-AI-42590 and by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (U01-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). Additional support provided by the Einstein-Montefiore Center for AIDS Research (P30-AI-51519) and Institute for Clinical and Translational Research (UL1 RR025750). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 22 TC 7 Z9 8 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0882-8245 EI 1557-8976 J9 VIRAL IMMUNOL JI Viral Immunol. PD FEB 1 PY 2014 VL 27 IS 1 BP 20 EP 25 DI 10.1089/vim.2013.0097 PG 6 WC Immunology; Virology SC Immunology; Virology GA AA7DV UT WOS:000331258300005 PM 24494969 ER PT J AU Cortes-Malagon, EM Bonilla-Delgado, J Diaz-Chavez, J Hidalgo-Miranda, A Romero-Cordoba, S Uren, A Celik, H McCormick, M Munguia-Moreno, JA Ibarra-Sierra, E Escobar-Herrera, J Lambert, PF Mendoza-Villanueva, D Bermudez-Cruz, RM Gariglio, P AF Cortes-Malagon, Enoc M. Bonilla-Delgado, Jose Diaz-Chavez, Jose Hidalgo-Miranda, Alfredo Romero-Cordoba, Sandra Ueren, Aykut Celik, Haydar McCormick, Matthew Munguia-Moreno, Jose A. Ibarra-Sierra, Eloisa Escobar-Herrera, Jaime Lambert, Paul F. Mendoza-Villanueva, Daniel Bermudez-Cruz, Rosa M. Gariglio, Patricio TI Gene expression profile regulated by the HPV16 E7 oncoprotein and estradiol in cervical tissue (vol 447, pg 155, 2013) SO VIROLOGY LA English DT Correction C1 [Cortes-Malagon, Enoc M.; Munguia-Moreno, Jose A.; Bermudez-Cruz, Rosa M.; Gariglio, Patricio] Ctr Invest & Estudios Avanzados Cinvestav, Dept Genet & Mol Biol, Mexico City 07360, DF, Mexico. [Escobar-Herrera, Jaime] Ctr Invest & Estudios Avanzados Cinvestav, Dept Cell Biol, Mexico City 07360, DF, Mexico. [Cortes-Malagon, Enoc M.; Bonilla-Delgado, Jose] Hosp Juarez Mexico, Res Unit, Mexico City 07760, DF, Mexico. [Diaz-Chavez, Jose] UNAM Inst Nacl Cancerol INCan, Unit Biomed Res Canc, Mexico City 14080, DF, Mexico. [Hidalgo-Miranda, Alfredo; Romero-Cordoba, Sandra] Inst Nacl Med Genom INMEGEN, Oncogen Dept, Mexico City 14610, DF, Mexico. [Ueren, Aykut; Celik, Haydar; McCormick, Matthew] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC 20057 USA. [Ibarra-Sierra, Eloisa] Inst Estatal Cancerol, Res Lab, Acapulco Gro 39570, Mexico. [Lambert, Paul F.] Univ Wisconsin, McArdle Lab Canc Res, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Mendoza-Villanueva, Daniel] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Gariglio, P (reprint author), Ctr Invest & Estudios Avanzados Cinvestav, Dept Genet & Mol Biol, Mexico City 07360, DF, Mexico. EM enoc.cortes@salud.gob.mx; jose.bonilla@salud.gob.mx; josediaz030178@hotmail.com; ahidalgo@inmegen.gob.mx; sromero_cordoba@hotmail.com; au26@georgetown.edu; hc547@georgetown.edu; mjm444@georgetown.edu; antoniomgeminis@yahoo.com.mx; eibarra@cinvestav.mx; moemras@yahoo.com; plambert@wisc.edu; daniel.mendozavillanueva@nih.gov; roberm@cinvestav.mx; vidal@cinvestav.mx RI Romero-Cordoba, Sandra Lorena/A-2246-2014 OI Romero-Cordoba, Sandra Lorena/0000-0002-5591-696X NR 1 TC 0 Z9 0 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB PY 2014 VL 450 BP 1 EP 1 DI 10.1016/j.virol.2013.11.028 PG 1 WC Virology SC Virology GA AB0MC UT WOS:000331485500001 ER PT J AU Yamasaki, T Baron, GS Suzuki, A Hasebe, R Horiuchi, M AF Yamasaki, Takeshi Baron, Gerald S. Suzuki, Akio Hasebe, Rie Horiuchi, Motohiro TI Characterization of intracellular dynamics of inoculated PrP-res and newly generated PrPSc during early stage prion infection in Neuro2a cells SO VIROLOGY LA English DT Article DE Prions; Membrane trafficking; Endosomes; Neurodegenerative diseases; Rab proteins ID MOUSE NEUROBLASTOMA-CELLS; LYSOSOME BIOGENESIS; CULTURED-CELLS; ELECTRON-MICROSCOPY; PROTEIN; SURFACE; ENDOSOMES; RECEPTOR; TRAFFICKING; TRANSPORT AB To clarify the cellular mechanisms for the establishment of prion infection, we analyzed the intracellular dynamics of inoculated and newly generated abnormal isoform of prion protein (PrPSc) in Neuro2a cells. Within 24 h after inoculation, the newly generated PrPSc was evident at the plasma membrane, in early endosomes, and in late endosomes, but this PrPSc was barely evident in lysosomes; in contrast, the majority of the inoculated PrPSc was evident in late endosomes and lysosomes. However, during the subsequent 48 h, the newly generated PrPSc increased remarkably in early endosomes and recycling endosomes. Overexpression of wild-type and mutant Rab proteins showed that membrane trafficking along not only the endocytic-recycling pathway but also the endo-lysosomal pathway is involved in de novo PrPSc generation. These results suggest that the trafficking of exogenously introduced PrPSc from the endo-lysosomal pathway to the endocytic-recycling pathway is important for the establishment of prion infection. (C) 2013 Elsevier Inc. All rights reserved. C1 [Yamasaki, Takeshi; Suzuki, Akio; Hasebe, Rie; Horiuchi, Motohiro] Hokkaido Univ, Grad Sch Vet Med, Lab Vet Hyg, Kita Ku, Sapporo, Hokkaido 0600818, Japan. [Baron, Gerald S.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Horiuchi, M (reprint author), Hokkaido Univ, Grad Sch Vet Med, Lab Vet Hyg, Kita Ku, Kita 18,Nishi 9, Sapporo, Hokkaido 0600818, Japan. EM horiuchi@vetmed.hokudai.ac.jp FU Global CUE Program [22.4181, 23248050, F-001]; Program for Leading Graduate Schools [F01]; Japan Initiative for Global Research Network on Infectious Diseases (J-GRID); Ministry of Education, Culture, Sports, Science, and Technology, Japan; Research on Measures for Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan; National Institute of Allergy and Infectious Diseases, National Institutes of Health; [H23-Shokuhin-Ippan-005] FX T.Y. is supported by a Grant-in-Aid for JSPS Fellows (No. 22.4181). This work was supported by a Grant-in-Aid for Science Research (A) (Grant no. 23248050), a Grant from the Global CUE Program (F-001) and the Program for Leading Graduate Schools (F01), and the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID), from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. This work was also supported by grants for TSE research (H23-Shokuhin-Ippan-005) and Research on Measures for Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan and in part by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We also thank Zensho Co. Ltd. for BSL3 facility. NR 54 TC 11 Z9 11 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB PY 2014 VL 450 BP 324 EP 335 DI 10.1016/j.virol.2013.11.007 PG 12 WC Virology SC Virology GA AB0MC UT WOS:000331485500036 PM 24503096 ER PT J AU Liyanage, NPM Gordon, SN Doster, MN Pegu, P Vaccari, M Shukur, N Schifanella, L Pise-Masison, CA Lipinska, D Grubczak, K Moniuszko, M Franchini, G AF Liyanage, Namal P. M. Gordon, Shari N. Doster, Melvin N. Pegu, Poonam Vaccari, Monica Shukur, Nebiyu Schifanella, Luca Pise-Masison, Cynthia A. Lipinska, Danuta Grubczak, Kamil Moniuszko, Marcin Franchini, Genoveffa TI Antiretroviral therapy partly reverses the systemic and mucosal distribution of NK cell subsets that is altered by SIVmac251 infection of macaques SO VIROLOGY LA English DT Article DE HIV; SIV; NK cell; Macaques; Innate immunity; ART; Mucosal; Innate lymphoid cells; HAART; Chemokine receptor ID NATURAL-KILLER-CELL; INNATE LYMPHOID-CELLS; ACUTE HIV-1 INFECTION; IMMUNODEFICIENCY-VIRUS; SIV INFECTION; HIV-1-INFECTED INDIVIDUALS; RHESUS MACAQUES; IMMUNITY; GUT; TRANSMISSION AB We characterized three subsets of NK cells in blood, and two subsets in mucosal tissues. SIVmac251 infection increased total and CD16(+) NK cells in the blood. In the rectum, we observed a significant increase in total and NKG2A(+) NK cells during SIV infection. In contrast, the NKp44(+) subset significantly depleted in acute infection and continued to decline in frequency during chronic phase. During SIV infection, blood CD16 and mucosal NKG2A(+) subsets had increased cytotoxic potential. Intriguingly, the NKp44(+) NK cell subtype that likely mediates mucosal homeostasis via the production of cytokines, acquired cytotoxicity. Antiretroviral therapy significantly increased the frequency of mucosal NKG2A(+) NK cells and peripheral CD16(+) NK cells. However, it failed to restore the normal frequency of NKp44(+) NK cells in the rectum. Thus, SIVmac251 infection causes changes in the distribution and function of NK cells and antiretrovii-al therapy during chronic infection only partially restores NK homeostasis and function. Published by Elsevier Inc. C1 [Liyanage, Namal P. M.; Gordon, Shari N.; Doster, Melvin N.; Pegu, Poonam; Vaccari, Monica; Shukur, Nebiyu; Schifanella, Luca; Pise-Masison, Cynthia A.; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. [Lipinska, Danuta] Med Univ Bialystok, Dept Endocrinol Diabetol & Internal Med, PL-15269 Bialystok, Poland. [Grubczak, Kamil] Med Univ Bialystok, Dept Immunol, PL-15269 Bialystok, Poland. [Moniuszko, Marcin] Med Univ Bialystok, Dept Regenerat Med & Immune Regulat, PL-15269 Bialystok, Poland. [Moniuszko, Marcin] Med Univ Bialystok, Dept Allergol & Internal Med, PL-15269 Bialystok, Poland. RP Franchini, G (reprint author), NCI, 41,Room D-804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Teresa Habina for manuscript editing, Katherine McKinnon for flow cytometric support and M. Colonna for helpful discussions. FTC and PMPA was a generous gift from Gilead Sciences, Inc. NR 41 TC 4 Z9 4 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB PY 2014 VL 450 BP 359 EP 368 DI 10.1016/j.virol.2013.12.003 PG 10 WC Virology SC Virology GA AB0MC UT WOS:000331485500040 PM 24503100 ER PT J AU Marete, I Tenge, C Pasha, O Goudar, S Chomba, E Patel, A Althabe, F Garces, A McClure, EM Saleem, S Esamai, F Kodkany, BS Belizan, JM Derman, RJ Hibberd, PL Krebs, N Buekens, P Goldenberg, RL Carlo, WA Wallace, D Moore, J Koso-Thomas, M Wright, LL Liechty, EA AF Marete, Irene Tenge, Constance Pasha, Omrana Goudar, Shivaprasad Chomba, Elwyn Patel, Archana Althabe, Fernando Garces, Ana McClure, Elizabeth M. Saleem, Sarah Esamai, Fabian Kodkany, Bhala S. Belizan, Jose M. Derman, Richard J. Hibberd, Patricia L. Krebs, Nancy Buekens, Pierre Goldenberg, Robert L. Carlo, Waldemar A. Wallace, Dennis Moore, Janet Koso-Thomas, Marion Wright, Linda L. Liechty, Edward A. TI Perinatal Outcomes of Multiple-Gestation Pregnancies in Kenya, Zambia, Pakistan, India, Guatemala, and Argentina: A Global Network Study SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE multiples gestation; twins; developing countries; stillbirth; perinatal mortality rate ID UNITED-STATES; DELIVERY; TRENDS; BIRTH; CARE AB AimTo determine the rates of multiple gestation, stillbirth, and perinatal and neonatal mortality and to determine health care system characteristics related to perinatal mortality of these pregnancies in low- and middle-income countries. MethodsPregnant women residing within defined geographic boundaries located in six countries were enrolled and followed to 42 days postpartum. ResultsMultiple gestations were 0.9% of births. Multiple gestations were more likely to deliver in a health care facility compared with singletons (70 and 66%, respectively, p<0.001), to be attended by skilled health personnel (71 and 67%, p<0.001), and to be delivered by cesarean (18 versus 9%, p<0.001). Multiple-gestation fetuses had a relative risk (RR) for stillbirth of 2.65 (95% confidence interval [CI] 2.06, 3.41) and for perinatal mortality rate (PMR) a RR of 3.98 (95% CI 3.40, 4.65) relative to singletons (both p<0.0001). Neither delivery in a health facility nor the cesarean delivery rate was associated with decreased PMR. Among multiple-gestation deliveries, physician-attended delivery relative to delivery by other health providers was associated with a decreased risk of perinatal mortality. ConclusionsMultiple gestations contribute disproportionately to PMR in low-resource countries. Neither delivery in a health facility nor the cesarean delivery rate is associated with improved PMR. C1 [Marete, Irene; Tenge, Constance; Esamai, Fabian] Moi Univ, Sch Med, Dept Child Hlth & Paediat, Eldoret, Kenya. [Pasha, Omrana; Saleem, Sarah] Aga Khan Univ, Dept Community Hlth Serv, Karachi, Pakistan. [Goudar, Shivaprasad; Kodkany, Bhala S.] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Althabe, Fernando; Belizan, Jose M.] Inst Clin Effectiveness, Buenos Aires, DF, Argentina. [Garces, Ana] Francisco Marroquin Univ, Multidisciplinary Hlth Inst, Guatemala City, Guatemala. [McClure, Elizabeth M.; Wallace, Dennis; Moore, Janet] Res Triangle Inst Int, Durham, NC USA. [Liechty, Edward A.] Indiana Univ, Dept Pediat, Riley Hosp, Indianapolis, IN 46202 USA. [Derman, Richard J.] Christiana Care Hlth Syst, Wilmington, DE USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Divs Global Hlth, Boston, MA 02114 USA. [Krebs, Nancy] Univ Colorado, Dept Pediat, Denver, CO 80202 USA. [Buekens, Pierre] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Goldenberg, Robert L.] Columbia Univ, New York, NY USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Koso-Thomas, Marion; Wright, Linda L.] NICHHD, Bethesda, MD 20892 USA. RP Liechty, EA (reprint author), Indiana Univ, Dept Pediat, Riley Hosp R208, 699 Riley Hosp Dr, Indianapolis, IN 46202 USA. EM eliecht@iupui.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053; Belizan, Jose/0000-0002-8412-3010 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health within the U.S. Department of Health and Human Services [U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058322, U01 HD058326, U01 HD040636] FX Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health within the U.S. Department of Health and Human Services by grants U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058322, U01 HD058326, and U01 HD040636. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 20 TC 6 Z9 6 U1 0 U2 3 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 FEB PY 2014 VL 31 IS 2 BP 125 EP 131 DI 10.1055/s-0033-1338173 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AA6FW UT WOS:000331195200006 PM 23512321 ER PT J AU Menke, A Rust, KF Savage, PJ Cowie, CC AF Menke, Andy Rust, Keith F. Savage, Peter J. Cowie, Catherine C. TI Hemoglobin A1c, fasting plasma glucose, and 2-hour plasma glucose distributions in US population subgroups: NHANES 2005-2010 SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Hemoglobin A1c; Fasting plasma glucose; 2-hour plasma glucose; Kernel density estimation; NHANES ID HISPANIC WHITE ADULTS; GLYCATED HEMOGLOBIN; GENDER-DIFFERENCES; HBA(1C) LEVELS; PIMA-INDIANS; HBA1C LEVELS; S TRAITS; TOLERANCE; AGE; BIMODALITY AB Purpose: Although mean concentrations of hemoglobin A1c (A1C), fasting plasma glucose, and 2-hour plasma glucose differ by demographics, it is unclear what other characteristics of the distributions may differ, such as the amount of asymmetry of the distribution (skewness) and shift left or right compared with another distribution (shift). Methods: Using kernel density estimation, we created smoothed plots of the distributions of fasting plasma glucose (N = 7250), 2-hour plasma glucose (N = 5851), and A1C (N = 16,209) by age, raceethnicity, and sex in the 2005-2010 National Health and Nutrition Examination Survey, a nationally representative sample of U.S. adults including people with and without diabetes. We tested differences in distributions using cumulative logistic regression. Results: The distributions were generally unimodal and right-skewed. All distributions were shifted higher and more right-skewed for older age groups (P < .001 for each marker). Compared with nonHispanic whites, the distribution of fasting plasma glucose was shifted higher for Mexican-Americans (P = .01), whereas the distribution of Al C was shifted higher for non-Hispanic blacks (P < .001). The distribution of fasting plasma glucose was shifted higher for men (P < .001) and the distribution of 2-hour plasma glucose was shifted higher for women (P = .01). Conclusions: We provide a graphic reference for comparing these distributions and diabetes cut-points by demographic factors. (C) 2014 Elsevier Inc. All rights reserved. C1 [Menke, Andy] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Rust, Keith F.] WESTAT Corp, Rockville, MD 20850 USA. [Savage, Peter J.; Cowie, Catherine C.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Menke, A (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM amenke@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [GS10F0381L] FX This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (GS10F0381L). NR 42 TC 9 Z9 9 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2014 VL 24 IS 2 BP 83 EP 89 DI 10.1016/j.annepidem.2013.10.008 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA2GO UT WOS:000330913300001 PM 24246264 ER PT J AU Beydoun, HA Khanal, S Zonderman, AB Beydoun, MA AF Beydoun, Hind A. Khanal, Suraj Zonderman, Alan B. Beydoun, May A. TI Sex differences in the association of urinary bisphenol-A concentration with selected indices of glucose homeostasis among US adults SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Bisphenol-A; Endocrine disruptor; Glucose homeostasis; Survey ID BETA-CELL FUNCTION; ENDOCRINE DISRUPTORS; INSULIN-RESISTANCE; OBESITY EPIDEMIC; NEONATAL EXPOSURE; MODEL ASSESSMENT; IN-UTERO; RISK; DIETHYLSTILBESTROL; ABNORMALITIES AB Purpose: Emerging evidence suggests that exposure to endocrine disruptors may initiate or exacerbate adiposity and associated health problems. This study examined sex differences in the association of urinary level of bisphenol-A (BPA) with selected indices of glucose homeostasis among U.S. adults. Methods: Data analyses were performed using a sample of 1586 participants from the 2005 to 2008 National Health and Nutrition Examination Surveys. BPA level and the ratio of BPA-to-creatinine level were defined as log-transformed variables and in quartiles. Selected indices of glucose homeostasis were defined using fasting glucose and insulin data. Multivariate linear and logistic regression models for the hypothesized relationships were constructed after controlling for age, sex, race, education, marital status, smoking status, physical activity, total dietary intake, and urinary creatinine concentration. Results: Taking the first quartile as a referent, the third quartile of BPA level was positively associated with log-transformed level of insulin and beta-cell function (homeostasis model assessment for beta-cell function) as well as insulin resistance (log-transformed homeostasis model assessment for insulin resistance; homeostasis model assessment for insulin resistance >= 2.5), with significant BPA-by-sex interaction; these associations were stronger among males than among females. Irrespective of sex, the ratio of BPA-to-creatinine level was not predictive of indices of glucose homeostasis. Conclusions: A complex association may exist between BPA and hyperinsulinemia among adult U.S. men. Prospective cohort studies are needed to further elucidate endocrine disruptors as determinants of adiposity-related disturbances. Published by Elsevier Inc. C1 [Beydoun, Hind A.; Khanal, Suraj] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Zonderman, Alan B.; Beydoun, May A.] NIA, Lab Behav Neurosci, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, Intramural Res Program, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM mbaydoun2002@yahoo.com OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health, National Institute on Aging FX The authors have no conflict of interest to disclose. No funding was provided for this project. However, this research was supported in part by the intramural research program of the National Institutes of Health, National Institute on Aging. NR 68 TC 9 Z9 9 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2014 VL 24 IS 2 BP 90 EP 97 DI 10.1016/j.annepidem.2013.07.014 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA2GO UT WOS:000330913300002 PM 23954568 ER PT J AU Major, JM Sargent, JD Graubard, BI Carlos, HA Hollenbeck, AR Altekruse, SF Freedman, ND McGlynn, KA AF Major, Jacqueline M. Sargent, James D. Graubard, Barry I. Carlos, Heather A. Hollenbeck, Albert R. Altekruse, Sean F. Freedman, Neal D. McGlynn, Katherine A. TI Local geographic variation in chronic liver disease and hepatocellular carcinoma: contributions of socioeconomic deprivation, alcohol retail outlets, and lifestyle SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Neighborhood; Socioeconomic disparities; Health care; Liver cancer; Liver disease; Cohort; Kernel density estimation; Multilevel; Census ID UNITED-STATES; RACIAL DISPARITY; SURVIVAL; ASSOCIATION; MORTALITY; HEALTH; RISK AB Purpose: Hepatocellular carcinoma (HCC) incidence rates continue to increase in the United States. Geographic variation in rates suggests a potential contribution of area-based factors, such as neighborhood socioeconomic deprivation, retail alcohol availability, and access to health care. Methods: Using the National Institutes of Health-American Association of Retired Persons Diet and Health Study, we prospectively examined area socioeconomic variations in HCC incidence (n = 434 cases) and chronic liver disease (CLD) mortality (n = 805 deaths) and assessed contribution of alcohol outlet density, health care infrastructure, diabetes, obesity, and health behaviors. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from hierarchical Cox regression models. Results: Area socioeconomic deprivation was associated with increased risk of HCC incidence and CLD mortality (HR, 1.48; 95% CI, 1.03-2.14 and HR, 2.36; 95% CI, 1.79-3.11, respectively) after accounting for age, sex, and race. After additionally accounting for educational attainment and health risk factors, associations for HCC incidence were no longer significant; associations for CLD mortality remained significant (HR, 1.78; 95% CI, 1.34-2.36). Socioeconomic status differences in alcohol outlet density and health behaviors explained the largest proportion of socioeconomic status-CLD mortality association, 10% and 29%, respectively. No associations with health care infrastructure were observed. Conclusions: Our results suggest a greater effect of area-based factors for CLD than HCC. Personal risk factors accounted for the largest proportion of variance for HCC but not for CLD mortality. Published by Elsevier Inc. C1 [Major, Jacqueline M.; Graubard, Barry I.; Freedman, Neal D.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Major, Jacqueline M.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. [Sargent, James D.; Carlos, Heather A.] Dartmouth Coll, Norris Cotton Canc Ctr, Canc Control Res Program, Lebanon, NH 03756 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Altekruse, Sean F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Major, JM (reprint author), US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM jacqueline.major@fda.hhs.gov RI Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. 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 Florida Cancer Data System or Florida 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. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. The views expressed in this manuscript do not necessarily represent those of the Department of Health and Human Services or the U.S. Food and Drug Administration. NR 33 TC 8 Z9 8 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2014 VL 24 IS 2 BP 104 EP 110 DI 10.1016/j.annepidem.2013.11.006 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA2GO UT WOS:000330913300004 PM 24332863 ER PT J AU Michels, KA Edwards, DRV Baird, DD Savitz, DA Hartmann, KE AF Michels, Kara A. Edwards, Digna R. Velez Baird, Donna D. Savitz, David A. Hartmann, Katherine E. TI Uterine leiomyomata and cesarean birth risk: a prospective cohort with standardized imaging SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Leiomyoma; Cesarean section; Epidemiology; Prospective studies ID OBSTETRIC OUTCOMES; PREGNANCY; DELIVERY; MYOMAS AB Purpose: To determine if women with leiomyomata detected using uniform ultrasound methods are at increased risk of cesarean birth, without regard to indication. Methods: Women were enrolled in Right from the Start (2000-2010), a prospective pregnancy cohort. Leiomyomata were counted, categorized, and measured during first trimester ultrasounds. Women provided information about demographics and reproductive history during first trimester interviews. Route of delivery was extracted from medical records or vital records, if the former were unavailable. Generalized estimating equations were used to calculate risk ratios (RR) and 95% confidence intervals (CIs) for the risk of cesarean birth by leiomyoma presence and characteristics. Results: Among 2635 women, the prevalences of leiomyomata and cesarean birth were 11.2% and 29.8%, respectively. Women with leiomyomata, compared with those without, had a 27% increase in cesarean risk (RR, 1.27; CI, 1.17-1.37). The association was weaker following adjustment for maternal body mass index and age (adjusted risk ratio [ARR], 1.11; CI, 1.02-1.20). The adjusted risk was elevated for women with a single leiomyoma 3 cm or more in diameter (ARR, 1.22; CI, 1.14-1.32) and women with the largest total leiomyoma volumes (ARR, 1.59; CI, 1.44-1.76). Conclusions: Women with leiomyomata were at increased risk for cesarean birth particularly, those with larger tumor volumes. (C) 2014 Elsevier Inc. All rights reserved. C1 [Michels, Kara A.; Edwards, Digna R. Velez; Hartmann, Katherine E.] Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr, Nashville, TN 37235 USA. [Michels, Kara A.; Edwards, Digna R. Velez; Hartmann, Katherine E.] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37232 USA. [Edwards, Digna R. Velez] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Savitz, David A.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Savitz, David A.] Brown Univ, Dept Obstet & Gynecol, Providence, RI USA. RP Edwards, DRV (reprint author), Vanderbilt Epidemiol Ctr, 2525 West End Ave,Suite 600,6th Floor, Nashville, TN 37203 USA. EM digna.r.velez.edwards@vanderbilt.edu RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Michels, Kara/0000-0003-2431-2079 FU National Institute of Child and Human Development [R01HD043883, R01HD049675]; American Water Works Association Research Foundation [2579]; Building Interdisciplinary Research Careers in Women's Health career development program [5K12HD04383-12]; Vanderbilt CTSA grant [UL1 RR024975-01]; NIH, National Institute of Environmental Health Sciences FX The research was supported by grants from the National Institute of Child and Human Development (R01HD043883 and R01HD049675) and the American Water Works Association Research Foundation (2579). Additional funds were provided by the Building Interdisciplinary Research Careers in Women's Health career development program (5K12HD04383-12) and the Vanderbilt CTSA grant UL1 RR024975-01. This research was also supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (i.e., support for coauthor DDB). NR 15 TC 8 Z9 9 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2014 VL 24 IS 2 BP 122 EP 126 DI 10.1016/j.annepidem.2013.10.017 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA2GO UT WOS:000330913300007 PM 24321612 ER PT J AU Ahrens, KA Vladutiu, CJ Mumford, SL Schliep, KC Perkins, NJ Wactawski-Wende, J Schisterman, EF AF Ahrens, Katherine A. Vladutiu, Catherine J. Mumford, Sunni L. Schliep, Karen C. Perkins, Neil J. Wactawski-Wende, Jean Schisterman, Enrique F. TI The effect of physical activity across the menstrual cycle on reproductive function SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Hormones; Leisure activity; Menstrual cycle; Motor activity; Women ID PREMENOPAUSAL WOMEN; BREAST-CANCER; SEX-HORMONE; ASSOCIATION; EXERCISE; STRESS; AGE; PREVALENCE; ESTRADIOL; PATTERNS AB Purpose: To evaluate the association between physical activity (PA) across the menstrual cycle and reproductive function. Methods: The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for up to two menstrual cycles (N = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and testosterone were measured five to eight times per cycle. Linear mixed models were used to estimate the effect of past-week PA (measured four times during each cycle) on hormone levels. Past-week PA was categorized into tertiles based on metabolic equivalent of task hours per week (cut-points were 15.3 and 35.7). Risk ratios for sporadic anovulation were estimated using generalized linear models. Analyses adjusted for habitual PA (assessed at baseline), body mass index, race, age, and perceived stress. Linear mixed models used inverse probability weights to control for concurrent reproductive hormones and caloric intake. Results: High past-week PA was inversely associated with leptin (-6.6%; 95% confidence interval, 10.6 to 2.5) and luteal phase progesterone (-22.1%; 36.2 to 4.7) as compared with low past-week PA. High past-week PA was not significantly associated with sporadic anovulation (adjusted risk ratio, 1.5; 0.6 to 3.4). Conclusions: High levels of PA were modestly associated with changes in select hormones but not sporadic anovulation among moderate to highly active premenopausal women. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ahrens, Katherine A.; Mumford, Sunni L.; Schliep, Karen C.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Vladutiu, Catherine J.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Ahrens, KA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, MSC 7510 6100 Execut Blvd,7B03, Bethesda, MD 20892 USA. EM katherine.ahrens@nih.gov OI Perkins, Neil/0000-0002-6802-4733; 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]; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland [T32-HL007055] FX Funding: This study 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 # HHSN275200403394C). CV received financial support from grant T32-HL007055 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. NR 33 TC 4 Z9 4 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2014 VL 24 IS 2 BP 127 EP 134 DI 10.1016/j.annepidem.2013.11.002 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA2GO UT WOS:000330913300008 PM 24345590 ER PT J AU Prieto, DA Johann, DJ Wei, BR Ye, XY Chan, KC Nissley, DV Simpson, RM Citrin, DE Mackall, CL Linehan, WM Blonder, J AF Prieto, DaRue A. Johann, Donald J., Jr. Wei, Bih-Rong Ye, Xiaoying Chan, King C. Nissley, Dwight V. Simpson, R. Mark Citrin, Deborah E. Mackall, Crystal L. Linehan, W. Marston Blonder, Josip TI Mass spectrometry in cancer biomarker research: a case for immunodepletion of abundant blood-derived proteins from clinical tissue specimens SO BIOMARKERS IN MEDICINE LA English DT Article DE blood; cancer biomarker discovery; clinical proteomics; clinical specimens; high-resolution; accurate LC-MS; immunoaffinity depletion; tissue ID RENAL-CELL CARCINOMA; PLASMA-PROTEOME-PROJECT; ACID-BINDING PROTEINS; KIDNEY CANCER; QUANTITATIVE PROTEOMICS; INTERSTITIAL CYSTITIS; LIGAND LIBRARIES; MESSENGER-RNA; DISCOVERY; EXPRESSION AB The discovery of clinically relevant cancer biomarkers using mass spectrometry (MS)-based proteomics has proven difficult, primarily because of the enormous dynamic range of blood-derived protein concentrations and the fact that the 22 most abundant blood-derived proteins constitute approximately 99% of the total plasma protein mass. Immunodepletion of clinical body fluid specimens (e.g., serum/plasma) for the removal of highly abundant proteins is a reasonable and reproducible solution. Often overlooked, clinical tissue specimens also contain a formidable amount of highly abundant blood-derived proteins present in tissue-embedded networks of blood/lymph capillaries and interstitial fluid. Hence, the dynamic range impediment to biomarker discovery remains a formidable obstacle, regardless of clinical sample type (solid tissue and/or body fluid). Thus, we optimized and applied simultaneous immunodepletion of blood-derived proteins from solid tissue and peripheral blood, using clear cell renal cell carcinoma as a model disease. Integrative analysis of data from this approach and genomic data obtained from the same type of tumor revealed concordant key pathways and protein targets germane to clear cell renal cell carcinoma. This includes the activation of the lipogenic pathway characterized by increased expression of adipophilin (PLIN2) along with cadherin switching', a phenomenon indicative of transcriptional reprogramming linked to renal epithelial dedifferentiation. We also applied immunodepletion of abundant blood-derived proteins to various tissue types (e.g., adipose tissue and breast tissue) showing unambiguously that the removal of abundant blood-derived proteins represents a powerful tool for the reproducible profiling of tissue proteomes. Herein, we show that the removal of abundant blood-derived proteins from solid tissue specimens is of equal importance to depletion of body fluids and recommend its routine use in the context of biological discovery and/or cancer biomarker research. Finally, this perspective presents the background, rationale and strategy for using tissue-directed high-resolution/accuracy MS-based shotgun proteomics to detect genuine tumor proteins in the peripheral blood of a patient diagnosed with nonmetastatic cancer, employing concurrent liquid chromatography-MS analysis of immunodepleted clinical tissue and blood specimens. C1 [Prieto, DaRue A.; Ye, Xiaoying; Chan, King C.; Nissley, Dwight V.; Blonder, Josip] NCI, Lab Prote & Analyt Technol, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Johann, Donald J., Jr.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Wei, Bih-Rong; Simpson, R. Mark] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Citrin, Deborah E.] NCI, Immunol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mackall, Crystal L.] NCI, Sect Translat Radiat Oncol, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Linehan, W. Marston] NCI, Urol Surg & Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Blonder, J (reprint author), NCI, Lab Prote & Analyt Technol, Canc Res Technol Program, Frederick Natl Lab Canc Res, POB B, Frederick, MD 21702 USA. EM blonderj@mail.nih.gov FU National Cancer Institute, NIH [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under Contract HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. 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 85 TC 10 Z9 10 U1 1 U2 13 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PD FEB PY 2014 VL 8 IS 2 BP 269 EP 286 DI 10.2217/bmm.13.101 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AA6MM UT WOS:000331212400023 PM 24521024 ER PT J AU Zustiak, S Nossal, R Sackett, DL AF Zustiak, Silviya Nossal, Ralph Sackett, Dan L. TI Multiwell Stiffness Assay for the Study of Cell Responsiveness to Cytotoxic Drugs SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE substrate stiffness; polyacrylamide; cancer; paclitaxel (Taxol (R)); drug resistance ID ATOMIC-FORCE MICROSCOPY; CREASING INSTABILITY; EPITHELIAL-CELLS; MATRIX STIFFNESS; SUBSTRATE; TISSUE; CHEMOSENSITIVITY; PROLIFERATION; MORPHOLOGY; HYDROGELS AB It is now well understood that the cell microenvironment, including the surrounding matrix, profoundly affects cell fate. This is especially true for solid tumors where, for example, matrix stiffness is believed to be an important factor in tumorogenesis. Our hypothesis is that since matrix stiffness affects cell fate, it may also be important in drug resistance. To test this hypothesis, we designed and built a multiwell polyacrylamide (PA) gel-based stiffness assay, in which the gels were coated with collagen in order to facilitate cell attachment and proliferation. This PA-based assay was used to examine the effect of stiffness on cultured cell responsiveness to cytotoxic drugs. In particular, we tested multiple cancer cell lines and their susceptibility to paclitaxel, a microtubule-targeting agent. By assessing cell proliferation, morphology, and the IC50 of the drug, we were able to establish that the stiffness affects responsiveness to cytotoxic drugs in a cell-dependent manner. (C) 2013 Wiley Periodicals, Inc. C1 [Zustiak, Silviya; Nossal, Ralph; Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Zustiak, S (reprint author), St Louis Univ, Parks Coll Engn, Dept Biomed Engn, 3507 Lindell Blvd, St Louis, MO 63103 USA. EM szustiak@slu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health FX Contract grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Contract grant sponsor: National Institutes of Health NR 37 TC 12 Z9 13 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 EI 1097-0290 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD FEB PY 2014 VL 111 IS 2 BP 396 EP 403 DI 10.1002/bit.25097 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AA3CA UT WOS:000330969300017 PM 24018833 ER PT J AU Loud, JT Gierach, GL Veenstra, TD Falk, RT Nichols, K Guttmann, A Xu, X Greene, MH Gail, MH AF Loud, Jennifer T. Gierach, Gretchen L. Veenstra, Timothy D. Falk, Roni T. Nichols, Kathryn Guttmann, Allison Xu, Xia Greene, Mark H. Gail, Mitchell H. TI Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE BRCA1/2; Estrogens; Parent estrogens; Estrogen metabolites; Nipple aspirate fluid; Ductal lavage supernatant; LC/MS/MS; Postmenopausal ID HORMONE REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; TANDEM MASS-SPECTROMETRY; NIPPLE ASPIRATE FLUID; DUCTAL LAVAGE; MAMMARY CARCINOGENESIS; ENDOGENOUS ESTROGENS; HIGH-RISK; CANCER; WOMEN AB Accurately quantifying parent estrogens (PE) estrone (E-1) and estradiol (E-2) and their metabolites (EM) within breast tissue and serum may permit detailed investigations of their contributions to breast carcinogenesis among BRCA1/2 mutation carriers. We conducted a study of PE/EM in serum, nipple aspirate fluid (NAF), and ductal lavage supernatant (DLS) among postmenopausal BRCA1/2 mutation carriers. PE/EM (conjugated and unconjugated) were measured in paired serum/NAF (n = 22 women) and paired serum/DLS samples (n = 24 women) using quantitative liquid chromatography-tandem mass spectrometry (LC/MS/MS). The relationships between serum and tissue-specific PE/EM were measured using Pearson's correlation coefficients. Conjugated forms of PE/EM constituted the majority of estrogen in serum (88 %), NAF (59 %) and DLS (69 %). PE/EM in NAF and serum were highly correlated [E-1 (r = 0.97, p < 0.0001), E-2 (r = 0.90, p < 0.0001) and estriol (E-3) (r = 0.74, p < 0.0001)] as they were in DLS and serum [E-1 (r = 0.92, p < 0.0001; E-2 (r = 0.70, p = 0.0001; E-3 (r = 0.67, p = 0.0004)]. Analyses of paired total estrogen values for NAF and serum, and DLS and serum yielded ratios of 0.22 (95 % CI 0.19-0.25) and 0.28 (95 % CI 0.24-0.32), respectively. This report is the first to employ LC/MS/MS to quantify PE/EM in novel breast tissue-derived biospecimens (i.e., NAF and DLS). We demonstrate that circulating PE and EM are strongly and positively correlated with tissue-specific PE and EM measured in NAF and DLS among postmenopausal BRCA1/2 mutation carriers. If confirmed, future etiologic studies could utilize the more readily obtainable serum hormone levels as a reliable surrogate measure of exposure at the tissue level. C1 [Loud, Jennifer T.; Guttmann, Allison; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20850 USA. [Gierach, Gretchen L.; Falk, Roni T.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20850 USA. [Veenstra, Timothy D.; Xu, Xia] SAIC Frederick Inc, Adv Technol Program, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. [Veenstra, Timothy D.; Xu, Xia] NCI, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nichols, Kathryn] WESTAT Corp, Rockville, MD 20850 USA. [Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20850 USA. RP Loud, JT (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 9609 Med Ctr Dr,Room 6E536, Bethesda, MD 20850 USA. EM loudj@mail.nih.gov; gierachg@mail.nih.gov; veenstrat@mail.nih.gov; falkr@mail.nih.gov; kathrynnichols@westat.com; allison.guttman@gmail.com; Xia.xu2@nih.gov; greenem@mail.nih.gov; gailm@mail.nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the National Cancer Institute; Westat, Inc. [NO2-CP-11019-50, NO2-CP-65504-50]; Molecular Epidemiology Award from Division of Cancer Epidemiology and Genetics, National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The Breast Imaging Study (NCI Protocol # 01-C-0009). We wish to thank Ruthann Giusti, Christine Mueller and Phuong L. Mai for clinical support; Phuong L. Mai for reviewing the manuscript; Nicole Dupree, Jason Hu, Beth Mittl, and Usha Singh for their help in data preparation. Special thanks to all our study participants; without whose cooperation this study could not have been done. This project was supported by the Intramural Research Program of the National Cancer Institute, by contracts NO2-CP-11019-50 and NO2-CP-65504-50 with Westat, Inc. and by a Molecular Epidemiology Award from the Division of Cancer Epidemiology and Genetics, National Cancer Institute. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. By acceptance of this article, the publisher or recipient acknowledges the right of the United States Government to retain a nonexclusive, royalty-free license and to any copyright covering the article. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the United States Government. NR 43 TC 9 Z9 9 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD FEB PY 2014 VL 143 IS 3 BP 517 EP 529 DI 10.1007/s10549-013-2821-6 PG 13 WC Oncology SC Oncology GA AA3DS UT WOS:000330973700011 PM 24442642 ER PT J AU Di Gaetano, M Mazza, F Ferrari, E Maineri, P Barabino, G Ratto, GB AF Di Gaetano, Marina Mazza, Federico Ferrari, Enrico Maineri, Paola Barabino, Giorgio Ratto, Giovanni Battista TI Selective bilateral main stem bronchial intubation for the management of severe respiratory distress syndrome due to iatrogenic carinal perforation SO CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE LA English DT Letter C1 [Di Gaetano, Marina; Barabino, Giorgio] Santa Corona Hosp, Intens Care Unit, Pietra Ligure, SV, Italy. [Mazza, Federico; Maineri, Paola] Santa Corona Hosp, Thorac Surg Unit, Pietra Ligure, SV, Italy. [Ferrari, Enrico; Ratto, Giovanni Battista] Natl Canc Inst, Thorac Surg Unit, Genoa, Italy. RP Mazza, F (reprint author), Santa Corona Hosp, Thorac Surg Unit, Pietra Ligure, SV, Italy. EM mazza-federico@libero.it NR 3 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0832-610X EI 1496-8975 J9 CAN J ANESTH JI Can. J. Anesth. PD FEB PY 2014 VL 61 IS 2 BP 211 EP 212 DI 10.1007/s12630-013-0083-8 PG 2 WC Anesthesiology SC Anesthesiology GA AA3PT UT WOS:000331005500016 PM 24318727 ER PT J AU Khoury, MJ AF Khoury, Muin J. TI Q&A: Muin Khoury on Cancer Epidemiology SO CANCER DISCOVERY LA English DT Editorial Material C1 [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Khoury, Muin J.] Natl Canc Inst, Div Canc Control & Populat Sci, Epidemiol & Genom Res Program, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD FEB PY 2014 VL 4 IS 2 BP 140 EP 140 DI 10.1158/2159-8290.CD-ND2014-001 PG 1 WC Oncology SC Oncology GA AA4SC UT WOS:000331085400008 PM 24501292 ER PT J AU Lockwood, W Politi, K AF Lockwood, William Politi, Katerina TI MYCxing It Up with FGFR1 in Squamous Cell Lung Cancer SO CANCER DISCOVERY LA English DT Editorial Material ID ADENOCARCINOMA; MUTATIONS AB Recurrent amplification of 8p12 is observed in squamous cell lung cancer, and FGFR1 is thought to be the main oncogenic driver in this region. In this issue of Cancer Discovery, Malchers and colleagues perform a detailed characterization of 8p12 in squamous cell lung cancer and find remarkable genomic heterogeneity in this region, raising the possibility that other genes in addition to FGFR1 may play a role in squamous cell lung cancer. Mechanistic studies of the FGFR1-amplified subset of squamous cell lung cancer reveal potential roles for fibroblast growth factor (FGF) ligands and MYC expression levels in modulating the response of these tumors to FGF receptor inhibition. (C) 2014 AACR. C1 [Lockwood, William] NHGRI, Canc Biol & Genet Sect, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Politi, Katerina] Yale Univ, Sch Med, Dept Pathol, Yale Canc Ctr, New Haven, CT 06510 USA. [Politi, Katerina] Yale Univ, Sch Med, Dept Med Med Oncol, Yale Canc Ctr, New Haven, CT 06510 USA. RP Politi, K (reprint author), Yale Univ, Sch Med, Dept Pathol, Yale Canc Ctr, 333 Cedar St,SHM-I 234D, New Haven, CT 06510 USA. EM katerina.politi@yale.edu FU Canadian Institutes of Health Research; NCI NIH HHS [R01 CA120247] NR 15 TC 3 Z9 3 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD FEB PY 2014 VL 4 IS 2 BP 152 EP 154 DI 10.1158/2159-8290.CD-13-1049 PG 3 WC Oncology SC Oncology GA AA4SC UT WOS:000331085400021 PM 24501305 ER PT J AU Shern, JF Chen, L Chmielecki, J Wei, JS Patidar, R Rosenberg, M Ambrogio, L Auclair, D Wang, JJ Song, YK Tolman, C Hurd, L Liao, HL Zhang, SL Bogen, D Brohl, AS Sindiri, S Catchpoole, D Badgett, T Getz, G Mora, J Anderson, JR Skapek, SX Barr, FG Meyerson, M Hawkins, DS Khan, J AF Shern, Jack F. Chen, Li Chmielecki, Juliann Wei, Jun S. Patidar, Rajesh Rosenberg, Mara Ambrogio, Lauren Auclair, Daniel Wang, Jianjun Song, Young K. Tolman, Catherine Hurd, Laura Liao, Hongling Zhang, Shile Bogen, Dominik Brohl, Andrew S. Sindiri, Sivasish Catchpoole, Daniel Badgett, Thomas Getz, Gad Mora, Jaume Anderson, James R. Skapek, Stephen X. Barr, Frederic G. Meyerson, Matthew Hawkins, Douglas S. Khan, Javed TI Comprehensive Genomic Analysis of Rhabdomyosarcoma Reveals a Landscape of Alterations Affecting a Common Genetic Axis in Fusion-Positive and Fusion-Negative Tumors SO CANCER DISCOVERY LA English DT Article ID CHILDRENS ONCOLOGY GROUP; DNA-SEQUENCING DATA; EMBRYONAL RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; CHILDHOOD RHABDOMYOSARCOMA; INTERGROUP RHABDOMYOSARCOMA; SOMATIC MUTATIONS; CDNA MICROARRAYS; RAS GENES; RNA-SEQ AB Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/ normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma. SIGNIFICANCE: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and B COR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention. C1 [Shern, Jack F.; Chen, Li; Wei, Jun S.; Patidar, Rajesh; Wang, Jianjun; Song, Young K.; Tolman, Catherine; Hurd, Laura; Liao, Hongling; Zhang, Shile; Bogen, Dominik; Brohl, Andrew S.; Sindiri, Sivasish; Badgett, Thomas; Khan, Javed] NCI, Pediat Oncol Branch, Oncogenom Sect, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Barr, Frederic G.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Chmielecki, Juliann; Rosenberg, Mara; Ambrogio, Lauren; Auclair, Daniel; Getz, Gad; Meyerson, Matthew] Broad Inst MIT & Harvard, Cambridge, MA USA. [Chmielecki, Juliann; Meyerson, Matthew] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Chmielecki, Juliann; Meyerson, Matthew] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Anderson, James R.] Univ Nebraska Med Ctr, Omaha, NE USA. [Skapek, Stephen X.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Div Hematol Oncol, Dallas, TX 75390 USA. [Catchpoole, Daniel] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Childrens Hosp, Dept Pediat, Seattle, WA 98195 USA. [Catchpoole, Daniel] Childrens Hosp Westmead, Childrens Canc Res Unit, Tumour Bank, Westmead, NSW, Australia. [Mora, Jaume] Hosp Sant Joan de Deu Barcelona, Dept Oncol, Barcelona, Spain. RP Khan, J (reprint author), NCI, Oncogenom Sect, Pediat Oncol Branch, Ctr Canc Res, 37 Convent Dr,Room 2016B, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; sindiri, sivasish/0000-0003-2516-969X FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; American Cancer Society AstraZeneca Postdoctoral Fellowship; Discipline of Pediatrics and Child Health, Sydney Medical School, University of Sydney; Kids Cancer Project FX J.F. Shern, L. Chen, J.S. Wei, R. Patidar, J. Wang, Y.K. Song, C. Tolman, L. Hurd, H. Liao, S. Zhang, D. Bogen, A. S. Brohl, S. Sindiri, T. Badgett, F. G. Barr, and J. Khan are supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. M. Meyerson is supported by M. B. Zuckerman and Team Dragonfly of the Pan-Mass Challenge. J. Chmielecki is supported by an American Cancer Society AstraZeneca Postdoctoral Fellowship. D. Catchpoole is supported by a joint appointment with the Discipline of Pediatrics and Child Health, Sydney Medical School, University of Sydney, and receives funding support through The Kids Cancer Project. NR 67 TC 108 Z9 114 U1 0 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD FEB PY 2014 VL 4 IS 2 BP 216 EP 231 DI 10.1158/2159-8290.CD-13-0639 PG 16 WC Oncology SC Oncology GA AA4SC UT WOS:000331085400027 PM 24436047 ER PT J AU Coultrap, SJ Freund, RK O'Leary, H Sanderson, JL Roche, KW Dell'Acqua, ML Bayer, KU AF Coultrap, Steven J. Freund, Ronald K. O'Leary, Heather Sanderson, Jennifer L. Roche, Katherine W. Dell'Acqua, Mark L. Bayer, K. Ulrich TI Autonomous CaMKII Mediates Both LTP and LTD Using a Mechanism for Differential Substrate Site Selection SO CELL REPORTS LA English DT Article ID LONG-TERM POTENTIATION; DEPENDENT PROTEIN-KINASE; SYNAPTIC PLASTICITY; AMPA RECEPTORS; GLUTAMATE RECEPTORS; CA2+ OSCILLATIONS; GLUR1 SUBUNIT; MUTANT MICE; AREA CA1; HIPPOCAMPUS AB Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced "autonomous'' (Ca2+-independent) activity. However, whereas LTP is known to induce phosphorylation of theAMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKIImediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by "autonomous'' CaMKII was further stimulated by Ca-2+/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference. C1 [Coultrap, Steven J.; Freund, Ronald K.; O'Leary, Heather; Sanderson, Jennifer L.; Dell'Acqua, Mark L.; Bayer, K. Ulrich] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. [O'Leary, Heather] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Roche, Katherine W.] NINDS, NIH, Bethesda, MD 20892 USA. RP Dell'Acqua, ML (reprint author), Univ Colorado, Sch Med, Dept Pharmacol, Anschutz Med Campus, Aurora, CO 80045 USA. EM mark.dellacqua@ucdenver.edu; ulli.bayer@ucdenver.edu OI Dell'Acqua, Mark/0000-0003-3798-3461; Roche, Katherine/0000-0001-7282-6539 FU National Institutes of Health (Rocky Mountain Neurological Disorders Center) [NS048154, NS080851, NS081248, NS040701] FX We thank Drs. Matt Kennedy, Paco Herson, and Guiying Deng (U. Colorado) for helpful discussions and critical reading of the manuscript. We thank Drs. Giese, Silva, and Yasuda for the T286A mutant mice. We thank Dr. Wallace Chick for generating the gene targeting vector. The research was supported by National Institutes of Health grants NS048154 (Rocky Mountain Neurological Disorders Center grant), NS040701 (to M.L.D.), NS080851, and NS081248 (to K.U.B.). The University of Colorado is currently seeking patent protection for tatCN21, its derivatives, and its uses. NR 41 TC 40 Z9 41 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB PY 2014 VL 6 IS 3 BP 431 EP 437 DI 10.1016/j.celrep.2014.01.005 PG 7 WC Cell Biology SC Cell Biology GA AA5VT UT WOS:000331168400003 PM 24485660 ER PT J AU Hull, SC Berkman, BE AF Hull, Sara Chandros Berkman, Benjamin E. TI Grappling With Genomic Incidental Findings in the Clinical Realm SO CHEST LA English DT Article ID NEXT-GENERATION; RECOMMENDATIONS; EXOME; PARTICIPANTS; MEDICINE; LUNG; CHALLENGE; FRAMEWORK; ETHICS AB We have learned a remarkable amount in recent decades about genomics and its potential contributions to human health and medical practice. However, genomic sequencing technology, which is starting to become incorporated into clinical care, also raises ethical challenges. In particular, there has been significant debate about the appropriate management of genomic incidental findings (GIFs), which we define as pathogenic or likely pathogenic test results that are not apparently relevant to the diagnostic indications for which the tests were ordered. Although there is an emerging consensus that clinicians will have at least some obligation to disclose GIFs to patients, the scope of that obligation is unclear. This commentary identifies nuanced issues that clinicians will likely face in the foreseeable future regarding their emerging obligations to disclose clinically actionable GIFs. Will clinicians be expected to look actively for GIFs? Should GIFs for adult-onset disorders be disclosed to children? What obligations will clinicians have to disclose GIFs to family members of deceased patients? What role should informed consent play? There is value to exploring the range of views on these questions at this time, before genomic sequencing has fully matured as a technology, so that clinicians can anticipate how they will respond to the discovery of GIFs once sequencing becomes a more routine part of clinical care. Genomics is ultimately going to play an important role in the practice of pulmonary medicine, and it is important for pulmonologists and other subspecialists to be well informed about what to expect. C1 NHGRI, Off Clin Director, Bethesda, MD 20892 USA. NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Hull, SC (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Ste 1C118, Bethesda, MD 20892 USA. EM shull@mail.nih.gov FU intramural research program of the National Human Genome Research Institute, National Institutes of Health FX This research was funded in part by the intramural research program of the National Human Genome Research Institute, National Institutes of Health. NR 32 TC 0 Z9 0 U1 2 U2 7 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2014 VL 145 IS 2 BP 226 EP 230 DI 10.1378/chest.13-1976 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AA2WO UT WOS:000330955100013 PM 24493507 ER PT J AU Freidlin, B Korn, EL Gray, R AF Freidlin, Boris Korn, Edward L. Gray, Robert TI Marker Sequential Test (MaST) design SO CLINICAL TRIALS LA English DT Article ID RANDOMIZED CLINICAL-TRIALS; BIOMARKERS; CANCER AB Background New targeted anticancer therapies often benefit only a subset of patients with a given cancer. Definitive evaluation of these agents may require phase III randomized clinical trial designs that integrate evaluation of the new treatment and the predictive ability of the biomarker that putatively determines the sensitive subset. Purpose We propose a new integrated biomarker design, the Marker Sequential Test (MaST) design, that allows sequential testing of the treatment effect in the biomarker subgroups and overall population while controlling the relevant type I error rates. Methods After defining the testing and error framework for integrated biomarker designs, we review the commonly used approaches to integrated biomarker testing. We then present a general form of the MaST design and describe how it can be used to provide proper control of false-positive error rates for biomarker-positive and biomarker-negative subgroups. The operating characteristics of the MaST design are compared by analytical methods and simulations to the sequential subgroup-specific design that sequentially assesses the treatment effect in the biomarker subgroups. Practical aspects of MaST design implementation are discussed. Results The MaST design is shown to have higher power relative to the sequential subgroup-specific design in situations where the treatment effect is homogeneous across biomarker subgroups, while preserving the power for settings where treatment benefit is limited to biomarker-positive subgroup. For example, in the time-to-event setting considered with 30% biomarker-positive prevalence, the MaST design provides up to a 30% increase in power in the biomarker-positive and biomarker-negative subgroups when the treatment benefits all patients equally, while sustaining less than a 2% loss of power against alternatives where the benefit is limited to the biomarker-positive subgroup. Limitations The proposed design is appropriate for settings where it is reasonable to assume that the treatment will not be effective in the biomarker-negative patients unless it is effective in the biomarker-positive patients. Conclusion The MaST trial design is a useful alternative to the sequential subgroup-specific design when it is important to consider the treatment effect in the biomarker-positive and biomarker-negative subgroups. C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Gray, Robert] Dana Farber Canc Inst, Eastern Cooperat Oncol Grp, Boston, MA 02115 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 15 TC 8 Z9 8 U1 1 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2014 VL 11 IS 1 BP 19 EP 27 DI 10.1177/1740774513503739 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AA6QI UT WOS:000331222500005 PM 24085774 ER PT J AU Peay, HL Tibben, A Fisher, T Brenna, E Biesecker, BB AF Peay, Holly L. Tibben, Aad Fisher, Tyler Brenna, Ethan Biesecker, Barbara B. TI Expectations and experiences of investigators and parents involved in a clinical trial for Duchenne/Becker muscular dystrophy SO CLINICAL TRIALS LA English DT Article ID ETHICAL-ISSUES; AGENT; CARE AB Background The social context of rare disease research is changing, with increased community engagement around drug development and clinical trials. This engagement may benefit patients and families but may also lead to heightened trial expectations and therapeutic misconception. Clinical investigators are also susceptible to harboring high expectations. Little is known about parental motivations and expectations for clinical trials for rare pediatric disorders. Purpose We describe the experience of parents and clinical investigators involved in a phase II clinical trial for Duchenne and Becker muscular dystrophy: their expectations, hopes, motivations, and reactions to the termination of the trial. Methods This qualitative study was based on interviews with clinical investigators and parents of sons with Duchenne and Becker muscular dystrophy (DBMD) who participated in the phase IIa or IIb ataluren clinical trial in the United States. Interviews were transcribed and coded for thematic analysis. Results Participants were 12 parents of affected boys receiving active drug and 9 clinical investigators. High trial expectations of direct benefit were reported by parents and many clinicians. Investigators described monitoring and managing parents' expectations; several worried about their own involvement in increasing parents' expectations. Most parents were able to differentiate their expectations from their optimistic hopes for a cure. Parents' expectations arose from other parents, advocacy organizations, and the sponsor. All parents reported some degree of clinical benefit to their children. Secondary benefits were hopefulness and powerful feelings associated with active efforts to affect the disease course. Parents and clinical investigators reported strong, close relationships that were mutually important. Parents and clinicians felt valued by the sponsor for the majority of the trial. When the trial abruptly stopped, they described loss of engagement, distress, and feeling unprepared for the possibility of trial termination. Limitations This was a retrospective study of one clinical trial. We were unable to recruit participants whose children received placebo. The interviews occurred during a time of significant uncertainty and distress for many of the participants. Conclusion This pilot study reflects complex outcomes of strong community engagement. The findings highlight a need for renewed education about, and support for, clinical trial termination and loss of drug access. The primary positive outcome was demonstration of strong relationships among committed parents and study teams. These relationships were highly valued by both parties and may suggest an ideal intervention opportunity for efforts to improve psychological well-being. A negative outcome attributed, in part, to community engagement was inappropriately high trial expectations. More optimistically, high expectations were attributed, in part, to the importance of hope and powerful feelings associated with active efforts to affect the disease course. C1 [Peay, Holly L.; Fisher, Tyler; Brenna, Ethan; Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Peay, Holly L.; Tibben, Aad] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands. RP Peay, HL (reprint author), NHGRI, Social & Behav Res Branch, Bldg 31,Room B1B36,31 Ctr Dr MSC 2073, Bethesda, MD 20892 USA. EM hpeay@mail.nih.gov OI Tibben, Aad/0000-0002-4560-1710 FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 22 TC 7 Z9 7 U1 3 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2014 VL 11 IS 1 BP 77 EP 85 DI 10.1177/1740774513512726 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AA6QI UT WOS:000331222500011 PM 24311736 ER PT J AU Barrett, AJ AF Barrett, A. John TI Clinical trials in cytotherapy SO CYTOTHERAPY LA English DT Editorial Material C1 [Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, NIH, Stem Cell Allogen Transplantat Sect, Bldg 10 CRC Room 3-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD FEB PY 2014 VL 16 IS 2 BP 147 EP 148 DI 10.1016/j.jcyt.2013.12.007 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA AA2GT UT WOS:000330913800001 PM 24438895 ER PT J AU Bettahi, I Sun, HJ Gao, N Wang, F Mi, XF Chen, WP Liu, ZG Yu, FSX AF Bettahi, Ilham Sun, Haijing Gao, Nan Wang, Feng Mi, Xiaofan Chen, Weiping Liu, Zuguo Yu, Fu-Shin X. TI Genome-Wide Transcriptional Analysis of Differentially Expressed Genes in Diabetic, Healing Corneal Epithelial Cells: Hyperglycemia-Suppressed TGF beta 3 Expression Contributes to the Delay of Epithelial Wound Healing in Diabetic Corneas SO DIABETES LA English DT Article ID GROWTH-FACTOR-BETA; EPOXIDE HYDROLASE GENE; NON-SMAD; SUBCONJUNCTIVAL BEVACIZUMAB; MICROARRAY ANALYSIS; ISOFORMS; REPAIR; RATS; NEOVASCULARIZATION; S100A8/A9 AB Patients with diabetes mellitus (DM) may develop corneal complications and delayed wound healing. The aims of this study are to characterize the molecular signatures and biological pathways leading to delayed epithelial wound healing and to delineate the involvement of TGF3 therein. Genome-wide cDNA microarray analysis revealed 1,888 differentially expressed genes in the healing epithelia of normal (NL) versus type 1 DM rat corneas. Gene ontology and enrichment analyses indicated TGF signaling as a major altered pathway. Among three TGF isoforms, TGF-1 and 3 were upregulated in response to wounding in NL corneal epithelial cells (CECs), whereas the latter was greatly suppressed by hyperglycemia in rat type 1 and 2 and mouse type 1 DM models. Functional analysis indicated that TGF-3 contributed to wound healing in NL corneas. Moreover, exogenously added TGF-3 accelerated epithelial wound closure in type 2 rat and type 1 mouse DM corneas via Smad and PI3K-AKT signaling pathways, autoregulation, and/or upregulation of Serpine1, a well-known TGF target gene. Taken together, our study for the first time provides a comprehensive list of genes differentially expressed in the healing CECs of NL versus diabetic corneas and suggests the therapeutic potential of TGF-3 for treating corneal and skin wounds in diabetic patients. C1 [Bettahi, Ilham; Sun, Haijing; Gao, Nan; Wang, Feng; Mi, Xiaofan; Yu, Fu-Shin X.] Wayne State Univ, Sch Med, Dept Ophthalmol, Detroit, MI 48202 USA. [Bettahi, Ilham; Sun, Haijing; Gao, Nan; Wang, Feng; Mi, Xiaofan; Yu, Fu-Shin X.] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Chen, Weiping] NIDDKD, Genom Core Lab, Bethesda, MD USA. [Liu, Zuguo] Xiamen Univ, Xiamen Eye Ctr, Key Lab Ophthalmol & Visual Sci Fujian Prov, Xiamen, Fujian, Peoples R China. RP Yu, FSX (reprint author), Wayne State Univ, Sch Med, Dept Ophthalmol, Detroit, MI 48202 USA. EM fyu@med.wayne.edu FU National Institutes of Health/National Eye Institute [R01-EY-10869, R01-EY-17960, P30-EY-04078]; Research to Prevent Blindness FX The authors received support from National Institutes of Health/National Eye Institute R01-EY-10869, R01-EY-17960 (to F.-S.X.Y.), P30-EY-04078 (National Eye Institute core to Wayne State University), and Research to Prevent Blindness (to Kresge Eye Institute). NR 50 TC 12 Z9 13 U1 1 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2014 VL 63 IS 2 BP 715 EP 727 DI 10.2337/db13-1260 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA5BG UT WOS:000331110000037 PM 24306208 ER PT J AU Kugelman, JR Johnston, SC Mulembakani, PM Kisalu, N Lee, MS Koroleva, G McCarthy, SE Gestole, MC Wolfe, ND Fair, JN Schneider, BS Wright, LL Huggins, J Whitehouse, CA Wemakoy, EO Muyembe-Tamfum, JJ Hensley, LE Palacios, GF Rimoin, AW AF Kugelman, Jeffrey R. Johnston, Sara C. Mulembakani, Prime M. Kisalu, Neville Lee, Michael S. Koroleva, Galina McCarthy, Sarah E. Gestole, Marie C. Wolfe, Nathan D. Fair, Joseph N. Schneider, Bradley S. Wright, Linda L. Huggins, John Whitehouse, Chris A. Wemakoy, Emile Okitolonda Muyembe-Tamfum, Jean Jacques Hensley, Lisa E. Palacios, Gustavo F. Rimoin, Anne W. TI Genomic Variability of Monkeypox Virus among Humans, Democratic Republic of the Congo SO EMERGING INFECTIOUS DISEASES LA English DT Article ID ROCHE LIGHTCYCLER; SMALLPOX; INFECTION; TRANSMISSION; POXVIRUSES; SQUIRRELS; EVOLUTION; OUTBREAK; SEQUENCE; ECOLOGY AB Monkeypox virus is a zoonotic virus endemic to Central Africa. Although active disease surveillance has assessed monkeypox disease prevalence and geographic range, information about virus diversity is lacking. We therefore assessed genome diversity of viruses in 60 samples obtained from humans with primary and secondary cases of infection from 2005 through 2007. We detected 4 distinct lineages and a deletion that resulted in gene loss in 10 (16.7%) samples and that seemed to correlate with human-to-human transmission (p = 0.0544). The data suggest a high frequency of spillover events from the pool of viruses in nonhuman animals, active selection through genomic destabilization and gene loss, and increased disease transmissibility and severity. The potential for accelerated adaptation to humans should be monitored through improved surveillance. C1 [Kugelman, Jeffrey R.] US Army Med Res Inst Infect Dis, Ctr Genome Sci, Ft Detrick, MD USA. [Johnston, Sara C.; Lee, Michael S.; Koroleva, Galina; McCarthy, Sarah E.; Gestole, Marie C.; Huggins, John; Whitehouse, Chris A.; Palacios, Gustavo F.] US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. [Mulembakani, Prime M.; Wemakoy, Emile Okitolonda] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Kisalu, Neville; Rimoin, Anne W.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Wolfe, Nathan D.; Fair, Joseph N.; Schneider, Bradley S.] Global Viral Forecasting, San Francisco, CA USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Muyembe-Tamfum, Jean Jacques] Natl Inst Biomed Res, Kinshasa, Zaire. [Hensley, Lisa E.] US FDA, Silver Spring, MD USA. RP Rimoin, AW (reprint author), Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, 640 Charles E Young Dr S, Los Angeles, CA 90024 USA. EM gustavo.f.palacios.ctr@us.army.mil; arimoin@ucla.edu RI Palacios, Gustavo/I-7773-2015; OI Palacios, Gustavo/0000-0001-5062-1938; Schneider, Bradley S/0000-0001-7642-0018 FU Defense Threat Reduction Agency [1881290]; Metabiota; US Department of Defense Armed Forces Health Surveillance Center, Division of Global Emerging Infections, Surveillance Operations; Henry M. Jackson Foundation for the Advancement of Military Medicine; Defense Threat Reduction Agency Cooperative Biological Engagement Program; Google.org; Skoll Foundation; US Agency for International Development Emerging Pandemic Threats Program, PREDICT project [GHN-A-OO-09-00010-00] FX This work was funded by the Defense Threat Reduction Agency Project no. 1881290. The sample collection and epidemiologic study was partially financed by Metabiota, whose contribution was supported by the US Department of Defense Armed Forces Health Surveillance Center, Division of Global Emerging Infections, Surveillance Operations; the Henry M. Jackson Foundation for the Advancement of Military Medicine; the Defense Threat Reduction Agency Cooperative Biological Engagement Program; Google.org; the Skoll Foundation; and the US Agency for International Development Emerging Pandemic Threats Program, PREDICT project, under the terms of cooperative agreement no. GHN-A-OO-09-00010-00. NR 40 TC 9 Z9 9 U1 1 U2 10 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2014 VL 20 IS 2 BP 232 EP 239 DI 10.3201/eid2002.130118 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 301TA UT WOS:000330553800008 PM 24457084 ER PT J AU Millum, J AF Millum, Joseph TI Consent Under Pressure: The Puzzle of Third Party Coercion SO ETHICAL THEORY AND MORAL PRACTICE LA English DT Article DE Coercion; Consent; Applied ethics; Medical research AB Coercion by the recipient of consent renders that consent invalid. But what about when the coercive force comes from a third party, not from the person to whom consent would be proffered? In this paper I analyze how threats from a third party affect consent. I argue that, as with other cases of coercion, we should distinguish threats that render consent invalid from threats whose force is too weak to invalidate consent and threats that are legitimate. Illegitimate controlling third party threats render consent invalid just as they do in two party cases. However, knowing that the consent is invalid is not sufficient to tell the recipient of consent what she may or should do. I argue that when presented with a token of consent from someone whom she thinks is experiencing an illegitimate controlling threat, the recipient may act on that token if and only if doing so represents a reasonable joint decision for her and the victim of coercion. The appropriate action for someone faced with third party coercion therefore depends on the other options open to her and those open to the victim of coercion. C1 NIH, Clin Ctr Dept Bioeth, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Millum, J (reprint author), NIH, Clin Ctr Dept Bioeth, Fogarty Int Ctr, Bldg 10,1C118,10 Ctr Dr, Bethesda, MD 20892 USA. EM millumj@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 18 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-2820 EI 1572-8447 J9 ETHICAL THEORY MORAL JI Ethical Theory Moral Pract. PD FEB PY 2014 VL 17 IS 1 BP 113 EP 127 DI 10.1007/s10677-013-9419-2 PG 15 WC Philosophy SC Philosophy GA AA3LI UT WOS:000330993600009 PM 26997905 ER PT J AU Covo, S Puccia, CM Argueso, JL Gordenin, DA Resnick, MA AF Covo, Shay Puccia, Christopher M. Argueso, Juan Lucas Gordenin, Dmitry A. Resnick, Michael A. TI The Sister Chromatid Cohesion Pathway Suppresses Multiple Chromosome Gain and Chromosome Amplification SO GENETICS LA English DT Article DE chromosome gain; cohesin; genome instability; sister chromatid cohesion ID DOUBLE-STRAND BREAKS; YEAST SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; DNA-DAMAGE; S-PHASE; GENE AMPLIFICATION; REPLICATION FORK; KLEISIN SUBUNIT; COPY-NUMBER; ANEUPLOIDY AB Gain or loss of chromosomes resulting in aneuploidy can be important factors in cancer and adaptive evolution. Although chromosome gain is a frequent event in eukaryotes, there is limited information on its genetic control. Here we measured the rates of chromosome gain in wild-type yeast and sister chromatid cohesion (SCC) compromised strains. SCC tethers the newly replicated chromatids until anaphase via the cohesin complex. Chromosome gain was measured by selecting and characterizing copper-resistant colonies that emerged due to increased copies of the metallothionein gene CUP1. Although all defective SCC diploid strains exhibited increased rates of chromosome gain, there were 15-fold differences between them. Of all mutants examined, a hypomorphic mutation at the cohesin complex caused the highest rate of chromosome gain while disruption of WPL1, an important regulator of SCC and chromosome condensation, resulted in the smallest increase in chromosome gain. In addition to defects in SCC, yeast cell type contributed significantly to chromosome gain, with the greatest rates observed for homozygous mating-type diploids, followed by heterozygous mating type, and smallest in haploids. In fact, wpl1-deficient haploids did not show any difference in chromosome gain rates compared to wild-type haploids. Genomic analysis of copper-resistant colonies revealed that the driver chromosome for which selection was applied could be amplified to over five copies per diploid cell. In addition, an increase in the expected driver chromosome was often accompanied by a gain of a small number of other chromosomes. We suggest that while chromosome gain due to SCC malfunction can have negative effects through gene imbalance, it could also facilitate opportunities for adaptive changes. In multicellular organisms, both factors could lead to somatic diseases including cancer. C1 [Covo, Shay; Gordenin, Dmitry A.; Resnick, Michael A.] NIEHS, Res Triangle Pk, NC 27709 USA. [Puccia, Christopher M.; Argueso, Juan Lucas] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Covo, S (reprint author), Hebrew Univ Jerusalem, Dept Plant Pathol & Microbiol, POB 12, IL-76100 Rehovot, Israel. EM shay.covo@mail.huji.ac.il OI Argueso, Juan Lucas/0000-0002-7157-1519; Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural Research Program of the National Institute of Environmental Sciences (National Institutes of Health, Department of Health and Human Services) [1Z01ES065073]; American Cancer Society grant ACS IRG [57-001-53]; Webb-Waring Biomedical Research Award from the Boettcher Foundation FX We thank Kerry Bloom for discussion of the results and useful advice. We greatly appreciate the critical evaluation of the manuscript by Jessica Williams and Thuy-Ai Nguyen. This work was supported by the Intramural Research Program of the National Institute of Environmental Sciences (National Institutes of Health, Department of Health and Human Services) under project 1Z01ES065073 (to M.A.R.), American Cancer Society grant ACS IRG no. 57-001-53, and a Webb-Waring Biomedical Research Award from the Boettcher Foundation (to J.L.A.). NR 80 TC 12 Z9 12 U1 0 U2 7 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 1943-2631 J9 GENETICS JI Genetics PD FEB PY 2014 VL 196 IS 2 BP 373 EP + DI 10.1534/genetics.113.159202 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA AA7KX UT WOS:000331277400002 PM 24298060 ER PT J AU Zhang, XL Johnson, AD Hendricks, AE Hwang, SJ Tanriverdi, K Ganesh, SK Smith, NL Peyser, PA Freedman, JE O'Donnell, CJ AF Zhang, Xiaoling Johnson, Andrew D. Hendricks, Audrey E. Hwang, Shih-Jen Tanriverdi, Kahraman Ganesh, Santhi K. Smith, Nicholas L. Peyser, Patricia A. Freedman, Jane E. O'Donnell, Christopher J. TI Genetic associations with expression for genes implicated in GWAS studies for atherosclerotic cardiovascular disease and blood phenotypes SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; INTIMA-MEDIA THICKNESS; HEART-DISEASE; MYOCARDIAL-INFARCTION; CHARGE CONSORTIUM; DNA VARIANTS; FACTOR-VII; LOCI; RISK AB Genome-wide association studies (GWAS) have uncovered many genetic associations for cardiovascular disease (CVD). However, data are limited regarding causal genetic variants within implicated loci. We sought to identify regulatory variants (cis-and trans-eQTLs) affecting expression levels of 93 genes selected by their proximity to SNPs with significant associations in prior GWAS for CVD traits. Expression levels were measured by qRT-PCR in leukocytes from 1846 Framingham Heart Study participants. An additive genetic model was applied to 2.5 million imputed SNPs for each gene. Approximately 45% of genes (N = 38) harbored at least one cis-eSNP after a regional multiple-test adjustment. Applying a more rigorous significance threshold (P < 5 x 10(-8)), we found the expression level of 10 genes was significantly associated with more than one cis-eSNP. The top cis-eSNPs for 7 of these 10 genes exhibited moderate-to-strong association with >= 1 CVD clinical phenotypes. Several eSNPs or proxy SNPs (r(2) = 1) were replicated by other eQTL studies. After adjusting for the lead GWAS SNPs for the 10 genes, expression variances explained by top cis-eSNPs were attenuated markedly for LPL, FADS2 and C6orf184, suggesting a shared genetic basis for the GWAS and expression trait. A significant association between cis-eSNPs, gene expression and lipid levels was discovered for LPL and C6orf184. In conclusion, strong cis-acting variants are localized within nearly half of the GWAS loci studied, with particularly strong evidence for a regulatory role of the top GWAS SNP for expression of LPL, FADS2 and C6orf184. C1 [Zhang, Xiaoling; Johnson, Andrew D.; Hendricks, Audrey E.; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA 01702 USA. [Zhang, Xiaoling; Johnson, Andrew D.; Hendricks, Audrey E.; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Tanriverdi, Kahraman; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Ganesh, Santhi K.] Univ Michigan Hlth Care Syst, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, VA Off Res & Dev, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Framingham, MA USA. RP O'Donnell, CJ (reprint author), NHLBI, Div Intramural Res, NHLBIs Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov RI Hendricks, Audrey/I-4127-2016; Johnson, Andrew/G-6520-2013 OI Hendricks, Audrey/0000-0002-7152-0287; FU National Heart, Lung and Blood Institute, Division of Intramural Research FX This work was supported by the National Heart, Lung and Blood Institute, Division of Intramural Research. NR 61 TC 16 Z9 16 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 1 PY 2014 VL 23 IS 3 BP 782 EP 795 DI 10.1093/hmg/ddt461 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AA1FK UT WOS:000330841700018 PM 24057673 ER PT J AU Nalls, MA Saad, M Noyce, AJ Keller, MF Schrag, A Bestwick, JP Traynor, BJ Gibbs, JR Hernandez, DG Cookson, MR Morris, HR Williams, N Gasser, T Heutink, P Wood, N Hardy, J Martinez, M Singleton, AB AF Nalls, Mike A. Saad, Mohamad Noyce, Alastair J. Keller, Margaux F. Schrag, Anette Bestwick, Jonathan P. Traynor, Bryan J. Gibbs, J. Raphael Hernandez, Dena G. Cookson, Mark R. Morris, Huw R. Williams, Nigel Gasser, Thomas Heutink, Peter Wood, Nick Hardy, John Martinez, Maria Singleton, Andrew B. CA IPDGC WTCCC2 NABEC UKBEC TI Genetic comorbidities in Parkinson's disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; PSORIASIS SUSCEPTIBILITY LOCI; C-REACTIVE PROTEIN; COLITIS-RISK LOCI; MENDELIAN RANDOMIZATION; SEQUENCE VARIANTS; COMMON VARIANTS; IDENTIFIES 3; CARDIOVASCULAR-DISEASE AB Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain. C1 [Nalls, Mike A.; Keller, Margaux F.; Traynor, Bryan J.; Gibbs, J. Raphael; Hernandez, Dena G.; Cookson, Mark R.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Saad, Mohamad; Martinez, Maria] Ctr Physiopathol Toulouse Purpan, Inst Natl Sante & Rech Med, UMR 1043, Toulouse, France. [Saad, Mohamad; Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Noyce, Alastair J.] UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, London, England. [Schrag, Anette; Morris, Huw R.] UCL Inst Neurol, Dept Clin Neurosci, London, England. [Keller, Margaux F.] Temple Univ, Dept Biol Anthropol, Philadelphia, PA 19122 USA. [Bestwick, Jonathan P.] Queen Mary Univ London, Wolfson Inst Prevent Med, Barts & London Sch Med & Dent, London, England. [Morris, Huw R.; Williams, Nigel] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Sch Med, Cardiff CF10 3AX, S Glam, Wales. [Gasser, Thomas] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany. [Gasser, Thomas; Heutink, Peter] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Gibbs, J. Raphael; Hernandez, Dena G.; Wood, Nick; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Wood, Nick] UCL, UCL Genet Inst, London, England. RP Nalls, MA (reprint author), NIA, Neurogenet Lab, NIH, Bldg 35,35 Convent Dr, Bethesda, MD 20892 USA. EM nallsm@mail.nih.gov RI Wood, Nicholas/C-2505-2009; van de Warrenburg, Bart/D-1935-2010; Martinez, Maria/B-3111-2013; Guerreiro, Rita/A-1327-2011; corvol, jean-christophe/I-6387-2012; Revesz, Tamas/A-8732-2010; Trabzuni, Daniah/C-4034-2012; Hardy, John/C-2451-2009; Jankowski, Janusz/H-2706-2012; Singleton, Andrew/C-3010-2009; Morris, Huw/B-8527-2008; Traynor, Bryan/G-5690-2010; O'Sullivan, Sean/C-9333-2012; Cooper, J Mark/D-5826-2013; Weale, Michael/F-2587-2010; Schapira, Anthony/A-1245-2010; Bras, Jose/A-1428-2011; Deloukas, Panos/B-2922-2013; Deuschl, Gunther/A-7986-2010; Scheffer, Hans/E-4644-2012; lambert, jean-charles/F-8787-2013; OI Wood, Nicholas/0000-0002-9500-3348; Martinez, Maria/0000-0003-2180-4537; corvol, jean-christophe/0000-0001-7325-0199; Revesz, Tamas/0000-0003-2501-0259; Trabzuni, Daniah/0000-0003-4826-9570; Bras, Jose/0000-0001-8186-0333; Stefansson, Hreinn/0000-0002-9331-6666; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Jankowski, Janusz/0000-0003-2130-9181; Morris, Huw/0000-0002-5473-3774; O'Sullivan, Sean/0000-0002-0583-7956; Cooper, J Mark/0000-0002-3007-3054; Weale, Michael/0000-0003-4593-1186; Schapira, Anthony/0000-0002-3018-3966; Deloukas, Panos/0000-0001-9251-070X; Scheffer, Hans/0000-0002-2986-0915; Plagnol, Vincent/0000-0002-5597-9215; Bhatia, Kailash/0000-0001-8185-286X FU Medical Research Council [MC_PC_09003, G0701075, G1100479, G1100643, MC_G0901330, MC_G1000735]; NIA NIH HHS [AG000932-04, Z01-AG000949-02]; NIEHS NIH HHS [Z01-ES101986]; NINDS NIH HHS [R01 NS041509, R01 NS075321]; Parkinson's UK [F-1201, F-1202, G-0907, G-1107, J-0804]; Wellcome Trust [089698, 090532] NR 87 TC 12 Z9 12 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 1 PY 2014 VL 23 IS 3 BP 831 EP 841 DI 10.1093/hmg/ddt465 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AA1FK UT WOS:000330841700022 PM 24057672 ER PT J AU Nelson, LM AF Nelson, Lawrence M. TI The Flat Earth Society: a rose by any other name? SO HUMAN REPRODUCTION LA English DT Editorial Material ID PRIMARY OVARIAN INSUFFICIENCY; FAILURE C1 NICHD, Integrat Reprod Med Grp, NIH, Bethesda, MD 20814 USA. RP Nelson, LM (reprint author), NICHD, Integrat Reprod Med Grp, NIH, Bethesda, MD 20814 USA. EM lawrence_nelson@nih.gov NR 7 TC 3 Z9 3 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2014 VL 29 IS 2 BP 190 EP 192 DI 10.1093/humrep/det443 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AA1FV UT WOS:000330842800002 PM 24345580 ER PT J AU Eisenberg, ML Kim, S Chen, Z Sundaram, R Schisterman, EF Louis, GMB AF Eisenberg, Michael L. Kim, Sungduk Chen, Zhen Sundaram, Rajeshwari Schisterman, Enrique F. Louis, Germaine M. Buck TI The relationship between male BMI and waist circumference on semen quality: data from the LIFE study SO HUMAN REPRODUCTION LA English DT Article DE male infertility; oligospermia; fertility; obesity; overweight ID BODY-MASS INDEX; PHYSICALLY ACTIVE MEN; REPRODUCTIVE HORMONES; SPERM PARAMETERS; MALE-INFERTILITY; HEALTHY-MEN; OBESITY; METAANALYSIS; FERTILITY; PROFILE AB What is the relationship between body size, physical activity and semen parameters among male partners of couples attempting to become pregnant? Overweight and obesity are associated with a higher prevalence of low ejaculate volume, sperm concentration and total sperm count. Higher BMI is associated with impaired semen parameters, while increasing waist circumference (WC) is also associated with impaired semen parameters in infertile men. Data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study were utilized. The LIFE study is a population-based prospective cohort of 501 couples attempting to conceive in two geographic areas (Texas and Michigan, USA) recruited in 20052009. Couples were recruited from four counties in Michigan and 12 counties in Texas to ensure a range of environmental exposures and lifestyle characteristics. In person interviews were conducted to ascertain demographic, health and reproductive histories followed by anthropometric assessment. We categorized BMI (kg/m(2)) as 25.0 (underweight and normal), 25.029.9 (overweight) 30.034.9 (obese, class I) and 35 (obese, class II) for analysis. Data were available for analysis in 468 men (93 participation), with a mean SD age of 31.8 4.8 years, BMI of 29.8 5.6 kg/m(2) and WC of 100.8 14.2 cm. The majority of the cohort (82) was overweight or obese with 58 reporting physical activity 1 time/week. The median sperm concentration for the men in the cohort was 60.2 M/ml with 8.6 having oligospermia (15 M/ml). When examining semen parameters, ejaculate volume showed a linear decline with increasing BMI and WC (P 0.01). Similarly, the total sperm count showed a negative linear association with WC (P 0.01). No significant relationship was seen between body size (i.e. BMI or WC) and semen concentration, motility, vitality, morphology or DNA fragmentation index. The percentage of men with abnormal volume, concentration and total sperm increased with increasing body size (P 0.05). No relationship between physical activity and semen parameters was identified. Our cohort was largely overweight and sedentary, which may result in limited external validity, i.e. generalizability. The lack of physical activity did preclude examination of exercise more frequently than once per week, thus our ability to examine more active individuals is limited. Body size (as measured by BMI or WC) is negatively associated with semen parameters with little influence of physical activity. Our findings are the first showing a relationship between WC and semen parameters in a sample of men without known infertility. Given the worldwide obesity epidemic, further study of the role of weight loss to improve semen parameters is warranted. Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). There are no competing interests. C1 [Eisenberg, Michael L.] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA. [Eisenberg, Michael L.] Stanford Univ, Sch Med, Dept Obstet & Gynecol, Stanford, CA 94305 USA. [Kim, Sungduk; Chen, Zhen; Sundaram, Rajeshwari; Schisterman, Enrique F.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. RP Eisenberg, ML (reprint author), Stanford Univ, Sch Med, Dept Urol, 300 Pasteur Dr, Stanford, CA 94305 USA. EM eisenberg@stanford.edu OI Eisenberg, Michael/0000-0001-5482-0141; Sundaram, Rajeshwari/0000-0002-6918-5002; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural research of NICHD [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] FX Intramural research of NICHD (Contracts #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). NR 33 TC 50 Z9 54 U1 2 U2 30 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2014 VL 29 IS 2 BP 193 EP 200 DI 10.1093/humrep/det428 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AA1FV UT WOS:000330842800003 PM 24306102 ER PT J AU Fawcett, GL Dettmer, AM Kay, D Raveendran, M Higley, JD Ryan, ND Cameron, JL Rogers, J AF Fawcett, G. L. Dettmer, A. M. Kay, D. Raveendran, M. Higley, J. D. Ryan, N. D. Cameron, J. L. Rogers, J. TI Quantitative Genetics of Response to Novelty and Other Stimuli by Infant Rhesus Macaques (Macaca mulatta) Across Three Behavioral Assessments SO INTERNATIONAL JOURNAL OF PRIMATOLOGY LA English DT Article DE Anxiety; Heritability; Maternal environmental effects; Temperament ID SEROTONIN TRANSPORTER GENE; LINKED POLYMORPHIC REGION; ENVIRONMENT INTERACTIONS; ALCOHOL-CONSUMPTION; LONGITUDINAL TWIN; PAN-TROGLODYTES; VERVET MONKEYS; STRESS; TEMPERAMENT; HERITABILITY AB Primate behavior is influenced by both heritable factors and environmental experience during development. Previous studies of rhesus macaques (Macaca mulatta) examined the effects of genetic variation on expressed behavior and related neurobiological traits (heritability and/or genetic association) using a variety of study designs. Most of these prior studies examined genetic effects on the behavior of adults or adolescent rhesus macaques, not in young macaques early in development. To assess environmental and additive genetic variation in behavioral reactivity and response to novelty among infants, we investigated a range of behavioral traits in a large number (N = 428) of pedigreed infants born and housed in large outdoor corrals at the Oregon National Primate Research Center (ONPRC). We recorded the behavior of each subject during a series of brief tests, involving exposure of each infant to a novel environment, to a social threat without the mother present, and to a novel environment with its mother present but sedated. We found significant heritability (h (2) ) for willingness to move away from the mother and explore a novel environment (h (2) = 0.25 +/- 0.13; P = 0.003). The infants also exhibited a range of heritable behavioral reactions to separation stress or to threat when the mother was not present (h (2) = 0.23 +/- 0.13-0.24 +/- 0.15, P < 0.01). We observed no evidence of maternal environmental effects on these traits. Our results extend knowledge of genetic influences on temperament and reactivity in nonhuman primates by demonstrating that several measures of behavioral reactivity among infant rhesus macaques are heritable. C1 [Fawcett, G. L.; Raveendran, M.; Rogers, J.] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA. [Dettmer, A. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Kay, D.] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL 32610 USA. [Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Ryan, N. D.; Cameron, J. L.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Cameron, J. L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. RP Fawcett, GL (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA. EM glfawcet@bcm.edu FU NIH from the National Institute for Mental Health [MH41712, MH062568]; National Institute of Research Resources [RR024153, RR15383]; John D. and Catherine T. MacArthur Foundation; James S. McDonnell Foundation Research Network on "Early Experience and Brain Development"; NIH [F32NS074574] FX We thank Snekalatha Raveendran for DNA sample organization and inventory. We also thank Roy Garcia, Ann Arya, Wendy Shelledy, and Amanda Vinson for contributions to the pedigree construction. We thank Jim Cheverud for advice on statistical analysis, and the editor and reviewers for their efforts to improve this manuscript. This work was supported by NIH grants from the National Institute for Mental Health (MH41712 to J. L. Cameron and MH062568 to J. L. Cameron and J. Rogers), the National Institute of Research Resources (RR024153 to J. L. Cameron and RR15383 to J. Rogers), funds from the John D. and Catherine T. MacArthur Foundation and James S. McDonnell Foundation Research Network on "Early Experience and Brain Development" (to J. L. Cameron), and a National Research Service Award from the NIH (F32NS074574 to A. M. Dettmer). Excellent technical assistance in behavioral phenotyping of macaques was provided by K. Coleman, R. Clark, C. Cannon, M. Bulechowsky, L. Sinko, J. Zhang, A. Paine, J. Broderick, S. Broderick, M. Gammill, E. Stein, and R. Flygare. NR 62 TC 3 Z9 3 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0164-0291 EI 1573-8604 J9 INT J PRIMATOL JI Int. J. Primatol. PD FEB PY 2014 VL 35 IS 1 BP 325 EP 339 DI 10.1007/s10764-014-9750-z PG 15 WC Zoology SC Zoology GA AA2WH UT WOS:000330954400017 PM 24701001 ER PT J AU Rubinson, DA Hochster, HS Ryan, DP Wolpin, BM McCleary, NJ Abrams, TA Chan, JA Iqbal, S Lenz, HJ Lim, D Rose, J Bekaii-Saab, T Chen, HX Fuchs, CS Ng, K AF Rubinson, Douglas A. Hochster, Howard S. Ryan, David P. Wolpin, Brian M. McCleary, Nadine Jackson Abrams, Thomas A. Chan, Jennifer A. Iqbal, Syma Lenz, Heinz J. Lim, Dean Rose, Jeffrey Bekaii-Saab, Tanios Chen, Helen X. Fuchs, Charles S. Ng, Kimmie TI Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: Results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Pertuzumab; Cetuximab; Phase I; Phase II; Colorectal Cancer ID GROWTH-FACTOR RECEPTOR; DIMERIZATION INHIBITOR; ACQUIRED-RESISTANCE; CLINICAL ACTIVITY; OVARIAN-CANCER; SOLID TUMORS; CHEMOTHERAPY; TRIAL; EGFR; COMBINATION AB Purpose Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. Patients and methods This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. Results Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9). Conclusion Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities. C1 [Rubinson, Douglas A.; Wolpin, Brian M.; McCleary, Nadine Jackson; Abrams, Thomas A.; Chan, Jennifer A.; Fuchs, Charles S.; Ng, Kimmie] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Hochster, Howard S.] Yale Univ, Ctr Canc, Dept Med Oncol, New Haven, CT USA. [Ryan, David P.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Iqbal, Syma; Lenz, Heinz J.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Div Med Oncol,Sharon A Carpenter Lab, Los Angeles, CA 90033 USA. [Lim, Dean] City Hope Natl Med Ctr, Div Med Oncol & Therapeut Res, Duarte, CA 91010 USA. [Rose, Jeffrey] Lowcountry Hematol & Oncol, Mt Pleasant, MI USA. [Bekaii-Saab, Tanios] Ohio State Univ, Coll Med, Dept Pharmacol, Columbus, OH 43210 USA. [Chen, Helen X.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Ng, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Kimmie_Ng@dfci.harvard.edu FU NCI; Genentech FX Pertuzumab was supplied by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) in Bethesda, MD. The trial was conducted under a Phase 2 Consortium contract with the NCI. Genentech also provided supplementary funding for the study. NR 35 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD FEB PY 2014 VL 32 IS 1 BP 113 EP 122 DI 10.1007/s10637-013-9956-5 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AA3BY UT WOS:000330969100012 PM 23568716 ER PT J AU Kreimer, AR Johansson, M Hildesheim, A Pawlita, M Brennan, P AF Kreimer, Aimee R. Johansson, Mattias Hildesheim, Allan Pawlita, Michael Brennan, Paul TI Teaching Moment: Why Promising Biomarkers Do Not Always Translate Into Clinically Useful Tests Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID NECK-CANCER; PAPILLOMAVIRUS; HEAD C1 [Kreimer, Aimee R.; Hildesheim, Allan] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. [Johansson, Mattias; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Pawlita, Michael] German Canc Res Ctr, Heidelberg, Germany. RP Kreimer, AR (reprint author), Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. EM kreimera@mail.nih.gov RI Hildesheim, Allan/B-9760-2015; Kreimer, Aimee/H-1687-2015; Waterboer, Tim/G-1252-2010 OI Hildesheim, Allan/0000-0003-0257-2363; NR 8 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2014 VL 32 IS 4 BP 361 EP 362 DI 10.1200/JCO.2013.53.2697 PG 2 WC Oncology SC Oncology GA AA4LH UT WOS:000331066600019 PM 24366940 ER PT J AU Chadwick, RS Lamb, JS Manoussaki, D AF Chadwick, Richard S. Lamb, Jessica S. Manoussaki, Daphne TI Stimulated acoustic emissions from coupled strings SO JOURNAL OF ENGINEERING MATHEMATICS LA English DT Article DE Acoustic emissions; Asymptotic matching of inner and outer expansions; Coupled wave propagation; Mode conversion; WKB approximation ID MODE-CONVERSION AB We consider traveling transverse waves on two identical uniform taut strings that are elastically coupled through springs that gradually decrease their stiffness over a region of finite length. The wave system can be decomposed into two modes: an in-phase mode (+) that is transparent to the coupling springs, and an out-of-phase mode (-) that engages the coupling springs and can resonate at a particular location depending on the excitation frequency. The system exhibits linear mode conversion whereby an incoming (+) wave is reflected back from the resonance location both as a propagating (+) wave and an evanescent (-) wave, while both types emerge as propagating forward through the resonance location. We match a local transition layer expansion to the WKB expansion to obtain estimates of the reflection and transmission coefficients. The reflected waves may be an analog for stimulated emissions from the ear. C1 [Chadwick, Richard S.; Lamb, Jessica S.] NIDCD Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, Bethesda, MD 20892 USA. [Manoussaki, Daphne] Tech Univ Crete, Div Appl Math, Dept Sci, Iraklion, NE, Greece. RP Chadwick, RS (reprint author), NIDCD Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov FU Intramural Program of the National Institute of Deafness and Other Communication Disorders [DC000033-17] FX This work was supported by Grant DC000033-17 from the Intramural Program of the National Institute of Deafness and Other Communication Disorders. Correspondence and requests for materials should be addressed to R. S. C., who would like to acknowledge his gratitude to Milton van Dyke for teaching mathematical techniques that hopefully will never be forgotten. Specifically, his courses at Stanford on Perturbation Methods in Fluid Mechanics, and Symmetry and Similitude techniques were invaluable for my career. The authors also thank Professors Sonya Smith and Leonard Schwartz for their useful comments, and the reviewers whose comments greatly improved the presentation. NR 6 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0022-0833 EI 1573-2703 J9 J ENG MATH JI J. Eng. Math. PD FEB PY 2014 VL 84 IS 1 SI SI BP 147 EP 153 DI 10.1007/s10665-013-9635-8 PG 7 WC Engineering, Multidisciplinary; Mathematics, Interdisciplinary Applications SC Engineering; Mathematics GA AA2WN UT WOS:000330955000014 PM 24523564 ER PT J AU Johnson, RA Block, LF Danis, M AF Johnson, Rebecca A. Block, Lisa F. Danis, Marion TI Optimizing the Involvement of Language Interpreters During the Clinical Encounter SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE language barriers; patient activation; cultural competence ID CARE C1 [Johnson, Rebecca A.; Danis, Marion] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Johnson, RA (reprint author), NIH, Dept Bioeth, 10 Ctr Dr, Bethesda, MD 20892 USA. EM Johnsonra4@mail.nih.gov FU Intramural NIH HHS NR 5 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2014 VL 29 IS 2 BP 276 EP 278 DI 10.1007/s11606-013-2610-2 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AA2WS UT WOS:000330955500006 PM 24018627 ER PT J AU Danis, M Sommers, R Logan, J Weidmer, B Chen, S Goold, SD Pearson, S Donley, G McGlynn, E AF Danis, Marion Sommers, Roseanna Logan, Jean Weidmer, Beverly Chen, Shirley Goold, Susan Dorr Pearson, Steven Donley, Greer McGlynn, Elizabeth TI Exploring Public Attitudes Towards Approaches to Discussing Costs in the Clinical Encounter (vol 29, pg 223, 2014) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Correction C1 [Danis, Marion; Sommers, Roseanna; Logan, Jean; Pearson, Steven; Donley, Greer] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Weidmer, Beverly; McGlynn, Elizabeth] RAND Corp, Santa Monica, CA USA. [Chen, Shirley; Goold, Susan Dorr] Univ Michigan, Ann Arbor, MI 48109 USA. [McGlynn, Elizabeth] Kaiser Permanente, Oakland, CA USA. RP Danis, M (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2014 VL 29 IS 2 BP 421 EP 421 DI 10.1007/s11606-013-2718-4 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AA2WS UT WOS:000330955500041 ER PT J AU Ding, J Wai, KL McGeechan, K Ikram, MK Kawasaki, R Xie, J Klein, R Klein, BBK Cotch, MF Wang, JJ Mitchell, P Shaw, JE Takamasa, K Sharrett, AR Wong, TY AF Ding, Jie Wai, Khin Lay McGeechan, Kevin Ikram, M. Kamran Kawasaki, Ryo Xie, Jing Klein, Ronald Klein, Barbara B. K. Cotch, Mary Frances Wang, Jie Jin Mitchell, Paul Shaw, Jonathan E. Takamasa, Kayama Sharrett, A. Richey Wong, Tien Y. CA Meta-Eye Study Grp TI Retinal vascular caliber and the development of hypertension: a meta-analysis of individual participant data SO JOURNAL OF HYPERTENSION LA English DT Review DE hypertension; meta-analysis; microvascular dysfunction ID INCIDENT SEVERE HYPERTENSION; CORONARY-HEART-DISEASE; BLOOD-PRESSURE; VESSEL DIAMETERS; MICROVASCULAR DYSFUNCTION; ATHEROSCLEROSIS RISK; ARTERIOLAR DIAMETER; DIABETES-MELLITUS; ASSOCIATIONS; COMMUNITIES AB Objective:Microvascular dysfunction has been suggested to be a major pathogenic factor for the development of hypertension. We examined the association between retinal vascular caliber, a marker of systemic microvascular dysfunction, and incident hypertension on a meta-analysis of individual participant data.Methods:We performed a systematic review with relevant studies identified through a search of electronic databases, a review of reference lists, and correspondence with experts. Studies were included if participants were selected from a general population, retinal vascular caliber was measured from photographs using computer-assisted methods at baseline, and individuals were followed up to ascertain the incidence of hypertension. Prespecified individual recorded data from six population-based prospective cohort studies were included. Discrete time proportional odds models were constructed for each study with adjustment for hypertension risk factors. Log odds ratios (ORs) per 20-m difference were pooled using random-effects meta-analysis.Results:Among 10229 participants without prevalent hypertension, diabetes, or cardiovascular disease, 2599 developed new-onset hypertension during median follow-up periods ranging from 2.9 to 10 years. Both narrower retinal arterioles [pooled multivariate-adjusted OR per 20-m difference 1.29, 95% confidence interval (CI) 1.20-1.39] and wider venules (OR per 20-m difference 1.14, 95% CI 1.06-1.23) were associated with an increased risk of hypertension. Each 20m narrower arterioles at baseline were associated with a 1.12mmHg (95% CI 0.25-1.99) greater increase in SBP over 5 years.Conclusions:Retinal arteriolar narrowing and venular widening were independently associated with an increased risk of hypertension. These findings underscore the importance of microvascular remodeling in the pathogenesis of hypertension. C1 [Ding, Jie; Ikram, M. Kamran; Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore Natl Eye Ctr, Singapore 117548, Singapore. [Ding, Jie; Ikram, M. Kamran; Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Wai, Khin Lay] Natl Univ Singapore, Invest Med Unit, Singapore 117548, Singapore. [McGeechan, Kevin] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Ikram, M. Kamran; Wong, Tien Y.] Duke NUS Grad Med Sch, Eye Acad Clin Program, Singapore, Singapore. [Kawasaki, Ryo; Xie, Jing; Wang, Jie Jin] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic 3010, Australia. [Klein, Ronald; Klein, Barbara B. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Millennium Inst, Ctr Vis Res, Sydney, NSW 2006, Australia. [Shaw, Jonathan E.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Takamasa, Kayama] Yamagata Univ, Global COE Investigators, Yamagata 990, Japan. [Sharrett, A. Richey] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Wong, TY (reprint author), Natl Eye Ctr, Singapore Eye Res Inst, 11 Third Hosp Ave, Singapore 168751, Singapore. EM ophwty@nus.edu.sg; ophwty@nus.edu.sg RI Shaw, Jonathan/E-7388-2010; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Ding, Jie/K-9943-2015; OI Shaw, Jonathan/0000-0002-6187-2203; Wang, Jie Jin/0000-0001-9491-4898; Ikram, Mohammad Kamran/0000-0003-0173-9571 FU National Heart, Lung and Blood Institute (Bethesda, Maryland, USA); National Eye Institute, USA; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820 1100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Eye Institute, National Institutes of Health [EY-06594]; Research to Prevent Blindness New York, New York; Australian National Health & Medical Research Council; National Health and Medical Research Council [350448, 233200]; Sylvia and Charles Viertel Charitable Foundation; Global Century Center of Excellence (COE) program of the Japan Society for the Promotion of Science; National Medical Research Council, Singapore [STaR/0003/2008, CG/SERI/2010] FX We used restricted access datasets of the Atherosclerosis Risk in Communities (ARIC) study and the Multiethnic Study of Atherosclerosis (MESA). The authors thank the staff and participants of the ARIC study for their important contributions. The MESA was supported by the National Heart, Lung and Blood Institute (Bethesda, Maryland, USA) and the National Eye Institute, USA. This article does not necessarily convey the opinions or views of the ARIC study, MESA, or the National Heart, Lung and Blood Institute. The authors also thank the staff and participants of all studies for their important contributions.; The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820 1100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The Beaver Dams Eye Study was supported by the National Eye Institute, National Institutes of Health Grant EY-06594, and by Research to Prevent Blindness New York, New York. The Blue Mountains Eye Study was supported by the Australian National Health & Medical Research Council. The Australian Diabetes, Obesity and Lifestyle (AusDiab) study was supported by National Health and Medical Research Council Grants 350448 and 233200, and a Sylvia and Charles Viertel Charitable Foundation grant. The Funagata study was supported by a grant-in-aid from the Global Century Center of Excellence (COE) program of the Japan Society for the Promotion of Science.; Sources of funding: The study was funded by grants from the National Medical Research Council, Singapore (STaR/0003/2008 and CG/SERI/2010), which had no role in study design, data analysis, or interpretation of results. NR 47 TC 31 Z9 32 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD FEB PY 2014 VL 32 IS 2 BP 207 EP 215 DI 10.1097/HJH.0b013e32836586f4 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AA1SM UT WOS:000330876000001 PM 24322199 ER PT J AU Schmeisser, H Bekisz, J Zoon, KC AF Schmeisser, Hana Bekisz, Joseph Zoon, Kathryn C. TI New Function of Type I IFN: Induction of Autophagy SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Review ID PLASMACYTOID DENDRITIC CELLS; BREAST-CANCER CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; INTERFERON-ALPHA; VIRUS-INFECTION; REGULATES AUTOPHAGY; GROWTH-INHIBITION; PROMOTES SURVIVAL; DEFENSE-MECHANISM; KINASE PATHWAY C1 [Schmeisser, Hana; Bekisz, Joseph; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, Cytokine Biol Sect, NIH, 33 North Dr,Bldg 33,Room 2N09G-2, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU Intramural Research Program of the NIH (NIAID) FX We thank Drs. A.L. Snow (USUHS), M. Lenardo (NIAID), F. Schmeisser (FDA), C. Balinsky (NIAID), and C. Johnson (NIAID) for reviewing the article and valuable discussions. This research was supported by the Intramural Research Program of the NIH (NIAID). We also thank Ms. Lydia Kibiuk (NIH, Medical Arts Branch) for her help in generating Figs. 1 and 2. NR 80 TC 26 Z9 28 U1 1 U2 16 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD FEB 1 PY 2014 VL 34 IS 2 BP 71 EP 78 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AA7PN UT WOS:000331289500001 PM 24428799 ER PT J AU Ayithan, N Bradfute, SB Anthony, SM Stuthman, KS Dye, JM Bavari, S Bray, M Ozato, K AF Ayithan, Natarajan Bradfute, Steven B. Anthony, Scott M. Stuthman, Kelly S. Dye, John M. Bavari, Sina Bray, Mike Ozato, Keiko TI Ebola Virus-Like Particles Stimulate Type I Interferons and Proinflammatory Cytokine Expression Through the Toll-Like Receptor and Interferon Signaling Pathways SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID PATTERN-RECOGNITION RECEPTORS; PLASMACYTOID DENDRITIC CELLS; INNATE IMMUNE-RESPONSES; MARBURG VIRUSES; ACTIVATION; INFECTION; VACCINE; MICE; GLYCOPROTEIN; MECHANISMS C1 [Ayithan, Natarajan; Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Bradfute, Steven B.; Anthony, Scott M.; Stuthman, Kelly S.; Dye, John M.; Bavari, Sina] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Bray, Mike] NIAID, Div Clin Res, NIH, Ft Detrick, MD USA. RP Ozato, K (reprint author), NICHHD, Program Genom Differentiat, NIH, Bldg 6,Ctr Dr,Room 2A01, Bethesda, MD 20892 USA. EM ozatok@nih.gov FU Intramural Program of NICHD; Trans-NIH FDA intramural Bio-defense Program, National Institutes of Health, USA FX This work was supported by the Intramural Program of NICHD and the Trans-NIH FDA intramural Bio-defense Program, National Institutes of Health, USA. The content of this publication does not necessarily reflect the views or policies of the US Department of Defense or the US Department of the Army. NR 56 TC 5 Z9 6 U1 1 U2 24 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD FEB 1 PY 2014 VL 34 IS 2 BP 79 EP 89 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AA7PN UT WOS:000331289500002 PM 24102579 ER PT J AU Pivovarova, NB Stanika, RI Kazanina, G Villanueva, I Andrews, SB AF Pivovarova, Natalia B. Stanika, Ruslan I. Kazanina, Galina Villanueva, Idalis Andrews, S. Brian TI The interactive role of zinc and calcium in mitochondrial dysfunction and neurodegeneration SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cell death; electron microscopy; excitotoxicity; hippocampal neurons; ischemia ID HIPPOCAMPAL-NEURONS; CELL-DEATH; RECEPTOR ACTIVATION; CORTICAL-NEURONS; ZN2+; GLUTAMATE; CHANNELS; DEPOLARIZATION; ACCUMULATION; BRAIN AB Zinc has been implicated in neurodegeneration following ischemia. In analogy with calcium, zinc has been proposed to induce toxicity via mitochondrial dysfunction, but the relative role of each cation in mitochondrial damage remains unclear. Here, we report that under conditions mimicking ischemia in hippocampal neurons - normal (2mM) calcium plus elevated (>100M) exogenous zinc - mitochondrial dysfunction evoked by glutamate, kainate or direct depolarization is, despite significant zinc uptake, primarily governed by calcium. Thus, robust mitochondrial ion accumulation, swelling, depolarization, and reactive oxygen species generation were only observed after toxic stimulation in calcium-containing media. This contrasts with the lack of any mitochondrial response in zinc-containing but calcium-free medium, even though zinc uptake and toxicity were strong under these conditions. Indeed, abnormally high, ionophore-induced zinc uptake was necessary to elicit any mitochondrial depolarization. In calcium- and zinc-containing media, depolarization-induced zinc uptake facilitated cell death and enhanced accumulation of mitochondrial calcium, which localized to characteristic matrix precipitates. Some of these contained detectable amounts of zinc. Together these data indicate that zinc uptake is generally insufficient to trigger mitochondrial dysfunction, so that mechanism(s) of zinc toxicity must be different from that of calcium. C1 [Pivovarova, Natalia B.; Stanika, Ruslan I.; Kazanina, Galina; Villanueva, Idalis; Andrews, S. Brian] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Andrews, SB (reprint author), NIH, 49-3A62,49 Convent Dr, Bethesda, MD 20892 USA. EM sba@helix.nih.gov FU NIH, NINDS [Z01 NS002610] FX We would like to thank Ms. Christine A. Winters, and the staff of the NINDS EM facility, Dr. Jung-Hwa Tao-Cheng, Director, for excellent technical assistance. This research was supported by the Intramural Research Program of the NIH, NINDS (Z01 NS002610). The authors declare no conflicts of interest. NR 32 TC 9 Z9 10 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2014 VL 128 IS 4 BP 592 EP 602 DI 10.1111/jnc.12489 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AA0FH UT WOS:000330770400010 PM 24127746 ER PT J AU Fahey, F Zukotynski, K Capala, J Knight, N AF Fahey, Frederic Zukotynski, Katherine Capala, Jacek Knight, Nancy CA NCI SNMMI Joint Workshop Targeted TI Targeted Radionuclide Therapy: Proceedings of a Joint Workshop Hosted by the National Cancer Institute and the Society of Nuclear Medicine and Molecular Imaging SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article ID NON-HODGKIN-LYMPHOMA; GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS; RANDOMIZED CONTROLLED-TRIAL; METASTATIC PROSTATE-CANCER; RADIOLABELED SOMATOSTATIN ANALOG; MITOXANTRONE PLUS PREDNISONE; STEM-CELL TRANSPLANTATION; PHASE-II TRIAL; MALIGNANT PHEOCHROMOCYTOMA; I-131 METAIODOBENZYLGUANIDINE AB The growing interest in targeted radionuclide therapy (TRT) for a broad range of applications is shared by a diverse group of medical professionals, including but not limited to physicians and basic scientists in several fields, as well as members of industry, regulatory bodies, and patients. However, no organizational structure is available to regularly bring these stakeholders together to discuss the latest findings and the most productive strategies to ensure that the potential benefits of TRT are realized. Recognizing the need for a forum to discuss the advances and challenges of TRT relating to availability, supporting technology, and interdisciplinary training and research, the National Cancer Institute (NCI) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) hosted a joint workshop on March 18 and 19, 2013, at the National Institutes of Health campus in Bethesda, Maryland (I). Plans for the workshop were initiated in 2012 by Dr. Frederic Fahey, SNMMI president, and Dr. Jacek Capala of the NCI, and the 2-d event was cochaired by Dr. Fahey and Dr. Katherine Zukotynski. The event was designed to bring a small but diverse group of stakeholders together (Fig. 1) to discuss contemporary TRT in both structured and open-forum formats, to assess approaches for collaboration, and to evaluate strategies to bring the most promising therapies into routine clinical use. This white paper briefly reviews the discussion on TRT that took place at the workshop and offers next-step recommendations from attendees as summarized in presentations by subject matter experts. C1 [Fahey, Frederic] Boston Childrens Hosp, Boston, MA USA. [Fahey, Frederic] Harvard Univ, Sch Med, Boston, MA USA. [Zukotynski, Katherine] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON M5S 1A1, Canada. [Zukotynski, Katherine] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Capala, Jacek] NCI, Bethesda, MD 20892 USA. [Knight, Nancy] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Fahey, F (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM frederic.fahey@childrens.harvard.edu RI Quinn, David/F-4343-2015 OI Quinn, David/0000-0002-1411-0417 NR 132 TC 7 Z9 7 U1 2 U2 10 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2014 VL 55 IS 2 BP 337 EP 348 DI 10.2967/jnumed.113.135178 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AA2LN UT WOS:000330926200053 PM 24396032 ER PT J AU Casciotti, DM Smith, KC Andon, L Vernick, J Tsui, A Klassen, AC AF Casciotti, Dana M. Smith, Katherine C. Andon, Lindsay Vernick, Jon Tsui, Amy Klassen, Ann C. TI Print News Coverage of School-Based Human Papillomavirus Vaccine Mandates SO JOURNAL OF SCHOOL HEALTH LA English DT Article DE cervical cancer; HPV; media; newspapers; vaccination programs ID HPV VACCINE; US NEWSPAPERS; MEDIA; CONTROVERSY; ACCEPTABILITY; PARENTS; CANCER; IMPACT AB BACKGROUNDIn 2007, legislation was proposed in 24 states and the District of Columbia for school-based human papillomavirus (HPV) vaccine mandates, and mandates were enacted in Texas, Virginia, and the District of Columbia. Media coverage of these events was extensive, and media messages both reflected and contributed to controversy surrounding these legislative activities. Messages communicated through the media are an important influence on adolescent and parent understanding of school-based vaccine mandates. METHODSWe conducted structured text analysis of newspaper coverage, including quantitative analysis of 169 articles published in mandate jurisdictions from 2005 to 2009, and qualitative analysis of 63 articles from 2007. Our structured analysis identified topics, key stakeholders and sources, tone, and the presence of conflict. Qualitative thematic analysis identified key messages and issues. RESULTSMedia coverage was often incomplete, providing little context about cervical cancer or screening. Skepticism and autonomy concerns were common. Messages reflected conflict and distrust of government activities, which could negatively impact this and other youth-focused public health initiatives. CONCLUSIONSIf school health professionals are aware of the potential issues raised in media coverage of school-based health mandates, they will be more able to convey appropriate health education messages and promote informed decision-making by parents and students. C1 [Casciotti, Dana M.] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Smith, Katherine C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD 21205 USA. [Andon, Lindsay] Johns Hopkins Hlth Syst, Baltimore, MD 21205 USA. [Vernick, Jon] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Tsui, Amy] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD 21205 USA. [Klassen, Ann C.] Drexel Univ, Sch Publ Hlth, Dept Community Hlth & Prevent, Philadelphia, PA 19102 USA. RP Klassen, AC (reprint author), Drexel Univ, Sch Publ Hlth, Dept Community Hlth & Prevent, 1501 Cherry St, Philadelphia, PA 19102 USA. EM danacasciotti@yahoo.com; kasmith@jhsph.edu; landon1@jhmi.edu; jvernick@jhsph.edu; atsui@jhsph.edu; ack57@drexel.edu FU NCI NIH HHS [T32 CA009314] NR 50 TC 6 Z9 7 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4391 EI 1746-1561 J9 J SCHOOL HEALTH JI J. Sch. Health PD FEB PY 2014 VL 84 IS 2 BP 71 EP 81 DI 10.1111/josh.12126 PG 11 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA AA0KN UT WOS:000330784100001 PM 25099421 ER PT J AU Primack, BA Douglas, EL Land, SR Miller, E Fine, MJ AF Primack, Brian A. Douglas, Erika L. Land, Stephanie R. Miller, Elizabeth Fine, Michael J. TI Comparison of Media Literacy and Usual Education to Prevent Tobacco Use: A Cluster-Randomized Trial SO JOURNAL OF SCHOOL HEALTH LA English DT Article DE adolescents; attitudes; media education; media literacy; normative beliefs; school-based; smoking; social influences; tobacco; youth ID LOW HEALTH LITERACY; ADOLESCENT SMOKING; CIGARETTE-SMOKING; VIEWING SMOKING; ASSOCIATION; MOVIES; INITIATION; EXPOSURE; CHILDREN; ALCOHOL AB BACKGROUNDMedia literacy programs have shown potential for reduction of adolescent tobacco use. We aimed to determine if an anti-smoking media literacy curriculum improves students' media literacy and affects factors related to adolescent smoking. METHODSWe recruited 1170 9th-grade students from 64 classrooms in 3 public urban high schools. Students were randomized by classroom to a media literacy curriculum versus a standard educational program. In an intent-to-treat analysis, we used multilevel modeling to determine if changes in study outcomes were associated with the curricular intervention, controlling for baseline student covariates and the clustering of students within classrooms. RESULTSAmong participants, mean age was 14.5 years and 51% were male, with no significant differences in baseline characteristics between groups. Smoking media literacy changed more among intervention participants compared with control participants (0.24 vs. 0.08, p < .001). Compared with controls, intervention students exhibited a greater reduction in the perceived prevalence of smoking (-14.0% vs. -4.6%, p < .001). Among those initially susceptible to smoking, intervention participants more commonly reverted to being nonsusceptible post-intervention (24% vs. 16%, p = .08). CONCLUSIONSA school-based media literacy curriculum is more effective than a standard educational program in teaching media literacy and improving perceptions of the true prevalence of smoking among adolescents. C1 [Primack, Brian A.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Douglas, Erika L.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15219 USA. [Land, Stephanie R.] NCI, NIH, Bethesda, MD 20892 USA. [Miller, Elizabeth] Univ Pittsburgh, Sch Med, Dept Pediat, Div Adolescent Med, Pittsburgh, PA 15213 USA. [Fine, Michael J.] VA Pittsburgh Healthcare Syst, CHERP, Pittsburgh, PA 15240 USA. RP Primack, BA (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, 230 McKee Pl Suite 600, Pittsburgh, PA 15213 USA. EM bprimack@pitt.edu; douglasel@upmc.edu; stephanie.land@nih.gov; elizabeth.miller@chp.edu; finemj@upmc.edu FU Maurice Falk Foundation; Robert Wood Johnson Foundation; National Cancer Institute [K07-CA114315] FX B.A.P. was supported in part by a grant from the Maurice Falk Foundation, a Physician Faculty Scholar Award from the Robert Wood Johnson Foundation, and a career development award from the National Cancer Institute (K07-CA114315). NR 45 TC 5 Z9 5 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4391 EI 1746-1561 J9 J SCHOOL HEALTH JI J. Sch. Health PD FEB PY 2014 VL 84 IS 2 BP 106 EP 115 DI 10.1111/josh.12130 PG 10 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA AA0KN UT WOS:000330784100005 PM 25099425 ER PT J AU Schepkin, VD Elumalai, M Kitchen, JA Qian, CQ Gor'kov, PL Brey, WW AF Schepkin, Victor D. Elumalai, Malathy Kitchen, Jason A. Qian, Chunqi Gor'kov, Peter L. Brey, William W. TI In vivo chlorine and sodium MRI of rat brain at 21.1 T SO MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE LA English DT Article DE Chlorine; Sodium; MR imaging; Ultrahigh magnetic field; Rat; In vivo; Glioma; Bi-exponential; Fid ID APOPTOTIC VOLUME DECREASE; TUMOR-CELLS ROLE; MAGNETIC-RESONANCE; INTRACELLULAR CHLORIDE; IONIC MOVEMENTS; NA-23; CHANNELS; DEREGULATION AB MR imaging of low-gamma nuclei at the ultrahigh magnetic field of 21.1 T provides a new opportunity for understanding a variety of biological processes. Among these, chlorine and sodium are attracting attention for their involvement in brain function and cancer development. MRI of Cl-35 and Na-23 were performed and relaxation times were measured in vivo in normal rat (n = 3) and in rat with glioma (n = 3) at 21.1 T. The concentrations of both nuclei were evaluated using the center-out back-projection method. T (1) relaxation curve of chlorine in normal rat head was fitted by bi-exponential function (T (1a) = 4.8 ms (0.7) T (1b) = 24.4 +/- A 7 ms (0.3) and compared with sodium (T (1) = 41.4 ms). Free induction decays (FID) of chlorine and sodium in vivo were bi-exponential with similar rapidly decaying components of ms and ms, respectively. Effects of small acquisition matrix and bi-exponential FIDs were assessed for quantification of chlorine (33.2 mM) and sodium (44.4 mM) in rat brain. The study modeled a dramatic effect of the bi-exponential decay on MRI results. The revealed increased chlorine concentration in glioma (similar to 1.5 times) relative to a normal brain correlates with the hypothesis asserting the importance of chlorine for tumor progression. C1 [Schepkin, Victor D.; Elumalai, Malathy; Kitchen, Jason A.; Gor'kov, Peter L.; Brey, William W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Qian, Chunqi] NINDS, NIH, Bethesda, MD 20892 USA. RP Schepkin, VD (reprint author), Florida State Univ, Natl High Magnet Field Lab, 1800 East Paul Dirac Dr, Tallahassee, FL 32310 USA. EM schepkin@magnet.fsu.edu FU National Science Foundation [DMR-0654118] FX Special thanks to Ashley Blue, Richard Desilets, for their valuable help and contribution to the project. The study was supported by National Science Foundation Grant No. DMR-0654118. NR 26 TC 8 Z9 8 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0968-5243 EI 1352-8661 J9 MAGN RESON MATER PHY JI Magn. Reson. Mat. Phys. Biol. Med. PD FEB PY 2014 VL 27 IS 1 SI SI BP 63 EP 70 DI 10.1007/s10334-013-0387-2 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AA3MY UT WOS:000330997900007 PM 23748497 ER PT J AU Simmons, JM Quinn, KJ AF Simmons, Janine M. Quinn, Kevin J. TI The NIMH Research Domain Criteria (RDoC) Project: implications for genetics research SO MAMMALIAN GENOME LA English DT Review ID DISORDERS; BRAIN AB Heterogeneity of disorders, comorbidity across diagnoses, and reification of existing disease classifications are some of the challenges facing psychiatry in the twenty-first century. NIMH's Research Domain Criteria (RDoC) Project seeks to address these issues by defining basic dimensions of function that cut across disorders as traditionally defined and can be studied across multiple units of analysis, from genes to neural circuits to behaviors. The intent is to translate rapid progress in basic genetic, neurobiological, and behavioral research to an improved integrative understanding of psychopathology. In so doing, RDoC seeks to facilitate the development of new and/or optimally targeted treatments for mental disorders. The RDoC project would not have been possible without NIMH's long-term investment in basic research. Without the continuation of basic research, both related and unrelated to current RDoC domains and constructs, it will not be possible to sustain the RDoC effort. This article seeks to outline the relationship between RDoC and NIMH's ongoing support for broad-based basic research, from genetics to behavior. C1 [Simmons, Janine M.; Quinn, Kevin J.] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Quinn, KJ (reprint author), NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM kquinn@mail.nih.gov NR 15 TC 16 Z9 17 U1 3 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 EI 1432-1777 J9 MAMM GENOME JI Mamm. Genome PD FEB PY 2014 VL 25 IS 1-2 SI SI BP 23 EP 31 DI 10.1007/s00335-013-9476-9 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA AA3GH UT WOS:000330980400004 PM 24085332 ER PT J AU Rasmussen, DA Boni, MF Koelle, K AF Rasmussen, David A. Boni, Maciej F. Koelle, Katia TI Reconciling Phylodynamics with Epidemiology: The Case of Dengue Virus in Southern Vietnam SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE phylodynamics; coalescent; demographic inference; infectious diseases ID AEDES-AEGYPTI DIPTERA; EFFECTIVE POPULATION-SIZE; EVOLUTIONARY DYNAMICS; MOLECULAR EVOLUTION; BAYES FACTORS; PUERTO-RICO; COALESCENT; GENEALOGIES; CULICIDAE; PATTERNS AB Coalescent methods are widely used to infer the demographic history of populations from gene genealogies. These approaches-often referred to as phylodynamic methods-have proven especially useful for reconstructing the dynamics of rapidly evolving viral pathogens. Yet, population dynamics inferred from viral genealogies often differ widely from those observed from other sources of epidemiological data, such as hospitalization records. We demonstrate how a modeling framework that allows for the direct fitting of mechanistic epidemiological models to genealogies can be used to test different hypotheses about what ecological factors cause phylodynamic inferences to differ from observed dynamics. We use this framework to test different hypotheses about why dengue serotype 1 (DENV-1) population dynamics in southern Vietnam inferred using existing phylodynamic methods differ from hospitalization data. Specifically, we consider how factors such as seasonality, vector dynamics, and spatial structure can affect inferences drawn from genealogies. The coalescent models we derive to take into account vector dynamics and spatial structure reveal that these ecological complexities can substantially affect coalescent rates among lineages. We show that incorporating these additional ecological complexities into coalescent models can also greatly improve estimates of historical population dynamics and lead to new insights into the factors shaping viral genealogies. C1 [Rasmussen, David A.; Koelle, Katia] Duke Univ, Dept Biol, Durham, NC 27706 USA. [Boni, Maciej F.] Univ Oxford, Clin Res Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam. [Boni, Maciej F.] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Rasmussen, DA (reprint author), Duke Univ, Dept Biol, Durham, NC 27706 USA. EM david.rasmussen@duke.edu FU US National Science Foundation; National Science Foundation [NSF-EF-08-27416]; Science and Technology Directorate, Department of Homeland Security; Fogarty International Centre; James S. McDonnell Foundation FX The authors thank Katherine Anders, Nguyen Van Vinh Chau, and Cameron Simmons for sharing the hospital data and critiquing the manuscript. This work was supported by a US National Science Foundation Graduate Research Fellowship award to D. A. R.; a National Science Foundation grant (NSF-EF-08-27416) to K. K; and the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Centre, and by a Complex Systems grant from the James S. McDonnell Foundation to K. K. M. F. B. is a Wellcome Trust/Royal Society Sir Henry Dale Fellow (098511/Z/12/Z). NR 63 TC 13 Z9 13 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD FEB PY 2014 VL 31 IS 2 BP 258 EP 271 DI 10.1093/molbev/mst203 PG 14 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA AA1DQ UT WOS:000330836900002 PM 24150038 ER PT J AU Campbell, MC Ranciaro, A Zinshteyn, D Rawlings-Goss, R Hirbo, J Thompson, S Woldemeskel, D Froment, A Rucker, JB Omar, SA Bodo, JM Nyambo, T Belay, G Drayna, D Breslin, PAS Tishkoff, SA AF Campbell, Michael C. Ranciaro, Alessia Zinshteyn, Daniel Rawlings-Goss, Renata Hirbo, Jibril Thompson, Simon Woldemeskel, Dawit Froment, Alain Rucker, Joseph B. Omar, Sabah A. Bodo, Jean-Marie Nyambo, Thomas Belay, Gurja Drayna, Dennis Breslin, Paul A. S. Tishkoff, Sarah A. TI Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE selection on standing variation; African genetic diversity; genotype-phenotype association; salicin taste perception ID STANDING GENETIC-VARIATION; DNA POLYMORPHISM DATA; POSITIVE SELECTION; STATISTICAL-METHOD; RECEPTOR HTAS2R16; HUMAN GENOME; ADAPTATION; EVOLUTION; HISTORY; POPULATIONS AB Bitter taste perception influences human nutrition and health, and the genetic variation underlying this trait may play a role in disease susceptibility. To better understand the genetic architecture and patterns of phenotypic variability of bitter taste perception, we sequenced a 996 bp region, encompassing the coding exon of TAS2R16, a bitter taste receptor gene, in 595 individuals from 74 African populations and in 94 non-Africans from 11 populations. We also performed genotype-phenotype association analyses of threshold levels of sensitivity to salicin, a bitter anti-inflammatory compound, in 296 individuals from Central and East Africa. In addition, we characterized TAS2R16 mutants in vitro to investigate the effects of polymorphic loci identified at this locus on receptor function. Here, we report striking signatures of positive selection, including significant Fay and Wu's H statistics predominantly in East Africa, indicating strong local adaptation and greater genetic structure among African populations than expected under neutrality. Furthermore, we observed a "star-like" phylogeny for haplotypes with the derived allele at polymorphic site 516 associated with increased bitter taste perception that is consistent with a model of selection for "high-sensitivity" variation. In contrast, haplotypes carrying the "low-sensitivity" ancestral allele at site 516 showed evidence of strong purifying selection. We also demonstrated, for the first time, the functional effect of nonsynonymous variation at site 516 on salicin phenotypic variance in vivo in diverse Africans and showed that most other nonsynonymous substitutions have weak or no effect on cell surface expression in vitro, suggesting that one main polymorphism at TAS2R16 influences salicin recognition. Additionally, we detected geographic differences in levels of bitter taste perception in Africa not previously reported and infer an East African origin for high salicin sensitivity in human populations. C1 [Campbell, Michael C.; Ranciaro, Alessia; Rawlings-Goss, Renata; Hirbo, Jibril; Thompson, Simon; Woldemeskel, Dawit; Tishkoff, Sarah A.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Zinshteyn, Daniel; Tishkoff, Sarah A.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Woldemeskel, Dawit; Belay, Gurja] Univ Addis Ababa, Dept Biol, Addis Ababa, Ethiopia. [Froment, Alain] Musee Homme Paris, UMR 208, IRD MNHN, Paris, France. [Rucker, Joseph B.] Integral Mol Inc, Philadelphia, PA USA. [Omar, Sabah A.] Kenya Govt Med Res Ctr, Ctr Biotechnol Res & Dev, Nairobi, Kenya. [Bodo, Jean-Marie] Minist Sci Res & Innovat, Yaounde, Cameroon. [Nyambo, Thomas] Muhimbili Univ Hlth & Allied Sci, Dept Biochem, Dar Es Salaam, Tanzania. [Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD USA. [Breslin, Paul A. S.] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Breslin, Paul A. S.] Rutgers Univ New Brunswick, Dept Nutr Sci, New Brunswick, NJ USA. RP Tishkoff, SA (reprint author), Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. EM tishkoff@mail.med.upenn.edu FU US National Science Foundation [BCS-0552486, BCS-0827436]; US National Institutes of Health [R01GM076637, 5DP1ES022577 05, RO1 DC02995, DC010105] FX The authors thank Fathya Abdo, Eva Aluvalla, Birhanu Mekaunintie, Alemayehu Moges, Hussein Musa, Lilian Nyindodo, and Solomon Taye who helped with the field work, as well as the various institutions in West Central, Central, and East Africa for their generous support. They thank Edgar Davidson, Felicia Gomez, Dongbo Hu, Wen-Ya Ko, Joseph Lachance, Laura Scheinfeldt, Sameer Soi, and Anu Thomas for data collection and/or useful discussions. They also express our deepest appreciation to the many Africans who generously donated their DNA and time so that we could learn more about the origins of salicin bitter taste sensitivity in Africa. This work was supported by the US National Science Foundation (grant numbers BCS-0552486, BCS-0827436 to S. A. T.), US National Institutes of Health (grant numbers R01GM076637, 5DP1ES022577 05 to S. A. T.); US National Institutes of Health (grant number RO1 DC02995 to P. A. S. B.); and US National Institutes of Health (grant number DC010105 to J.B.R.). NR 50 TC 8 Z9 8 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD FEB PY 2014 VL 31 IS 2 BP 288 EP 302 DI 10.1093/molbev/mst211 PG 15 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA AA1DQ UT WOS:000330836900004 PM 24177185 ER PT J AU Sano, K Nakajima, T Choyke, PL Kobayashi, H AF Sano, Kohei Nakajima, Takahito Choyke, Peter L. Kobayashi, Hisataka TI The Effect of Photoimmunotherapy Followed by Liposomal Daunorubicin in a Mixed Tumor Model: A Demonstration of the Super-Enhanced Permeability and Retention Effect after Photoimmunotherapy SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID IN-VIVO; PHOTODYNAMIC THERAPY; UVC IRRADIATION; CANCER-CELLS; EFFICACY; MICE; PROGRESSION; METASTASIS; GROWTH; VITRO AB In general, de novo solid tumors are composed of phenotypically and functionally heterogeneous malignant cells. This heterogeneity interferes with the effectiveness of targeted molecular cancer therapies. Even if most of the tumor is killed by a targeted treatment, recurrences are common and can be lethal. In this study, a mixed tumor model, which is predominantly a population of epidermal growth factor receptor (EGFR)-positive A431 cells combined with a smaller population of EGFR-negative Balb3T3/DsRed cells, was established. This mixed tumor was then treated with photoimmunotherapy, a newly developed target-cell-selective cancer therapy using a monoclonal antibody (mAb)-photosensitizer (IR700 fluorescence dye) conjugate and exposure of near-infrared light. Although photoimmunotherapy successfully treated EGFR-positive A431 cells in the mixed tumor, EGFR-negative Balb/DsRed cells were not responsive. However, photoimmunotherapy also induced a large increase in tumor permeability, known as the super-enhanced permeability and retention (SUPR) effect, which allowed a 5-fold increase in the accumulation of a liposomal chemotherapy (DaunoXome) and resulted in more effective therapy than either photoimmunotherapy or liposomal daunorubicin alone. The liposomal daunorubicin, administered 1 hour after EGFR-targeted photoimmunotherapy, was homogeneously distributed, allowing delivery to tiny surviving nests of EGFR-negative Balb3T3/DsRed cells, resulting in prolonged survival of mice. Mol Cancer Ther; 13(2); 426-32. (C) 2013 AACR. C1 [Sano, Kohei; Nakajima, Takahito; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,10 Ctr Dr,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 20 TC 13 Z9 13 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2014 VL 13 IS 2 BP 426 EP 432 DI 10.1158/1535-7163.MCT-13-0633 PG 7 WC Oncology SC Oncology GA AA4LX UT WOS:000331068200014 PM 24356818 ER PT J AU Murai, J Huang, SYN Renaud, A Zhang, YP Ji, JP Takeda, S Morris, J Teicher, B Doroshow, JH Pommier, Y AF Murai, Junko Huang, Shar-Yin N. Renaud, Amelie Zhang, Yiping Ji, Jiuping Takeda, Shunichi Morris, Joel Teicher, Beverly Doroshow, James H. Pommier, Yves TI Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE INHIBITORS; TUMOR-CELL LINES; HOMOLOGOUS RECOMBINATION; DNA-DAMAGE; CANCER-CELLS; REPLICATION FORKS; STRAND BREAKS; MUTANT-CELLS; REPAIR; THERAPY AB Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacologic concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP-DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically modified chicken DT40 and human cancer cell lines. Although BMN 673, olaparib, and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is similar to 100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as single agent than olaparib, whereas olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient. BMN 673 is also approximately 100-fold more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP-DNA complexes. Mol Cancer Ther; 13(2); 433-43. (C) 2013 AACR. C1 [Murai, Junko; Huang, Shar-Yin N.; Renaud, Amelie; Doroshow, James H.; Pommier, Yves] NCI, Dev Therapeut Branch, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Zhang, Yiping; Ji, Jiuping] NCI, Natl Clin Target Validat Lab, NIH, Bethesda, MD 20892 USA. [Morris, Joel; Teicher, Beverly; Doroshow, James H.; Pommier, Yves] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Murai, Junko; Takeda, Shunichi] Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto, Japan. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Mol Pharmacol Lab, Ctr Canc Res,NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU John Mung Program (Kyoto University); Kyoto University Foundation; National Cancer Institute, Center for Cancer Research [Z01 BC 006150]; JSPS Core-to-Core Program; JSPS KAKENHI [25740016]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX J. Murai was a recipient of fellowships from the John Mung Program (Kyoto University) and the Kyoto University Foundation. Y. Pommier and J. Murai were supported by the Intramural Program of the National Cancer Institute, Center for Cancer Research (Z01 BC 006150). J. Murai and S. Takeda were supported by JSPS Core-to-Core Program. J. Murai was supported by JSPS KAKENHI Grant Number 25740016. J. Ji was supported by the federal fund from the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800001E). NR 50 TC 88 Z9 89 U1 3 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2014 VL 13 IS 2 BP 433 EP 443 DI 10.1158/1535-7163.MCT-13-0803 PG 11 WC Oncology SC Oncology GA AA4LX UT WOS:000331068200015 PM 24356813 ER PT J AU Chatterjee, A Cutler, SJ Khan, IA Williamson, JS AF Chatterjee, Arindam Cutler, Stephen J. Khan, Ikhlas A. Williamson, John S. TI Efficient synthesis of 4-oxo-4,5-dihydrothieno[3,2-]quinoline-2-carboxylic acid derivatives from aniline SO MOLECULAR DIVERSITY LA English DT Article DE Nucleophilic aromatic substitution; Cyclization; Heterocycles; Kinase inhibitors; Convergent analog synthesis ID ANTIPROLIFERATIVE ACTIVITY; ONE-POT; INHIBITORS; QUINOLINE AB The first reported synthesis of potential kinase inhibitors, 4-oxo-4,5-dihydrothieno[3,2-]quinoline-2-carboxylic acid derivatives starting from aniline is described. This efficient high yielding sequence was carried out in six steps without any chromatographic purification. A tandem nucleophilic aromatic substitution/cyclization reaction was used as a key step in the sequence. The versatile intermediate 2-carboxylic acid was used as a suitable precursor to access the functionalization of the C-ring, by convergent analog synthesis of several novel derivatives. C1 [Chatterjee, Arindam; Cutler, Stephen J.; Williamson, John S.] Univ Mississippi, Sch Pharm, Dept Med Chem, University, MS 38677 USA. [Khan, Ikhlas A.] Univ Mississippi, Natl Ctr Nat Product Res, University, MS 38677 USA. [Williamson, John S.] NIH, Div Extramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Cutler, SJ (reprint author), Univ Mississippi, Sch Pharm, Dept Med Chem, University, MS 38677 USA. EM cutler@olemiss.edu; john.williamson@nih.gov FU National Institute of Health National Center for Research Resources [C06RR14503-01] FX This investigation was conducted with support from the Research facilities improvement program C06RR14503-01 obtained from the National Institute of Health National Center for Research Resources. The authors would like to thank Dr. Bharati Avula for the HRMS data. We would also like to thank Dr. Ronald F. Borne for careful review of this manuscript. We would like to acknowledge Dr. Mitchell Avery, Dr. Francisco Leon and Dr. Robert J. Doerksen for their helpful discussions. NR 20 TC 3 Z9 3 U1 2 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1381-1991 EI 1573-501X J9 MOL DIVERS JI Mol. Divers. PD FEB PY 2014 VL 18 IS 1 BP 51 EP 59 DI 10.1007/s11030-013-9476-4 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA AA3FS UT WOS:000330978900005 PM 24026508 ER PT J AU Yang, J Yoshida, Y Cisar, JO AF Yang, J. Yoshida, Y. Cisar, J. O. TI Genetic basis of coaggregation receptor polysaccharide biosynthesis in Streptococcus sanguinis and related species SO MOLECULAR ORAL MICROBIOLOGY LA English DT Article DE biofilm; coaggregation; galactose epimerase; interbacterial adhesion; receptor polysaccharide; rps locus; Streptococcus sanguinis ID UDP-GALACTOSE 4-EPIMERASE; CELL-WALL POLYSACCHARIDES; MOLECULAR CHARACTERIZATION; N-ACETYLGLUCOSAMINE; CRYSTAL-STRUCTURE; DENTAL PLAQUE; ORALIS; ACTINOMYCES; RECOGNITION; SPECIFICITY AB Interbacterial adhesion between streptococci and actinomyces promotes early dental plaque biofilm development. Recognition of coaggregation receptor polysaccharides (RPS) on strains of Streptococcus sanguinis, Streptococcus gordonii and Streptococcus oralis by Actinomyces spp. type 2 fimbriae is the principal mechanism of these interactions. Previous studies of genetic loci for synthesis of RPS (rps) and RPS precursors (rml, galE1 and galE2) in S. gordonii 38 and S. oralis 34 revealed differences between these strains. To determine whether these differences are strain-specific or species-specific, we identified and compared loci for polysaccharide biosynthesis in additional strains of these species and in several strains of the previously unstudied species, S. sanguinis. Genes for synthesis of RPS precursors distinguished the rps loci of different streptococci. Hence, rml genes for synthesis of TDP-L-Rha were in rps loci of S. oralis strains but at other loci in S. gordonii and S. sanguinis. Genes for two distinct galactose epimerases were also distributed differently. Hence, galE1 for epimerization of UDPGlc and UDP-Gal was in galactose operons of S. gordonii and S. sanguinis strains but surprisingly, this gene was not present in S. oralis. Moreover, galE2 for epimerization of both UDP-Glc and UDP-Gal and UDP-GlcNAc and UDP-GalNAc was at a different locus in each species, including rps operons of S. sanguinis. The findings provide insight into cell surface properties that distinguish different RPS-producing streptococci and open an approach for identifying these bacteria based on the arrangement of genes for synthesis of polysaccharide precursors. C1 [Yang, J.; Cisar, J. O.] Natl Inst Dent & Craniofacial Res, Microbial Receptors Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Yoshida, Y.] Aichi Gakuin Univ, Sch Dent, Dept Microbiol, Nagoya, Aichi 464, Japan. RP Cisar, JO (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bldg 30,Room 209,30 Convent Dr, Bethesda, MD 20892 USA. EM john.cisar@nih.gov FU NIDCR FX We thank Medha Bhagwat for phylogenetic analysis of GalE sequences and both Robert Palmer and John Thompson for helpful reviews of the manuscript. Support for this work was received from the Intramural Research Program of NIDCR. NR 27 TC 7 Z9 8 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2041-1006 EI 2041-1014 J9 MOL ORAL MICROBIOL JI Mol. Oral Microbiol. PD FEB PY 2014 VL 29 IS 1 BP 24 EP 31 DI 10.1111/mom.12042 PG 8 WC Dentistry, Oral Surgery & Medicine; Microbiology SC Dentistry, Oral Surgery & Medicine; Microbiology GA AA2VD UT WOS:000330951400003 PM 24397790 ER PT J AU Kennedy, JJ Abbatiello, SE Kim, K Yan, P Whiteaker, JR Lin, CW Kim, JS Zhang, YZ Wang, XL Ivey, RG Zhao, L Min, H Lee, Y Yu, MH Yang, EG Lee, C Wang, P Rodriguez, H Kim, Y Carr, SA Paulovich, AG AF Kennedy, Jacob J. Abbatiello, Susan E. Kim, Kyunggon Yan, Ping Whiteaker, Jeffrey R. Lin, Chenwei Kim, Jun Seok Zhang, Yuzheng Wang, Xianlong Ivey, Richard G. Zhao, Lei Min, Hophil Lee, Youngju Yu, Myeong-Hee Yang, Eun Gyeong Lee, Cheolju Wang, Pei Rodriguez, Henry Kim, Youngsoo Carr, Steven A. Paulovich, Amanda G. TI Demonstrating the feasibility of large-scale development of standardized assays to quantify human proteins SO NATURE METHODS LA English DT Article ID MONITORING MASS-SPECTROMETRY; GENE-EXPRESSION SIGNATURE; CANCER CELL-LINES; BREAST-CANCER; BIOMARKER VERIFICATION; TARGETED PROTEOMICS; YEAST PROTEOME; QUANTITATION; SUBTYPES; DATABASE AB Multiple reaction monitoring (MRM) mass spectrometry has been successfully applied to monitor targeted proteins in biological specimens, raising the possibility that assays could be configured to measure all human proteins. We report the results of a pilot study designed to test the feasibility of a large-scale, international effort for MRM assay generation. We have configured, validated across three laboratories and made publicly available as a resource to the community 645 novel MRM assays representing 319 proteins expressed in human breast cancer. Assays were multiplexed in groups of >150 peptides and deployed to quantify endogenous analytes in a panel of breast cancer-related cell lines. The median assay precision was 5.4%, with high interlaboratory correlation (R-2 > 0.96). Peptide measurements in breast cancer cell lines were able to discriminate among molecular subtypes and identify genome-driven changes in the cancer proteome. These results establish the feasibility of a large-scale effort to develop an MRM assay resource. C1 [Kennedy, Jacob J.; Yan, Ping; Whiteaker, Jeffrey R.; Lin, Chenwei; Zhang, Yuzheng; Wang, Xianlong; Ivey, Richard G.; Zhao, Lei; Wang, Pei; Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Abbatiello, Susan E.; Carr, Steven A.] Broad Inst MIT, Cambridge, MA USA. [Abbatiello, Susan E.; Carr, Steven A.] Harvard Univ, Cambridge, MA 02138 USA. [Kim, Kyunggon; Min, Hophil; Kim, Youngsoo] Seoul Natl Univ, Coll Med, Dept Biomed Engn, Seoul, South Korea. [Kim, Jun Seok; Lee, Youngju; Yu, Myeong-Hee; Yang, Eun Gyeong; Lee, Cheolju] Korea Inst Sci & Technol, Ctr Theragnosis, Seoul, South Korea. [Rodriguez, Henry] NCI, Off Canc Clin Prote, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Paulovich, AG (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. EM apaulovi@fhcrc.org RI Kim, Youngsoo/D-6046-2012 FU Breast Cancer Relief Foundation; Foster Foundation; Hutchinson Center funds; Office of the Director, US National Institutes of Health (NIH OD); NCI; American Recovery and Reinvestment Act [RC2CA148286]; NIH from the NCI Clinical Proteomics Tumor Analysis Consortium Initiative [U24CA160034]; NIH from the NCI Specialized Programs of Research Excellence (SPORE) [P50CA138293]; Proteogenomic Research Program through the National Research Foundation of Korea; Korea government (MSIP) FX We are grateful to the Fred Hutchinson Cancer Research Center-University of Washington Breast Specimen Repository and Registry (BSRR) for specimens used in this study. The BSRR is generously supported by the Breast Cancer Relief Foundation, The Foster Foundation and Hutchinson Center funds. All BSRR specimens and data have been obtained in accordance with all applicable human subjects laws and regulations, including any requiring informed consent. The authors thank S. Skates, D. Ransohoff and L. Anderson for helpful discussions. Research reported in this publication was supported in part by the Office of the Director, US National Institutes of Health (NIH OD), and the NCI with funds from the American Recovery and Reinvestment Act of 2009 under grant RC2CA148286. The research was also partially supported by NIH grant U24CA160034 from the NCI Clinical Proteomics Tumor Analysis Consortium Initiative and NIH grant P50CA138293 from the NCI Specialized Programs of Research Excellence (SPORE). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This research was also partially supported by the Proteogenomic Research Program through the National Research Foundation of Korea, funded by the Korea government (MSIP), and correspondence to the Seoul site should be addressed to Y.K. (biolab@snu.ac.kr). NR 50 TC 69 Z9 69 U1 4 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD FEB PY 2014 VL 11 IS 2 BP 149 EP + DI 10.1038/NMETH.2763 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AA5LW UT WOS:000331141600015 PM 24317253 ER PT J AU Bautista, DM Wilson, SR Hoon, MA AF Bautista, Diana M. Wilson, Sarah R. Hoon, Mark A. TI Why we scratch an itch: the molecules, cells and circuits of itch SO NATURE NEUROSCIENCE LA English DT Review ID PROTEINASE-ACTIVATED RECEPTOR-2; SPINOTHALAMIC TRACT NEURONS; GASTRIN-RELEASING-PEPTIDE; CHRONIC ATOPIC-DERMATITIS; TOLL-LIKE RECEPTORS; SENSORY NEURONS; SPINAL-CORD; BEHAVIORAL-RESPONSES; MOUSE MODEL; DRY SKIN AB Itch is described as an irritating sensation that triggers a desire to scratch. However, this definition hardly seems fitting for the millions of people who suffer from intractable itch. Indeed, the Buddhist philosopher Nagarjuna more aptly stated, "There is pleasure when an itch is scratched. But to be without an itch is more pleasurable still." Chronic itch is widespread and very difficult to treat. In this review we focus on the molecules, cells and circuits in the peripheral and central nervous systems that drive acute and chronic itch transmission. Understanding the itch circuitry is critical to developing new therapies for this intractable disease. C1 [Bautista, Diana M.; Wilson, Sarah R.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Bautista, Diana M.; Wilson, Sarah R.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Hoon, Mark A.] Natl Inst Dent & Craniofacial Res, Mol Genet Unit, Lab Sensory Biol, NIH, Bethesda, MD USA. RP Bautista, DM (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM dbautista@berkeley.edu FU US National Institutes of Health (NIH) [AR059385, DOD007123A]; NIH NIDCR; US National Science Foundation Fellowship FX We are grateful to M. Pellegrino for critical comments on the manuscript. This work was supported by US National Institutes of Health (NIH) grants AR059385 and DOD007123A (D.M.B.), the intramural research program of the NIH NIDCR (M.A.H.) and a US National Science Foundation Fellowship (S.R.W.). NR 98 TC 65 Z9 69 U1 6 U2 56 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2014 VL 17 IS 2 BP 175 EP 182 DI 10.1038/nn.3619 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AA2FH UT WOS:000330910000009 PM 24473265 ER PT J AU Xiong, W Chen, SR He, LM Cheng, KJ Zhao, YL Chen, H Li, DP Homanics, GE Peever, J Rice, KC Wu, LG Pan, HL Zhang, L AF Xiong, Wei Chen, Shao-Rui He, Liming Cheng, Kejun Zhao, Yi-Lin Chen, Hong Li, De-Pei Homanics, Gregg E. Peever, John Rice, Kenner C. Wu, Ling-gang Pan, Hui-Lin Zhang, Li TI Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease SO NATURE NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; BETA-SUBUNIT; STARTLE DISEASE; NEUROPATHIC PAIN; ALPHA-1 SUBUNIT; BRAIN-STEM; MUTATIONS; MICE; NEURONS; ETHANOL AB Although postsynaptic glycine receptors (GlyRs) as alpha beta heteromers attract considerable research attention, little is known about the role of presynaptic GlyRs, likely alpha homomers, in diseases. Here, we demonstrate that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing point mutations in alpha 1 GlyRs that are responsible for a hereditary startle-hyperekplexia disease. The GlyRs expressed as alpha 1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in the auditory brainstem are more vulnerable than heteromers to hyperekplexia mutation-induced impairment. Homomeric mutants are more sensitive to DH-CBD than are heteromers, suggesting presynaptic GlyRs as a primary target. Consistent with this idea, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic alpha 1 GlyRs emerge as a potential therapeutic target for dominant hyperekplexia disease and other diseases with GlyR deficiency. C1 [Xiong, Wei; Zhang, Li] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Xiong, Wei] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China. [Chen, Shao-Rui; Zhao, Yi-Lin; Chen, Hong; Li, De-Pei; Rice, Kenner C.; Pan, Hui-Lin] Univ Texas MD Anderson Canc Ctr, Ctr Neurosci & Pain Res, Houston, TX 77030 USA. [He, Liming; Wu, Ling-gang] Natl Inst Neurol & Stroke Disorders, Synapt Transmiss Sect, NIH, Bethesda, MD USA. [Cheng, Kejun] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD USA. [Cheng, Kejun] NIAAA, NIH, Bethesda, MD USA. [Homanics, Gregg E.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Homanics, Gregg E.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA. [Peever, John] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON, Canada. RP Zhang, L (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. EM lzhang@mail.nih.gov OI Homanics, Gregg/0000-0003-3641-8153 FU National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse and US National Institutes of Health [AA10422]; National Institute of Neurological Disorders and Stroke [NS045602, NS073935] FX We thank A. Harris and Y. Blednov (University of Texas at Austin) for providing the alpha 1 Q266I, alpha 1 S267Q and alpha 1 M287L, mutant mice. We thank D.M. Lovinger for instrumental support and comments on the manuscript. This work was supported by funds from the intramural programs of the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse and US National Institutes of Health grants to G.E.H. (AA10422) and from the National Institute of Neurological Disorders and Stroke to H.-L.P. (NS045602 and NS073935). NR 44 TC 18 Z9 19 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2014 VL 17 IS 2 BP 232 EP 239 DI 10.1038/nn.3615 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AA2FH UT WOS:000330910000017 PM 24390226 ER PT J AU Freidlin, B Korn, EL AF Freidlin, Boris Korn, Edward L. TI Biomarker enrichment strategies: matching trial design to biomarker credentials SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; RANDOMIZED PHASE-II; CLINICAL-TRIAL; BREAST-CANCER; 1ST-LINE TREATMENT; DOUBLE-BLIND; STANDARD CHEMOTHERAPY; ADJUVANT CHEMOTHERAPY; 2ND-LINE TREATMENT AB The use of biomarkers to identify patients who can benefit from treatment with a specific anticancer agent has the potential to both improve patient care and accelerate drug development. The development of targeted agents and their accompanying biomarkers frequently occurs contemporaneously, and confidence in a putative biomarker's performance might, therefore, be insufficient to restrict the definitive testing of a new agent to the subgroup of biomarker-positive patients. This Review considers which clinical trial designs and analysis strategies are appropriate for use in phase III, biomarker-driven, randomized clinical trials, on the basis of pre-existing evidence that the biomarker can successfully identify patients who will respond to the treatment in question. The types of interim monitoring that are appropriate for these trials are also discussed. In addition, enrichment strategies based on the use of prognostic biomarkers to separate a population into subgroups with better and worse outcomes, regardless of treatment, are described. Finally, the possibility of formally using a biomarker during phase II drug development, to select what type of biomarker-driven strategy should be used in the phase III trial, is discussed. C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 53 TC 28 Z9 30 U1 4 U2 23 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 FEB PY 2014 VL 11 IS 2 BP 81 EP 90 DI 10.1038/nrclinonc.2013.218 PG 10 WC Oncology SC Oncology GA AA5MV UT WOS:000331144600008 PM 24281059 ER PT J AU Becker, RE Greig, NH Giacobini, E Schneider, LS Ferrucci, L AF Becker, Robert E. Greig, Nigel H. Giacobini, Ezio Schneider, Lon S. Ferrucci, Luigi TI A new roadmap for drug development for Alzheimer's disease SO NATURE REVIEWS DRUG DISCOVERY LA English DT Letter ID PRESYMPTOMATIC TREATMENTS; PREVENTION; TRIALS C1 [Becker, Robert E.] Aristea Translat Med, Carrabassett Valley, ME USA. [Becker, Robert E.; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Giacobini, Ezio] Univ Geneva, Univ Hosp Geneva, Sch Med, Dept Internal Med Rehabil & Geriatr, Thonex Geneva, Switzerland. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Gerontol, Los Angeles, CA 90033 USA. [Ferrucci, Luigi] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Becker, RE (reprint author), Aristea Translat Med, 5011 Mt View Rd 63,O4947, Carrabassett Valley, ME USA. EM rebecker@AristeaTM.com NR 14 TC 6 Z9 6 U1 12 U2 27 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 FEB PY 2014 VL 13 IS 2 BP 157 EP 159 DI 10.1038/nrd3842-c2 PG 3 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AA5NG UT WOS:000331145900019 ER PT J AU Chang, HW Kulaeva, OI Shaytan, AK Kibanov, M Kuznedelov, K Severinov, KV Kirpichnikov, MP Clark, DJ Studitsky, VM AF Chang, Han-Wen Kulaeva, Olga I. Shaytan, Alexey K. Kibanov, Mikhail Kuznedelov, Konstantin Severinov, Konstantin V. Kirpichnikov, Mikhail P. Clark, David J. Studitsky, Vasily M. TI Analysis of the mechanism of nucleosome survival during transcription SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; HISTONE H3 EXCHANGE; ANGSTROM RESOLUTION; ELONGATION COMPLEX; GENOME-WIDE; IN-VIVO; REPLICATION; DISPLACEMENT; DYNAMICS; BARRIER AB Maintenance of nucleosomal structure in the cell nuclei is essential for cell viability, regulation of gene expression and normal aging. Our previous data identified a key intermediate (a small intranucleosomal DNA loop, circle divide-loop) that is likely required for nucleosome survival during transcription by RNA polymerase II (Pol II) through chromatin, and suggested that strong nucleosomal pausing guarantees efficient nucleosome survival. To evaluate these predictions, we analysed transcription through a nucleosome by different, structurally related RNA polymerases and mutant yeast Pol II having different histone-interacting surfaces that presumably stabilize the circle divide-loop. The height of the nucleosomal barrier to transcription and efficiency of nucleosome survival correlate with the net negative charges of the histone-interacting surfaces. Molecular modeling and analysis of Pol II-nucleosome intermediates by DNase I footprinting suggest that efficient circle divide-loop formation and nucleosome survival are mediated by electrostatic interactions between the largest subunit of Pol II and core histones. C1 [Chang, Han-Wen; Kulaeva, Olga I.; Kibanov, Mikhail; Studitsky, Vasily M.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Biochem & Mol Biol, Piscataway, NJ 08854 USA. [Shaytan, Alexey K.; Kirpichnikov, Mikhail P.; Studitsky, Vasily M.] Moscow MV Lomonosov State Univ, Sch Biol, MSU, Moscow 119991, Russia. [Kuznedelov, Konstantin; Severinov, Konstantin V.] Rutgers State Univ, Waksman Inst Microbiol, Piscataway, NJ 08854 USA. [Severinov, Konstantin V.] Russian Acad Sci, Inst Gene Biol, Moscow 1190334, Russia. [Clark, David J.] NICHHD, Program Genom Differentiat, NIH, Rockville, MD 20847 USA. RP Studitsky, VM (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Biochem & Mol Biol, 675 Hoes Lane, Piscataway, NJ 08854 USA. EM vasily.studitsky@fccc.edu RI Studitskaia, Olga/D-8551-2014; Severinov, Konstantin/C-8545-2016; Shaytan, Alexey/D-7306-2012 OI Studitskaia, Olga/0000-0001-5417-9964; Shaytan, Alexey/0000-0003-0312-938X FU National Institute of Allergy and Infectious Diseases (NIAID) [R21-AI090558]; National Institutes of Health (NIH) [GM58650]; Russian Foundation for Basic Research (RFBR) [12-04-31942]; Intramural Research Program of the National Institutes of Health (NICHD); NIH [GM58650] FX National Institute of Allergy and Infectious Diseases (NIAID) [R21-AI090558 to K.K.]; National Institutes of Health (NIH) [GM58650 to V.M.S.]; Russian Foundation for Basic Research (RFBR) [12-04-31942 to A.K.S.]; Intramural Research Program of the National Institutes of Health (NICHD) (to D.J.C.). Funding for open access charge: Grant of NIH [GM58650 to V.M.S.]. NR 40 TC 7 Z9 8 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2014 VL 42 IS 3 BP 1619 EP 1627 DI 10.1093/nar/gkt1120 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5KX UT WOS:000331138800023 PM 24234452 ER PT J AU Afonin, KA Desai, R Viard, M Kireeva, ML Bindewald, E Case, CL Maciag, AE Kasprzak, WK Kim, T Sappe, A Stepler, M KewalRamani, VN Kashlev, M Blumenthal, R Shapiro, BA AF Afonin, Kirill A. Desai, Ravi Viard, Mathias Kireeva, Maria L. Bindewald, Eckart Case, Christopher L. Maciag, Anna E. Kasprzak, Wojciech K. Kim, Taejin Sappe, Alison Stepler, Marissa KewalRamani, Vineet N. Kashlev, Mikhail Blumenthal, Robert Shapiro, Bruce A. TI Co-transcriptional production of RNA-DNA hybrids for simultaneous release of multiple split functionalities SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MALACHITE GREEN APTAMER; DOUBLE-STRANDED-RNA; R-LOOP FORMATION; SACCHAROMYCES-CEREVISIAE; PROTEIN INTERACTIONS; SECONDARY STRUCTURE; POLYMERASE-II; IN-VIVO; INTERFERENCE; GENOME AB Control over the simultaneous delivery of different functionalities and their synchronized intracellular activation can greatly benefit the fields of RNA and DNA biomedical nanotechnologies and allow for the production of nanoparticles and various switching devices with controllable functions. We present a system of multiple split functionalities embedded in the cognate pairs of RNA-DNA hybrids which are programmed to recognize each other, re-associate and form a DNA duplex while also releasing the split RNA fragments which upon association regain their original functions. Simultaneous activation of three different functionalities (RNAi, Forster resonance energy transfer and RNA aptamer) confirmed by multiple in vitro and cell culture experiments prove the concept. To automate the design process, a novel computational tool that differentiates between the thermodynamic stabilities of RNA-RNA, RNA-DNA and DNA-DNA duplexes was developed. Moreover, here we demonstrate that besides being easily produced by annealing synthetic RNAs and DNAs, the individual hybrids carrying longer RNAs can be produced by RNA polymerase II-dependent transcription of single-stranded DNA templates. C1 [Afonin, Kirill A.; Desai, Ravi; Viard, Mathias; Kasprzak, Wojciech K.; Kim, Taejin; Sappe, Alison; Stepler, Marissa; Blumenthal, Robert; Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. [Viard, Mathias; Bindewald, Eckart; Maciag, Anna E.; Kasprzak, Wojciech K.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Kireeva, Maria L.; Kashlev, Mikhail] NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Case, Christopher L.; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Maciag, Anna E.] NCI, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov FU intramural research program of the NIH, National Cancer Institute, Center for Cancer Research; NCI/CCR Intramural Program FX This research was supported (in part) by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research. Funding for open access charge: NCI/CCR Intramural Program. NR 58 TC 16 Z9 16 U1 4 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2014 VL 42 IS 3 BP 2085 EP 2097 DI 10.1093/nar/gkt1001 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5KX UT WOS:000331138800059 PM 24194608 ER PT J AU Virk-Baker, MK Barnes, S Krontiras, H Nagy, TR AF Virk-Baker, Mandeep K. Barnes, Stephen Krontiras, Helen Nagy, Tim R. TI S-(-)equol producing status not associated with breast cancer risk among low isoflavone-consuming US postmenopausal women undergoing a physician-recommended breast biopsy SO NUTRITION RESEARCH LA English DT Article DE Dietary soy isoflavones; S-(-)equol status; Postmenopausal women; Breast biopsy; Ductal hyperplasia; Breast cancer ID DAIDZEIN-METABOLIZING PHENOTYPES; DIETARY PHYTOESTROGEN INTAKE; ASIAN-AMERICAN WOMEN; EQUOL-PRODUCING BACTERIUM; SOY ISOFLAVONES; S-EQUOL; MAMMOGRAPHIC DENSITY; PREMENOPAUSAL WOMEN; PHYTO-ESTROGENS; SUBSEQUENT RISK AB Soy foods are the richest sources of isoflavones, mainly daidzein and genistein. Soy isoflavones are structurally similar to the steroid hormone 17 beta-estradiol and may protect against breast cancer. S-(-)equol, a metabolite of the soy isoflavone daidzein, has a higher bioavailability and greater affinity for estrogen receptor beta than daidzein. Approximately one-third of the Western population is able to produce S-(-)equol, and the ability is linked to certain gut microbes. We hypothesized that the prevalence of breast cancer, ductal hyperplasia, and overall breast pathology will be lower among S-(-)equol producing, as compared with nonproducing, postmenopausal women undergoing a breast biopsy. We tested our hypothesis using a cross-sectional study design. Usual diets of the participants were supplemented with 1 soy bar per day for 3 consecutive days. Liquid chromatography-multiple reaction ion monitoring mass spectrometry analysis of urine from 143 subjects revealed 25 (17.5%) as S-(-)equol producers. We found no statistically significant associations between S-(-)equol producing status and overall breast pathology (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.23-1.89), ductal hyperplasia (OR, 0.84; 95% CI, 0.20-3.41), or breast cancer (OR, 0.56; 95% CI, 0.16-1.87). However, the mean dietary isoflavone intake was Much lower (0.3 mg/d) than in previous reports. Given that the amount of S-(-) equol produced in the gut depends on the amount of daidzein exposure, the low soy intake coupled with lower prevalence of S-(-)equol producing status in the study population favors toward null associations. Findings from our study could be used for further investigations on S-(-)equol producing status and disease risk. Published by Elsevier Inc. C1 [Virk-Baker, Mandeep K.; Nagy, Tim R.] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Barnes, Stephen] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL 35294 USA. [Barnes, Stephen; Nagy, Tim R.] UAB Comprehens Canc Ctr, Birmingham, AL USA. [Krontiras, Helen] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. RP Virk-Baker, MK (reprint author), NCI, 3E 632, Rockville, MD 20892 USA. EM mandeep.virk-baker@nih.gov; sbames@uab.edu; helen.krontiras@ccc.uab.edu; tnagy@uab.edu FU SDE/GWIS Nell Mondy Award; UAB Health Services Foundation General Endowment Fund; [R25 CA047888]; [U54 CA100949]; [P50 AT00477]; [P30 DK079337]; [P30 AR50948] FX The authors would like to thank the radiologists and technologists of the Mammography Department at the Kirklin Clinic of UAB, Birmingham, for their cooperation with subject recruitment. The authors would also like to thank James Shikany and Maria Johnson for proof reading this manuscript and Edmond Kabagambe for statistical overview of our data analyses. Ali Arabshahi performed the LC-UV diode array analyses and D. Ray Moore the LC-MRM-MS analyses of the soy bar isoflavones. This work is supported by R25 CA047888; SDE/GWIS Nell Mondy Award 2009-2010; U54 CA100949; P50 AT00477; P30 DK079337; P30 AR50948; UAB Health Services Foundation General Endowment Fund. The content of this work is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or any other institution with which the authors may be affiliated. NR 68 TC 6 Z9 7 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0271-5317 J9 NUTR RES JI Nutr. Res. PD FEB PY 2014 VL 34 IS 2 BP 116 EP 125 DI 10.1016/j.nutres.2013.12.002 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AA2KV UT WOS:000330924400003 PM 24461312 ER PT J AU Eysteinsdottir, T Halldorsson, TI Thorsdottir, I Sigurdsson, G Sigurosson, S Harris, T Launer, LJ Gudnason, V Gunnarsdottir, I Steingrimsdottir, L AF Eysteinsdottir, T. Halldorsson, T. I. Thorsdottir, I. Sigurdsson, G. Sigurosson, S. Harris, T. Launer, L. J. Gudnason, V. Gunnarsdottir, I. Steingrimsdottir, L. TI Milk consumption throughout life and bone mineral content and density in elderly men and women SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE AGES-Reykjavik Study; Bone mineral content; Bone mineral density; Elderly; Milk intake ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; FOOD FREQUENCY QUESTIONNAIRE; CALCIUM INTAKE; OSTEOPOROTIC FRACTURES; POSTMENOPAUSAL WOMEN; HIP FRACTURE; AGE; ADOLESCENCE; CHILDHOOD; MASS AB Association between bone mineral density and bone mineral content in old age and milk consumption in adolescence, midlife, and old age was assessed. The association was strongest for milk consumption in midlife: those drinking milk daily or more often had higher bone mineral density and content in old age than those drinking milk seldom or never. The role of lifelong milk consumption for bone mineral density (BMD) and bone mineral content (BMC) in old age is not clear. Here we assess the association between hip BMD and BMC in old age and milk consumption in adolescence, midlife, and current old age. Participants of the Age, Gene/Environment Susceptibility-Reykjavik Study, aged 66-96 years (N = 4,797), reported retrospective milk intake during adolescence and midlife as well as in current old age, using a validated food frequency questionnaire. BMC of femoral neck and trochanteric area was measured by volumetric quantitative computed tomography and BMD obtained. Association was assessed using linear regression models. Differences in BMC, bone volume, and BMD in relation to milk intake were portrayed as gender-specific Z-scores. Men consuming milk a parts per thousand yenaEuro parts per thousand once/day during midlife had 0.21 higher Z-scores for BMD and 0.18 for BMC in femoral neck (95 % confidence interval 0.05-0.39 and 0.01-0.35, respectively) compared with < once/week. Results were comparable for trochanter. For women the results were similar, with slightly lower differences according to midlife milk consumption. For current and adolescent milk consumption, differences in Z-scores were smaller and only reached statistical significance in the case of BMD for current consumption in men, while this association was less pronounced for BMC. Our data suggest that regular milk consumption throughout life, from adolescence to old age, is associated with higher BMC and BMD in old age, with no differences seen in bone volume. The strongest associations are seen for midlife milk consumption in both genders. C1 [Eysteinsdottir, T.; Halldorsson, T. I.; Thorsdottir, I.; Gunnarsdottir, I.; Steingrimsdottir, L.] Univ Iceland, Unit Nutr Res, Reykjavik, Iceland. [Eysteinsdottir, T.; Halldorsson, T. I.; Thorsdottir, I.; Sigurdsson, G.; Gunnarsdottir, I.; Steingrimsdottir, L.] Natl Univ Hosp Reykjavik, Landspitali, Reykjavik, Iceland. [Halldorsson, T. I.; Thorsdottir, I.; Gudnason, V.; Gunnarsdottir, I.; Steingrimsdottir, L.] Univ Iceland, Sch Hlth Sci, Fac Food Sci & Human Nutr, Reykjavik, Iceland. [Sigurdsson, G.; Sigurosson, S.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Sigurdsson, G.] Univ Iceland, Sch Hlth Sci, Fac Med, Reykjavik, Iceland. [Harris, T.; Launer, L. J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Steingrimsdottir, L (reprint author), Univ Iceland, Sch Hlth Sci, Fac Food Sci & Human Nutr, Reykjavik, Iceland. EM tinnaey@landspitali.is; tih@hi.is; ingathor@landspitali.is; gunnars@landspitali.is; sigurdur@hjarta.is; harris99@nia.nih.gov; launerl@nia.nih.gov; v.gudnason@hjarta.is; ingigun@landspitali.is; laufey@hi.is RI Gudnason, Vilmundur/K-6885-2015; Gunnarsdottir, Ingibjorg/L-9371-2015; Halldorsson, Tohrhallur/M-1823-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Halldorsson, Tohrhallur/0000-0001-5115-0162; Gunnarsdottir, Ingibjorg/0000-0001-9447-8627 FU Icelandic Research Fund for Graduate Students; Nordforsk NCoE Program HELGA; National Institutes of Health (NIH) [N01-AG-12100]; Intramural Research Program of the National Institute on Aging; Icelandic Heart Association; Icelandic Parliament, Iceland FX Funding for the present work was provided by the Icelandic Research Fund for Graduate Students and the Nordforsk NCoE Program HELGA. The AGES-Reykjavik Study was funded by the National Institutes of Health (NIH) contract N01-AG-12100, the Intramural Research Program of the National Institute on Aging, and by the Icelandic Heart Association and the Icelandic Parliament, Iceland. We thank all the participants of the AGES-Reykjavik Study and the clinic staff at the Icelandic Heart Association for their invaluable contribution. NR 47 TC 1 Z9 1 U1 1 U2 13 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD FEB PY 2014 VL 25 IS 2 BP 663 EP 672 DI 10.1007/s00198-013-2476-5 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA3GO UT WOS:000330981100030 PM 23948877 ER PT J AU Taylor, TJ Tai, CH Huang, YJP Block, J Bai, HJ Kryshtafovych, A Montelione, GT Lee, B AF Taylor, Todd J. Tai, Chin-Hsien Huang, Yuanpeng J. Block, Jeremy Bai, Hongjun Kryshtafovych, Andriy Montelione, Gaetano T. Lee, Byungkook TI Definition and classification of evaluation units for CASP10 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article ID PROTEIN STRUCTURES; TARGET CLASSIFICATION; STRUCTURE ALIGNMENT; DOMAIN DEFINITION; GENERATION; PRECISION; ALGORITHM; ACCURACY; PROGRAM; SERVER C1 [Taylor, Todd J.; Tai, Chin-Hsien; Bai, Hongjun; Lee, Byungkook] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Huang, Yuanpeng J.; Block, Jeremy; Montelione, Gaetano T.] Rutgers State Univ, Robert Wood Johnson Med Sch, Northeast Struct Genom Consortium, Ctr Adv Biotechnol & Med,Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Kryshtafovych, Andriy] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. RP Montelione, GT (reprint author), Rutgers State Univ, Robert Wood Johnson Med Sch, Northeast Struct Genom Consortium, Ctr Adv Biotechnol & Med,Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. EM guy@cabm.rutgers.edu; bk@nih.gov FU Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco [NIGMS P41-GM103311]; Intramural Research Program of the NIH, National Cancer Institute; US National Institute of General Medical Sciences [U54-GM094597, RO1-GM100482] FX Grant sponsor: Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco; Grant number: NIGMS P41-GM103311 (for Chimera); Grant sponsor: Intramural Research Program of the NIH, National Cancer Institute, and US National Institute of General Medical Sciences; Grant numbers: U54-GM094597 (to GTM) and RO1-GM100482 (to AK). NR 33 TC 10 Z9 10 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD FEB PY 2014 VL 82 SU 2 SI SI BP 14 EP 25 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AA5NY UT WOS:000331147900003 PM 24123179 ER PT J AU Tai, CH Bai, HJ Taylor, TJ Lee, B AF Tai, Chin-Hsien Bai, Hongjun Taylor, Todd J. Lee, Byungkook TI Assessment of template-free modeling in CASP10 and ROLL SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article ID STRUCTURE PREDICTIONS; TARGET PREDICTIONS; PROTEIN STRUCTURES; CLASSIFICATION; ALGORITHM C1 [Tai, Chin-Hsien; Bai, Hongjun; Taylor, Todd J.; Lee, Byungkook] NCI, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Lee, B (reprint author), NCI, NIH, Mol Biol Lab, Bldg 37,Room 5120,37 Convent Dr MSC 4264, Bethesda, MD 20892 USA. EM BKLee@mail.nih.gov FU National Institutes of Health [NCRR 2P41RR001081, NIGMS 9P41GM103311]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsor: National Institutes of Health; Grant numbers: NCRR 2P41RR001081 and NIGMS; 9P41GM103311 for Resource for Biocomputing, Visualization, and Inofrmatics at the University of Caifornia, San Francisco; Grant sponsor: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 28 Z9 28 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD FEB PY 2014 VL 82 SU 2 SI SI BP 57 EP 83 PG 27 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AA5NY UT WOS:000331147900006 PM 24343678 ER PT J AU Taylor, TJ Bai, HJ Tai, CH Lee, B AF Taylor, Todd J. Bai, Hongjun Tai, Chin-Hsien Lee, Byungkook TI Assessment of CASP10 contact-assisted predictions SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article ID PROTEIN-STRUCTURE DETERMINATION; TEMPLATE FREE TARGETS; SPARSE NMR DATA; SIMILARITIES; ROSETTA; MODELS C1 [Taylor, Todd J.; Bai, Hongjun; Tai, Chin-Hsien; Lee, Byungkook] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD USA. RP Lee, B (reprint author), Bldg 37,Room 5120,37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. EM bk@nih.gov FU NIGMS [P41-GM103311]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors thank the experimental groups who provided the target structures and the prediction groups who provided the predictions. They also thank Dr. Andriy Kryshtafovych and the staff of the Prediction Center for the extensive support provided for this work. Molecule pictures were generated by the UCSF Chimera package33 and PyMOL (the PyMOL Molecular Graphics System, Version 1.4, Schroedinger, LLC). Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311). This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 6 Z9 6 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD FEB PY 2014 VL 82 SU 2 SI SI BP 84 EP 97 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AA5NY UT WOS:000331147900007 PM 23873510 ER PT J AU Salsman, JM Lai, JS Hendrie, HC Butt, Z Zill, N Pilkonis, PA Peterson, C Stoney, CM Brouwers, P Cella, D AF Salsman, John M. Lai, Jin-Shei Hendrie, Hugh C. Butt, Zeeshan Zill, Nicholas Pilkonis, Paul A. Peterson, Christopher Stoney, Catherine M. Brouwers, Pim Cella, David TI Assessing psychological well-being: self-report instruments for the NIH Toolbox SO QUALITY OF LIFE RESEARCH LA English DT Article DE Psychological assessment; Well-being; Positive affect; Life satisfaction; Meaning ID ITEM BANKS; POSITIVE PSYCHOLOGY; RESPONSE THEORY; LIFE; HEALTH; SCALES; UNIDIMENSIONALITY; INDEPENDENCE; SATISFACTION; EMOTIONS AB Psychological well-being (PWB) has a significant relationship with physical and mental health. As a part of the NIH Toolbox for the Assessment of Neurological and Behavioral Function, we developed self-report item banks and short forms to assess PWB. Expert feedback and literature review informed the selection of PWB concepts and the development of item pools for positive affect, life satisfaction, and meaning and purpose. Items were tested with a community-dwelling US Internet panel sample of adults aged 18 and above (N = 552). Classical and item response theory (IRT) approaches were used to evaluate unidimensionality, fit of items to the overall measure, and calibrations of those items, including differential item function (DIF). IRT-calibrated item banks were produced for positive affect (34 items), life satisfaction (16 items), and meaning and purpose (18 items). Their psychometric properties were supported based on the results of factor analysis, fit statistics, and DIF evaluation. All banks measured the concepts precisely (reliability a parts per thousand yen0.90) for more than 98 % of participants. These adult scales and item banks for PWB provide the flexibility, efficiency, and precision necessary to promote future epidemiological, observational, and intervention research on the relationship of PWB with physical and mental health. C1 [Salsman, John M.; Lai, Jin-Shei; Butt, Zeeshan; Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Salsman, John M.; Lai, Jin-Shei; Cella, David] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Salsman, John M.; Lai, Jin-Shei; Butt, Zeeshan; Cella, David] Northwestern Univ, Feinberg Sch Med, Ctr Patient Ctr Outcomes, Chicago, IL 60611 USA. [Hendrie, Hugh C.] Indiana Univ Sch Med, Ctr Aging Res, Indianapolis, IN 46202 USA. [Butt, Zeeshan] Northwestern Univ, Comprehens Transplant Ctr, Chicago, IL 60611 USA. [Zill, Nicholas] Westat Corp, Rockville, MD USA. [Pilkonis, Paul A.] Univ Pittsburgh, Dept Psychiat, Med Ctr, Pittsburgh, PA USA. [Peterson, Christopher] Univ Michigan, Dept Psychol, Ann Arbor, MI USA. [Stoney, Catherine M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Brouwers, Pim] NIMH, Div AIDS Res, Bethesda, MD 20892 USA. RP Salsman, JM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, 625 North Michigan Ave,Suite 2700, Chicago, IL 60611 USA. EM j-salsman@northwestern.edu FU Blueprint for Neuroscience Research; Office of Behavioral and Social Sciences Research; National Institutes of Health [HHS-N-260-2006-00007-C]; NIH from the National Center for Research Resources [KL2RR025740]; National Cancer Institute [5K07CA158008-01A1] FX This project was funded in whole or in part with federal funds from the Blueprint for Neuroscience Research and the Office of Behavioral and Social Sciences Research, National Institutes of Health, under Contract No. HHS-N-260-2006-00007-C. Preparation of this manuscript was supported in part by NIH grants KL2RR025740 from the National Center for Research Resources and 5K07CA158008-01A1 from the National Cancer Institute. The authors would like to thank the subdomain consultants, Felicia Huppert, Ph.D., Alice Carter, Ph.D., Marianne Brady, Ph.D., Dilip Jeste, MD, Colin Depp, Ph.D., and Bruce Cuthbert, Ph.D., and members of the NIH project team, Gitanjali Taneja, Ph.D., and Sarah Knox, Ph.D., who provided critical and constructive expertise during the development of the NIH Toolbox Emotion measurement battery. NR 52 TC 9 Z9 9 U1 3 U2 21 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD FEB PY 2014 VL 23 IS 1 BP 205 EP 215 DI 10.1007/s11136-013-0452-3 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AA1BL UT WOS:000330831100022 PM 23771709 ER PT J AU Hay, JL Atkinson, TM Reeve, BB Mitchell, SA Mendoza, TR Willis, G Minasian, LM Clauser, SB Denicoff, A O'Mara, A Chen, A Bennett, AV Paul, DB Gagne, J Rogak, L Sit, L Viswanath, V Schrag, D Basch, E AF Hay, Jennifer L. Atkinson, Thomas M. Reeve, Bryce B. Mitchell, Sandra A. Mendoza, Tito R. Willis, Gordon Minasian, Lori M. Clauser, Steven B. Denicoff, Andrea O'Mara, Ann Chen, Alice Bennett, Antonia V. Paul, Diane B. Gagne, Joshua Rogak, Lauren Sit, Laura Viswanath, Vish Schrag, Deborah Basch, Ethan CA NCI PRO-CTCAE Study Grp TI Cognitive interviewing of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO QUALITY OF LIFE RESEARCH LA English DT Article DE Drug toxicity; Neoplasms; Psychometrics; Reproducibility of results; Qualitative research ID TASK-FORCE REPORT; TOXICITY DATA; SELF-REPORTS; DRUG-SAFETY; CLINICIAN; TRIALS; RECOMMENDATIONS; QUESTIONNAIRE; INSTRUMENTS; EXPERIENCES AB The National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a library of question items that enables patient reporting of adverse events (AEs) in clinical trials. This study contributes content validity evidence of the PRO-CTCAE by incorporating cancer patient input of the relevance and comprehensiveness of the item library. Cognitive interviews were conducted among patients undergoing chemotherapy or radiation therapy at multiple sites to evaluate comprehension, memory retrieval, judgment, and response mapping related to AE terms (e.g., nausea), attribute terms (regarding frequency, severity, or interference), response options, and recall period. Three interview rounds were conducted with a parts per thousand yen20 patients completing each item per round. Items were modified and retested if a parts per thousand yen3 patients exhibited cognitive difficulties or if experienced by a parts per thousand currency sign25 % patients. One hundred and twenty-seven patients participated (35 % a parts per thousand currency signhigh school, 28 % non-white, and 59 % female). Most AE terms (63/80) generated no cognitive difficulties. The remaining 17 were modified without further difficulties by Round 3. Terms were comprehended regardless of education level. Attribute terms and response options required no modifications. Patient adherence to recall period (7 days) was improved when the reference period was incorporated. This study provides evidence confirming comprehension of the US English language versions of items in the PRO-CTCAE library for measuring symptomatic AEs from the patient perspective within the context of cancer treatment. Several minor changes were made to the items to improve item clarity, comprehension, and ease of response judgment. This study helps to establish the content validity of PRO-CTCAE items for patient reporting of AEs during cancer treatment. C1 [Hay, Jennifer L.; Atkinson, Thomas M.; Rogak, Lauren; Sit, Laura; Basch, Ethan] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10022 USA. [Reeve, Bryce B.; Bennett, Antonia V.; Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. [Mitchell, Sandra A.; Willis, Gordon; Minasian, Lori M.; Clauser, Steven B.; Denicoff, Andrea; O'Mara, Ann; Chen, Alice] United States Natl Canc Inst, Rockville, MD USA. [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gagne, Joshua; Viswanath, Vish; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hay, JL (reprint author), Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 641 Lexington Ave,7th Floor, New York, NY 10022 USA. EM hayj@mskcc.org FU United States National Cancer Institute [HHSN261201000043C, HHSN261201000063C] FX Work described in this report was supported by contracts from the United States National Cancer Institute, HHSN261201000043C and HHSN261201000063C. Each author met all International Committee of Medical Journal Editors (ICMJE) requirements (i.e., conception/design/acquisition/analysis, drafting/revising article, and final approval) for authorship. NR 48 TC 22 Z9 22 U1 2 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD FEB PY 2014 VL 23 IS 1 BP 257 EP 269 DI 10.1007/s11136-013-0470-1 PG 13 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AA1BL UT WOS:000330831100027 PM 23868457 ER PT J AU Sueyoshi, T Li, LH Wang, HB Moore, R Kodavanti, PRS Lehmler, HJ Negishi, M Birnbaum, LS AF Sueyoshi, Tatsuya Li, Linhao Wang, Hongbing Moore, Rick Kodavanti, Prasada Rao S. Lehmler, Hans-Joachim Negishi, Masahiko Birnbaum, Linda S. TI Flame Retardant BDE-47 Effectively Activates Nuclear Receptor CAR in Human Primary Hepatocytes SO TOXICOLOGICAL SCIENCES LA English DT Article DE PBDE; CAR; PXR; xenobiotic receptor ID CONSTITUTIVE ANDROSTANE RECEPTOR; POLYBROMINATED DIPHENYL ETHERS; PREGNANE-X-RECEPTOR; DEVELOPMENTAL EXPOSURE; XENOBIOTIC RECEPTORS; CELL-PROLIFERATION; DRUG-METABOLISM; ENHANCER MODULE; ADIPOSE-TISSUE; LIVER-DISEASE AB Polybrominated diphenyl ether BDE-47 (2,2,4,4-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car(/) and Pxr(/) mice as well as human primary hepatocytes, here we have demonstrated that BDE-47 activated both mouse and human nuclear receptor constitutive activated/androstane receptor (CAR). In mouse livers, CAR, not PXR, was responsible for Cyp2b10 mRNA induction by BDE-47. In human primary hepatocytes, BDE-47 was able to induce translocation of YFP-tagged human CAR from the cytoplasm to the nucleus andCYP2B6 and CYP3A4 mRNAs expressions. BDE-47 activated human CAR in a manner akin to the human CAR ligand CITCO (6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) in luciferase-reporter assays using Huh-7 cells. In contrast, mouse CAR was not potently activated by BDE-47 in the same reporter assays. Furthermore, human pregnane X receptor (PXR) was effectively activated by BDE-47 while mouse PXR was weakly activated in luciferase-reporter assays. Our results indicate that BDE-47 induces CYP genes through activation of human CAR in addition to the previously identified pathway through human PXR. C1 [Sueyoshi, Tatsuya; Moore, Rick; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NCI,NIHES, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, Lab Toxicokinet, NCI, NIHES, Res Triangle Pk, NC 27709 USA. [Li, Linhao; Wang, Hongbing] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Kodavanti, Prasada Rao S.] US EPA, Neurotoxicol Branch, NHEERL ORD, Res Triangle Pk, NC 27711 USA. [Lehmler, Hans-Joachim] Univ Iowa, Coll Publ Hlth, Dept Occupat & Environm Hlth, Iowa City, IA USA. RP Sueyoshi, T (reprint author), NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM sueyoshi@niehs.nih.gov RI Li, Linhao/A-6348-2013; OI Lehmler, Hans-Joachim/0000-0001-9163-927X FU NIH, National Institute of Environmental Health Sciences (NIEHS) [Zo1Es71005-01]; National Cancer Institute (NCI) [ZIA BC 011476]; NIH [DK061652]; NIEHS/NIH [ES013661] FX This study was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIEHS), Zo1Es71005-01, and National Cancer Institute (NCI) ZIA BC 011476. L.L and H.W. were supported by NIH grant DK061652. The BDE-47 was provided by the Synthesis Core of the Iowa Superfund Research program, funded by NIEHS/NIH grant ES013661. BDE-47 purity was analyzed by Izabela Kania-Korwel. Statsitical anlalysis evalulation was done by Grace Kissling at NIEHS. We thank Yin Li, Wendy Jefferson, and Bill Schrader for their critical reading of the manuscript. NR 62 TC 11 Z9 12 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2014 VL 137 IS 2 BP 292 EP 302 DI 10.1093/toxsci/kft243 PG 11 WC Toxicology SC Toxicology GA AA2RU UT WOS:000330942600003 PM 24218150 ER PT J AU Yang, CZ Casey, W Stoner, MA Kollessery, GJ Wong, AW Bittner, GD AF Yang, Chun Z. Casey, Warren Stoner, Matthew A. Kollessery, Gayathri J. Wong, Amy W. Bittner, George D. TI A Robotic MCF-7:WS8 Cell Proliferation Assay to Detect Agonist and Antagonist Estrogenic Activity SO TOXICOLOGICAL SCIENCES LA English DT Article DE estrogen; estrogenic activity; endocrine disruptor ID BISPHENOL-A; RECEPTOR-BETA; HUMAN HEALTH; EXPOSURE; URINARY; RAT AB Endocrine-disrupting chemicals with estrogenic activity (EA) or anti-EA (AEA) have been extensively reported to possibly have many adverse health effects. We have developed robotized assays using MCF-7:WS8 cell proliferation (or suppression) to detect EA (or AEA) of 78 test substances supplied by the Interagency Coordinating Committee on the Validation of Alternative Methods and the National Toxicology Programs Interagency Center for the Evaluation of Alternative Toxicological Methods for validation studies. We also assayed ICI 182,780, a strong estrogen antagonist. Chemicals to be assayed were initially examined for solubility and volatility to determine optimal assay conditions. For both EA and AEA determinations, a Range-Finder assay was conducted to determine the concentration range for testing, followed by a Comprehensive assay. Test substances with potentially positive results from an EA Comprehensive assay were subjected to an EA Confirmation assay that evaluated the ability of ICI 182,780 to reverse chemically induced MCF-7 cell proliferation. The AEA assays examined the ability of chemicals to decrease MCF-7 cell proliferation induced by nonsaturating concentrations of 17-estradiol (E2), relative to ICI or raloxifene, also a strong estrogen antagonist. To be classified as having AEA, a saturating concentration of E2 had to significantly reverse the decrease in cell proliferation produced by the test substance in nonsaturating E2. We conclude that our robotized MCF-7 EA and AEA assays have accuracy, sensitivity, and specificity values at least equivalent to validated test methods accepted by the U.S. Environmental Protection Agency and the Organisation for Economic Co-operation and Development. C1 [Yang, Chun Z.; Stoner, Matthew A.; Kollessery, Gayathri J.; Wong, Amy W.; Bittner, George D.] CertiChem Inc, Austin, TX 78758 USA. [Casey, Warren] NICEATM, Res Triangle Pk, NC 27709 USA. [Bittner, George D.] Univ Texas Austin, Neurobiol Sect, Sch Biol, Austin, TX 78712 USA. RP Casey, W (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM caseywm@nih.gov FU NIH/NIEHS [R43 ES011469, R44 ES011469, R43 ES011806, R4 ES014806]; ICCVAM FX NIH/NIEHS (R43 ES011469, R44 ES011469, R43 ES011806, R4 ES014806 to C.Z.Y.); ICCVAM to CCI. NR 29 TC 3 Z9 3 U1 3 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2014 VL 137 IS 2 BP 335 EP 349 DI 10.1093/toxsci/kft250 PG 15 WC Toxicology SC Toxicology GA AA2RU UT WOS:000330942600007 PM 24213142 ER PT J AU Prikhodko, VG Sandoval-Jaime, C Abente, EJ Bok, K Parra, GI Rogozin, IB Ostlund, EN Green, KY Sosnovtsev, SV AF Prikhodko, Victor G. Sandoval-Jaime, Carlos Abente, Eugenio J. Bok, Karin Parra, Gabriel I. Rogozin, Igor B. Ostlund, Eileen N. Green, Kim Y. Sosnovtsev, Stanislav V. TI Genetic characterization of feline calicivirus strains associated with varying disease manifestations during an outbreak season in Missouri (1995-1996) SO VIRUS GENES LA English DT Article DE Caliciviridae; Feline calicivirus; Novel strains; Complete genome; FCV phylogeny ID CAPSID PROTEIN GENE; NUCLEOTIDE-SEQUENCE; PHYLOGENETIC ANALYSIS; HYPERVARIABLE REGION; STRUCTURAL INSIGHTS; RESPIRATORY-TRACT; CARRIER STATE; IN-VITRO; CATS; VIRUS AB Feline calicivirus (FCV) is a common cause of mild to severe upper respiratory tract disease (URTD) in cats. FCV strain 21223 was isolated from a kitten with severe pneumonia in a disease outbreak with unusually high mortality (35 %) that occurred in a Missouri feline colony in 1995-1996. Phylogenetic analysis of the genome sequence of strain 21223 indicated the emergence of a new FCV strain. Analysis of the full-length genome sequence of a closely related (99.5 % nucleotide identity) strain, 3786, obtained from an asymptomatic animal in the same colony four months later, showed the presence of seven amino acid substitutions, with six of them located in the VP1 capsid sequence encoded by ORF2. Comparative analysis of the E-region sequences (426-521 aa ORF2) presumably involved in virus-host cell receptor interactions did not identify amino acid substitutions unique to the virulent strain. We determined the complete genome sequences of four virus isolates that were collected in regional catteries in the months following the outbreak that were associated with different manifestations of the disease (URTD, chronic stomatitis, and gingivitis). We show that genetically distinct FCV strains were cocirculating in the area, and no apparent correlation could be made between overall sequence and observed disease. C1 [Prikhodko, Victor G.; Sandoval-Jaime, Carlos; Abente, Eugenio J.; Bok, Karin; Parra, Gabriel I.; Green, Kim Y.; Sosnovtsev, Stanislav V.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, NLM, Bethesda, MD 20894 USA. [Ostlund, Eileen N.] Anim & Plant Hlth Inspect Serv, Diagnost Virol Lab, Natl Vet Serv Labs, USDA, Ames, IA 50010 USA. RP Sosnovtsev, SV (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr MSC8007,Bldg 50,Room 6316, Bethesda, MD 20892 USA. EM ssosnovtse@niaid.nih.gov OI Abente, Eugenio/0000-0002-3390-2786; Parra, Gabriel/0000-0002-1102-4740 FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 71 TC 5 Z9 6 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-8569 EI 1572-994X J9 VIRUS GENES JI Virus Genes PD FEB PY 2014 VL 48 IS 1 BP 96 EP 110 DI 10.1007/s11262-013-1005-0 PG 15 WC Genetics & Heredity; Virology SC Genetics & Heredity; Virology GA AA6LZ UT WOS:000331211100012 PM 24217871 ER PT J AU Machado-Vieira, R Soeiro-De-Souza, MG Richards, EM Teixeira, AL Zarate, CA AF Machado-Vieira, Rodrigo Soeiro-De-Souza, Marcio G. Richards, Erica M. Teixeira, Antonio L. Zarate, Carlos A., Jr. TI Multiple levels of impaired neural plasticity and cellular resilience in bipolar disorder: Developing treatments using an integrated translational approach SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Review DE Bipolar disorder; depression; treatment; neurobiology; brain ID PROTEIN-KINASE-C; MAGNETIC-RESONANCE-SPECTROSCOPY; MAJOR DEPRESSIVE DISORDER; SUBGENUAL PREFRONTAL CORTEX; OXIDATIVE STRESS PARAMETERS; GLYCOGEN-SYNTHASE KINASE-3; MEDICATION-FREE PATIENTS; GENOME-WIDE ASSOCIATION; CEREBRAL CORTICAL-CELLS; D-ASPARTATE ANTAGONIST AB Objectives. This paper reviews the neurobiology of bipolar disorder (BD), particularly findings associated with impaired cellular resilience and plasticity. Methods. PubMed/Medline articles and book chapters published over the last 20 years were identified using the following keyword combinations: BD, calcium, cytokines, endoplasmic reticulum (ER), genetics, glucocorticoids, glutamate, imaging, ketamine, lithium, mania, mitochondria, neuroplasticity, neuroprotection, neurotrophic, oxidative stress, plasticity, resilience, and valproate. Results. BD is associated with impaired cellular resilience and synaptic dysfunction at multiple levels, associated with impaired cellular resilience and plasticity. These findings were partially prevented or even reversed with the use of mood stabilizers, but longitudinal studies associated with clinical outcome remain scarce. Conclusions. Evidence consistently suggests that BD involves impaired neural plasticity and cellular resilience at multiple levels. This includes the genetic and intra-and intercellular signalling levels, their impact on brain structure and function, as well as the final translation into behaviour/cognitive changes. Future studies are expected to adopt integrated translational approaches using a variety of methods (e.g., microarray approaches, neuroimaging, genetics, electrophysiology, and the new generation of -omics techniques). These studies will likely focus on more precise diagnoses and a personalized medicine paradigm in order to develop better treatments for those who need them most. C1 [Machado-Vieira, Rodrigo; Richards, Erica M.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Sch Med, Inst & Dept Psychiat, LIM27,Lab Neurosci, Sao Paulo, Brazil. [Soeiro-De-Souza, Marcio G.] Univ Sao Paulo, Sch Med, Inst & Dept Psychiat, Mood Disorders Unit GRUDA, Sao Paulo, Brazil. [Teixeira, Antonio L.] Univ Fed Minas Gerais, Sch Med, Dept Internal Med, Neurol Grp, Belo Horizonte, MG, Brazil. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, Brazil. RP Machado-Vieira, R (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bldg 10,Room 3N210,10 Ctr Dr, Bethesda, MD 20892 USA. EM machadovieirar@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX Funding for this work was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). Dr Machado-Vieira also acknowledges Fapesp (2009/14891-9) and NAPNA-Sao Paulo, Brazil. Ioline Henter (NIMH) provided invaluable editorial assistance. NR 94 TC 20 Z9 20 U1 0 U2 10 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD FEB PY 2014 VL 15 IS 2 BP 84 EP 95 DI 10.3109/15622975.2013.830775 PG 12 WC Psychiatry SC Psychiatry GA AA5JO UT WOS:000331132400002 PM 23998912 ER PT J AU Cohen, BE AF Cohen, B. Eleazar TI Functional Linkage between Genes That Regulate Osmotic Stress Responses and Multidrug Resistance Transporters: Challenges and Opportunities for Antibiotic Discovery SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Review ID CATIONIC ANTIMICROBIAL PEPTIDES; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; STAPHYLOCOCCUS-AUREUS; ENVIRONMENTAL-STRESS; MEMBRANE-PROTEINS; ANTIFUNGAL AGENTS; CANDIDA-ALBICANS; DRUG-RESISTANCE; AMPHOTERICIN-B AB All cells need to protect themselves against the osmotic challenges of their environment by maintaining low permeability to ions across their cell membranes. This is a basic principle of cellular function, which is reflected in the interactions among ion transport and drug efflux genes that have arisen during cellular evolution. Thus, upon exposure to pore-forming antibiotics such as amphotericin B (AmB) or daptomycin (Dap), sensitive cells overexpress common resistance genes to protect themselves from added osmotic challenges. These genes share pathway interactions with the various types of multidrug resistance (MDR) transporter genes, which both preserve the native lipid membrane composition and at the same time eliminate disruptive hydrophobic molecules that partition excessively within the lipid bilayer. An increased understanding of the relationships between the genes (and their products) that regulate osmotic stress responses and MDR transporters will help to identify novel strategies and targets to overcome the current stalemate in drug discovery. C1 NIAID, Div Extramural Act, Bethesda, MD 20892 USA. RP Cohen, BE (reprint author), NIAID, Div Extramural Act, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ECOHEN@niaid.nih.gov NR 64 TC 7 Z9 7 U1 2 U2 23 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2014 VL 58 IS 2 BP 640 EP 646 DI 10.1128/AAC.02095-13 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 302XD UT WOS:000330637500002 PM 24295980 ER PT J AU Hu, ZY Lan, KH He, SS Swaroop, M Hu, X Southall, N Zheng, W Liang, TJ AF Hu, Zongyi Lan, Keng-Hsin He, Shanshan Swaroop, Manju Hu, Xin Southall, Noel Zheng, Wei Liang, T. Jake TI Novel Cell-Based Hepatitis C Virus Infection Assay for Quantitative High-Throughput Screening of Anti-Hepatitis C Virus Compounds SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID 5-HT2C RECEPTOR ANTAGONIST; DNA RECOMBINATION; MAMMALIAN-CELLS; CRE RECOMBINASE; CYCLOSPORINE-A; HOST FACTORS; LIFE-CYCLE; ENTRY; REPLICATION; INHIBITORS AB Therapy for hepatitis C virus (HCV) infection has advanced with the recent approval of direct-acting antivirals in combination with peginterferon and ribavirin. New antivirals with novel targets are still needed to further improve the treatment of hepatitis C. Previously reported screening methods for HCV inhibitors either are limited to a virus-specific function or apply a screening method at a single dose, which usually leads to high false-positive or -negative rates. We developed a quantitative high-throughput screening (qHTS) assay platform with a cell-based HCV infection system. This highly sensitive assay can be miniaturized to a 1,536-well format for screening of large chemical libraries. All candidates are screened over a 7-concentration dose range to give EC(50)s (compound concentrations at 50% efficacy) and dose-response curves. Using this assay format, we screened a library of pharmacologically active compounds (LOPAC). Based on the profile of dose-dependent curves of HCV inhibition and cytotoxicity, 22 compounds with adequate curves and EC(50)s of < 10 mu M were selected for validation. In two additional independent assays, 17 of them demonstrated specific inhibition of HCV infection. Ten potential candidates with efficacies of >70% and CC(50)s (compound concentrations at 50% cytotoxicity) of < 30 mu M from these validated hits were characterized for their target stages in the HCV replication cycle. In this screen, we identified both known and novel hits with diverse structural and functional features targeting various stages of the HCV replication cycle. The pilot screen demonstrates that this assay system is highly robust and effective in identifying novel HCV inhibitors and that it can be readily applied to large-scale screening of small-molecule libraries. C1 [Hu, Zongyi; Lan, Keng-Hsin; He, Shanshan; Liang, T. Jake] Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD USA. [Swaroop, Manju; Hu, Xin; Southall, Noel; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD USA. EM jliang@nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health. NR 47 TC 12 Z9 12 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2014 VL 58 IS 2 BP 995 EP 1004 DI 10.1128/AAC.02094-13 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 302XD UT WOS:000330637500045 PM 24277038 ER PT J AU Rudkin, JK Laabei, M Edwards, AM Joo, HS Otto, M Lennon, KL O'Gara, JP Waterfield, NR Massey, RC AF Rudkin, Justine K. Laabei, Maisem Edwards, Andrew M. Joo, Hwang-Soo Otto, Michael Lennon, Katrina L. O'Gara, James P. Waterfield, Nicholas R. Massey, Ruth C. TI Oxacillin Alters the Toxin Expression Profile of Community-Associated Methicillin-Resistant Staphylococcus aureus SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; QUORUM-SENSING SYSTEM; SUBINHIBITORY CONCENTRATIONS; ALPHA-TOXIN; VIRULENCE; INFECTIONS; STRAINS; ANTIBIOTICS; GENE; PNEUMONIA AB The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a growing cause for concern. These strains are more virulent than health care-associated MRSA (HA-MRSA) due to higher levels of toxin expression. In a previous study, we showed that the high-level expression of PBP2a, the alternative penicillin binding protein encoded by the mecA gene on type II staphylococcal cassette chromosome mec (SCCmec) elements, reduced toxicity by interfering with the Agr quorum sensing system. This was not seen in strains carrying the CA-MRSA-associated type IV SCCmec element. These strains express significantly lower levels of PBP2a than the other MRSA type, which may explain their relatively high toxicity. We hypothesized that as oxacillin is known to increase mecA expression levels, it may be possible to attenuate the toxicity of CA-MRSA by using this antibiotic. Subinhibitory oxacillin concentrations induced PBP2a expression, repressed Agr activity, and, as a consequence, decreased phenol-soluble modulin (PSM) secretion by CA-MRSA strains. However, consistent with other studies, oxacillin also increased the expression levels of alpha-toxin and Panton-Valentine leucocidin (PVL). The net effect of these changes on the ability to lyse diverse cell types was tested, and we found that where the PSMs and alpha-toxin are important, oxacillin reduced overall lytic activity, but where PVL is important, it increased lytic activity, demonstrating the pleiotropic effect of oxacillin on toxin expression by CA-MRSA. C1 [Rudkin, Justine K.; Laabei, Maisem; Lennon, Katrina L.; Waterfield, Nicholas R.; Massey, Ruth C.] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. [Edwards, Andrew M.] Univ London Imperial Coll Sci Technol & Med, Ctr Mol Bacteriol & Infect, London, England. [Joo, Hwang-Soo; Otto, Michael] NIAID, NIH, Bethesda, MD 20892 USA. [Rudkin, Justine K.; O'Gara, James P.] NUI Galway, Dept Microbiol, Sch Nat Sci, Galway, Ireland. RP Massey, RC (reprint author), Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. EM r.c.massey@bath.ac.uk OI Edwards, Andrew/0000-0002-7173-7355; Laabei, Maisem/0000-0002-8425-3704; JOO, HWANG-SOO/0000-0003-4668-3225; Otto, Michael/0000-0002-2222-4115; O'Gara, James/0000-0003-3866-7161 NR 32 TC 15 Z9 17 U1 0 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2014 VL 58 IS 2 BP 1100 EP 1107 DI 10.1128/AAC.01618-13 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 302XD UT WOS:000330637500058 PM 24295979 ER PT J AU Gomez-Mejiba, SE Zhai, ZL Della-Vedova, MC Munoz, MD Chatterjee, S Towner, RA Hensley, K Floyd, RA Mason, RP Ramirez, DC AF Gomez-Mejiba, Sandra E. Zhai, Zili Della-Vedova, Maria C. Munoz, Marcos D. Chatterjee, Saurabh Towner, Rheal A. Hensley, Kenneth Floyd, Robert A. Mason, Ronald P. Ramirez, Dario C. TI Immuno-spin trapping from biochemistry to medicine: Advances, challenges, and pitfalls. Focus on protein-centered radicals SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Reactive chemical species; Protein radical; Spin trap; Anti-DMPO; Immuno-spin trapping; Disease/exposure model ID PEROXIDASE-CATALYZED OXIDATION; ISCHEMIA-REPERFUSION INJURY; OXIDE NITRONE ADDUCT; HYDROGEN-PEROXIDE; MEDIATED OXIDATION; MASS-SPECTROMETRY; DNA RADICALS; IMMUNOCHEMICAL DETECTION; POTENTIAL MECHANISM; S-GLUTATHIONYLATION AB Background: Immuno-spin trapping (IST) is based on the reaction of a spin trap with a free radical to form a stable nitrone adduct followed by the use of antibodies, rather than traditional electron paramagnetic resonance spectroscopy, to detect the nitrone adduct. IST has been successfully applied to mechanistic in vitro studies, and recently, macromolecule-centered radicals have been detected in models of drug-induced agranulocytosis, hepatotoxicity, cardiotoxicity, and ischemia/reperfusion, as well as in models of neurological, metabolic and immunological diseases. Scope of the review: To critically evaluate advances, challenges, and pitfalls as well as the scientific opportunities of IST as applied to the study of protein-centered free radicals generated in stressed organelles, cells, tissues and animal models of disease and exposure. Major conclusions: Because the spin trap has to be present at high enough concentrations in the microenvironment where the radical is formed, the possible effects of the spin trap on gene expression, metabolism and cell physiology have to be considered in the use of IST and in the interpretation of results. These factors have not yet been thoroughly dealt with in the literature. General significance: The identification of radicalized proteins during cell/tissue response to stressors will help define their role in the complex cellular response to stressors and pathogenesis; however, the fidelity of spin trapping/immuno-detection and the effects of the spin trap on the biological system should be considered. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. (C) 2013 Elsevier B.V. All rights reserved. C1 [Gomez-Mejiba, Sandra E.; Della-Vedova, Maria C.; Munoz, Marcos D.; Ramirez, Dario C.] Consejo Nacl Invest Cient & Tecn, Inst Multidisciplinary Biol Invest San Lui IMIBIO, Lab Expt Med & Therapeut, Natl Bur Sci & Technol, RA-5700 San Luis, San Luis, Argentina. [Gomez-Mejiba, Sandra E.; Della-Vedova, Maria C.; Munoz, Marcos D.; Ramirez, Dario C.] Natl Univ San Luis, RA-5700 San Luis, Argentina. [Zhai, Zili] Univ Chicago, Dept Gastroenterol, Gastroenterol Sect, Chicago, IL 60637 USA. [Chatterjee, Saurabh] Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. [Towner, Rheal A.] Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, Oklahoma City, OK 73104 USA. [Hensley, Kenneth] Univ Toledo, Med Ctr, Dept Pathol, Toledo, OH 43614 USA. [Floyd, Robert A.] Oklahoma Med Res Fdn, Lab Expt Therapeut, Oklahoma City, OK 74104 USA. [Mason, Ronald P.] NIEHS, Lab Pharmacol & Toxicol, Res Triangle Pk, NC 27709 USA. [Ramirez, Dario C.] Natl Univ San Luis, Dept Biochem & Biol Sci, Mol Biol Sect, RA-5700 San Luis, San Luis, Argentina. RP Ramirez, DC (reprint author), IMIBIO SL CONICET UNSL, Lab Expt Med & Therapeut, Suite 13X,First Floor, RA-5700 San Luis, San Luis, Argentina. EM ramirezlabimibiosl@ymail.com RI RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 FU CONICET, Government of the Republic of Argentina [1488]; National Institute of Environmental Health Sciences [5R00ES015415-04]; NIEHS, NIH [4R00ES019875-02]; MDA [MDA217526]; Oklahoma Medical Research Foundation; NIEHS, NIH, DHHS FX DCR and SEGM acknowledge the Re-insertion Grant from the CONICET, Government of the Republic of Argentina (Res. D No 1488). MCD-V and MDM are fellows from the CONICET. The project was supported in part by Award Number 5R00ES015415-04 to DCR from the National Institute of Environmental Health Sciences. SC is supported by grant 4R00ES019875-02 from NIEHS, NIH. KH's research is supported by an MDA grant (MDA217526). RAT research is supported by the Oklahoma Medical Research Foundation. RPM's research is supported by the Intramural Research Program of the NIEHS, NIH, DHHS. The authors acknowledge Dr. Ann Motten and Mary Mason for helping to edit this manuscript and Dr Maria S. Gimenez and Sergio E. Alvarez (IMIBIO-SL-CONICET) for critical reading of this manuscript The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Institutes of Health. Due to space limitations, we were unable to review all relevant work and apologize to those colleagues whose contributions were not discussed in this review article. NR 83 TC 10 Z9 10 U1 2 U2 45 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD FEB PY 2014 VL 1840 IS 2 SI SI BP 722 EP 729 DI 10.1016/j.bbagen.2013.04.039 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AA0WS UT WOS:000330818700003 PM 23644035 ER PT J AU Kim, G Weiss, SJ Levine, RL AF Kim, Geumsoo Weiss, Stephen J. Levine, Rodney L. TI Methionine oxidation and reduction in proteins SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Methionine; Methionine sulfoxide; Methionine sulfoxide reductase; Oxidant defense ID SULFOXIDE REDUCTASE; GLUTAMINE-SYNTHETASE; ALPHA-1-PROTEINASE INHIBITOR; HYDROGEN-PEROXIDE; RESIDUES; COMPLEXES; MECHANISM; DAMAGE; STRESS; CELLS AB Background: Cysteine and methionine are the two sulfur containing amino acids in proteins. While the roles of protein-bound cysteinyl residues as endogenous antioxidants are well appreciated, those of methionine remain largely unexplored. Scope: We summarize the key roles of methionine residues in proteins. Major conclusion: Recent studies establish that cysteine and methionine have remarkably similar functions. General significance: Both cysteine and methionine serve as important cellular antioxidants, stabilize the structure of proteins, and can act as regulatory switches through reversible oxidation and reduction. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. (C) 2013 Elsevier B.V. All rights reserved. C1 [Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. [Weiss, Stephen J.] Univ Michigan, Dept Internal Med, Inst Life Sci, Div Mol Med & Genet, Ann Arbor, MI 48109 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU National Heart, Lung, and Blood Institute FX This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. NR 67 TC 31 Z9 31 U1 1 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD FEB PY 2014 VL 1840 IS 2 SI SI BP 901 EP 905 DI 10.1016/j.bbagen.2013.04.038 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AA0WS UT WOS:000330818700019 PM 23648414 ER PT J AU Kotoshiba, S Gopinathan, L Pfeiffenberger, E Rahim, A Vardy, LA Nakayama, K Nakayama, KI Kaldis, P AF Kotoshiba, Shuhei Gopinathan, Lakshmi Pfeiffenberger, Elisabeth Rahim, Anisa Vardy, Leah A. Nakayama, Keiko Nakayama, Keiichi I. Kaldis, Philipp TI p27 is regulated independently of Skp2 in the absence of Cdk2 SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Cyclin-dependent kinase; Knockout mice; Cdk2; Skp2; p27 ID DEPENDENT KINASE INHIBITOR; SCFSKP2 UBIQUITIN LIGASE; CELL-DIVISION; MICE LACKING; DNA-DAMAGE; CULLIN 4A; G1 PHASE; S-PHASE; P27(KIP1); DEGRADATION AB Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdlcs. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27K1P1, which is able to inhibit Cdk2 and Cdkl. Knockdown of Cdk2 abrogated proliferation of Skp2(-/-) mouse embryonic fibroblasts, encouraging us to generate Cdk2(-/-)Skp2(-/-) double knockout mice. Cdk2(-/-)Skp2(-/-) double knockout mice are viable and display similar phenotypes as Cdk2(-/-) and Skp2(-/-) mice. Unexpectedly, fibroblasts generated from Cdk2(-/-)Skp2(-/-) double knockout mice proliferated at normal rates. The increased stability of p27 observed in Skp2(-/-) MEFs was not observed in Cdk2(-/-)Skp2(-/-) double knockout fibroblasts indicating that in the absence of Cdk2, p27 is regulated by Skp2-independent mechanisms. Ablation of other ubiquitin ligases for p27 such as KPCI, DDBI, and Pirh2 did not restore stability of p27 in Cdk2(-/-)Skp2(-/-) MEFs. Our findings point towards novel and alternate pathways for p27 regulation. (C) 2013 Elsevier B.V. All rights reserved. C1 [Kotoshiba, Shuhei; Gopinathan, Lakshmi; Pfeiffenberger, Elisabeth; Kaldis, Philipp] ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore. [Kaldis, Philipp] Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore. [Nakayama, Keiko] Tohoku Univ, Dept Dev Genet, Grad Sch Med, Ctr Translat & Adv Anim Res,Aoba Ku, Sendai, Miyagi 980, Japan. [Nakayama, Keiichi I.] Kyushu Univ, Med Inst Bioregulat, Dept Mol & Cellular Biol, Higashi Ku, Fukuoka 8128582, Japan. [Nakayama, Keiichi I.] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan. [Rahim, Anisa; Vardy, Leah A.] ASTAR, Inst Med Biol, Singapore 138648, Singapore. [Kotoshiba, Shuhei; Kaldis, Philipp] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Vardy, Leah A.] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore. RP Kaldis, P (reprint author), ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr,Proteos 3-09, Singapore 138673, Singapore. EM kaldis@imcb.a-star.edu.sg RI Kaldis, Philipp/G-2714-2010; ASTAR, IMCB/E-2320-2012; U-ID, Kyushu/C-5291-2016 OI Kaldis, Philipp/0000-0002-7247-7591; FU Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore; Intramural Research Program of the NIH, the National Cancer Institute, Center for Cancer Research; Japan Society for the Promotion of Science (JSPS) Research Fellowship in Biomedical and Behavioral Research at NIH FX We thank all Kaldis lab members for their support and comments on the manuscript. We are very grateful to Piotr Sicinski for providing the Cdk2 shRNA construct. This work was supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore and in part by the Intramural Research Program of the NIH, the National Cancer Institute, Center for Cancer Research. SK was supported in part by the Japan Society for the Promotion of Science (JSPS) Research Fellowship in Biomedical and Behavioral Research at NIH. NR 39 TC 6 Z9 6 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD FEB PY 2014 VL 1843 IS 2 BP 436 EP 445 DI 10.1016/j.bbamcr.2013.11.005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 302LQ UT WOS:000330606400019 PM 24269842 ER PT J AU Carliner, H Collins, PY Cabassa, LJ McNallen, A Joestl, SS Lewis-Fernandez, R AF Carliner, Hannah Collins, Pamela Y. Cabassa, Leopoldo J. McNallen, Ann Joestl, Sarah S. Lewis-Fernandez, Roberto TI Prevalence of cardiovascular risk factors among racial and ethnic minorities with schizophrenia spectrum and bipolar disorders: a critical literature review SO COMPREHENSIVE PSYCHIATRY LA English DT Review ID SERIOUS MENTAL-ILLNESS; CLINICAL ANTIPSYCHOTIC TRIALS; RANDOMIZED CONTROLLED-TRIAL; METABOLIC SYNDROME; DIABETES-MELLITUS; UNITED-STATES; HEALTH-CARE; SCHIZOAFFECTIVE DISORDER; EXCESS MORTALITY; MEDICAL-CARE AB Objective: People with serious mental illness (SMI) die at least 11 years earlier than the general U.S. population, on average, due largely to cardiovascular disease (CVD). Disparities in CVD morbidity and mortality also occur among some U.S. racial and ethnic minorities. The combined effect of race/ethnicity and SMI on CVD-related risk factors, however, remains unclear. To address this gap, we conducted a critical literature review of studies assessing the prevalence of CVD risk factors (overweight/obesity, diabetes mellitus, metabolic syndrome, hypercholesterolemia, hypertension, cigarette smoking, and physical inactivity) among U.S. racial/ethnic groups with schizophreniaspectrum and bipolar disorders. Methods and Results: We searched MEDLINE and PsycINFO for articles published between 1986 and 2013. The search ultimately yielded 40 articles. There was great variation in sampling, methodology, and study populations. Results were mixed, though there was some evidence for increased risk for obesity and diabetes mellitus among African Americans, and to a lesser degree for Hispanics, compared to non-Hispanic Whites. Sex emerged as an important possible effect modifier of risk, as women had higher CVD risk among all racial/ethnic subgroups where stratified analyses were reported. Conclusions: Compared to general population estimates, there was some evidence for an additive risk for CVD risk factors among racial/ethnic minorities with SMI. Future studies should include longitudinal assessment, stratification by sex, subgroup analyses to clarify the mechanisms leading to potentially elevated risk, and the evaluation of culturally appropriate interventions to eliminate the extra burden of disease in this population. (C) 2014 Elsevier Inc. All rights reserved. C1 [Carliner, Hannah] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Collins, Pamela Y.] NIMH, Off Res Dispar & Global Mental Hlth, NIH, Bethesda, MD 20892 USA. [Cabassa, Leopoldo J.; Lewis-Fernandez, Roberto] Columbia Univ, Dept Psychiat, New York, NY USA. [Cabassa, Leopoldo J.; Lewis-Fernandez, Roberto] New York State Psychiat Inst & Hosp, New York State Ctr Excellence Cultural Competence, New York, NY 10032 USA. [Cabassa, Leopoldo J.] Columbia Univ, Sch Social Work, New York, NY USA. [McNallen, Ann] Columbia Univ, Dept Populat & Family Hlth, Mailman Sch Publ Hlth, New York, NY USA. [Joestl, Sarah S.] Columbia Univ, Dept Sociomed Sci, Mailman Sch Publ Hlth, New York, NY USA. [Lewis-Fernandez, Roberto] New York State Psychiat Inst & Hosp, Hispan Treatment Program, New York, NY 10032 USA. RP Carliner, H (reprint author), Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 665 Huntington Ave, Boston, MA 02115 USA. EM hcarliner@mail.harvard.edu FU New York State Office of Mental Health; NIH [L60 MD001850, K01 MH09118]; National Institute of Mental Health [R25 MH080916]; Department of Veterans Affairs, Health Services Research & Development, Quality Enhancement Research Initiative (QUERI); Eli Lilly Co. FX The authors wish to thank Andel Nicasio, Elizabeth Siantz, Madeline Tavarez, and Ron Turner for administrative and review support for this manuscript. This work was supported in part by the New York State Office of Mental Health (HC, PYC, LJC, RLF), by institutional support from the New York State Psychiatric Institute (RLF), and NIH grants L60 MD001850 (LJC), K01 MH09118 (LJC), and by the Implementation Research Institute (IRI) at the George Warren Brown School of Social Work, Washington University in St. Louis through an award from the National Institute of Mental Health (R25 MH080916) and the Department of Veterans Affairs, Health Services Research & Development, Quality Enhancement Research Initiative (QUERI). Dr. Lewis-Fernandez receives research support from Eli Lilly & Co. The views expressed in this article do not necessarily represent the views of the NIMH or the federal government. NR 105 TC 18 Z9 18 U1 5 U2 19 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD FEB PY 2014 VL 55 IS 2 BP 233 EP 247 DI 10.1016/j.comppsych.2013.09.009 PG 15 WC Psychiatry SC Psychiatry GA 301SA UT WOS:000330551200001 PM 24269193 ER PT J AU Ferreira, T Ou, YM Li, S Giniger, E van Meyel, DJ AF Ferreira, Tiago Ou, Yimiao Li, Sally Giniger, Edward van Meyel, Donald J. TI Dendrite architecture organized by transcriptional control of the F-actin nucleator Spire SO DEVELOPMENT LA English DT Article DE Neuron; Drosophila; Dendrite; Arborization; F-actin; Nociception; Sholl ID FINGER PROTEIN ABRUPT; DROSOPHILA LARVAE; IMAGE-ANALYSIS; SENSORY NEURONS; NERVOUS-SYSTEM; LOLA ENCODES; AXON GROWTH; SPINAL-CORD; CELL; MORPHOGENESIS AB The architectures of dendritic trees are crucial for the wiring and function of neuronal circuits because they determine coverage of receptive territories, as well as the nature and strength of sensory or synaptic inputs. Here, we describe a cell-intrinsic pathway sculpting dendritic arborization (da) neurons in Drosophila that requires Longitudinals Lacking (Lola), a BTB/POZ transcription factor, and its control of the F-actin cytoskeleton through Spire (Spir), an actin nucleation protein. Loss of Lola from da neurons reduced the overall length of dendritic arbors, increased the expression of Spir, and produced inappropriate F-actin-rich dendrites at positions too near the cell soma. Selective removal of Lola from only class IV da neurons decreased the evasive responses of larvae to nociception. The increased Spir expression contributed to the abnormal F-actin-rich dendrites and the decreased nocifensive responses because both were suppressed by reduced dose of Spir. Thus, an important role of Lola is to limit expression of Spir to appropriate levels within da neurons. We found Spir to be expressed in dendritic arbors and to be important for their development. Removal of Spir from class IV da neurons reduced F-actin levels and total branch number, shifted the position of greatest branch density away from the cell soma, and compromised nocifensive behavior. We conclude that the Lola-Spir pathway is crucial for the spatial arrangement of branches within dendritic trees and for neural circuit function because it provides balanced control of the F-actin cytoskeleton. C1 [Ferreira, Tiago; Ou, Yimiao; Li, Sally; van Meyel, Donald J.] McGill Univ, Ctr Hlth, McGill Ctr Res Neurosci, Montreal, PQ H3G 1A4, Canada. [Ou, Yimiao; van Meyel, Donald J.] McGill Univ, Integrated Program Neurosci, Montreal, PQ H3A 2B4, Canada. [Giniger, Edward] NINCDS, NIH, Basic Neurosci Program, Bethesda, MD 20892 USA. [van Meyel, Donald J.] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [van Meyel, Donald J.] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H3G 1A4, Canada. RP van Meyel, DJ (reprint author), McGill Univ, Ctr Hlth, McGill Ctr Res Neurosci, 1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. EM don.vanmeyel@mcgill.ca RI Giniger, Edward/C-1764-2015; OI Giniger, Edward/0000-0002-8340-6158; Ferreira, Tiago/0000-0001-6866-1540; van Meyel, Donald/0000-0002-6075-8599 FU Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Canada Foundation for Innovation; Intramural Research Program of the National Institutes of Health; National Institute of Neurological Disorders and Stroke [Z01-NS003013]; Research Institute of McGill University Health Center; McGill Faculty of Medicine FX Supported by grants to D.J.v.M. from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Canada Foundation for Innovation, and by grants to E.G. from the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke [Z01-NS003013]. Training/salary awards came from the Research Institute of McGill University Health Center (Y.O. and T.F.) and from the McGill Faculty of Medicine (Y.O. and D.J.v.M.). Deposited in PMC for release after 12 months. NR 72 TC 13 Z9 13 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD FEB 1 PY 2014 VL 141 IS 3 BP 650 EP 660 DI 10.1242/dev.099655 PG 11 WC Developmental Biology SC Developmental Biology GA 302AL UT WOS:000330573500016 PM 24449841 ER PT J AU Rios, CI Cassatt, DR DiCarlo, AL Macchiarini, F Ramakrishnan, N Norman, MK Maidment, BW AF Rios, Carmen I. Cassatt, David R. DiCarlo, Andrea L. Macchiarini, Francesca Ramakrishnan, Narayani Norman, Mai-Kim Maidment, Bert W. TI Building the Strategic National Stockpile Through the NIAID Radiation Nuclear Countermeasures Program SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE radiation; nuclear; medical countermeasures; dosimetry; animal models; mitigators; treatment ID DOSE IRRADIATED MICE; GASTROINTESTINAL SYNDROME; MEDICAL COUNTERMEASURES; MODEL; INJURY AB The possibility of a public health radiological or nuclear emergency in the United States remains a concern. Media attention focused on lost radioactive sources and international nuclear threats, as well as the potential for accidents in nuclear power facilities (e.g., Windscale, Three Mile Island, Chernobyl, and Fukushima) highlight the need to address this critical national security issue. To date, no drugs have been licensed to mitigate/treat the acute and longaEuroterm radiation injuries that would result in the event of largeaEuroscale, radiation, or nuclear public health emergency. However, recent evaluation of several candidate radiation medical countermeasures (MCMs) has provided initial proofaEuroofaEuroconcept of efficacy. The goal of the Radiation Nuclear Countermeasures Program (RNCP) of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) is to help ensure the government stockpiling of safe and efficacious MCMs to treat radiation injuries, including, but not limited to, hematopoietic, gastrointestinal, pulmonary, cutaneous, renal, cardiovascular, and central nervous systems. In addition to supporting research in these areas, the RNCP continues to fund research and development of decorporation agents targeting internal radionuclide contamination, and biodosimetry platforms (e.g., biomarkers and devices) to assess the levels of an individual's radiation exposure, capabilities that would be critical in a mass casualty scenario. New areas of research within the program include a focus on special populations, especially pediatric and geriatric civilians, as well as combination studies, in which drugs are tested within the context of expected medical care management (e.g., antibiotics and growth factors). Moving forward, challenges facing the RNCP, as well as the entire radiation research field, include further advancement and qualification of animal models, dose conversion from animal models to humans, biomarker identification, and formulation development. This paper provides a review of recent work and collaborations supported by the RNCP. Published 2013 Wiley-Periodicals, Inc. C1 [Rios, Carmen I.; Cassatt, David R.; DiCarlo, Andrea L.; Macchiarini, Francesca; Ramakrishnan, Narayani; Norman, Mai-Kim; Maidment, Bert W.] NIAID, Radiat Nucl Countermeasures Program, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. RP Maidment, BW (reprint author), NIAID, Radiat & Nucl Countermeasures Program, NIH, 6610 Rockledge Dr,Room 5321, Bethesda, MD 20892 USA. EM maidmentb@niaid.nih.gov NR 15 TC 3 Z9 3 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0272-4391 EI 1098-2299 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD FEB PY 2014 VL 75 IS 1 SI SI BP 23 EP 28 DI 10.1002/ddr.21163 PG 6 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AA0ND UT WOS:000330791000004 PM 24648046 ER PT J AU Foster, BL Nociti, FH Somerman, MJ AF Foster, Brian L. Nociti, Francisco H., Jr. Somerman, Martha J. TI The Rachitic Tooth SO ENDOCRINE REVIEWS LA English DT Review ID VITAMIN-D-RECEPTOR; D-RESISTANT RICKETS; DOMINANT HYPOPHOSPHATEMIC RICKETS; DENTIN MATRIX PROTEIN-1; ALKALINE-PHOSPHATASE ACTIVITY; TUMOR-INDUCED OSTEOMALACIA; X-LINKED HYPOPHOSPHATEMIA; HORMONE-RELATED PROTEIN; GROWTH-FACTOR 23; AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIA AB Teeth are mineralized organs composed of three unique hard tissues, enamel, dentin, and cementum, and supported by the surrounding alveolar bone. Although odontogenesis differs from osteogenesis in several respects, tooth mineralization is susceptible to similar developmental failures as bone. Here we discuss conditions fitting under the umbrella of rickets, which traditionally referred to skeletal disease associated with vitamin D deficiency but has been more recently expanded to include newly identified factors involved in endocrine regulation of vitamin D, phosphate, and calcium, including phosphate-regulating endopeptidase homolog, X-linked, fibroblast growth factor 23, and dentin matrix protein 1. Systemic mineral metabolism intersects with local regulation of mineralization, and factors including tissue nonspecific alkaline phosphatase are necessary for proper mineralization, where rickets can result from loss of activity of tissue nonspecific alkaline phosphatase. Individuals suffering from rickets often bear the additional burden of a defective dentition, and transgenic mouse models have aided in understanding the nature and mechanisms involved in tooth defects, which may or may not parallel rachitic bone defects. This report reviews dental effects of the range of rachitic disorders, including discussion of etiologies of hereditary forms of rickets, a survey of resulting bone and tooth mineralization disorders, and a discussion of mechanisms, known and hypothesized, involved in the observed dental pathologies. Descriptions of human pathology are augmented by analysis of transgenic mouse models, and new interpretations are brought to bear on questions of how teeth are affected under conditions of rickets. In short, the rachitic tooth will be revealed. C1 [Foster, Brian L.; Nociti, Francisco H., Jr.; Somerman, Martha J.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Foster, BL (reprint author), 9000 Rockville Pike,Bldg 50,Room 4120, Bethesda, MD 20892 USA. EM brian.foster@nih.gov RI Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH. NR 344 TC 15 Z9 15 U1 1 U2 10 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0163-769X EI 1945-7189 J9 ENDOCR REV JI Endocr. Rev. PD FEB PY 2014 VL 35 IS 1 BP 1 EP 34 DI 10.1210/er.2013-1009 PG 34 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA0DV UT WOS:000330766200001 PM 23939820 ER PT J AU Hill, MJ Cooper, JC Levy, G Alford, C Richter, KS DeCherney, AH Katz, CL Levens, ED Wolff, EF AF Hill, Micah J. Cooper, Janelle C. Levy, Gary Alford, Connie Richter, Kevin S. DeCherney, Alan H. Katz, Charles L. Levens, Eric D. Wolff, Erin F. TI Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location SO FERTILITY AND STERILITY LA English DT Article DE ART; ectopic; methotrexate; ovarian stimulation; pregnancy of unknown location; salpingectomy ID VITRO FERTILIZATION TREATMENT; CHEMOTHERAPY; STIMULATION; FERTILITY; CYCLE; PERFORMANCE; GROWTH AB Objective: To assess ovarian reserve after methotrexate treatment for ectopic pregnancy or pregnancy of unknown location after assisted reproductive technology (ART). Design: Retrospective cohort study. Setting: Large ART practice. Patient(s): Women receiving methotrexate or surgery after ART. Intervention(s): None. Main Outcome Measure(s): Follicle-stimulating hormone (FSH), antral follicle count (AFC), and oocyte yield compared between women treated with methotrexate or surgery, with secondary outcomes of clinical pregnancy and live birth. Result(s): There were 153 patients in the methotrexate group and 36 patients in the surgery group. Neither group demonstrated differences in ovarian reserve or oocyte yield in a comparison of the before and after treatment values. The change in ovarian reserve and oocyte yield after treatment were similar between the two groups. The number of doses of methotrexate was not correlated with changes in ovarian reserve, indicating no dose-dependent effect. Time between treatment and repeat ART was not correlated with outcomes. Live birth in subsequent cycles was similar in the two groups. Conclusion(s): Ovarian reserve and subsequent ART cycle outcomes were reassuring after methotrexate or surgical management of ectopic pregnancy. No adverse impact of methotrexate was detected in this large fertility cohort as has been previously described elsewhere. (C) 2014 by American Society for Reproductive Medicine. C1 [Hill, Micah J.; Levy, Gary; Alford, Connie; DeCherney, Alan H.; Katz, Charles L.; Wolff, Erin F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Cooper, Janelle C.] Washington Hosp Ctr, Washington, DC 20010 USA. [Richter, Kevin S.; Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Hill, MJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM hillmicah@mail.nih.gov FU Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported in part by the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 24 TC 10 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2014 VL 101 IS 2 BP 413 EP + DI 10.1016/j.fertnstert.2013.10.027 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 302CD UT WOS:000330578000024 PM 24269042 ER PT J AU Louis, GMB Sundaram, R Schisterman, EF Sweeney, A Lynch, CD Kim, S Maisog, JM Gore-Langton, R Eisenberg, ML Chen, Z AF Louis, Germaine M. Buck Sundaram, Rajeshwari Schisterman, Enrique F. Sweeney, Anne Lynch, Courtney D. Kim, Sungduk Maisog, Jose M. Gore-Langton, Robert Eisenberg, Michael L. Chen, Zhen TI Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study SO FERTILITY AND STERILITY LA English DT Article DE Epidemiology; fecundity; semen; sperm; time to pregnancy ID MALE REPRODUCTIVE HEALTH; 4 EUROPEAN CITIES/; REGIONAL DIFFERENCES; GENERAL-POPULATION; PROSPECTIVE COHORT; CONCEPTION RATES; MALE-INFERTILITY; DNA INTEGRITY; WAITING TIME; MEN AB Objective: To assess semen parameters and couple fecundity as measured by time to pregnancy (TTP). Design: Observational prospective cohort with longitudinal measurement of TTP. Setting: Sixteen Michigan/Texas counties. Patient(s): A total of 501 couples discontinuing contraception were followed for 1 year while trying to conceive; 473 men (94%) provided one semen sample, and 80% provided two samples. Intervention(s): None. Main Outcome Measure(s): Using prospectively measured TTP, fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated for 36 individual semen quality parameters accounting for repeated semen samples, time off contraception, abstinence, enrollment site, and couples' ages, body mass indices, and serum cotinine concentrations. Result(s): In adjusted models, semen quality parameters were associated with significantly shorter TTP as measured by FORs > 1: percent motility, strict and traditional morphology, sperm head width, elongation factor, and acrosome area. Significantly longer TTPs or FORs < 1 were observed for morphologic categories amorphous and round sperm heads and neck/midpiece abnormalities. No semen quality parameters achieved significance when simultaneously modeling all other significant semen parameters and covariates, except for percent coiled tail when adjusting for sperm concentration (FOR 0.99; 95% CI 0.99-1.00). Male age was consistently associated with reduced couple fecundity (FOR 0.96; 95% CI 0.93-0.99), reflecting a longer TTP across all combined models. Female but not male body mass index also conferred a longer TTP (FOR 0.98; 95% CI 0.96-0.99). Conclusion(s): Several semen measures were significantly associated with TTP when modeled individually but not jointly and in the context of relevant couple-based covariates. (C) 2014 by American Society for Reproductive Medicine. C1 [Louis, Germaine M. Buck; Sundaram, Rajeshwari; Schisterman, Enrique F.; Kim, Sungduk; Maisog, Jose M.; Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20854 USA. [Sweeney, Anne] Texas A&M Univ, Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX USA. [Lynch, Courtney D.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Gore-Langton, Robert] EMMES Corp, Rockville, MD USA. [Eisenberg, Michael L.] Stanford Univ, Dept Urol, Palo Alto, CA 94304 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20854 USA. EM louisg@mail.nih.gov OI Eisenberg, Michael/0000-0001-5482-0141; Sundaram, Rajeshwari/0000-0002-6918-5002; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358]; Memo of Understanding; National Institute of Occupational Safety and Health FX Funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (grants N01-HD-3-3355, N01-HD-3-3356, and NOH-HD-3-3358), and a Memo of Understanding with the National Institute of Occupational Safety and Health for semen analysis. NR 78 TC 26 Z9 26 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2014 VL 101 IS 2 BP 453 EP 462 DI 10.1016/j.fertnstert.2013.10.022 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 302CD UT WOS:000330578000030 ER PT J AU Hill, MJ Levens, ED Wolff, EF AF Hill, Micah J. Levens, Eric D. Wolff, Erin F. TI Methotrexate for assisted reproductive technology (ART) ectopic pregnancy SO FERTILITY AND STERILITY LA English DT Letter C1 [Hill, Micah J.; Wolff, Erin F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Hill, MJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HD999999] NR 3 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2014 VL 101 IS 2 BP E11 EP E11 DI 10.1016/j.fertnstert.2013.11.124 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 302CD UT WOS:000330578000001 PM 24485505 ER PT J AU Akagi, K Li, JF Broutian, TR Padilla-Nash, H Xiao, WH Jiang, B Rocco, JW Teknos, TN Kumar, B Wangsa, D He, DD Ried, T Symer, DE Gillison, ML AF Akagi, Keiko Li, Jingfeng Broutian, Tatevik R. Padilla-Nash, Hesed Xiao, Weihong Jiang, Bo Rocco, James W. Teknos, Theodoros N. Kumar, Bhavna Wangsa, Danny He, Dandan Ried, Thomas Symer, David E. Gillison, Maura L. TI Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability SO GENOME RESEARCH LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; SQUAMOUS-CELL CARCINOMA; HEPATITIS-B-VIRUS; HEPATOCELLULAR-CARCINOMA; CERVICAL-CARCINOMA; RNA-SEQ; STRUCTURAL ALTERATIONS; REPLICATION CENTERS; GENETIC INSTABILITY; DNA AB Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of "looping" by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability. C1 [Akagi, Keiko; Li, Jingfeng; He, Dandan; Symer, David E.] Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. [Akagi, Keiko; Li, Jingfeng; Broutian, Tatevik R.; Xiao, Weihong; Jiang, Bo; He, Dandan; Symer, David E.; Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Viral Oncol Program, Columbus, OH 43210 USA. [Akagi, Keiko; Li, Jingfeng; He, Dandan; Symer, David E.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Broutian, Tatevik R.; Xiao, Weihong; Jiang, Bo; Symer, David E.; Gillison, Maura L.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Padilla-Nash, Hesed; Wangsa, Danny; Ried, Thomas] NCI, Canc Genom Sect, Ctr Canc Res, Bethesda, MD 20814 USA. [Rocco, James W.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Rocco, James W.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Rocco, James W.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02115 USA. [Teknos, Theodoros N.; Kumar, Bhavna] Ohio State Univ, Wexner Med Ctr, Dept Otolaryngol Head & Neck Surg, Columbus, OH 43210 USA. [Symer, David E.] Ohio State Univ, Dept Biomed Informat, Columbus, OH 43210 USA. RP Symer, DE (reprint author), Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. EM david.symer@osumc.edu; maura.gillison@osumc.edu FU Ohio State University Comprehensive Cancer Center; Ohio Supercomputer Center [PAS0425]; Ohio Cancer Research Associate grant [GRT00024299]; Oral Cancer Foundation; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Douglas Lowy (National Cancer Institute) for insightful comments on the manuscript; Anthony S. Baker for expert help preparing graphical figures; Dr. Yanqiang Wang (OSUCCC) for help with Northern blots; Sylwia Wojcik for help with initial characterization of insertional breakpoints; and other members of the Gillison and Symer laboratories for helpful discussions. We thank Drs. Thomas Carey (University of Michigan), Susanne M. Gollin (University of Pittsburgh), and Henning Bier (University of Dusseldorf) for their kind gifts of cell lines. This study was funded by The Ohio State University Comprehensive Cancer Center (D.E.S., M.L.G.), the Ohio Supercomputer Center (PAS0425; K.A., D.E.S.), an Ohio Cancer Research Associate grant (GRT00024299; K.A.), the Oral Cancer Foundation (M.L.G.), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (T.R.). NR 85 TC 65 Z9 68 U1 5 U2 32 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 EI 1549-5469 J9 GENOME RES JI Genome Res. PD FEB PY 2014 VL 24 IS 2 BP 185 EP 199 DI 10.1101/gr.164806.113 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 303TG UT WOS:000330696800002 PM 24201445 ER PT J AU Faraji, F Hu, Y Wu, G Goldberger, NE Walker, RC Zhang, JH Hunter, KW AF Faraji, Farhoud Hu, Ying Wu, Gang Goldberger, Natalie E. Walker, Renard C. Zhang, Jinghui Hunter, Kent W. TI An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease SO GENOME RESEARCH LA English DT Article ID BREAST-CANCER METASTASIS; TO-MESENCHYMAL TRANSITION; SUPPRESSES TUMOR-GROWTH; MAMMARY-TUMOR; CCR4-NOT COMPLEX; HEPATOCELLULAR-CARCINOMA; EXPRESSION PROFILES; NETWORK ANALYSIS; DNA METHYLATION; MICRORNA AB Metastasis is the result of stochastic genomic and epigenetic events leading to gene expression profiles that drive tumor dissemination. Here we exploit the principle that metastatic propensity is modified by the genetic background to generate prognostic gene expression signatures that illuminate regulators of metastasis. We also identify multiple microRNAs whose germline variation is causally linked to tumor progression and metastasis. We employ network analysis of global gene expression profiles in tumors derived from a panel of recombinant inbred mice to identify a network of co-expressed genes centered on Cnot2 that predicts metastasis-free survival. Modulating Cnot2 expression changes tumor cell metastatic potential in vivo, supporting a functional role for Cnot2 in metastasis. SmallRNA sequencing of the same tumor set revealed a negative correlation between expression of the Mir216/217 cluster and tumor progression. Expression quantitative trait locus analysis (eQTL) identified cis-eQTLs at the Mir216/217 locus, indicating that differences in expression may be inherited. Ectopic expression of Mir216/217 in tumor cells suppressed metastasis in vivo. Finally, small RNA sequencing and mRNA expression profiling data were integrated to reveal that miR-3470a/b target a high proportion of network transcripts. In vivo analysis of Mir3470a/b demonstrated that both promote metastasis. Moreover, Mir3470b is a likely regulator of the Cnot2 network as its overexpression down-regulated expression of network hub genes and enhanced metastasis in vivo, phenocopying Cnot2 knockdown. The resulting data from this strategy identify Cnot2 as a novel regulator of metastasis and demonstrate the power of our systems-level approach in identifying modifiers of metastasis. C1 [Faraji, Farhoud; Goldberger, Natalie E.; Walker, Renard C.; Hunter, Kent W.] NCI, Metastasis Susceptibil Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Faraji, Farhoud] St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA. [Faraji, Farhoud] Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Chevy Chase, MD 20815 USA. [Hu, Ying] NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wu, Gang; Zhang, Jinghui] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA. RP Hunter, KW (reprint author), NCI, Metastasis Susceptibil Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov OI Faraji, Farhoud/0000-0001-5078-813X FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Howard Hughes Medical Institute Research Scholars Program FX We thank Jude Alsarraj, Thomas R. Geiger, Jeffrey E. Green, Ngoc-Han Ha, and James J. Morrow for critical review of this manuscript and stimulating discussion. We thank Dominic Esposito of the Protein Expression Laboratory, SAIC-Frederick, for constructing the myc-Cnot2 expression vector. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Howard Hughes Medical Institute Research Scholars Program. NR 93 TC 11 Z9 11 U1 1 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 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD FEB PY 2014 VL 24 IS 2 BP 227 EP 240 DI 10.1101/gr.166223.113 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 303TG UT WOS:000330696800005 PM 24322557 ER PT J AU Menon, MP Evbuomwan, MO Rosai, J Jaffe, ES Pittaluga, S AF Menon, Madhu P. Evbuomwan, Moses O. Rosai, Juan Jaffe, Elaine S. Pittaluga, Stefania TI A subset of Rosai-Dorfman disease cases show increased IgG4-positive plasma cells: another red herring or a true association with IgG4-related disease? SO HISTOPATHOLOGY LA English DT Letter ID MASSIVE LYMPHADENOPATHY; SINUS HISTIOCYTOSIS; SCLEROSING DISEASE; FEATURES C1 [Menon, Madhu P.; Evbuomwan, Moses O.; Jaffe, Elaine S.; Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Rosai, Juan] Ctr Consulenze Anat Patol Oncol, Milan, Italy. RP Menon, MP (reprint author), NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. OI Jaffe, Elaine/0000-0003-4632-0301 FU Intramural NIH HHS [Z99 CA999999] NR 15 TC 12 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD FEB PY 2014 VL 64 IS 3 BP 455 EP 459 DI 10.1111/his.12274 PG 5 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 302XP UT WOS:000330638700015 PM 24215263 ER PT J AU Rossi, CC Fuentes, J Van de Water, J Amaral, DG AF Rossi, Christy C. Fuentes, Joaquin Van de Water, Judy Amaral, David G. TI Brief Report: Antibodies Reacting to Brain Tissue in Basque Spanish Children with Autism Spectrum Disorder and Their Mothers SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism spectrum disorders; Autoantibody; Brain; International ID FETAL-BRAIN; PLASMA AUTOANTIBODIES; ANTIBRAIN ANTIBODIES; PREVALENCE; ACTIVATION; PROTEINS; SERUM AB Previous investigations found that a subset of children with autism spectrum disorder (ASD) in California possessed plasma autoantibodies that reacted intensely with brain interneurons or other neural profiles. Moreover, for several cohorts of American women, maternal autoantibody reactivity to specific fetal brain proteins was highly specific to mothers of children with ASD. We sought to determine whether children and their mothers from a regionally specific cohort from the Basque Country of Spain demonstrated similar reactivity. Some children's plasma reacted to interneurons, beaded axons or other neural profiles with no difference in the occurrence of these antibodies in children with or without ASD. Findings on the maternal antibodies confirmed previous research; plasma reactivity to fetal brain a combination of proteins at 37 and 73 kDa or 39 and 73 kDa was found exclusively in mothers of children with ASD. C1 [Rossi, Christy C.; Amaral, David G.] Univ Calif Davis, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Rossi, Christy C.; Van de Water, Judy; Amaral, David G.] Univ Calif Davis, MIND Inst, Sacramento, CA 95817 USA. [Rossi, Christy C.] Univ Denver, Dept Psychol, Denver, CO 80208 USA. [Fuentes, Joaquin] Policlin Guipuzkoa, Child & Adolescent Psychiat Unit, Donostia San Sebastian, Spain. [Fuentes, Joaquin] Gautena Autism Soc, Donostia San Sebastian, Spain. [Van de Water, Judy] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Sacramento, CA 95817 USA. [Van de Water, Judy] Univ Calif Davis, NIEHS Ctr Childrens Environm Hlth, Sacramento, CA 95817 USA. [Amaral, David G.] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Amaral, David G.] Univ Calif Davis, Calif Natl Primate Res Ctr, Sacramento, CA 95817 USA. RP Amaral, DG (reprint author), Univ Calif Davis, MIND Inst, 2825 50th St, Sacramento, CA 95817 USA. EM dgamaral@ucdavis.edu NR 29 TC 1 Z9 1 U1 1 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD FEB PY 2014 VL 44 IS 2 SI SI BP 459 EP 465 DI 10.1007/s10803-013-1859-y PG 7 WC Psychology, Developmental SC Psychology GA 302TJ UT WOS:000330627500022 ER PT J AU Famakin, BM Mou, YS Johnson, K Spatz, M Hallenbeck, J AF Famakin, Bolanle M. Mou, Yongshan Johnson, Kory Spatz, Maria Hallenbeck, John TI A new role for downstream Toll-like receptor signaling in mediating immediate early gene expression during focal cerebral ischemia SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE acute stroke; chemokines; focal ischemia; gene regulation; inflammation ID INSULIN-DEGRADING ENZYME; EARLY GROWTH RESPONSE-1; NECROSIS-FACTOR-ALPHA; TRANSCRIPTION FACTORS; IMMUNE-RESPONSE; CELLS; BRAIN; EGR-1; RAT; TOLL-LIKE-RECEPTOR-4 AB To better understand the role of downstream Toll-like receptor (TLR) signaling during acute cerebral ischemia, we performed cDNA microarrays, on brain RNA, and cytokine arrays, on serum, from wild type (WT), MyD88-/- and TRIF-mutant mice, at baseline and following permanent middle cerebral artery occlusion (pMCA0). The acute stress response pathway was among the top pathways identified by Ingenuity Pathway Analysis of microarray data. We used real-time polymerase chain reaction to confirm the expression of four immediate early genes; EGR1, EGR2, ARC, Nurr77, in this pathway, and insulin degrading enzyme (IDE). Compared to WT, baseline immediate early gene expression was increased up to 10-fold in MyD88-/- and TRIF-mutant mice. However, following pMCAO, immediate early gene expression remained unchanged, from this elevated baseline in these mice, but increased up to 12-fold in WT. Furthermore, expression of IDE, which also degrades beta-amyloid, decreased significantly only in TRIF-mutant mice. Finally, sE-Selectin, sICAM, sVCAM-1, and MMP-9 levels were significantly decreased only in MyD88-/- compared with WT mice. We thus report a new role for downstream TLR signaling in immediate early gene expression during acute cerebral ischemia. We also show that the TRIF pathway regulates IDE expression; a major enzyme that clears beta-amyloid from the brain. C1 [Famakin, Bolanle M.; Mou, Yongshan; Spatz, Maria; Hallenbeck, John] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. [Johnson, Kory] NINDS, Sect Bioinformat, Informat Technol & Bioinformat Program, NIH, Bethesda, MD 20892 USA. RP Famakin, BM (reprint author), NINDS, NIH, Stroke Branch, 10 Ctr Dr,Rm 5806,MSC 1401, Bethesda, MD 20892 USA. EM famakinb@ninds.nih.gov FU Division of Intramural Research; National Institute of Neurological Disorders and Stroke; National institutes of Health, Bethesda, MD, USA FX This research was supported by the Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National institutes of Health, Bethesda, MD, USA. NR 49 TC 6 Z9 6 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2014 VL 34 IS 2 BP 258 EP 267 DI 10.1038/jcbfm.2013.182 PG 10 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 304LK UT WOS:000330748200010 PM 24301291 ER PT J AU Cao, HM AF Cao, Haiming TI Adipocytokines in obesity and metabolic disease SO JOURNAL OF ENDOCRINOLOGY LA English DT Review DE adipocytokine; obesity; adipokine; metabolic inflammation; adipocyte ID ACID-BINDING PROTEIN; TUMOR-NECROSIS-FACTOR; INDUCED INSULIN-RESISTANCE; MICE LACKING ADIPONECTIN; ACTIVATED-RECEPTOR-GAMMA; FATTY LIVER-DISEASE; NF-KAPPA-B; ADIPOSE-TISSUE; FACTOR-ALPHA; GLUCOSE-HOMEOSTASIS AB The current global obesity pandemic is the leading cause for the soaring rates of metabolic diseases, especially diabetes, cardiovascular disease, hypertension, and non-alcoholic hepatosteatosis. Efforts devoted to find cures for obesity and associated disorders in the past two decades have prompted intensive interest in adipocyte biology, and have led to major advances in the mechanistic understanding of adipose tissue as an essential endocrine organ. Adipose tissue secretes an array of hormones (adipokines) that signal key organs to maintain metabolic homeostasis, and their dysfunction has been causally linked to a wide range of metabolic diseases. In addition, obesity induces production of inflammatory cytokines (often referred to together with adipokines as adipocytokines) and infiltration of immune cells into adipose tissue, which creates a state of chronic low-grade inflammation. Metabolic inflammation has been increasingly recognized as a unifying mechanism linking obesity to a broad spectrum of pathological conditions. This review focuses on classic examples of adipocytokines that have helped to form the basis of the endocrine and inflammatory roles of adipose tissue, and it also details a few newly characterized adipocytokines that provide fresh insights into adipose biology. Studies of adipocytokines in clinical settings and their therapeutic potential are also discussed. C1 NHLBI, NIH, Ctr Mol Med, Bethesda, MD 20892 USA. RP Cao, HM (reprint author), NHLBI, NIH, Ctr Mol Med, 10 Ctr Dr,Bldg 10,8N109,MSC 1760, Bethesda, MD 20892 USA. EM haiming.cao@nih.gov RI Cao, Haiming/P-4634-2016 FU Division of Intramural Research of the National Heart, Lung and Blood Institute of the NIH, USA [HL006103-02] FX H C is funded by the Division of Intramural Research of the National Heart, Lung and Blood Institute (HL006103-02) of the NIH, USA. The author expresses his apology for not being able to cite all worthy papers owing to space limitation. NR 146 TC 95 Z9 99 U1 8 U2 49 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD FEB PY 2014 VL 220 IS 2 BP T47 EP T59 DI 10.1530/JOE-13-0339 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 302SQ UT WOS:000330625600004 PM 24403378 ER PT J AU Toombes, GES Swartz, KJ AF Toombes, Gilman E. S. Swartz, Kenton J. TI Divining the design principles of voltage sensors SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Editorial Material ID GATED PROTON CHANNEL; SHAKER K+ CHANNEL; GATING CHARGE; POTASSIUM CHANNELS; SODIUM-CHANNELS; PADDLE MOTIF; DOMAIN; PHARMACOLOGY; EXPRESSION; RESIDUE C1 [Toombes, Gilman E. S.; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Toombes, GES (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Gilman.Toombes@nih.gov; swartz@ninds.nih.gov OI Toombes, Gilman/0000-0001-8346-1790 FU Intramural NIH HHS NR 35 TC 0 Z9 0 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 EI 1540-7748 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD FEB PY 2014 VL 143 IS 2 BP 139 EP 144 DI 10.1085/jgp.201411162 PG 6 WC Physiology SC Physiology GA 302TT UT WOS:000330628500003 PM 24470485 ER PT J AU Combs, CA Smirnov, A Glancy, B Karamzadeh, NS Gandjbakhche, AH Redford, G Kilborn, K Knutson, JR Balaban, RS AF Combs, C. A. Smirnov, A. Glancy, B. Karamzadeh, N. S. Gandjbakhche, A. H. Redford, G. Kilborn, K. Knutson, J. R. Balaban, R. S. TI Compact non-contact total emission detection for in vivo multiphoton excitation microscopy SO JOURNAL OF MICROSCOPY LA English DT Article DE Imaging; light collection; two-photon microscopy ID 2-PHOTON FLUORESCENCE MICROSCOPY; COLLECTION EFFICIENCY; LIGHT COLLECTION; SCATTERING; MUSCLE AB We describe a compact, non-contact design for a total emission detection (c-TED) system for intra-vital multiphoton imaging. To conform to a standard upright two-photon microscope design, this system uses a parabolic mirror surrounding a standard microscope objective in concert with an optical path that does not interfere with normal microscope operation. The non-contact design of this device allows for maximal light collection without disrupting the physiology of the specimen being examined. Tests were conducted on exposed tissues in live animals to examine the emission collection enhancement of the c-TED device compared to heavily optimized objective-based emission collection. The best light collection enhancement was seen from murine fat (5x-2x gains as a function of depth), whereas murine skeletal muscle and rat kidney showed gains of over two and just under twofold near the surface, respectively. Gains decreased with imaging depth (particularly in the kidney). Zebrafish imaging on a reflective substrate showed close to a twofold gain throughout the entire volume of an intact embryo (approximately 150 m deep). Direct measurement of bleaching rates confirmed that the lower laser powers, enabled by greater light collection efficiency, yielded reduced photobleaching in vivo. The potential benefits of increased light collection in terms of speed of imaging and reduced photo-damage, as well as the applicability of this device to other multiphoton imaging methods is discussed. C1 [Combs, C. A.] NHLBI, Light Microscopy Facil, NIH, Bethesda, MD 20892 USA. [Smirnov, A.; Knutson, J. R.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Glancy, B.; Balaban, R. S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Karamzadeh, N. S.; Gandjbakhche, A. H.] NICHD, Sect Biomed Stochast Phys, NIH, Bethesda, MD 20892 USA. [Redford, G.; Kilborn, K.] Intelligent Imaging Innovat Inc, Denver, CO 80216 USA. RP Combs, CA (reprint author), 9000 Rockville Pike,10-6N-309, Bethesda, MD 20892 USA. EM combsc@nih.gov RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU National Heart Lung and Blood Institute of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Heart Lung and Blood Institute of the National Institutes of Health. We wish to thank Alan Hoofring and Ethan Tyler of the NIH Medical Illustration group for help preparing Figure 1 in this work. We also wish to thank Dr. Damian Dalle Nogare (NICHD, NIH) for donating Zebrafish embryos. We also wish to thank S. Gordon Aiken for in-house for help in testing and setting up the c-TED. NR 17 TC 3 Z9 3 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-2720 EI 1365-2818 J9 J MICROSC-OXFORD JI J. Microsc.. PD FEB PY 2014 VL 253 IS 2 BP 83 EP 92 DI 10.1111/jmi.12099 PG 10 WC Microscopy SC Microscopy GA AA0NT UT WOS:000330792600001 PM 24251437 ER PT J AU Du, JH Romano, RA Si, H Mattox, A Bian, YS Yang, XP Sinha, S Van Waes, C Chen, Z AF Du, Jihui Romano, Rose-Anne Si, Han Mattox, Austin Bian, Yansong Yang, Xinping Sinha, Satrajit Van Waes, Carter Chen, Zhong TI Epidermal overexpression of transgenic Delta Np63 promotes type 2 immune and myeloid inflammatory responses and hyperplasia via NF-kappa B activation SO JOURNAL OF PATHOLOGY LA English DT Article DE p63; infiltrating cells; cytokines; chemokines; NF-kappa B; transgenic mouse ID SQUAMOUS-CELL CARCINOMA; PROINFLAMMATORY CYTOKINE EXPRESSION; REGULATORY T-CELLS; MASTER REGULATOR; NECK-CANCER; SIGNALING PATHWAYS; GENE-EXPRESSION; TARGET GENES; TUMOR-GROWTH; P53 FAMILY AB Np63 is known to be critical in skin development and cancer; however, how it triggers proliferation and inflammation in vivo remains to be elucidated. Here, we find that induced Np63 expression in skin of transgenic mice (TG) results in a hyperproliferative epidermis coupled with inflammatory infiltrates. In situ, infiltrating cells include CD45(+) leukocytes, CD19(+) B lymphocytes, CD3(+) T lymphocytes, CD4(+) T helper, CD25(+)/Foxp3(+) Treg, Ly6B(+) neutrophils, S-100(+) dendritic cells, and macrophages bearing CD11b(+), F4/80(+), CD68(+), and CD206(+) M2 type markers. Transcriptional profiling of TG skin revealed increased gene expression involved in inflammation and immune responses, including Th2/M2 cytokines and chemokines. These genes were co-regulated by Np63 and NF-B RelA or cRel, and enhanced by TNF-. Elevated cRel, RelA, and IKKs were observed in TG mouse skin and human squamous carcinomas with Np63 overexpression. Thus, our findings unveil a missing link connecting overexpressed Np63 with aberrant NF-B activation, pro-inflammatory and type 2 cytokines and chemokines, and host infiltrates during skin inflammation and hyperplasia. Our findings provide a missing link between Np63 overexpression and NF-B-mediated inflammation, of potential relevance to the pathogenesis of squamous carcinoma. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Du, Jihui; Si, Han; Mattox, Austin; Bian, Yansong; Yang, Xinping; Van Waes, Carter; Chen, Zhong] Natl Inst Deafness & Other Commun Disorders, Clin Genom Unit, NIH, Bethesda, MD 20892 USA. [Du, Jihui; Si, Han; Mattox, Austin; Bian, Yansong; Yang, Xinping; Van Waes, Carter; Chen, Zhong] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Du, Jihui] Guangdong Med Coll, Cent Lab, Nanshan Hosp, Shenzhen 518052, Guangdong, Peoples R China. [Romano, Rose-Anne; Sinha, Satrajit] SUNY Buffalo, Dept Biochem, Ctr Excellence Bioinformat & Life Sci, Buffalo, NY 14214 USA. RP Chen, Z (reprint author), NIDCD, Head & Neck Surg Branch, NIH, 10-5D55,MSC 1419, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov; chenz@nidcd.nih.gov FU NIDCD [ZIA-DC-00016, ZIA-DC-00073, ZIA-DC-00074]; NIH [R01AR049238] FX These studies were supported by NIDCD Intramural Projects ZIA-DC-00016, ZIA-DC-00073, and ZIA-DC-00074 (JD, HS, AM, YB, XY, CVW, ZC), and NIH grant R01AR049238 (SS, RR). We wish to thank Ms Jamie Coupar for her technical assistance and Mr Steven Lee and Mr Mark Chang for their assistance in IHC slide scanning and data analysis. We would like to express our appreciation to Drs James W Rocco and Leif W Ellisen (Massachusetts General Hospital and Harvard University, Boston, MA) for providing Delta p63 expression vectors, Dr Thomas Gilmore (Boston University, Boston, MA) for providing human c-Rel expression plasmids, and Dr Jorge Silvio Gutkind (NIDCR/NIH) for providing IL-6 promoter luciferase reporter plasmids with mutations. We are very appreciative of Drs Wanjun Chen (NIDCR/NIH), Christophe Cataisson (NCI/NIH) and Yongge Zhao (NIAID/NIH) for valuable suggestions and critique of the manuscript. NR 68 TC 5 Z9 5 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD FEB PY 2014 VL 232 IS 3 BP 356 EP 368 DI 10.1002/path.4302 PG 13 WC Oncology; Pathology SC Oncology; Pathology GA 304DG UT WOS:000330726500009 PM 24258200 ER PT J AU White, SF Clanton, R Brislin, SJ Meffert, H Hwang, S Sinclair, S Blair, RJR AF White, Stuart F. Clanton, Roberta Brislin, Sarah J. Meffert, Harma Hwang, Soonjo Sinclair, Stephen Blair, R. James R. TI TEMPORAL DISCOUNTING AND CONDUCT DISORDER IN ADOLESCENTS SO JOURNAL OF PERSONALITY DISORDERS LA English DT Article ID CALLOUS-UNEMOTIONAL TRAITS; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; VENTROMEDIAL PREFRONTAL CORTEX; DISRUPTIVE BEHAVIOR DISORDERS; BRAIN STRUCTURE ABNORMALITIES; IMPAIRED DECISION-MAKING; PASSIVE-AVOIDANCE; PSYCHOPATHIC TENDENCIES; REWARD ANTICIPATION; AMYGDALA RESPONSE AB The current study examined temporal discounting (the decrease in subjective reward value as a function of increasing delay) in youths with conduct disorder (CD) and the extent to which this was modulated by level of psychopathic traits. In the temporal discounting task, participants were asked to choose between immediate rewards of varying values and a larger reward, held at a constant value ($10), whose receipt was delayed by different time intervals across trials (e.g., 7 days, 360 days). The level of immediate reward necessary for selection over the larger, delayed reward is the measure of temporal discounting. Forty-six youths (21 with CD and 25 healthy youths) participated in this study. Compared with healthy youths, youths with CD chose significantly smaller amounts of immediate reward rather than the larger future rewards. This was the case even in youths with CD without comorbid attention-deficit/hyperactivity disorder. However, level of psychopathic traits did not modulate temporal discounting in this sample. These results are discussed in terms of neurobiological models of CD and psychopathic traits. C1 [White, Stuart F.; Clanton, Roberta; Meffert, Harma; Hwang, Soonjo; Sinclair, Stephen; Blair, R. James R.] NIMH, Sect Affect Cognit Neurosci, Bethesda, MD USA. [Brislin, Sarah J.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. RP White, SF (reprint author), 9000 Rockville Pike,Bldg 15k,Room 300C, Bethesda, MD 20892 USA. EM whitesf@mail.nih.gov OI Meffert, Harma/0000-0002-7298-7276 FU Intramural NIH HHS [Z01 MH002860-03]; NIMH NIH HHS [ZIA MH002860] NR 57 TC 14 Z9 14 U1 3 U2 15 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0885-579X J9 J PERS DISORD JI J. Pers. Disord. PD FEB PY 2014 VL 28 IS 1 SI SI BP 5 EP 18 PG 14 WC Psychiatry SC Psychiatry GA 304KT UT WOS:000330746500002 PM 24344883 ER PT J AU Enomoto, A Hirata, H Matsumoto, S Saito, K Subramanian, S Krishna, MC Devasahayam, N AF Enomoto, Ayano Hirata, Hiroshi Matsumoto, Shingo Saito, Keita Subramanian, Sankaran Krishna, Murali C. Devasahayam, Nallathamby TI Four-Channel Surface Coil Array for 300-MHz Pulsed EPR Imaging: Proof-of-Concept Experiments SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE FT-EPR imaging; surface coil array; Oxo63; single point imaging; in vivo imaging ID ELECTRON-PARAMAGNETIC-RESONANCE; TIME-DOMAIN EPR; TUMOR HYPOXIA; SPIN-ECHO; MRI; SPECTROSCOPY; ACQUISITION; RESOLUTION; SENSE; SCAN AB Time-domain electron paramagnetic resonance imaging is currently a useful preclinical molecular imaging modality in experimental animals such as mice and is capable of quantitatively mapping hypoxia in tumor implants. The microseconds range relaxation times (T-1 and T-2) of paramagnetic tracers and the large bandwidths (tens of MHz) to be excited by electron paramagnetic resonance pulses for spatial encoding makes imaging of large objects a challenging task. The possibility of using multiple array coils to permit studies on large sized object is the purpose of the present work. Toward this end, the use of planar array coils in different configurations to image larger objects than cannot be fully covered by a single resonator element is explored. Multiple circular surface coils, which are arranged in a plane or at suitable angles mimicking a volume resonator, are used in imaging a phantom and a tumor-bearing mouse leg. The image was formed by combining the images collected from the individual coils with suitable scaling. The results support such a possibility. By multiplexing or interleaving the measurements from each element of such array resonators, one can scale up the size of the subject and at the same time reduce the radiofrequency power requirements and increase the sensitivity. Magn Reson Med 71:853-858, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Enomoto, Ayano; Hirata, Hiroshi] Hokkaido Univ, Grad Sch Informat Sci & Technol, Div Bioengn & Bioinformat, Sapporo, Hokkaido, Japan. [Matsumoto, Shingo; Saito, Keita; Subramanian, Sankaran; Krishna, Murali C.; Devasahayam, Nallathamby] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Biophys Sect, Radiat Biol Branch, Ctr Canc Res,NIH, Bldg 10,Room B3 B35,10 Ctr Dr, Bethesda, MD 20892 USA. EM murali@helix.nih.gov FU Research Fellowship for Young Scientists [24-1486]; NEXT Program of Japan Society for the Promotion of Science [LR002]; Core-to-Core Program of JSPS (Center for Magnetic Resonance Molecular Imaging of In vivo Redox System at Kyushu University, Japan); Center for Cancer Research, NCI; NIH FX Grant sponsor: Research Fellowship for Young Scientists; Grant number: 24-1486; Grant sponsor: NEXT Program of Japan Society for the Promotion of Science; Grant number: LR002; Grant sponsors: Core-to-Core Program of JSPS (Center for Magnetic Resonance Molecular Imaging of In vivo Redox System at Kyushu University, Japan), Center for Cancer Research, NCI, NIH. NR 33 TC 3 Z9 3 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2014 VL 71 IS 2 BP 853 EP 858 DI 10.1002/mrm.24702 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AA0FA UT WOS:000330769700043 PM 23532721 ER PT J AU Kang, K Yamaji, D Yoo, KH Robinson, GW Hennighausen, L AF Kang, Keunsoo Yamaji, Daisuke Yoo, Kyung Hyun Robinson, Gertraud W. Hennighausen, Lothar TI Mammary-Specific Gene Activation Is Defined by Progressive Recruitment of STAT5 during Pregnancy and the Establishment of H3K4me3 Marks SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; CELL FATE; REGULATORY ELEMENTS; TRANSGENIC MICE; MOUSE-LIVER; C/EBP-BETA; GLAND; DIFFERENTIATION; EXPRESSION; PROMOTER AB Differentiation of mammary secretory epithelium during pregnancy is characterized by sequential activation of genes over several orders of magnitude. Although the transcription factor STAT5 is key to alveolar development, it is not clear to what extent it controls temporal activation of genetic programs in secretory epithelium. To uncover molecular mechanisms effecting progressive differentiation, we explored genome-wide STAT5 binding and H3K4me3 (i.e., trimethylated histone H3 at K4) marks in mammary tissues at early and midpregnancy and at parturition. STAT5 binding to genes induced during pregnancy was low in immature mammary tissue but increased with epithelial differentiation. Increased STAT5 binding was associated with the establishment of H3K4me3 marks and transcriptional activation. STAT5 binding preceded the formation of H3K4me3 marks in some mammary-specific genes. De novo STAT5 binding was also found at distal sites, indicating enhancers. Furthermore, we established an exhaustive mammary transcriptome. Through integration of RNA-seq and STAT5 and H3K4me4 ChIP-seq data, we discovered novel mammary-specific alternative promoters and genes, including noncoding RNAs. Our findings suggest that STAT5 is an early step in establishing transcription complexes on genes specifically expressed in mammary epithelium. This is the first study in an organ that links progressive chromatin occupancy of STAT5 to the acquisition of H3K4me3 marks and transcription during hormone-induced differentiation. C1 [Kang, Keunsoo; Yamaji, Daisuke; Yoo, Kyung Hyun; Robinson, Gertraud W.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM lotharh@niddk.nih.gov FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 40 TC 16 Z9 16 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2014 VL 34 IS 3 BP 464 EP 473 DI 10.1128/MCB.00988-13 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 302DQ UT WOS:000330582200015 PM 24277936 ER PT J AU Li, XL Hara, T Choi, YG Subramanian, M Francis, P Bilke, S Walker, RL Pineda, M Zhu, YL Yang, Y Luo, J Wakefield, LM Brabletz, T Park, B Sharma, S Chowdhury, D Meltzer, PS Lal, A AF Li, Xiao Ling Hara, Toshifumi Choi, Youngeun Subramanian, Murugan Francis, Princy Bilke, Sven Walker, Robert L. Pineda, Marbin Zhu, Yuelin Yang, Yuan Luo, Ji Wakefield, Lalage M. Brabletz, Thomas Park, Ben Ho Sharma, Sudha Chowdhury, Dipanjan Meltzer, Paul S. Lal, Ashish TI A p21-ZEB1 Complex Inhibits Epithelial-Mesenchymal Transition through the MicroRNA 183-96-182 Cluster SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BREAST-CANCER CELLS; GENE-EXPRESSION; MIR-200 FAMILY; C-MYC; TRANSCRIPTION FACTOR; TUMOR-METASTASIS; DOWN-REGULATION; TARGETING ZEB1; TGF-BETA; IN-VIVO AB The tumor suppressor p21 acts as a cell cycle inhibitor and has also been shown to regulate gene expression by functioning as a transcription corepressor. Here, we identified p21-regulated microRNAs (miRNAs) by sequencing small RNAs from isogenic p21(+/+) and p21(-/-) cells. Three abundant miRNA clusters, miR-200b-200a-429, miR-200c-141, and miR-183-96-182, were downregulated in p21-deficient cells. Consistent with the known function of the miR-200 family and p21 in inhibition of the epithelial-mesenchymal transition (EMT), we observed EMT upon loss of p21 in multiple model systems. To explore a role of the miR-183-96-182 cluster in EMT, we identified its genome-wide targets and found that miR-183 and miR-96 repressed common targets, including SLUG, ZEB1, ITGB1, and KLF4. Reintroduction of miR-200, miR-183, or miR-96 in p21(-/-) cells inhibited EMT, cell migration, and invasion. Conversely, antagonizing miR-200 and miR-183-96-182 cluster miRNAs in p21(+/+) cells increased invasion and elevated the levels of VIM, ZEB1, and SLUG mRNAs. Furthermore, we found that p21 forms a complex with ZEB1 at the miR-183-96-182 cluster promoter to inhibit transcriptional repression of this cluster by ZEB1, suggesting a reciprocal feedback loop. C1 [Li, Xiao Ling; Hara, Toshifumi; Choi, Youngeun; Subramanian, Murugan; Francis, Princy; Walker, Robert L.; Pineda, Marbin; Zhu, Yuelin; Meltzer, Paul S.; Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Choi, Youngeun; Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Yang, Yuan; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Luo, Ji] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Brabletz, Thomas] Univ Freiburg, Med Ctr, Dept Gen & Visceral Surg, Freiburg, Germany. [Brabletz, Thomas] Univ Freiburg, Med Ctr, Ctr Comprehens Canc, Freiburg, Germany. [Park, Ben Ho] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Breast Canc Res Program, Baltimore, MD USA. [Sharma, Sudha] Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC USA. RP Lal, A (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM ashish.lal@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; DFG [BR 1399/6-1, SFB 850/B2, SFB992/C6]; Deutsche Krebshilfe [109430]; National Institute of General Medical Sciences of the National Institutes of Health [SC1GM093999] FX Ashish Lal was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Thomas Brabletz was supported by the DFG (BR 1399/6-1, SFB 850/B2, and SFB992/C6) and the Deutsche Krebshilfe (grant no. 109430). Sudha Sharma was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number SC1GM093999. NR 68 TC 37 Z9 38 U1 1 U2 26 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2014 VL 34 IS 3 BP 533 EP 550 DI 10.1128/MCB.01043-13 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 302DQ UT WOS:000330582200021 PM 24277930 ER PT J AU Minetti, GC Feige, JN Bombard, F Heier, A Morvan, F Nurnberg, B Leiss, V Birnbaumer, L Glass, DJ Fornaro, M AF Minetti, Giulia C. Feige, Jerome N. Bombard, Florian Heier, Annabelle Morvan, Fredric Nuernberg, Bernd Leiss, Veronika Birnbaumer, Lutz Glass, David J. Fornaro, Mara TI G alpha i2 Signaling Is Required for Skeletal Muscle Growth, Regeneration, and Satellite Cell Proliferation and Differentiation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; DEACETYLASE INHIBITORS; EXPRESSION; MICRORNA-133; HYPERTROPHY; DISEASE; FUSION; MICE AB We have previously shown that activation of G alpha i2, an alpha subunit of the heterotrimeric G protein complex, induces skeletal muscle hypertrophy and myoblast differentiation. To determine whether G alpha i2 is required for skeletal muscle growth or regeneration, G alpha i2-null mice were analyzed. G alpha i2 knockout mice display decreased lean body mass, reduced muscle size, and impaired skeletal muscle regeneration after cardiotoxin-induced injury. Short hairpin RNA (shRNA)-mediated knockdown of G alpha i2 in satellite cells (SCs) leads to defective satellite cell proliferation, fusion, and differentiation ex vivo. The impaired differentiation is consistent with the observation that the myogenic regulatory factors MyoD and Myf5 are downregulated upon knockdown of G alpha i2. Interestingly, the expression of microRNA 1 (miR-1), miR-27b, and miR-206, three microRNAs that have been shown to regulate SC proliferation and differentiation, is increased by a constitutively active mutant of G alpha i2 [G alpha i2(Q205L)] and counter-regulated by G alpha i2 knockdown. As for the mechanism, this study demonstrates that G alpha i2(Q205L) regulates satellite cell differentiation into myotubes in a protein kinase C (PKC)- and histone deacetylase (HDAC)-dependent manner. C1 [Minetti, Giulia C.; Bombard, Florian; Heier, Annabelle; Morvan, Fredric; Fornaro, Mara] Novartis Inst Biomed Res, Basel, Switzerland. [Feige, Jerome N.] Nestle Inst Hlth Sci, Lausanne, Switzerland. [Nuernberg, Bernd; Leiss, Veronika] Univ Tubingen, Eberhard Karls Univ Hosp & Clin, Inst Expt & Clin Pharmacol & Toxicol, Dept Pharmacol & Expt Therapy, Tubingen, Germany. [Nuernberg, Bernd; Leiss, Veronika] Univ Tubingen, Interfac Ctr Pharmacogen & Pharmaceut Res, Tubingen, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Glass, David J.] Novartis Inst Biomed Res, Cambridge, MA USA. RP Fornaro, M (reprint author), Novartis Inst Biomed Res, Forum 1,Novartis Campus, Basel, Switzerland. EM david.glass@novartis.com; mara.fornaro@novartis.com FU intramural research program of the NIH [Z01-ES-101643]; NIBR Presidential Postdoctoral Fellowship; Deutsche Forschungsgemeinschaft FX This research was supported in part by the intramural research program of the NIH (project Z01-ES-101643 to L.B.). G.C.M. is the recipient of an NIBR Presidential Postdoctoral Fellowship. This work was also in part supported by the Deutsche Forschungsgemeinschaft (B.N. and V.L.). NR 29 TC 15 Z9 16 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2014 VL 34 IS 4 BP 619 EP 630 DI 10.1128/MCB.00957-13 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 302DX UT WOS:000330583000004 PM 24298018 ER PT J AU Gonzalez, A Valeiras, M Sidransky, E Tayebi, N AF Gonzalez, Ashley Valeiras, Mark Sidransky, Ellen Tayebi, Nahid TI Lysosomal integral membrane protein-2: A new player in lysosome-related pathology SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Lysosomal integral membrane protein-2; Lysosomal membrane protein; Gaucher disease; Action myoclonus renal failure; Glucocerebrosidase; Transporter ID CARBOXYL CYTOPLASMIC TAIL; LIGAND BETA-GLUCOCEREBROSIDASE; PARKINSONS-DISEASE; GAUCHER-DISEASE; LIMP-II; PERIPHERAL NEUROPATHY; MYOCLONUS EPILEPSY; STORAGE DISORDERS; ALPHA-SYNUCLEIN; ENTEROVIRUS 71 AB Lysosomes require the presence of many specialized proteins to facilitate their roles in cellular maintenance. One such protein that has proven to be an important player in the lysosomal field is lysosomal integral membrane protein-2 (LIMP-2), encoded by the gene SCARB2. LIMP-2 is required for the normal biogenesis and maintenance of lysosomes and endosomes and has been identified as the specific receptor for glucocerebrosidase, the enzyme deficient in Gaucher disease. Research into LIMP-2 and the SCARB2 gene indicate that it may be a factor contributing to the clinical heterogeneity Seen among patients with Gaucher disease. Mutations in SCARB2 have also been identified as the cause of action myoclonus renal failure (AMRF), and in some cases progressive myodonic epilepsy. A total of 14 disease-causing SCARB2 mutations have been identified to date. The role of LIMP-2 in human pathology has expanded with its identification as a component of the intercalated disk in cardiac muscle and as a receptor for specific enteroviruses, two unanticipated findings that reaffirm the myriad roles of lysosomal proteins. Studies into the full impact of LIMP-2 deficiency and the LIMP2/glucocerebrosidase molecular pathway will lead to a better understanding of disease pathogenesis in Gaucher disease and AMRF, and to new insights into lysosomal processing, trafficking and function. Published by Elsevier Inc. C1 [Gonzalez, Ashley; Valeiras, Mark; Sidransky, Ellen; Tayebi, Nahid] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Human Genome Research Institute; National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, and the National Institutes of Health. The authors thank Dr. Elma Aflaki and Julia Fekecs for their assistance with the figures. NR 74 TC 10 Z9 10 U1 0 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 BP 84 EP 91 DI 10.1016/j.ymgme.2013.12.005 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000285 PM 24389070 ER PT J AU Ginns, EI Mak, SKK Ko, N Karlgren, J Akbarian, S Chou, VP Guo, Y Lim, A Samuelsson, S LaMarca, ML Vazquez-DeRose, J Manning-Bog, AB AF Ginns, Edward I. Mak, Sally K-K. Ko, Novie Karlgren, Juliane Akbarian, Schahram Chou, Vivian P. Guo, Yin Lim, Arlene Samuelsson, Steven LaMarca, Mary L. Vazquez-DeRose, Jacqueline Manning-Bog, Amy B. TI Neuroinflammation and alpha-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gaucher disease; Parkinson's disease; alpha-Synuclein; Glucocerebrosidase; Synaptic dysfunction; Neuroinflammation ID INFANTILE GAUCHERS-DISEASE; ONSET PARKINSON-DISEASE; MOUSE MODEL; INDUCED NEURODEGENERATION; LYSOSOMAL DEGRADATION; BRAIN INFLAMMATION; ALZHEIMER-DISEASE; CHROMAFFIN CELLS; IN-VIVO; MUTATIONS AB Clinical, epidemiological and experimental studies confirm a connection between the common degenerative movement disorder Parkinson's disease (PD) that affects over 1 million individuals, and Gaucher disease, the most prevalent lysosomal storage disorder. Recently, human imaging studies have implicated impaired striatal dopaminergic neurotransmission in early PD pathogenesis in the context of Gaucher disease mutations, but the underlying mechanisms have yet to be characterized. In this report we describe and characterize two novel long-lived transgenic mouse models of Gba deficiency, along with a subchronic conduritol-beta-epoxide (CBE) exposure paradigm. All three murine models revealed striking glial activation within nigrostriatal pathways, accompanied by abnormal alpha-synuclein accumulation. Importantly, the CBE-induced, pharmacological Gaucher mouse model replicated this change in dopamine neurotransmission, revealing a markedly reduced evoked striatal dopamine release (approximately 2-fold) that indicates synaptic dysfunction. Other changes in synaptic plasticity markers, including microRNA profile and a 24.9% reduction in post-synaptic density size, were concomitant with diminished evoked dopamine release following CBE exposure. These studies afford new insights into the mechanisms underlying the Parkinson's-Gaucher disease connection, and into the physiological impact of related abnormal alpha-synuclein accumulation and neuroinflammation on nigrostriatal dopaminergic neurotransmission. (C) 2013 Elsevier Inc. All rights reserved. C1 [Ginns, Edward I.; Karlgren, Juliane; Lim, Arlene] Univ Massachusetts, Sch Med, Lysosomal Disorders Treatment & Res Program, Clin Labs, Worcester, MA 01545 USA. [Ginns, Edward I.; Akbarian, Schahram; Guo, Yin; Lim, Arlene] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01545 USA. [Ginns, Edward I.; LaMarca, Mary L.] NIMH, Clin Neurosci Branch, IRP, Bethesda, MD 20892 USA. [Samuelsson, Steven; Vazquez-DeRose, Jacqueline] SRI Int, Ctr Neurosci, Biosci Div, Menlo Pk, CA 94025 USA. [Mak, Sally K-K.; Ko, Novie; Chou, Vivian P.; Manning-Bog, Amy B.] SRI Int, Ctr Hlth Sci, Biosci Div, Menlo Pk, CA 94025 USA. RP Manning-Bog, AB (reprint author), SRI Int, Neurodegenerat Dis, Ctr Hlth Sci, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM amy.manningbog@sri.com FU NIH [NS054120]; National Gaucher Foundation; University of Massachusetts Medical School; Roy and Beatrice Backus Foundation; SRI International SBT Award FX The authors thank Dr. Maria Grazia Spillantini and Dr. Donato A. Di Monte for critical discussions. This research was supported by NIH (NS054120 to EIG), the National Gaucher Foundation (EIG), the University of Massachusetts Medical School, the Roy and Beatrice Backus Foundation (AMB) and an SRI International SBT Award (AMB). NR 95 TC 24 Z9 25 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 BP 152 EP 162 DI 10.1016/j.ymgme.2013.12.003 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000296 PM 24388731 ER PT J AU Aflaki, E Moaven, N Stubblefield, B Sidransky, E AF Aflaki, Elma Moaven, Nima Stubblefield, Barbara Sidransky, Ellen TI Studies in primary and iPSC-derived human Gaucher macrophages demonstrate impaired macrophage function and defective autophagy SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Aflaki, Elma; Moaven, Nima; Stubblefield, Barbara; Sidransky, Ellen] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 5 BP S17 EP S17 DI 10.1016/j.ymgme.2013.12.017 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000007 ER PT J AU King, R AF King, Rebecca TI A qHTS campaign to find compounds that upregulate endogenous NPC1 protein as an attractive therapeutic strategy to Niemann-Pick disease type C (NPC) SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [King, Rebecca] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 122 BP S61 EP S61 DI 10.1016/j.ymgme.2013.12.134 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000124 ER PT J AU Lim, JA Raben, N AF Lim, Jeong-A Raben, Nina TI Mitochondial abnormalities in Pompe disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Lim, Jeong-A; Raben, Nina] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 140 BP S67 EP S67 DI 10.1016/j.ymgme.2013.12.152 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000142 ER PT J AU Meng, XL Shen, JS Kong, M Brady, R Li, RA Schiffmann, R AF Meng, Xingli Shen, Jinsong Kong, Marco Brady, Roscoe Li, Ronald A. Schiffmann, Raphael TI Abnormal intracellular calcium handling: a key pathogenic and therapeutic target of the cardiac manifestations in Fabry disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Meng, Xingli; Shen, Jinsong; Schiffmann, Raphael] Baylor Res Inst, Dallas, TX USA. [Kong, Marco] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Brady, Roscoe] NIH, Bethesda, MD 20892 USA. [Li, Ronald A.] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 165 BP S77 EP S77 DI 10.1016/j.ymgme.2013.12.177 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000167 ER PT J AU Pierson, TM Renvoise, B Chang, J Toro, C Blackstone, C AF Pierson, Tyler Mark Renvoise, Benoit Chang, Jaerak Toro, Camilo Blackstone, Craig TI Hereditary spastic paraplegias types 15 and 11 are associated with lysosomal abnormalities SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Renvoise, Benoit; Chang, Jaerak; Blackstone, Craig] NINDS, NIH, Bethesda, MD 20892 USA. [Toro, Camilo] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 196 BP S86 EP S86 DI 10.1016/j.ymgme.2013.12.208 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000197 ER PT J AU Siebert, M Westbroek, W Chen, YC Moaven, N Li, Y Saraiva-Pereira, ML Martin, S Sidransky, E AF Siebert, Marina Westbroek, Wendy Chen, Yu-Chi Moaven, Nima Li, Yan Saraiva-Pereira, Maria Luiza Martin, Scott Sidransky, Ellen TI MiRNAs and glucocerebrosidase: lessons from miRNA mimic screening SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Siebert, Marina; Westbroek, Wendy; Moaven, Nima; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Siebert, Marina; Saraiva-Pereira, Maria Luiza] Univ Fed Rio Grande do Sul, Postgrad Program Cellular & Mol Biol, Oporto, Portugal. [Chen, Yu-Chi; Martin, Scott] NIH, RNAi Screening Facil, NCATS, Rockville, MD USA. [Li, Yan] NINDS, Prote Core, NIH, Bethesda, MD 20892 USA. [Saraiva-Pereira, Maria Luiza] HCPA, Lab Genet Identificat, Porto Alegre, RS, Brazil. [Saraiva-Pereira, Maria Luiza] HCPA, Med Genet Serv, Porto Alegre, RS, Brazil. [Saraiva-Pereira, Maria Luiza] Univ Fed Rio Grande do Sul, Dept Biochem, Porto Alegre, RS, Brazil. RI Saraiva-Pereira, Maria Luiza/H-6302-2013 OI Saraiva-Pereira, Maria Luiza/0000-0003-3905-9563 NR 0 TC 2 Z9 2 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 226 BP S98 EP S98 DI 10.1016/j.ymgme.2013.12.239 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000227 ER PT J AU Tifft, CJ Kwon, H Regier, DS Golas, GA Johnston, JM Yang, S Baker, EH Vezina, LG AF Tifft, Cynthia J. Kwon, Hj. Regier, Debra S. Golas, Gretchen A. Johnston, Jean M. Yang, Sandra Baker, Eva H. Vezina, L. G. TI Brain MRI in patients with GM1 gangliosidosis, type II: novel scoring system correlates with disease progression and severity SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Tifft, Cynthia J.; Kwon, Hj.; Regier, Debra S.; Golas, Gretchen A.; Johnston, Jean M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Yang, Sandra; Vezina, L. G.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Baker, Eva H.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 241 BP S103 EP S104 DI 10.1016/j.ymgme.2013.12.254 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000242 ER PT J AU Wang, MQ Yu, DZ Swaroop, M Yang, RZ Mckew, JC Gong, DW Zheng, W AF Wang, Mengqiao Yu, Daozhan Swaroop, Manju Yang, Rongze McKew, John C. Gong, Da-Wei Zheng, Wei TI Delta-tocopherol facilitates generation of induced pluripotent stem cells from fibroblasts with Niemann-Pick disease type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Wang, Mengqiao; Swaroop, Manju; McKew, John C.; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Yu, Daozhan; Yang, Rongze; Gong, Da-Wei] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 261 BP S110 EP S110 DI 10.1016/j.ymgme.2013.12.274 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000262 ER PT J AU Zhao, JY Ling, X Cao, SS Liu, XJ Wan, SBA Jiang, T Li, FZ AF Zhao, Jiuyang Ling, Xiang Cao, Shousong Liu, Xiaojun Wan, Shengbiao Jiang, Tao Li, Fengzhi TI Antitumor Activity of FL118, a Survivin, Mcl-1, XIAP, and cIAP2 Selective Inhibitor, Is Highly Dependent on Its Primary Structure and Steric Configuration SO MOLECULAR PHARMACEUTICS LA English DT Article DE IAP inhibitor; FL118; camptothecin analogue; SAR analysis; human tumor animal models; cancer cells ID TRAIL-INDUCED APOPTOSIS; DNA TOPOISOMERASE-I; CANCER-CELLS; TARGETING SURVIVIN; COLORECTAL-CANCER; PROSTATE-CANCER; DOWN-REGULATION; GROWTH-INHIBITION; RECTAL-CANCER; CAMPTOTHECIN AB We recently reported the identification and characterization of a novel small chemical molecule designated FL118. FL118 selectively inhibits multiple cancer survival and proliferation-associated antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and eliminates small and large human tumor xenografts in animal models (Ling et al., PLoS One 2012, 7, e45571). Here, we report a follow-up study on the structure-activity relationship (SAR) of the hydroxyl group in the lactone ring of FL118. We found that the superior antitumor efficacy of FL118 heavily depends on its steric configuration through comparing the antitumor activity of FL118 with FL113 (the racemic mixture of FL118). Consistently, FL118 proved much more effective in inhibiting the expression of survivin, Mcl-1, and cIAP2, both in vitro and in vivo, compared to FL113. Additionally, Tet-on controlled induction of survivin or forced expression of Mcl-1 protects cancer cells from FL118-mediated growth inhibition and cell death. To further explore the SAR, we synthesized seven position 20-esterifiable FL118 and FL113 derivatives. Studies on these seven new compounds revealed that keeping a free hydroxyl group of FL118 is also important for high antitumor efficacy. Together, these studies confirm the superior anticancer activity of FL118 and narrow the window for further SAR studies to generate novel analogues based on FL118 core structure on its other potential chemical positions. C1 [Zhao, Jiuyang; Wan, Shengbiao; Jiang, Tao] Ocean Univ China, Key Lab Marine Drugs, Minist Educ China, Sch Med & Pharm, Qingdao 266003, Shandong, Peoples R China. [Ling, Xiang; Liu, Xiaojun; Li, Fengzhi] Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. [Cao, Shousong] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Li, Fengzhi] Roswell Pk Canc Inst, NCI Supported Expt Therapeut Program, Buffalo, NY 14263 USA. RP Jiang, T (reprint author), Ocean Univ China, Key Lab Marine Drugs, Minist Educ China, Sch Med & Pharm, 5 Yushan Rd, Qingdao 266003, Shandong, Peoples R China. EM jiangtao@ouc.edu.cn; fengzhi.li@roswellpark.org FU Natural Science Foundation of China (NSF) [21171154]; Special Fund for Marine Scientific Research in the Public Interest of China [201005024]; US Army Department of Defense [PC110408]; Mesothelioma Applied Research Foundation (Alexandria, VA); Roswell Park Alliance Foundation (Buffalo, NY); NCI Cancer Center [CA016056] FX We would like to thank the Animal Center (DLAR) staff and attending veterinarians for daily care of our animals at RPCI and helping us to discover possible issues during our experiments. We also would like to thank Ms. Sumei Ren and Xiuli Zhang from the School of Pharmacy, Ocean University of China for their MS and NMR analysis. Additionally, we would like to thank other lab members from the Li and Jiang laboratories for being a part of our team and for their cooperation and support of these studies. We also would like to thank Editor David Hadbawnik of the English Department from the State University of New York (SUNY) at Buffalo (UB) for reading, correcting, and editing this manuscript. Finally, we sincerely thank Dr. Suzanne M. Hess (Research Support Services, Roswell Park Cancer Institute, Buffalo, NY) for critically reading and revision of this manuscript before publication. This work was sponsored in part by grants from Natural Science Foundation of China (NSF) (21171154) and a Special Fund for Marine Scientific Research in the Public Interest of China (201005024) to T.J.; by grants from US Army Department of Defense (PC110408), Mesothelioma Applied Research Foundation (Alexandria, VA), and the Roswell Park Alliance Foundation (Buffalo, NY) to F.L.; and by shared resources supported by NCI Cancer Center Core Support Grant to Roswell Park Cancer Institute (CA016056). Of note, S.C. was paid by grants in part from a grant to F.L. during this work. NR 57 TC 9 Z9 10 U1 4 U2 22 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 FEB PY 2014 VL 11 IS 2 BP 457 EP 467 DI 10.1021/mp4004282 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AA0UI UT WOS:000330812500009 PM 24329001 ER PT J AU Insel, TR AF Insel, T. R. TI Brain somatic mutations: the dark matter of psychiatric genetics? SO MOLECULAR PSYCHIATRY LA English DT Article DE mosaicism; single-cell biology; somatic mutation ID NEUROPSYCHIATRIC DISEASES; L1 RETROTRANSPOSITION; SCHIZOPHRENIA; ANEUPLOIDY; MOSAICISM; CELLS AB Although inherited DNA sequences have a well-demonstrated role in psychiatric disease risk, for even the most heritable mental disorders, monozygotic twins are discordant at a significant rate. The genetic variation associated with mental disorders has heretofore been based on the search for rare or common variation in blood cells. This search is based on the premise that every somatic cell shares an identical DNA sequence, so that variation found in lymphocytes should reflect variation present in brain cells. Evidence from the study of cancer cells, stem cells and now neurons demonstrate that this premise is false. Somatic mutation is common in human cells and has been implicated in a range of diseases beyond cancer. The exuberant proliferation of cortical precursors during fetal development provides a likely environment for somatic mutation in neuronal and glial lineages. Studies of rare neurodevelopmental disorders, such as hemimegencephaly, demonstrate somatic mutations in affected cortical cells that cannot be detected in unaffected parts of the brain or in peripheral cells. This perspective argues for the need to investigate somatic variation in the brain as an explanation of the discordance in monozygotic twins, a proximate cause of mental disorders in individuals with inherited risk, and a potential guide to novel treatment targets. C1 NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, 6001 Execut Blvd,Room 8129, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov NR 23 TC 17 Z9 18 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 FEB PY 2014 VL 19 IS 2 BP 156 EP 158 DI 10.1038/mp.2013.168 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 303WU UT WOS:000330706800010 PM 24342990 ER PT J AU Kunii, Y Hyde, TM Ye, T Li, C Kolachana, B Dickinson, D Weinberger, DR Kleinman, JE Lipska, BK AF Kunii, Y. Hyde, T. M. Ye, T. Li, C. Kolachana, B. Dickinson, D. Weinberger, D. R. Kleinman, J. E. Lipska, B. K. TI Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression SO MOLECULAR PSYCHIATRY LA English DT Article DE bipolar disorder; DARPP-32; dopamine; postmortem brain; schizophrenia; truncated ID AMP-REGULATED PHOSPHOPROTEIN; GENOME SCAN METAANALYSIS; BREAST-CANCER; T-DARPP; PREFRONTAL CORTEX; CEREBRAL-CORTEX; IMMUNOCYTOCHEMICAL LOCALIZATION; MESSENGER-RNA; CELL-GROWTH; DOPAMINE AB Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been of interest in schizophrenia owing to its critical function in integrating dopaminergic and glutaminergic signaling. In a previous study, we identified single-nucleotide polymorphisms (SNPs) and a frequent haplotype associated with cognitive and imaging phenotypes that have been linked with schizophrenia, as well as with expression of prefrontal cortical DARPP-32 messenger RNA (mRNA) in a relatively small sample of postmortem brains. In this study, we examined the association of expression of two major DARPP-32 transcripts, full-length (FL-DARPP-32) and truncated (t-DARPP-32), with genetic variants of DARPP-32 in three brain regions receiving dopaminergic input and implicated in schizophrenia (the dorsolateral prefrontal cortex (DLPFC), hippocampus and caudate) in a much larger set of postmortem samples from patients with schizophrenia, bipolar disorder, major depression and normal controls (>700 subjects). We found that the expression of t-DARPP-32 was increased in the DLPFC of patients with schizophrenia and bipolar disorder, and was strongly associated with genotypes at SNPs (rs879606, rs90974 and rs3764352), as well as the previously identified 7-SNP haplotype related to cognitive functioning. The genetic variants that predicted worse cognitive performance were associated with higher t-DARPP-32 expression. Our results suggest that variation in PPP1R1B affects the abundance of the splice variant t-DARPP-32 mRNA and may reflect potential molecular mechanisms implicated in schizophrenia and affective disorders. C1 [Kunii, Y.; Hyde, T. M.; Ye, T.; Li, C.; Kolachana, B.; Dickinson, D.; Weinberger, D. R.; Kleinman, J. E.; Lipska, B. K.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,Div Intramural R, Bethesda, MD 20892 USA. [Kunii, Y.] Fukushima Med Univ, Sch Med, Dept Neuropsychiat, Fukushima, Japan. [Hyde, T. M.; Ye, T.; Weinberger, D. R.] Lieber Inst Brain Dev, Baltimore, MD USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Div Intramural Res Programs, 10 Ctr Dr,Bldg 10,Room 4N306, Bethesda, MD 20892 USA. EM lipskab@mail.nih.gov RI Lipska, Barbara/E-4569-2017 FU Intramural Research Program of the National Institute of Mental Health; Weinberger and Kleinman laboratories FX We thank Liqin Wang and Vesna Imamovic for their technical expertise, Amy Deep-Soboslay and Dr Llewellyn Bigelow for their diagnostic contributions, Dr Mary Herman for her contribution to the Clinical Brain Disorders Branch/National Institute of Mental Health brain collection, and Dr Ronald Zielke, Robert Johnson and Robert Vigorito at the NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland School of Medicine, for their collection of brains. We thank Dr Andreas Meyer-Lindenberg for his valuable comments on the paper. We also thank the families of the deceased for the donations of brain tissue, and their time and effort devoted to the consent process and interviews. This research was supported by the Intramural Research Program of the National Institute of Mental Health funding of the Weinberger and Kleinman laboratories. NR 48 TC 20 Z9 20 U1 0 U2 9 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 FEB PY 2014 VL 19 IS 2 BP 192 EP 199 DI 10.1038/mp.2012.174 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 303WU UT WOS:000330706800015 PM 23295814 ER PT J AU Vandeleur, CL Merikangas, KR Strippoli, MPF Castelao, E Preisig, M AF Vandeleur, C. L. Merikangas, K. R. Strippoli, M-P F. Castelao, E. Preisig, M. TI Specificity of psychosis, mania and major depression in a contemporary family study SO MOLECULAR PSYCHIATRY LA English DT Article DE family aggregation patterns; mood disorders; psychosis; mania; hypomania; major depression ID TEST-RETEST RELIABILITY; INTER-INFORMANT AGREEMENT; GENETIC-STUDIES DIGS; AFFECTIVE-DISORDERS; SCHIZOAFFECTIVE DISORDER; DIAGNOSTIC INTERVIEW; HISTORY METHOD; BIPOLAR DISORDER; ROSCOMMON FAMILY; KRAEPELINIAN DICHOTOMY AB There has been increasing attention to the subgroups of mood disorders and their boundaries with other mental disorders, particularly psychoses. The goals of the present paper were (1) to assess the familial aggregation and co-aggregation patterns of the full spectrum of mood disorders (that is, bipolar, schizoaffective (SAF), major depression) based on contemporary diagnostic criteria; and (2) to evaluate the familial specificity of the major subgroups of mood disorders, including psychotic, manic and major depressive episodes (MDEs). The sample included 293 patients with a lifetime diagnosis of SAF disorder, bipolar disorder and major depressive disorder (MDD), 110 orthopedic controls, and 1734 adult first-degree relatives. The diagnostic assignment was based on all available information, including direct diagnostic interviews, family history reports and medical records. Our findings revealed specificity of the familial aggregation of psychosis (odds ratio (OR) 2.9, confidence interval (CI): 1.1-7.7), mania (OR = 6.4, CI: 2.2-18.7) and MDEs (OR = 2.0, CI: 1.5-2.7) but not hypomania (OR 1.3, CI: 0.5-3.6). There was no evidence for cross-transmission of mania and MDEs (OR = .7, CI:. 5-1.1), psychosis and mania (OR 1.0, CI:. 4-2.7) or psychosis and MDEs (OR = 1.0, CI:. 7-1.4). The strong familial specificity of psychotic, manic and MDEs in this largest controlled contemporary family study challenges the growing assertion that the major types of mood disorders are manifestations of a common underlying diathesis. C1 [Vandeleur, C. L.; Strippoli, M-P F.; Castelao, E.; Preisig, M.] Univ Lausanne Hosp, Dept Psychiat, CH-1008 Prilly, Switzerland. [Merikangas, K. R.] NIMH, Intramural Res Program, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. RP Vandeleur, CL (reprint author), Univ Lausanne Hosp, Dept Psychiat, Site Cery, CH-1008 Prilly, Switzerland. EM Caroline.Vandeleur@chuv.ch RI Strippoli, Marie-Pierre/K-8164-2013; Preisig, Martin/H-3441-2016 OI Strippoli, Marie-Pierre/0000-0003-3053-484X; FU Swiss National Foundation (SNF) [3200-040677, 32003B-105969, 32003B-118326, 3200-049746, 3200-061974]; GlaxoSmithKline Clinical Genetics FX This research was supported by five grants from the Swiss National Foundation (SNF: No.3200-040677, No.32003B-105969 and No.32003B-118326 to FF; No.3200-049746 and No.3200-061974 to MP), and a grant from GlaxoSmithKline Clinical Genetics. The funders had no involvement in any aspect of this study. We thank the participants and the collaborators who contributed to the coordination of the study and the collection of data. Special thanks to Professor Pierre-Francois Leyvraz, Dr Nicolas Favarger and Professor Daniel Egloff from the Orthopedic Department in Lausanne as well as to Professor Pierre Hoffmeyer from the Orthopedic Department in Geneva for their help with the recruitment of the comparison subjects of this study. The National Institute of Mental Health Intramural Program also contributed to this study. The views expressed herein are those of the author and do not represent those of the US federal government. NR 35 TC 15 Z9 15 U1 1 U2 8 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 FEB PY 2014 VL 19 IS 2 BP 209 EP 213 DI 10.1038/mp.2013.132 PG 5 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 303WU UT WOS:000330706800017 PM 24126925 ER PT J AU Merikangas, KR Cui, L Heaton, L Nakamura, E Roca, C Ding, J Qin, H Guo, W Yao-Shugart, Y Zarate, C Angst, J AF Merikangas, K. R. Cui, L. Heaton, L. Nakamura, E. Roca, C. Ding, J. Qin, H. Guo, W. Yao-Shugart, Y. Zarate, C. Angst, J. TI Independence of familial transmission of mania and depression: results of the NIMH family study of affective spectrum disorders SO MOLECULAR PSYCHIATRY LA English DT Article DE anxiety; bipolar; depression; family study; genetics; mania ID BIPOLAR-II DISORDERS; ANXIETY DISORDERS; UNIPOLAR DEPRESSION; PSYCHIATRIC-DISORDERS; AFFECTIVE-ILLNESS; CO-MORBIDITY; SCHIZOPHRENIA; AGGREGATION; RELATIVES; ALCOHOLISM AB The goal of this study is to investigate the familial transmission of the spectrum of bipolar disorder in a nonclinical sample of probands with a broad range of manifestations of mood disorders. The sample included a total of 447 probands recruited from a clinically enriched community screening and their 2082 adult living and deceased first-degree relatives. A best estimate diagnostic procedure that was based on either direct semistructured interview or structured family history information from multiple informants regarding non-interviewed relatives was employed. Results revealed that there was specificity of familial aggregation of bipolar I (BP I; odds ratio (OR) = 8.40; 3.27-20.97; h2 = 0.83) and major depressive disorder (OR = 2.26; 1.58-3.22; h2 = 0.20), but not BP II. The familial aggregation of BP I was primarily attributable to the familial specificity of manic episodes after adjusting for both proband and relative comorbid anxiety and substance use disorders. There was no significant cross-aggregation between mood disorder subtypes suggesting that the familial transmission of manic and major depressive episodes is independent despite the high magnitude of comorbidity between these mood states. These findings confirm those of earlier studies of the familial aggregation of bipolar disorder and major depression in the first nonclinical sample, and the largest family study of bipolar disorder in the USA using contemporary nonhierarchical diagnostic criteria for mood and anxiety disorders. The results suggest that these major components of bipolar disorder may represent distinct underlying pathways rather than increasingly severe manifestations of a common underlying diathesis. Therefore, dissection of the broad bipolar phenotype in genetic studies could actually generate new findings that could index novel biologic pathways underlying bipolar disorder. C1 [Merikangas, K. R.; Cui, L.; Heaton, L.; Nakamura, E.; Roca, C.] Natl Inst Mental Hlth, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Ding, J.] Natl Inst Aging, Neurogenet Lab, Bethesda, MD USA. [Qin, H.; Guo, W.; Yao-Shugart, Y.] Natl Inst Mental Hlth, Intramural Res Program, Unit Stat Genom, Bethesda, MD 20892 USA. [Zarate, C.] Natl Inst Mental Hlth, Expt Therapeut & Pathophysiol Res Branch, Bethesda, MD 20892 USA. [Angst, J.] Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. RP Merikangas, KR (reprint author), Natl Inst Mental Hlth, Genet Epidemiol Res Branch, Bldg 35,Room 1A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU Intramural Research Program of the National Institute of Mental Health [Z01 MH002804] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (Z01 MH002804). The authors wish to thank the following individuals who contributed to the development, implementation and analysis of the study: Shelli Avenevoli, PhD, Christina Beccue, PsyD, Francesca Belouad, MA, Marcy Burstein, PhD, Susan Goo, MSN, Jian-ping He, MSc, Suzan Khoromi, MD, Femke Lamers, PhD, Tarannum Lateef, MD, MPH, Nancy CP Low, MD, Andrea Marques, MD, PhD, Vetisha McClair, PhD, Suzanne McGarrity, PhD, Judith Mulvihill, LLD, Kelly Murphy, MSW, Anja Schmitz, PhD, Barbara Usher, PhD, Shreeram Srirangam, MD, April Szilagyi, MSW, Shannon Winters, MSW and Jihui Zhang, MD, PhD. The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US Government. NR 38 TC 35 Z9 37 U1 2 U2 9 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 FEB PY 2014 VL 19 IS 2 BP 214 EP 219 DI 10.1038/mp.2013.116 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 303WU UT WOS:000330706800018 PM 24126930 ER PT J AU De Ravin, SS Gray, JT Throm, RE Spindler, J Kearney, M Wu, XL Coffin, JM Hughes, SH Maiderelli, F Sorrentino, BP Malech, HL AF De Ravin, Suk See Gray, John T. Throm, Robert E. Spindler, Jon Kearney, Mary Wu, Xiaolin Coffin, John M. Hughes, Stephen H. Maiderelli, Frank Sorrentino, Brian P. Malech, Harry L. TI False-Positive HIV PCR Test Following Ex Vivo Lentiviral Gene Transfer Treatment of X-linked Severe Combined Immunodeficiency Vector SO MOLECULAR THERAPY LA English DT Letter ID REVERSE-TRANSCRIPTASE; CELL-LINES; THERAPY; CONSTRUCTION C1 [De Ravin, Suk See; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Gray, John T.; Throm, Robert E.; Sorrentino, Brian P.] St Jude Childrens Res Hosp, Memphis, TN USA. [Spindler, Jon; Kearney, Mary; Coffin, John M.; Hughes, Stephen H.; Maiderelli, Frank] NCI, HIV Drug Resistance Program, NIH, Frederick, MD USA. [Wu, Xiaolin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP De Ravin, SS (reprint author), NIAID, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sderavin@niaid.nih.gov OI Malech, Harry/0000-0001-5874-5775 FU Intramural NIH HHS; NCI NIH HHS [R37 CA089441]; NHLBI NIH HHS [P01HL 53749, P01 HL053749] NR 17 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD FEB PY 2014 VL 22 IS 2 BP 244 EP 245 DI 10.1038/mt.2013.296 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 304NP UT WOS:000330753900002 PM 24487563 ER PT J AU Evans, ME Kumkhaek, C Hsieh, MM Donahue, RE Tisdale, JF Uchida, N AF Evans, Molly E. Kumkhaek, Chutima Hsieh, Matthew M. Donahue, Robert E. Tisdale, John F. Uchida, Naoya TI TRIM5 alpha Variations Influence Transduction Efficiency With Lentiviral Vectors in Both Human and Rhesus CD34+Cells In Vitro and In Vivo SO MOLECULAR THERAPY LA English DT Article ID HEMATOPOIETIC REPOPULATING CELLS; MURINE BETA-THALASSEMIA; GENE-THERAPY; PHENOTYPIC CORRECTION; HIV-1 INFECTION; IMMUNODEFICIENCY; RESTRICTION; CYCLOPHILIN; SUSCEPTIBILITY; POLYMORPHISMS AB Human immunodeficiency virus type 1 (HIV-1) vectors can transduce human hematopoietic stem cells (HSC), but transduction efficiency varies among individuals. The innate immune factor tripartite motif-containing protein 5 alpha (TRIM5 alpha) plays an important role for restric-7 tion of retroviral infection. In this study, we examined whether TRIM5a could account for variations in transduction efficiency using both an established rhesus gene therapy model and human CD34(+) cell culture. Evaluation of TRIM5 alpha genotypes (Mamu-1, -2, -3, -4, -5, and TrimCyp) in 16 rhesus macaques that were transplanted with transduced CD34(+) cells showed a significant correlation between TRIM5a Mamu-4 and high gene marking in both lymphocytes and granulocytes 6 months after transplantation. Since significant human TRIM5a coding polymorphisnns were not known, we evaluated TRIM5a expression levels in human CD34(+) cells from 14 donors. Three days after HIV-1 vector transduction, measured transduction efficiency varied significantly among donors and was negatively correlated with TRIM5a expression levels. In summary, transduction efficiency in both rhesus and human CD34(+) cells was influenced by TRIM5 alpha variations (genotypes and expression levels). Our findings are important for both understanding and mitigating the variability of transduction efficiency for rhesus and human CD34(+) cells. C1 [Evans, Molly E.; Kumkhaek, Chutima; Hsieh, Matthew M.; Tisdale, John F.; Uchida, Naoya] NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD 20892 USA. [Donahue, Robert E.] NHLBI, Hematol Branch, NIH, Rockville, MD USA. RP Uchida, N (reprint author), Mol & Clin Hematol Branch, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM uchidan@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute; National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health. We thank Mark E. Metzger, Allen E. Krouse, Aylin C. Bonifacino, Barrington E. Thompson, and Sandra D. Price for the animal care and handling of the animal samples. We thank Kayo Uchida for her assistance in the statistical analysis. We thank J. Philip McCoy and Heidi Sardon for cell sorting. The authors declare no competing financial interests. NR 38 TC 7 Z9 7 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 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD FEB PY 2014 VL 22 IS 2 BP 348 EP 358 DI 10.1038/mt.2013.256 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 304NP UT WOS:000330753900016 PM 28147257 ER PT J AU Huang, XS Shah, S Wang, J Ye, ZH Dowey, SN Tsang, KM Mendelsohn, LG Kato, GJ Kickler, TS Cheng, LZ AF Huang, Xiaosong Shah, Siddharth Wang, Jing Ye, Zhaohui Dowey, Sarah N. Tsang, Kit Man Mendelsohn, Laurel G. Kato, Gregory J. Kickler, Thomas S. Cheng, Linzhao TI Extensive Ex Vivo Expansion of Functional Human Erythroid Precursors Established From Umbilical Cord Blood Cells by Defined Factors SO MOLECULAR THERAPY LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN PERIPHERAL-BLOOD; IN-VITRO; TERMINAL DIFFERENTIATION; MOUSE FIBROBLASTS; PROGENITOR CELLS; CD34(+) CELLS; ENUCLEATION; TRANSFUSION; GENERATION AB There is a constant shortage of red blood cells (RBCs) from sufficiently matched donors for patients who need chronic transfusion. Ex vivo expansion and maturation of human erythroid precursors (erythroblasts) from the patients or optimally matched donors could represent a potential solution. Proliferating erythroblasts can be expanded from umbilical cord blood mononuclear cells (CB MNCs) ex vivo for 10(6)-10(7)-fold (in similar to 50 days) before proliferation arrest and reaching sufficient number for broad application. Here, we report that ectopic expression of three genetic factors (Sox2, c-Myc, and an shRNA against TP53 gene) associated with iPSC derivation enables CB-derived erythroblasts to undergo extended expansion (similar to 10(68)-fold in similar to 12 months) in a serum-free culture condition without change of cell identity or function. These expanding erythroblasts maintain immature erythroblast phenotypes and morphology, a normal diploid karyotype and dependence on a specific combination of growth factors for proliferation throughout expansion period. When being switched to a terminal differentiation condition, these immortalized erythroblasts gradually exit cell cycle, decrease cell size, accumulate hemoglobin, condense nuclei and eventually give rise to enucleated hemoglobin-containing erythrocytes that can bind and release oxygen. Our result may ultimately lead to an alternative approach to generate unlimited numbers of RBCs for personalized transfusion medicine. C1 [Huang, Xiaosong; Shah, Siddharth; Wang, Jing; Ye, Zhaohui; Dowey, Sarah N.; Tsang, Kit Man; Kickler, Thomas S.; Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. [Huang, Xiaosong; Shah, Siddharth; Wang, Jing; Ye, Zhaohui; Dowey, Sarah N.; Tsang, Kit Man; Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA. [Mendelsohn, Laurel G.; Kato, Gregory J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kickler, Thomas S.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Cheng, LZ (reprint author), Edward Miller Res Bldg 747,733 North Broadway, Baltimore, MD 21205 USA. EM lcheng2@jhmi.edu RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Ye, Zhaohui/0000-0001-5272-9168 FU Maryland Stem Cell Research Fund [2010-MSCRFF-0095, 2011-MSCRFII-0088]; NIH [2R01-HL073781]; National Institutes of Health Intramural Research Program [1 ZIA HL006013] FX The authors thank the Johns Hopkins Deep Sequencing & Microarray Core Facility and Conover Talbot Jr for microarray data generation and analysis. The authors also thank other members of the Cheng lab for stimulating discussions. This work was supported in grants from Maryland Stem Cell Research Fund (2010-MSCRFF-0095 to X.H. and 2011-MSCRFII-0088 to L.C.), and a grant from NIH (2R01-HL073781 to L.C.), and Edythe Harris Lucas and Clara Lucas Lynn Chair in Hematology to L.C. G.J.K. is supported by funding from the National Institutes of Health Intramural Research Program (1 ZIA HL006013). The authors declare no conflict of interest. NR 50 TC 12 Z9 12 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD FEB PY 2014 VL 22 IS 2 BP 451 EP 463 DI 10.1038/mt.2013.201 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 304NP UT WOS:000330753900026 PM 24002691 ER PT J AU Lee, RE Hurdle, JG Liu, JY Bruhn, DF Matt, T Scherman, MS Vaddady, PK Zheng, Z Qi, JJ Akbergenov, R Das, S Madhura, DB Rathit, C Trivedi, A Villellas, C Lee, RB Rakesh Waidyarachchi, SL Sun, DQ McNeil, MR Ainsa, JA Boshoff, HI Gonzalez-Juarrero, M Meibohm, B Bottger, EC Lenaerts, AJ AF Lee, Richard E. Hurdle, Julian G. Liu, Jiuyu Bruhn, David F. Matt, Tanja Scherman, Michael S. Vaddady, Pavan K. Zheng, Zhong Qi, Jianjun Akbergenov, Rashid Das, Sourav Madhura, Dora B. Rathit, Chetan Trivedi, Ashit Villellas, Cristina Lee, Robin B. Rakesh Waidyarachchi, Samanthi L. Sun, Dianqing McNeil, Michael R. Ainsa, Jose A. Boshoff, Helena I. Gonzalez-Juarrero, Mercedes Meibohm, Bernd Boettger, Erik C. Lenaerts, Anne J. TI Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux SO NATURE MEDICINE LA English DT Article ID MEDICINAL CHEMISTS GUIDE; 16S RIBOSOMAL-RNA; MYCOBACTERIUM-TUBERCULOSIS; SPECTINOMYCIN MODIFICATION; RESISTANCE; GLYCYLCYCLINE; ANTIBIOTICS; SELECTIVITY; INHIBITION; PUMP AB Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic series of spectinomycin analogs with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross resistance with existing tuberculosis therapeutics, activity against multidrug-resistant (MDR) and extensively drug-resistant tuberculosis and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage-induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target-based tuberculosis drug discovery. C1 [Lee, Richard E.; Hurdle, Julian G.; Liu, Jiuyu; Bruhn, David F.; Zheng, Zhong; Qi, Jianjun; Das, Sourav; Lee, Robin B.; Rakesh; Waidyarachchi, Samanthi L.; Sun, Dianqing] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA. [Matt, Tanja; Akbergenov, Rashid; Boettger, Erik C.] Univ Zurich, Inst Med Mikrobiol, Natl Zentrum Mykobakterien, Zurich, Switzerland. [Scherman, Michael S.; McNeil, Michael R.; Gonzalez-Juarrero, Mercedes] Colorado State Univ, Dept Microbiol, Mycobacterial Res Labs, Ft Collins, CO 80523 USA. [Vaddady, Pavan K.; Madhura, Dora B.; Rathit, Chetan; Trivedi, Ashit; Meibohm, Bernd] Univ Tennessee, Ctr Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, Memphis, TN 38163 USA. [Villellas, Cristina; Ainsa, Jose A.] Univ Zaragoza, Dept Microbiol Med Prevent & Salud Publ, Zaragoza, Spain. [Ainsa, Jose A.] CIBER Enfermedades Resp CIBERES, Madrid, Spain. [Boshoff, Helena I.] NIAID, TB Res Stn, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lee, RE (reprint author), St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 332 N Lauderdale St, Memphis, TN 38105 USA. EM richard.lee@stjude.org RI Lee, Richard/J-4997-2013; Ainsa, Jose/G-5635-2010; Lenaerts, Anne/F-1353-2017 OI Lee, Richard/0000-0002-2397-0443; Ainsa, Jose/0000-0003-2076-844X; FU US National Institutes of Health (NIH) [AI090810]; National Institute of Allergy and Infectious Diseases (NIAID) Indefinite Delivery Indefinite Quantity (IDIQ); Contract Task Order [HHSN272201000009I/01]; American Lebanese Syrian Associated Charities (ALSAC); St. Jude Children's Research Hospital (SJCRH); Intramural Research Program of the NIAID, NIH; Spanish Government [BIO-2009-09405] FX This study was supported by US National Institutes of Health (NIH) grant AI090810 (R.E.L., E.C.B., A.J.L. and B.M.), the National Institute of Allergy and Infectious Diseases (NIAID) Indefinite Delivery Indefinite Quantity (IDIQ) (R.E.L. and M.G.) Contract Task Order HHSN272201000009I/01, the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children's Research Hospital (SJCRH) (R.E.L.) and in part by the Intramural Research Program of the NIAID, NIH (H.I.B.) and the Spanish Government (grant BIO-2009-09405) (J.A.A.). We thank L. Yang and J. Scarborough from SJCRH for their help with analysis of the final compounds, M. Maddox from SJCRH for technical assistance in determining MIC values, J. Ryman from the University of Tennessee Health Science Center for technical assistance in the performance of pharmacokinetic studies in mice, M. Butler from Microbiotix for coordination of the MDR tuberculosis testing and E. Tuomanen from SJCRH for critical evaluation of this manuscript. NR 44 TC 51 Z9 52 U1 7 U2 50 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD FEB PY 2014 VL 20 IS 2 BP 152 EP 158 DI 10.1038/nm.3458 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AA2HF UT WOS:000330915000016 PM 24464186 ER PT J AU Pattanayak, P Bluemke, DA AF Pattanayak, Puskar Bluemke, David A. TI CARDIOVASCULAR IMAGING IN 2013 New era of evidence-based medicine with noninvasive imaging SO NATURE REVIEWS CARDIOLOGY LA English DT Editorial Material ID FRACTIONAL FLOW RESERVE; CORONARY-ARTERY-DISEASE; COMPUTED-TOMOGRAPHY; CHILDHOOD-CANCER; ANGIOGRAPHY; SURVIVORS C1 [Pattanayak, Puskar; Bluemke, David A.] Natl Inst Biomed Imaging & Engn, NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Engn, NIH, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 NR 10 TC 0 Z9 0 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD FEB PY 2014 VL 11 IS 2 BP 74 EP 76 DI 10.1038/nrcardio.2013.215 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA2IP UT WOS:000330918600005 PM 24419259 ER PT J AU Cheng, YL Park, JS Manzanero, S Choi, Y Baik, SH Okun, E Gelderblom, M Fann, DYW Magnus, T Launikonis, BS Mattson, MP Sobey, CG Jo, DG Arumugam, TV AF Cheng, Yi-Lin Park, Jong-Sung Manzanero, Silvia Choi, Yuri Baik, Sang-Ha Okun, Eitan Gelderblom, Mathias Fann, David Yang-Wei Magnus, Tim Launikonis, Bradley S. Mattson, Mark P. Sobey, Christopher G. Jo, Dong-Gyu Arumugam, Thiruma V. TI Evidence that collaboration between HIF-1 alpha and Notch-1 promotes neuronal cell death in ischemic stroke SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Apoptosis; HIF-1 alpha; Ischemic stroke; Neuronal cell death; Notch ID HYPOXIA-INDUCIBLE FACTOR; NF-KAPPA-B; CEREBRAL-ARTERY OCCLUSION; FACTOR-I HIF-1; BRAIN-INJURY; REPERFUSION INJURY; SIGNALING PATHWAY; FOCAL ISCHEMIA; TARGET GENES; PIVOTAL ROLE AB Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1 alpha (HIF-1 alpha), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1 alpha pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, gamma-secretase, and a HIP-1 alpha inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIP-1 alpha further decreased neuronal death. HIP-1 alpha and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIP-1 alpha in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIP-1 alpha inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIP-1 alpha also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of gamma-secretase and HIF-1 alpha exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIP-1 alpha collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke. (C) 2013 Elsevier Inc. All rights reserved. C1 [Cheng, Yi-Lin; Arumugam, Thiruma V.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore. [Cheng, Yi-Lin; Manzanero, Silvia; Fann, David Yang-Wei; Launikonis, Bradley S.; Arumugam, Thiruma V.] Univ Queensland, Sch Biomed Sci, St Lucia, Qld 4072, Australia. [Park, Jong-Sung; Choi, Yuri; Baik, Sang-Ha; Jo, Dong-Gyu; Arumugam, Thiruma V.] Sungkyunkwan Univ, Sch Pharm, Suwon 440746, South Korea. [Okun, Eitan] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Leslie & Susan Gonda Multidisciplinary Brain Res, Ramat Gan, Israel. [Gelderblom, Mathias; Magnus, Tim] Univ Clin Hamburg Eppendorf, Dept Neurol, D-20246 Hamburg, Germany. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Sobey, Christopher G.] Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia. RP Jo, DG (reprint author), Sungkyunkwan Univ, Sch Pharm, 300 Cheoncheon Dong, Suwon 440746, South Korea. EM jodg@skku.edu; phstva@nus.edu.sg RI Arumugam, Thiruma/B-4898-2011; Launikonis, Bradley/K-6256-2015 FU National Research Foundation of Korea [2012R1A2A2A01047551, 2012R1A1A2009093]; Korea Healthcare technology R&D project from the Korean Government [A092042]; National Heart Foundation of Australia [G 09B 4272]; Australian National Health and Medical Research Council [NHMRC APP1008048]; Australian Research Council Future Fellowship [ARCFT100100427]; Intramural Research Program of the National Institute on Aging FX This research was supported by the National Research Foundation of Korea grants (2012R1A2A2A01047551 & 2012R1A1A2009093), a grant of the Korea Healthcare technology R&D project (A092042) from the Korean Government, a grant by the National Heart Foundation of Australia for a Grant-In-Aid (G 09B 4272), an Australian National Health and Medical Research Council grant (NHMRC APP1008048), an Australian Research Council Future Fellowship to TVA (ARCFT100100427) and an Intramural Research Program of the National Institute on Aging. NR 48 TC 15 Z9 20 U1 2 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2014 VL 62 BP 286 EP 295 DI 10.1016/j.nbd.2013.10.009 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 301SY UT WOS:000330553600026 PM 24141018 ER PT J AU Dwyer, JT Woteki, C Bailey, R Britten, P Carriquiry, A Gaine, PC Miller, D Moshfegh, A Murphy, MM Edge, MS AF Dwyer, Johanna T. Woteki, Catherine Bailey, Regan Britten, Patricia Carriquiry, Alicia Gaine, P. Courtney Miller, Dennis Moshfegh, Alanna Murphy, Mary M. Edge, Marianne Smith TI Fortification: new findings and implications SO NUTRITION REVIEWS LA English DT Review DE daily values; dietary patterns; fortification; upper levels ID DIETARY-SUPPLEMENT USE; UNITED-STATES; FOOD FORTIFICATION; IRON-ABSORPTION; PEARL-MILLET; US ADULTS; BIOFORTIFICATION; NUTRIENTS; CHILDREN; FOLATE AB This article reviews the current landscape regarding food fortification in the United States; the content is based on a workshop sponsored by the North American Branch of the International Life Sciences Institute. Fortification of the food supply with vitamins and minerals is a public health strategy to enhance nutrient intakes of the population without increasing caloric intake. Many individuals in the United States would not achieve recommended micronutrient intakes without fortification of the food supply. The achievement and maintenance of a desirable level of nutritional quality in the nation's food supply is, thus, an important public health objective. While the addition of nutrients to foods can help maintain and improve the overall nutritional quality of diets, indiscriminate fortification of foods could result in overfortification or underfortification in the food supply and nutrient imbalances in the diets of individuals. Any changes in food fortification policy for micronutrients must be considered within the context of the impact they will have on all segments of the population and of food technology and safety applications and their limitations. This article discusses and evaluates the value of fortification, the success of current fortification efforts, and the future role of fortification in preventing or reversing nutrient inadequacies. (C) 2014 International Life Sciences Institute C1 [Dwyer, Johanna T.] Tufts Med Sch, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Med Ctr, Frances Stern Nutr Ctr, Boston, MA 02111 USA. [Woteki, Catherine] USDA, Dept Res Educ & Econ, Washington, DC 20250 USA. [Bailey, Regan] NIH, Bethesda, MD 20892 USA. [Britten, Patricia] USDA Ctr Nutr Policy & Promot, Alexandria, VA USA. [Carriquiry, Alicia] Iowa State Univ, Dept Stat, Ames, IA USA. [Gaine, P. Courtney] Int Life Sci Inst, Washington, DC USA. [Miller, Dennis] Cornell Univ, Dept Food Sci, Ithaca, NY 14853 USA. [Moshfegh, Alanna] USDA ARS, Beltsville Human Nutr Res, Beltsville, MD USA. [Murphy, Mary M.] Exponent Inc, Washington, DC USA. [Edge, Marianne Smith] Int Food Informat Council, Washington, DC USA. RP Dwyer, JT (reprint author), Tufts Med Sch, 800 Washington St,Box 783, Boston, MA 02111 USA. EM Jdwyer1@tuftsmedicalcenter.org OI Dwyer, Johanna/0000-0002-0783-1769 FU ILSI North America Committee on Fortification FX Support in preparing the manuscript was provided by the ILSI North America Committee on Fortification. NR 66 TC 10 Z9 10 U1 6 U2 61 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD FEB PY 2014 VL 72 IS 2 BP 127 EP 141 DI 10.1111/nure.12086 PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 304NV UT WOS:000330754500007 PM 24447229 ER PT J AU Chew, EY Clemons, TE Bressler, SB Elman, MJ Danis, RP Domalpally, A Heier, JS Kim, JE Garfinkel, R AF Chew, Emily Y. Clemons, Traci E. Bressler, Susan B. Elman, Michael J. Danis, Ronald P. Domalpally, Amitha Heier, Jeffrey S. Kim, Judy E. Garfinkel, Richard CA AREDS2 HOME Study Res Grp TI Randomized Trial of a Home Monitoring System for Early Detection of Choroidal Neovascularization Home Monitoring of the Eye (HOME) Study SO OPHTHALMOLOGY LA English DT Article ID PREFERENTIAL HYPERACUITY PERIMETER; MACULAR DEGENERATION; VISUAL IMPAIRMENT; SUBGROUP ANALYSIS; UNITED-STATES; RANIBIZUMAB; PREVALENCE; MULTICENTER; BEVACIZUMAB; DISEASE AB Objective: To determine whether home monitoring with the ForeseeHome device (Notal Vision Ltd, Tel Aviv, Israel), using macular visual field testing with hyperacuity techniques and telemonitoring, results in earlier detection of age-related macular degenerationeassociated choroidal neovascularization (CNV), reflected in better visual acuity, when compared with standard care. The main predictor of treatment outcome from anti-vascular endothelial growth factor (VEGF) agents is the visual acuity at the time of CNV treatment. Design: Unmasked, controlled, randomized clinical trial. Participants: One thousand nine hundred and seventy participants 53 to 90 years of age at high risk of CNV developing were screened. Of these, 1520 participants with a mean age of 72.5 years were enrolled in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2 clinical centers. Interventions: In the standard care and device arms arm, investigator-specific instructions were provided for self-monitoring vision at home followed by report of new symptoms to the clinic. In the device arm, the device was provided with recommendations for daily testing. The device monitoring center received test results and reported changes to the clinical centers, which contacted participants for examination. Main Outcome Measures: The main outcome measure was the difference in best-corrected visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical examination, color fundus photography, fluorescein angiography, and optical coherence tomography findings. Masked graders at a central reading center evaluated the images using standardized protocols. Results: Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and April 2013. At the prespecified interim analysis, 82 participants progressed to CNV, 51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, -4 letters; interquartile range [IQR], -11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, -14.0 to -4.0 letters; P = 0.021), resulting in better visual acuity at CNV detection in the device arm. The Data and Safety Monitoring Committee recommended early study termination for efficacy. Conclusions: Persons at high risk for CNV developing benefit from the home monitoring strategy for earlier detection of CNV development, which increases the likelihood of better visual acuity results after intravitreal antiVEGF therapy. (C) 2014 by the American Academy of Ophthalmology. C1 [Chew, Emily Y.] NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Bressler, Susan B.] Johns Hopkins Univ, Wilmer Eye Inst, Retina Div, Baltimore, MD 21218 USA. [Elman, Michael J.] Elman Retina Grp, PA, Baltimore, MD USA. [Danis, Ronald P.; Domalpally, Amitha] Univ Wisconsin, Madison, WI USA. [Heier, Jeffrey S.] Ophthalm Consultants Boston, Boston, MA USA. [Kim, Judy E.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Garfinkel, Richard] Retina Grp Washington, Washington, DC USA. RP Chew, EY (reprint author), NIH, Bldg 10,CRC,Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov RI Domalpally, Amitha/B-2367-2015 FU Notal Vision Ltd; National Eye Institute, National Institutes of Health, Bethesda, Maryland [CTA-00833]; National Eye Institute, National Institutes of Health [HHS-N-260-2005-00007-C, N01-EY-5-0007]; Research to Prevent Blindness, Inc, New York, New York; Research to Prevent Blindness, Inc. FX Supported by Notal Vision Ltd through a clinical trial agreement with the National Eye Institute, National Institutes of Health, Bethesda, Maryland (grant no.: CTA-00833); and a service agreement with EMMES Corporation. The Age-Related Eye Disease Study 2 study is supported by the intramural program funds and contracts from the National Eye Institute, National Institutes of Health (contract nos.: HHS-N-260-2005-00007-C, N01-EY-5-0007). Susan B. Bressler is supported by a Physician-Scientist grant from Research to Prevent Blindness, Inc, New York, New York. Judy E. Kim is supported by Research to Prevent Blindness, Inc. Emily Chew and Traci Clemons had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses. The investigators designed and executed the study in collaboration with the sponsors of the study. The analyses were performed independently in the Coordinating Center. The Data and Safety Monitoring Committees evaluated both the study design and the study data. The manuscript was drafted by the investigators with collaboration and input from the sponsors. NR 26 TC 29 Z9 29 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2014 VL 121 IS 2 BP 535 EP 544 DI 10.1016/j.ophtha.2013.10.027 PG 10 WC Ophthalmology SC Ophthalmology GA 302CO UT WOS:000330579200019 ER PT J AU Levin, MH Pistilli, M Daniel, E Gangaputra, SS Nussenblatt, RB Rosenbaum, JT Suhler, EB Thorne, JE Foster, CS Jabs, DA Levy-Clarke, GA Kempen, JH AF Levin, Marc H. Pistilli, Maxwell Daniel, Ebenezer Gangaputra, Sapna S. Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Levy-Clarke, Grace A. Kempen, John H. CA Systemic Immunosuppressive Therapy TI Incidence of Visual Improvement in Uveitis Cases with Visual Impairment Caused by Macular Edema SO OPHTHALMOLOGY LA English DT Article ID INTRAOCULAR INFLAMMATORY DISEASE; OPTICAL COHERENCE TOMOGRAPHY; OCULAR INFLAMMATION; EYE DISEASES; RISK; ACUITY; COMPLICATIONS; INTERMEDIATE; THERAPY; SMOKING AB Purpose: Among cases of visually significant uveitic macular edema (ME), to estimate the incidence of visual improvement and identify predictive factors. Design: Retrospective cohort study. Participants: Eyes with uveitis, seen at 5 academic ocular inflammation centers in the United States, for which ME was documented to be currently present and the principal cause of reduced visual acuity (<20/40). Methods: Data were obtained by standardized chart review. Main Outcome Measures: Decrease of >= 0.2 base 10 logarithm of visual acuity decimal fraction-equivalent; risk factors for such visual improvement. Results: We identified 1510 eyes (of 1077 patients) with visual impairment to a level <20/40 attributed to ME. Most patients were female (67%) and white (76%), and had bilateral uveitis (82%). The estimated 6-month incidence of >= 2 lines of visual acuity improvement in affected eyes was 52% (95% confidence interval [CI], 49%-55%). Vision reduced by ME was more likely to improve by 2 lines in eyes initially with poor visual acuity (<= 20/200; adjusted hazard ratio [HR] 1.5; 95% CI, 1.3-1.7), active uveitis (HR, 1.3; 95% CI, 1.1-1.5), and anterior uveitis as opposed to intermediate (HR, 1.2), posterior (HR, 1.3), or panuveitis (HR, 1.4; overall P 0.02). During follow-up, reductions in anterior chamber or vitreous cellular activity or in vitreous haze each led to significant improvements in visual outcome (P < 0.001 for each). Conversely, snowbanking (HR, 0.7; 95% CI, 0.4-0.99), posterior synechiae (HR, 0.8; 95% CI, 0.6-0.9), and hypotony (HR, 0.2; 95% CI, 0.06-0.5) each were associated with lower incidence of visual improvement with respect to eyes lacking each of these attributes at a given visit. Conclusions: These results suggest that many, but not all, patients with ME causing low vision in a tertiary care setting will enjoy meaningful visual recovery in response to treatment. Evidence of significant ocular damage from inflammation (posterior synechiae and hypotony) portends a lower incidence of visual recovery. Better control of anterior chamber or vitreous activity is associated with a greater incidence of visual improvement, supporting an aggressive anti-inflammatory treatment approach for ME cases with active inflammation. (C) 2014 by the American Academy of Ophthalmology. C1 [Levin, Marc H.; Pistilli, Maxwell; Daniel, Ebenezer; Kempen, John H.] Univ Penn, Perelman Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gangaputra, Sapna S.] Univ Wisconsin, Sch Med, Dept Ophthalmol, Fundus Photograph Reading Ctr, Madison, WI 53706 USA. [Nussenblatt, Robert B.; Levy-Clarke, Grace A.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Preventat Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Pistilli, Maxwell/0000-0002-4266-4150 FU National Eye Institute [EY014943]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; Veteran's Affairs Administration; intramural funds of the National Eye Institute FX Supported primarily by National Eye Institute Grant EY014943 (Dr. Kempen). Additional support was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation. During part of the conduct of this project, Dr. Levin was a Heed Ophthalmic Society Fellowship recipient, Dr. Kempenwas a Research to Prevent Blindness James S. Adams Special Scholar Award recipient, Dr. Thorne was a Research to Prevent Blindness Harrington Special Scholar Award recipient, and Drs. Jabs and Rosenbaumwere Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Suhler receives support from the Veteran's Affairs Administration. Dr. LevyClarke was previously supported by and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute. The funding organizations had no role in the design or conduct of this research. NR 31 TC 14 Z9 15 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2014 VL 121 IS 2 BP 588 EP + DI 10.1016/j.ophtha.2013.09.023 PG 9 WC Ophthalmology SC Ophthalmology GA 302CO UT WOS:000330579200026 PM 24332536 ER PT J AU Avery, CL Sitlani, CM Arking, DE Arnett, DK Bis, JC Boerwinkle, E Buckley, BM Chen, YDI de Craen, AJM Eijgelsheim, M Enquobahrie, D Evans, DS Ford, I Garcia, ME Gudnason, V Harris, TB Heckbert, SR Hochner, H Hofman, A Hsueh, WC Isaacs, A Jukema, JW Knekt, P Kors, JA Krijthe, BP Kristiansson, K Laaksonen, M Liu, Y Li, X MacFarlane, PW Newton-Cheh, C Nieminen, MS Oostra, BA Peloso, GM Porthan, K Rice, K Rivadeneira, FF Rotter, JI Salomaa, V Sattar, N Siscovick, DS Slagboom, PE Smith, AV Sotoodehnia, N Stott, DJ Stricker, BH Sturmer, T Trompet, S Uitterlinden, AG van Duijn, C Westendorp, RGJ Witteman, JC Whitsel, EA Psaty, BM AF Avery, C. L. Sitlani, C. M. Arking, D. E. Arnett, D. K. Bis, J. C. Boerwinkle, E. Buckley, B. M. Chen, Y-D Ida de Craen, A. J. M. Eijgelsheim, M. Enquobahrie, D. Evans, D. S. Ford, I. Garcia, M. E. Gudnason, V. Harris, T. B. Heckbert, S. R. Hochner, H. Hofman, A. Hsueh, W-C Isaacs, A. Jukema, J. W. Knekt, P. Kors, J. A. Krijthe, B. P. Kristiansson, K. Laaksonen, M. Liu, Y. Li, X. MacFarlane, P. W. Newton-Cheh, C. Nieminen, M. S. Oostra, B. A. Peloso, G. M. Porthan, K. Rice, K. Rivadeneira, F. F. Rotter, J. I. Salomaa, V. Sattar, N. Siscovick, D. S. Slagboom, P. E. Smith, A. V. Sotoodehnia, N. Stott, D. J. Stricker, B. H. Stuermer, T. Trompet, S. Uitterlinden, A. G. van Duijn, C. Westendorp, R. G. J. Witteman, J. C. Whitsel, E. A. Psaty, B. M. TI Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval SO PHARMACOGENOMICS JOURNAL LA English DT Article DE gene-environment interaction; genetic epidemiology; QT interval ID GENOME-WIDE ASSOCIATION; CHRONIC HEPATITIS-C; TORSADE-DE-POINTES; HEART-RATE; CARDIAC REPOLARIZATION; COMMON VARIANTS; OLDER-ADULTS; PROLONGATION; MORTALITY; DURATION AB Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the ` missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use = 13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction > 5.0 x 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects. C1 [Avery, C. L.; Arnett, D. K.; Stuermer, T.; Whitsel, E. A.] Univ N Carolina, Dept Epidemiol, Bank Amer Ctr, Chapel Hill, NC 27514 USA. [Sitlani, C. M.; Bis, J. C.; Enquobahrie, D.; Heckbert, S. R.; Hochner, H.; Siscovick, D. S.; Psaty, B. M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Arking, D. E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Arking, D. E.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Arnett, D. K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Boerwinkle, E.] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77030 USA. [Boerwinkle, E.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Buckley, B. M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Chen, Y-D Ida; Li, X.; Rotter, J. I.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [de Craen, A. J. M.; Westendorp, R. G. J.] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, Leiden, Netherlands. [Eijgelsheim, M.; Hofman, A.; Kors, J. A.; Krijthe, B. P.; Rivadeneira, F. F.; Stricker, B. H.; Uitterlinden, A. G.; Witteman, J. C.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Evans, D. S.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Ford, I.] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Garcia, M. E.; Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Gudnason, V.; Smith, A. V.] Iceland Heart Assoc, Kopavogur, Iceland. [Heckbert, S. R.; Siscovick, D. S.; Psaty, B. M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Hofman, A.; Krijthe, B. P.; Rivadeneira, F. F.; Stricker, B. H.; Uitterlinden, A. G.; Witteman, J. C.] Netherlands Consortium Hlth Aging NCHA, Leiden, Netherlands. [Hsueh, W-C] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Isaacs, A.; Oostra, B. A.; van Duijn, C.] Erasmus Univ, Dept Epidemiol, Genet Epidemiol Unit, Med Ctr, Rotterdam, Netherlands. [Isaacs, A.; Oostra, B. A.; van Duijn, C.] Ctr Med Syst Biol, Leiden, Netherlands. [Jukema, J. W.; Trompet, S.] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Knekt, P.; Kristiansson, K.; Laaksonen, M.; Salomaa, V.] THL Natl Inst Hlth & Welf, Helsinki, Finland. [Kors, J. A.; Stricker, B. H.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Liu, Y.] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [MacFarlane, P. W.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Newton-Cheh, C.] Broad Inst Harvard, 4Program Med & Populat Genet, Cambridge, MA USA. [Newton-Cheh, C.] MIT, Cambridge, MA 02139 USA. [Newton-Cheh, C.] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Ctr Human Genet Res, Boston, MA USA. [Newton-Cheh, C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nieminen, M. S.; Porthan, K.] Univ Helsinki, Cent Hosp, Dept Med, Div Cardiol, Helsinki, Finland. [Peloso, G. M.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Peloso, G. M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Rice, K.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rivadeneira, F. F.; Stricker, B. H.; Uitterlinden, A. G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sattar, N.] BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow, Lanark, Scotland. [Slagboom, P. E.] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [Sotoodehnia, N.] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Stott, D. J.] Univ Glasgow, Inst Cardiovasc & Med Sci, Acad Sect Geriatr Med, Glasgow, Lanark, Scotland. [Whitsel, E. A.] Univ N Carolina, Dept Med, Chapel Hill, NC 27514 USA. [Psaty, B. M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, B. M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, B. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. RP Avery, CL (reprint author), Univ N Carolina, Dept Epidemiol, Bank Amer Ctr, 137 East Franklin St,Suite 306, Chapel Hill, NC 27514 USA. EM christy_avery@unc.edu RI Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Slagboom, P. Eline/R-4790-2016; OI Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Slagboom, P. Eline/0000-0002-2875-4723; Kristiansson, Kati/0000-0003-4688-107X; Rivadeneira, Fernando/0000-0001-9435-9441 FU National Heart, Lung and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C]; National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS) [UL1RR025005]; National Heart, Lung and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079-N01-HC-85086, N01-HC35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C]; NHLBI [HL080295, HL075366, HL087652, HL105756, N02-HL-6-4278]; NINDS [HL080295, HL075366, HL087652, HL105756]; NIA [AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Center for Research Resources CTSI [DK063491]; National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine [N01-HC-25195]; SNP Health Association Resource (SHARe) project [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Doris Duke Charitable Foundation and the Burroughs Wellcome Fund (Newton-Cheh); NIH [HL080025]; Orion-Farmos Research Foundation; Finnish Foundation for Cardiovascular Research; Academy of Finland [29494, 139635]; National Institutes of Health to The Johns Hopkins University [HHSN268200782096C]; Intramural Research Program of the NIH, National Institute on Aging; National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators; Clinical Translational Science Institute [UL1RR033176]; Cedars-Sinai General Clinical Research Center Grant [RR00425]; Established Clinical Investigator of the Netherlands Heart Foundation [2001 D 032]; seventh framework program of the European commission [223004]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant) [050-060-810]; Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly; Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; and the Municipality of Rotterdam; Netherlands Organization for Scientific Research (NWO) [175.010.2005.011, 911.03.012]; Research Institute for Diseases in the Elderly (RIDE); Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810]; National Heart, Lung, and Blood Institute; [N01 HC-95159-N01-HC-95169]; [RR-024156] FX Atherosclerosis Risk in Communities Study (ARIC): The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant No. UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS): This CHS research was supported by National Heart, Lung and Blood Institute (NHLBI) Contracts N01-HC-85239, N01-HC-85079-N01-HC-85086; N01-HC35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI Grants HL080295, HL075366, HL087652 and HL105756, with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the NIA. See also http://www. chs-nhlbi. org/pi. htm. DNA handling and genotyping was supported in part by National Center for Research Resources CTSI Grant UL 1RR033176, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK063491 to the Southern California Diabetes Endocrinology Research Center and the Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR). Framingham Heart Study (FHS): FHS work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (Contract No. N01-HC-25195), its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278), based on analyses by FHS investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II), funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Measurement of the Gen 3 ECGs was supported by grants from the Doris Duke Charitable Foundation and the Burroughs Wellcome Fund (Newton-Cheh) and the NIH (HL080025, Newton-Cheh). Health 2000: Supported by the Orion-Farmos Research Foundation (KK and KP), the Finnish Foundation for Cardiovascular Research (KK, KP) and the Academy of Finland (Grant Nos. 129494 and 139635 to VS). Health Aging, Body and Composition (Health ABC): This research 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 National Institutes of Health to The Johns Hopkins University, Contract No. HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Multi-Ethnic Study of Atherosclerosis (MESA): MESA and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by Grants and Contracts N01 HC-95159-N01-HC-95169 and RR-024156.; Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. Additional funding was supported in part by the Clinical Translational Science Institute Grant UL1RR033176 and the Cedars-Sinai General Clinical Research Center Grant RR00425. We also thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www. mesa-nhlbi. org. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Professor Dr J W Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (Grant No. 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (Grant No. 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant 050-060-810). Rotterdam Study (RS): The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research; The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by The Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Project No. 050-060-810. This collaborative effort was supported by an award from the National Heart, Lung and Blood Institute (R01-HL-103612, PI BMP). CLA was supported in part by Grant R00-HL-098458 from the National Heart, Lung, and Blood Institute. NR 62 TC 6 Z9 6 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X EI 1473-1150 J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD FEB PY 2014 VL 14 IS 1 BP 6 EP 13 DI 10.1038/tpj.2013.4 PG 8 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 302TL UT WOS:000330627700002 PM 23459443 ER PT J AU Boverhof, DR Ladics, G Luebke, B Botham, J Corsini, E Evans, E Germolec, D Holsapple, M Loveless, SE Lu, H van der Laan, JW White, KL Yang, Y AF Boverhof, Darrell R. Ladics, Greg Luebke, Bob Botham, Jane Corsini, Emanuela Evans, Ellen Germolec, Dori Holsapple, Michael Loveless, Scott E. Lu, Haitian van der Laan, Jan Willem White, Kimber L., Jr. Yang, Yung TI Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: A workshop summary SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE lmmunotoxicity; Environmental chemicals; Testing ID HAZARD IDENTIFICATION PURPOSES; REPRODUCTIVE-SYSTEM FUNCTION; ASSESSING HUMORAL IMMUNITY; RISK-ASSESSMENT; IN-VITRO; DEVELOPMENTAL IMMUNOTOXICOLOGY; SKIN SENSITIZATION; PREDICTIVE IDENTIFICATION; STANDARD TOXICOLOGY; SAFETY ASSESSMENT AB As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and' new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity. (C) 2013 Elsevier Inc. All rights reserved. C1 [Boverhof, Darrell R.] Dow Chem Co USA, Midland, MI 48674 USA. [Ladics, Greg] DuPont Pioneer, Wilmington, DE USA. [Luebke, Bob] US EPA, Cardiopulm & Immunotoxicol Branch, Res Triangle Pk, NC 27711 USA. [Botham, Jane] Syngenta Ltd, Macclesfield, Cheshire, England. [Corsini, Emanuela] Univ Milan, Dipartimento Sci Farmacol & Biomol, Toxicol Lab, Milan, Italy. [Evans, Ellen] Pfizer Inc, Groton, CT USA. [Germolec, Dori] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Holsapple, Michael] Battelle Mem Inst, Columbus, OH 43201 USA. [Loveless, Scott E.] DuPont Haskell Global Ctr Hlth & Environm Sci, Newark, DE USA. [Lu, Haitian] Dow AgroSci, Indianapolis, IN USA. [van der Laan, Jan Willem] Med Evaluat Board, Utrecht, Netherlands. [White, Kimber L., Jr.] ImmunoTox Inc, Richmond, VA USA. [Yang, Yung] US EPA, Off Pesticide Programs, Washington, DC 20460 USA. RP Boverhof, DR (reprint author), Dow Chem Co USA, 1803 Bldg, Midland, MI 48674 USA. EM rboverhof@dow.com NR 76 TC 7 Z9 8 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD FEB PY 2014 VL 68 IS 1 BP 96 EP 107 DI 10.1016/j.yrtph.2013.11.012 PG 12 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 302JT UT WOS:000330601500011 PM 24280359 ER PT J AU Raju, TNK Mercer, BM AF Raju, Tonse N. K. Mercer, Brian M. TI Periviable birth: Management and counseling issues-Part 2 SO SEMINARS IN PERINATOLOGY LA English DT Editorial Material C1 [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. [Mercer, Brian M.] Case Western Reserve Univ, Metrohlth Med Ctr, Soc Maternal Fetal Med, Cleveland, OH USA. RP Raju, TNK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD FEB PY 2014 VL 38 IS 1 BP 1 EP 1 DI 10.1053/j.semperi.2013.07.001 PG 1 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AA2HO UT WOS:000330915900001 PM 24468562 ER PT J AU Denton, KR Lei, L Grenier, J Rodionov, V Blackstone, C Li, XJ AF Denton, Kyle R. Lei, Ling Grenier, Jeremy Rodionov, Vladimir Blackstone, Craig Li, Xue-Jun TI Loss of Spastin Function Results in Disease-Specific Axonal Defects in Human Pluripotent Stem Cell-Based Models of Hereditary Spastic Paraplegia SO STEM CELLS LA English DT Article DE Induced pluripotent stem cells; Human embryonic stem cells; Spastin; Hereditary spastic paraplegia; Axonal degeneration; RNA interference ID SPINAL MUSCULAR-ATROPHY; NEURODEGENERATIVE DISEASES; HUNTINGTONS-DISEASE; TUBULIN ACETYLATION; PARKINSONS-DISEASE; TRANSPORT DEFECTS; CORTICAL-NEURONS; NERVOUS-SYSTEM; IPS CELLS; MICROTUBULE AB Human neuronal models of hereditary spastic paraplegias (HSP) that recapitulate disease-specific axonal pathology hold the key to understanding why certain axons degenerate in patients and to developing therapies. SPG4, the most common form of HSP, is caused by autosomal dominant mutations in the SPAST gene, which encodes the microtubule-severing ATPase spastin. Here, we have generated a human neuronal model of SPG4 by establishing induced pluripotent stem cells (iPSCs) from an SPG4 patient and differentiating these cells into telencephalic glutamatergic neurons. The SPG4 neurons displayed a significant increase in axonal swellings, which stained strongly for mitochondria and tau, indicating the accumulation of axonal transport cargoes. In addition, mitochondrial transport was decreased in SPG4 neurons, revealing that these patient iPSC-derived neurons recapitulate disease-specific axonal phenotypes. Interestingly, spastin protein levels were significantly decreased in SPG4 neurons, supporting a haploinsufficiency mechanism. Furthermore, cortical neurons derived from spastin-knockdown human embryonic stem cells (hESCs) exhibited similar axonal swellings, confirming that the axonal defects can be caused by loss of spastin function. These spastin-knockdown hESCs serve as an additional model for studying HSP. Finally, levels of stabilized acetylated-tubulin were significantly increased in SPG4 neurons. Vinblastine, a microtubule-destabilizing drug, rescued this axonal swelling phenotype in neurons derived from both SPG4 iPSCs and spastin-knockdown hESCs. Thus, this study demonstrates the successful establishment of human pluripotent stem cell-based neuronal models of SPG4, which will be valuable for dissecting the pathogenic cellular mechanisms and screening compounds to rescue the axonal degeneration in HSP. Stem Cells2014;32:414-423 C1 [Denton, Kyle R.; Lei, Ling; Grenier, Jeremy; Li, Xue-Jun] Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA. [Rodionov, Vladimir] Univ Connecticut, Ctr Hlth, Ctr Cell Anal & Modeling, Farmington, CT 06030 USA. [Rodionov, Vladimir] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Farmington, CT 06030 USA. [Li, Xue-Jun] Univ Connecticut, Ctr Hlth, Stem Cell Inst, Farmington, CT 06030 USA. [Blackstone, Craig] NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Li, XJ (reprint author), Univ Connecticut, Ctr Hlth, Dept Neurosci, Room E4029,MC-3401,263 Farmington Ave, Farmington, CT 06030 USA. EM xjli@uchc.edu FU Connecticut Stem Cell Research Grant [11SCB24]; Spastic Paraplegia Foundation; NIH [GM62290]; NINDS, National Institutes of Health FX We are grateful to Dr. Ricardo Roda for performing the skin biopsies. We also thank Dr. Gustavo Mostoslavsky for generously providing the lentiviral reprogramming vector. This study was supported by a Connecticut Stem Cell Research Grant (11SCB24) and the Spastic Paraplegia Foundation. V.R. was supported by NIH Grant GM62290. C.B. was supported by the Intramural Research Program of the NINDS, National Institutes of Health. NR 62 TC 27 Z9 28 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD FEB PY 2014 VL 32 IS 2 BP 414 EP 423 DI 10.1002/stem.1569 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 304JE UT WOS:000330742100008 PM 24123785 ER PT J AU Pogue, BW Busch, D Li, LZ Zhang, HM Shieh, DB AF Pogue, Brian W. Busch, David Li, Lin Z. Zhang, Huiming Shieh, Dar-Bin TI Introduction to the Special Issue: Britton Chance 100th Commemorative SO ACADEMIC RADIOLOGY LA English DT Editorial Material C1 [Pogue, Brian W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Busch, David] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Busch, David] Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA. [Li, Lin Z.] Univ Penn, Philadelphia, PA 19104 USA. [Zhang, Huiming] NCI, Div Canc Diag & Treatment, Bethesda, MD 20892 USA. [Shieh, Dar-Bin] Natl Cheng Kung Univ, Coll Med, Tainan 70101, Taiwan. RP Pogue, BW (reprint author), Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. EM Brian.W.Pogue@Dartmouth.EDU RI Li, Lin/D-1157-2009; Busch, David/B-5543-2013 OI Li, Lin/0000-0001-9447-7982; Busch, David/0000-0002-9488-944X NR 15 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD FEB PY 2014 VL 21 IS 2 SI SI BP 137 EP 138 DI 10.1016/j.acra.2013.11.018 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 298PH UT WOS:000330336200001 PM 24439326 ER PT J AU Zhang, HM AF Zhang, Huiming TI The Potential of Hyperpolarized C-13 MRI in Assessing Signaling Pathways in Cancer SO ACADEMIC RADIOLOGY LA English DT Article DE Hyperpolarized C-13 MRI; signaling pathways; cancer metabolism; metabolic imaging; cancer genomics-driven approach ID ENGINEERED MOUSE MODELS; IN-VIVO; CELL-METABOLISM; DRUG DEVELOPMENT; CHALLENGES; NMR; MYC; SPECTROSCOPY; EVOLUTION; POLARIZER AB Advances in genomics are enabling integration of various -omics to reveal the complexities underneath carcinogenesis. Multivariate signaling pathways are deregulated and evolve spatially and temporally depending on the tumor microenvironment. This finding shifts the focus of cancer research from "one disease-one target and drug" to "one disease-multiple pathway targets and combinational therapy" and imposes new challenges on the imaging community in terms of imaging targets, scales and information levels. In current clinical settings, most imaging modalities assess cancer risk through alternations in anatomy, function, metabolism, cellularity, or limited molecular events. Few clinical-translatable imaging modalities are capable of detecting aberrations in signaling pathways at the level of tissue biology. An exception to this is hyperpolarized C-13 magnetic resonance spectroscopic imaging (HP C-13 MRI), which is capable of imaging the molecular signatures of special metabolic enzymes using HP C-13-labeled substrates. HP C-13 MRI can identify multiple metabolites including intermediates and products simultaneously to allow extraction of critical parameters such as flux alterations for multiple metabolic pathways. Meanwhile, recent progress in cancer metabolism research affirms that metabolic alterations are directly controlled by signaling pathways. Thus, in vivo assessment of aberrations occurring in signaling pathways becomes feasible through HP C-13 imaging. This report briefly reviews the connections between signaling pathways and cancer metabolic phenotypes, the current status of HP C-13 MRI in assessing signal pathways, and recent advances in HP C-13 MRI techniques. Integrated with cancer genomics and animal models, HP C-13 MRI may hold high promise in exploring important issues in cancer that are linked to functionality of signaling pathways. Examples include genomic-driven therapy, intratumoral heterogeneity, and drug resistances. C1 NCI, Div Canc Treatment & Diag, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. RP Zhang, HM (reprint author), NCI, Div Canc Treatment & Diag, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. EM zhanghui@mail.nih.gov NR 48 TC 4 Z9 4 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD FEB PY 2014 VL 21 IS 2 SI SI BP 215 EP 222 DI 10.1016/j.acra.2013.11.015 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 298PH UT WOS:000330336200011 PM 24439335 ER PT J AU Kline-Simon, AH Weisner, CM Parthasarathy, S Falk, DE Litten, RZ Mertens, JR AF Kline-Simon, Andrea H. Weisner, Constance M. Parthasarathy, Sujaya Falk, Daniel E. Litten, Raye Z. Mertens, Jennifer R. TI Five-Year Healthcare Utilization and Costs Among Lower-Risk Drinkers Following Alchol Treatment SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Lower-Risk Drinking; Costs; Healthcare Utilization; Alcohol Outcomes; Alcohol Treatment ID ADDICTION SEVERITY INDEX; DRUG-TREATMENT OUTCOMES; SUBSTANCE USE OUTCOMES; ALCOHOL-DEPENDENCE; CONTROLLED-DRINKING; GENDER-DIFFERENCES; OLDER-ADULTS; 1ST YEAR; INDIVIDUALS; PREDICTOR AB BackgroundLower-risk drinking is increasingly being examined as a treatment outcome for some patients following addiction treatment. However, few studies have examined the relationship between drinking status (lower-risk drinking in particular) and healthcare utilization and cost, which has important policy implications. MethodsParticipants were adults with alcohol dependence and/or abuse diagnoses who received outpatient alcohol and other drug treatment in a private, nonprofit integrated healthcare delivery system and had a follow-up interview 6months after treatment entry (N=995). Associations between past 30-day drinking status at 6months (abstinence, lower-risk drinking defined as nonabstinence and no days of 5+ drinking, and heavy drinking defined as 1 or more days of 5+ drinking) and repeated measures of at least 1 emergency department (ED), inpatient or primary care visit, and their costs over 5years were examined using mixed-effects models. We modeled an interaction between time and drinking status to examine trends in utilization and costs over time by drinking group. ResultsHeavy drinkers and lower-risk drinkers were not significantly different from the abstainers in their cost or utilization at time 0 (i.e., 6months postintake). Heavy drinkers had increasing odds of inpatient (p<0.01) and ED (p<0.05) utilization over 5years compared with abstainers. Lower-risk drinkers and abstainers did not significantly differ in their service use in any category over time. No differences were found in changes in primary care use among the 3 groups over time. The cost analyses paralleled the utilization results. Heavy drinkers had increasing ED (p<0.05) and inpatient (p<0.001) costs compared with the abstainers; primary care costs did not significantly differ. Lower-risk drinkers did not have significantly different medical costs compared with those who were abstinent over 5years. However, post hoc analyses found lower-risk drinkers and heavy drinkers to not significantly differ in their ED use or costs over time. ConclusionsPerformance measures for treatment settings that consider treatment outcomes may need to take into account both abstinence and reduction to nonheavy drinking. Future research should examine whether results are replicated in harm reduction treatment, or whether such outcomes are found only in abstinence-based treatment. C1 [Kline-Simon, Andrea H.; Weisner, Constance M.; Parthasarathy, Sujaya; Mertens, Jennifer R.] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Weisner, Constance M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Falk, Daniel E.; Litten, Raye Z.] NIAAA, Bethesda, MD USA. RP Kline-Simon, AH (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM Andrea.H.Kline-Simon@kp.org FU National Institute on Alcohol Abuse and Alcoholism [R01 AA10359]; National Institute on Drug Abuse [R37 DA10572] FX This study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (R01 AA10359) and the National Institute on Drug Abuse (R37 DA10572). We thank Agatha Hinman, BA for editorial assistance. NR 41 TC 5 Z9 5 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2014 VL 38 IS 2 BP 579 EP 586 DI 10.1111/acer.12273 PG 8 WC Substance Abuse SC Substance Abuse GA 297PC UT WOS:000330266400035 PM 24117604 ER PT J AU Grange, L Dalal, M Nussenblatt, RB Sen, HN AF Grange, Landon Dalal, Monica Nussenblatt, Robert B. Sen, H. Nida TI Autoimmune Retinopathy SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CANCER-ASSOCIATED RETINOPATHY; ALPHA-ENOLASE; FUNDUS AUTOFLUORESCENCE; MACULAR DEGENERATION; AUTOANTIBODIES; ANTIBODIES; DISEASE; DISORDERS; RECOVERIN; PROTEIN AB PURPOSE: To provide a detailed review of current clinical guidelines for the diagnosis, work-up and treatment of autoimmune retinopathy and to preview briefly possible future therapies. DESIGN: Perspective based on literature review and clinical expertise. METHODS: Interpretation of current literature, relying on the authors' clinical experience. RESULTS: Autoimmune retinopathy is a rare immunologic disease characterized by the presence of circulating antiretinal antibodies along with electroretinographic and visual field abnormalities. An ophthalmic examination can be normal or show minimal findings. The diagnosis of autoimmune retinopathy is made difficult by diagnostic criteria that are both limited and nonstandardized. Currently, the diagnosis is made based on the demonstration of serum antiretinal antibodies and the presence of clinical manifestations (including abnormal electroretinographic findings). The mere presence of these antibodies is not diagnostic. Lack of an accepted gold standard for antiretinal antibodies detection and poor interlaboratory concordance make the diagnosis challenging. There are anecdotal reports of immunosuppressive therapy in autoimmune retinopathy; however, the response to treatment is variable, with more favorable results achieved in paraneoplastic retinopathy, particularly cancer-associated retinopathy, with a combination of chemotherapy and immunosuppression. Whether an earlier attempt to treat nonparaneoplastic autoimmune retinopathy would be more beneficial is unknown. Early treatment attempts are limited by lack of sensitive and specific assays and definitive clinical criteria. CONCLUSIONS: Little is known about the clinical course, prognosis and treatment of autoimmune retinopathy. Additional studies should examine the specificity and pathogenicity of antiretinal antibodies and screen for biomarkers, and they should be conducted concurrently with studies seeking to identify appropriate treatment. C1 [Grange, Landon; Dalal, Monica; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,10-10N112, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999, ZIA EY000501-04] NR 35 TC 13 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 2014 VL 157 IS 2 BP 266 EP 272 DI 10.1016/j.ajo.2013.09.019 PG 7 WC Ophthalmology SC Ophthalmology GA 299SN UT WOS:000330416100002 PM 24315290 ER EF