FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Koob, GF AF Koob, George F. TI Alcohol Use Disorders: Tracts, Twins, and Trajectories SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID SUBTHALAMIC NUCLEUS; PREFRONTAL CORTEX; DRUG-ADDICTION; INHIBITION; ADULTHOOD; CHILDHOOD C1 NIAAA, Rockville, MD 20852 USA. RP Koob, GF (reprint author), NIAAA, Rockville, MD 20852 USA. EM george.koob@nih.gov RI koob, george/P-8791-2016 NR 23 TC 1 Z9 1 U1 1 U2 8 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2015 VL 172 IS 6 BP 499 EP 501 DI 10.1176/appi.ajp.2015.15020240 PG 3 WC Psychiatry SC Psychiatry GA CJ6ZD UT WOS:000355642800001 PM 25982661 ER PT J AU van Sloten, TT Sigurdsson, S van Buchem, MA Phillips, CL Jonsson, PV Ding, J Schram, MT Harris, TB Gudnason, V Launer, LJ AF van Sloten, Thomas T. Sigurdsson, Sigurdur van Buchem, Mark A. Phillips, Caroline L. Jonsson, Palmi V. Ding, Jie Schram, Miranda T. Harris, Tamara B. Gudnason, Vilmundur Launer, Lenore J. TI Cerebral Small Vessel Disease and Association With Higher Incidence of Depressive Symptoms in a General Elderly Population: The AGES-Reykjavik Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID WHITE-MATTER LESIONS; LATE-LIFE DEPRESSION; CARDIOVASCULAR-DISEASE; VASCULAR DEPRESSION; BRAIN INFARCTS; OLDER-ADULTS; PROGRESSION; RISK; ATROPHY; MECHANISMS AB Objective: The vascular depression hypothesis postulates that cerebral small vessel disease (CSVD) leads to depressive symptoms by disruption of brain structures involved in mood regulation. However, longitudinal data on the association between CSVD and depressive symptoms are scarce. The authors investigated the association between CSVD and incident depressive symptoms. Method: Longitudinal data were taken from the Age, Gene/Environment Susceptibility-Reykjavik Study of 1,949 participants free of dementia and without baseline depressive symptoms (mean age: 74.6 years [SD=4.61; women, 56.6%). MRI markers of CSVD, detected at baseline (2002-2006) and follow-up (2007-2011), included white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces, and total brain parenchyma volume. Incident depressive symptoms were defined by a score >= 6 on the 15-item Geriatric Depression Scale and/or use of antidepressant medication. Results: Depressive symptoms occurred in 10.1% of the participants. The association for a greater onset of depressive symptoms was significant for participants with 1 standard deviation increase in white matter hyperintensity volume over time, new subcortical infarcts, new Virchow-Robin spaces, 1 standard deviation lower total brain volume at baseline, and 1 standard deviation decreased total brain volume overtime, after adjustments for cognitive function and sociodemographic and cardiovascular factors. Results were qualitatively similar when change in the Geriatric Depression Scale score over time was used as the outcome instead of incident depressive symptoms. Conclusions: Most markers of progression of CSVD overtime and some markers of baseline CSVD are associated with concurrently developing new depressive symptoms. These findings support the vascular depression hypothesis. C1 [Launer, Lenore J.] Maastricht Univ, Med Ctr, Dept Med, Cardiovasc Res Inst, NL-6200 MD Maastricht, Netherlands. Maastricht Univ, Med Ctr, Sch Nutr Toxicol & Metab, NL-6200 MD Maastricht, Netherlands. Iceland Heart Assoc, Kopavogur, Iceland. Leiden Univ, Dept Radiol, Med Ctr, Leiden, Netherlands. NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. Univ Iceland, Fac Med, Reykjavik, Iceland. RP Launer, LJ (reprint author), Maastricht Univ, Med Ctr, Dept Med, Cardiovasc Res Inst, NL-6200 MD Maastricht, Netherlands. EM LaunerL@nia.nih.gov RI Gudnason, Vilmundur/K-6885-2015; Ding, Jie/K-9943-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Schram, Miranda/0000-0003-0515-4124 FU AGES-Reykjavik Study - NIH [N01-AG-12100]; Intramural Research Program of the National Institute on Aging; Icelandic Heart Association; Icelandic Parliament FX Supported by the AGES-Reykjavik Study, funded by NIH (contract, N01-AG-12100); the Intramural Research Program of the National Institute on Aging; the Icelandic Heart Association; and the Icelandic Parliament NR 40 TC 9 Z9 9 U1 2 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2015 VL 172 IS 6 BP 570 EP 578 DI 10.1176/appi.ajp.2014.14050578 PG 9 WC Psychiatry SC Psychiatry GA CJ6ZD UT WOS:000355642800013 PM 25734354 ER PT J AU Sharp, D Millum, J AF Sharp, Daniel Millum, Joseph TI Perspective Piece The Post-2015 Development Agenda: Keeping Our Focus on the Worst Off SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID HEALTH-PROGRAMS; PRIORITY; DISEASES AB Non-communicable diseases now account for the majority of the global burden of disease and an international campaign has emerged to raise their priority on the post-2015 development agenda. We argue, to the contrary, that there remain strong reasons to prioritize maternal and child health. Policy-makers ought to assign highest priority to the health conditions that afflict the worst off. In virtue of how little healthy life they have had, children who die young are among the globally worst off. Moreover, many interventions to deal with the conditions that cause mortality in the young are low-cost and provide great benefits to their recipients. Consistent with the original Millennium Development Goals, the international community should continue to prioritize reductions in communicable diseases, neonatal conditions, and maternal health despite the shifts in the global burden of disease. C1 [Millum, Joseph] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Millum, Joseph] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Sharp, Daniel] Vienna Univ Econ & Business, Vienna, Austria. RP Millum, J (reprint author), NIH, Ctr Clin, Dept Bioeth, Bldg 10,Room 1C118,10 Ctr Dr, Bethesda, MD 20892 USA. EM sharpdaniele@gmail.com; joseph.millum@nih.gov FU National Institutes of Health Clinical Center and Fogarty International Center FX This work was supported, in part, by intramural funds from the National Institutes of Health Clinical Center and Fogarty International Center. We thank Austen Davis, Christine Grady, and David Wendler for helpful comments on earlier drafts. NR 19 TC 3 Z9 3 U1 0 U2 5 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2015 VL 92 IS 6 BP 1087 EP 1089 DI 10.4269/ajtmh.15-0087 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CJ8WY UT WOS:000355785400002 PM 25846294 ER PT J AU Huijben, S Chan, BHK Read, AF AF Huijben, Silvie Chan, Brian H. K. Read, Andrew F. TI Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID HETERODUPLEX TRACKING ASSAY; FLUORESCENT MICROSPHERE ASSAY; REVERSE-TRANSCRIPTION PCR; MEDIATING POLYMORPHISMS; FALCIPARUM INFECTIONS; ANTIMALARIAL TRIALS; DRUG-RESISTANCE; VALIDATION; CHEMOTHERAPY; DIVERSITY AB Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants can be extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance. C1 Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. Penn State Univ, Ctr Infect Dis Dynam, Dept Entomol, University Pk, PA 16802 USA. [Huijben, Silvie] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona, Spain. [Chan, Brian H. K.] Univ Liverpool, Inst Integrat Biol, Liverpool L69 3BX, Merseyside, England. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Read, Andrew F.] Penn State Univ, Ctr Dis Dynam, University Pk, PA 16802 USA. RP Read, AF (reprint author), Penn State Univ, Ctr Dis Dynam, University Pk, PA 16802 USA. EM silviehuijben@gmail.com; brian.chan@liverpool.ac.uk; a.read@psu.edu OI Chan, Brian/0000-0002-9451-4621 FU Institute of General Medical Science [R01 GM089932]; Branco Weiss Fellowship; Marie Curie Actions IIF Project [623703] FX This work was funded by the Institute of General Medical Science (R01 GM089932). Silvie Huijben was supported by a Branco Weiss Fellowship and Marie Curie Actions IIF Project 623703. NR 42 TC 0 Z9 0 U1 0 U2 3 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 JUN PY 2015 VL 92 IS 6 BP 1214 EP 1221 DI 10.4269/ajtmh.15-0036 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CJ8WY UT WOS:000355785400022 PM 25940195 ER PT J AU Marchant, NJ Kaganovsky, K AF Marchant, Nathan J. Kaganovsky, Konstantin TI A Critical Role of Nucleus Accumbens Dopamine D1-Family Receptors in Renewal of Alcohol Seeking After Punishment-Imposed Abstinence SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE alcohol; relapse; renewal; punishment; nucleus accumbens ID CONTEXT-INDUCED REINSTATEMENT; MEDIAL PREFRONTAL CORTEX; RAT VENTRAL STRIATUM; INDUCED RELAPSE; HEROIN SEEKING; COCAINE-SEEKING; LATERAL HYPOTHALAMUS; D-1-FAMILY RECEPTORS; PRIMED REINSTATEMENT; GLUTAMATE RECEPTORS AB In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment. C1 [Marchant, Nathan J.; Kaganovsky, Konstantin] NIDA, Behav Neurosci Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Marchant, Nathan J.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3010, Australia. RP Marchant, NJ (reprint author), NIDA, Suite 200,251 Bayview Blvd, Baltimore, MD 21224 USA. EM nathan.marchant@nih.gov OI Kaganovsky, Konstantin/0000-0002-1577-109X FU National Institute on Drug Abuse, Intramural Research Program funds; National Health and Medical Research Council [1053308] FX Research was supported by the National Institute on Drug Abuse, Intramural Research Program funds to the Neurobiology of Relapse Section (PI: Yavin Shaham). Nathan J. Marchant received support from Early Career Fellowship 1053308 by the National Health and Medical Research Council. We thank Yavin Shaham, Antonello Bonci, and Helen Nasser for their help in the conceptualization of the project and the write-up of the article. NR 52 TC 2 Z9 2 U1 0 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 EI 1939-0084 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD JUN PY 2015 VL 129 IS 3 BP 281 EP 291 DI 10.1037/bne0000050 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CJ9QV UT WOS:000355838200005 PM 25914922 ER PT J AU Sayeed, SK Zhao, J Sathyanarayana, BK Golla, JP Vinson, C AF Sayeed, Syed Khund Zhao, Jianfei Sathyanarayana, Bangalore K. Golla, Jaya Prakash Vinson, Charles TI C/EBP beta (CEBPB) protein binding to the C/EBP vertical bar CRE DNA 8-mer TTGC vertical bar GTCA is inhibited by 5hmC and enhanced by 5mC, 5fC, and 5caC in the CG dinucleotide SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE 5mC, 5hmC, 5fC, 5caC, carboxylation; C/EBP vertical bar CRE motif; CG dinucleotide; Basic-leucine zipper; DNA binding; C/EBP beta homodimer ID EMBRYONIC STEM-CELLS; GENE-EXPRESSION; TRANSCRIPTION FACTORS; CPG METHYLATION; ADIPOCYTE DIFFERENTIATION; DIMERIZATION SPECIFICITY; 5-HYDROXYMETHYLCYTOSINE; GENOME; 5-FORMYLCYTOSINE; 5-METHYLCYTOSINE AB During mammalian development, some methylated cytosines (5mC) in CG dinucleotides are iteratively oxidized by TET dioxygenases to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). The effect of these cytosine oxidative products on the sequence-specific DNA binding of transcription factors is being actively investigated. Here, we used the electrophoretic mobility shift assay (EMSA) to examine C/EBP alpha and C/EBP beta homodimers binding to all 25 chemical forms of a CG dinudeotide for two DNA sequences: the canonical C/EBP 8-mer TTGC vertical bar GCAA and the chimeric C/EBP vertical bar CRE 8-mer TTGC vertical bar GTCA. 5hmC in the CG dinucleotide in the C/EBP vertical bar CRE motif 8-mer TGAC vertical bar GCAA inhibits binding of C/EBP beta, but not C/EBP alpha. Binding was increased by 5mC, 5fC and 5caC Circular dichroism monitored thermal denaturations for C/EBP beta, bound to the C/EBP vertical bar CRE motif confirmed the EMSA. The structural differences between C/EBP alpha and C/EBP beta that may account for the difference in binding 5hmC in the 8-mer TGAC vertical bar GCAA are explored. Published by Elsevier B.V. C1 [Sayeed, Syed Khund; Zhao, Jianfei; Golla, Jaya Prakash; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Sathyanarayana, Bangalore K.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Room 3128,Bldg 37, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov FU National Cancer Institute, NIH, Bethesda, USA FX We thank our lab members for their encouragement and support. This work is supported by the intramural research project of the National Cancer Institute, NIH, Bethesda, USA. NR 56 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD JUN PY 2015 VL 1849 IS 6 BP 583 EP 589 DI 10.1016/j.bbagrm.2015.03.002 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CK0KY UT WOS:000355895300001 PM 25779641 ER PT J AU Ionescu, DF Luckenbaugh, DA Niciu, MJ Richards, EM Zarate, CA AF Ionescu, Dawn F. Luckenbaugh, David A. Niciu, Mark J. Richards, Erica M. Zarate, Carlos A., Jr. TI A single infusion of ketamine improves depression scores in patients with anxious bipolar depression SO BIPOLAR DISORDERS LA English DT Article DE anxious depression; bipolar disorder; ketamine; N-methyl-d-aspartate antagonist; predictors of response ID D-ASPARTATE ANTAGONIST; ADD-ON TRIAL; COMORBID ANXIETY; DOUBLE-BLIND; I DEPRESSION; DISORDER; SCALE; MONOTHERAPY; LURASIDONE; STATES AB ObjectivePatents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine's ability to decrease symptoms of depression. MethodsThirty-six patients with anxious (n=21) and non-anxious (n=15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5mg/kg) over 40min. Post-hoc analyses compared changes in the Montgomery-angstrom sberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non-anxious depressed patients with bipolar disorder through 14days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of 7. ResultsA linear mixed model revealed a significant effect of anxiety group on the MADRS (p=0.04) and HDRS (p=0.04). Significant drug effects (all p<0.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine. The drug-by-anxiety interactions were not significant (all p>0.28). ConclusionsBoth anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine's novel role in the treatment of anxious bipolar depression. C1 [Ionescu, Dawn F.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Ionescu, Dawn F.] Harvard Univ, Sch Med, Boston, MA USA. [Luckenbaugh, David A.; Niciu, Mark J.; Richards, Erica M.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ionescu, DF (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 1 Bowdoin Sq,Floor 6, Boston, MA 02114 USA. EM dionescu@mgh.harvard.edu RI Niciu, Mark/J-1766-2014; Ionescu, Dawn/K-5675-2015 OI Niciu, Mark/0000-0002-5612-3021; FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); NARSAD Independent Investigator; Brain & Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), by a NARSAD Independent Investigator to CAZ, and by the Brain & Behavior Mood Disorders Research Award to CAZ. NR 26 TC 5 Z9 5 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2015 VL 17 IS 4 BP 438 EP 443 DI 10.1111/bdi.12277 PG 6 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CJ9PV UT WOS:000355835600010 PM 25400146 ER PT J AU Morris, CR Kim, HY Klings, ES Wood, J Porter, JB Trachtenberg, F Sweeters, N Olivieri, NF Kwiatkowski, JL Virzi, L Hassell, K Taher, A Neufeld, EJ Thompson, AA Larkin, S Suh, JH Vichinsky, EP Kuypers, FA AF Morris, Claudia R. Kim, Hae-Young Klings, Elizabeth S. Wood, John Porter, John B. Trachtenberg, Felicia Sweeters, Nancy Olivieri, Nancy F. Kwiatkowski, Janet L. Virzi, Lisa Hassell, Kathryn Taher, Ali Neufeld, Ellis J. Thompson, Alexis A. Larkin, Sandra Suh, Jung H. Vichinsky, Elliott P. Kuypers, Frans A. CA Thalassemia Clinical Res Network TI Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE arginase; -thalassaemia; global arginine bioavailability ratio; haemolysis; pulmonary hypertension ID SICKLE-CELL-DISEASE; RIGHT HEART CATHETERIZATION; PULMONARY ARTERIAL-HYPERTENSION; REGURGITANT JET VELOCITY; NITRIC-OXIDE; RISK-FACTORS; BETA-THALASSEMIA; BIOAVAILABILITY RATIOS; FREE HEMOGLOBIN; MAJOR PATIENTS AB Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-min-walk-test, Borg Dyspnoea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanisms of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant-jet-velocity (TRV)25m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase (LDH) levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global-arginine-bioavailability and biomarkers of haemolytic rate, including LDH, haemoglobin and bilirubin. Thalassaemia patients with a TRV25m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in -thalassaemia. C1 [Morris, Claudia R.] Emory Univ, Sch Med, Emory Childrens Ctr Cyst Fibrosis & Airways Dis R, Dept Pediat,Div Emergency Med, Atlanta, GA 30329 USA. [Kim, Hae-Young; Trachtenberg, Felicia; Virzi, Lisa] New England Res Inst Watertown, Watertown, MA USA. [Klings, Elizabeth S.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Wood, John] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Porter, John B.] UCL, London, England. [Sweeters, Nancy; Vichinsky, Elliott P.] UCSF Benioff Childrens Hosp Oakland, Hematol Oncol, Oakland, CA USA. [Olivieri, Nancy F.] Toronto Gen Hosp, Toronto, ON, Canada. [Kwiatkowski, Janet L.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Hassell, Kathryn] NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. [Taher, Ali] Amer Univ Beirut, Beirut, Lebanon. [Neufeld, Ellis J.] Childrens Hosp Boston, Boston, MA USA. [Thompson, Alexis A.] Childrens Mem Hosp, Haematol Oncol & Stem Cell Transplant, Chicago, IL 60614 USA. [Larkin, Sandra; Suh, Jung H.; Kuypers, Frans A.] Childrens Hosp Oakland Res Inst, Oakland, CA USA. RP Morris, CR (reprint author), Emory Univ, Sch Med, Emory Childrens Ctr Cyst Fibrosis & Airways Dis R, Pediat & Emergency Med, 1760 Haygood Dr,NE W458, Atlanta, GA 30329 USA. EM claudia.r.morris@emory.edu OI Porter, John/0000-0003-3000-9359 FU NIH-NHLBI [U01 HL065238NIH, U01-HL65232]; CTSA [UL1 RR024131]; FDA [1R01FD003531-04]; Intramural Research Program of the NIH, NHLBI; NIH/NCRR [UL1-RR-024134, U01-HL72291]; Harvard Catalyst CTSC [U-01RR025758, U01-HL65233, UL1RR024131-01, U01-HL65244, CTSC UL1-RR024996, U01-HL65238] FX This is publication number 34 of the TCRN. A list of TCRN member institutions and staff appears in the Appendix. The authors would like to thank the agencies that funded this study. This study was supported by the NIH-NHLBI cooperative agreement U01 HL065238NIH grant and CTSA grant UL1 RR024131, FDA grant 1R01FD003531-04 (to CRM). This research was also supported in part by the Intramural Research Program of the NIH, NHLBI and by the following NIH-NHLBI cooperative agreements: U01-HL65232 and NIH/NCRR UL1-RR-024134 to the Children's Hospital of Philadelphia, U01-HL72291 and by Harvard Catalyst CTSC U-01RR025758 to Children's Hospital, Boston, U01-HL65233 to University Health Network Toronto General Hospital, UL1RR024131-01 to Children's Hospital & Research Centre Oakland, U01-HL65244 and CTSC UL1-RR024996 to Weill Medical College of Cornell University, and U01-HL65238 to New England Research Institutes. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI. The authors would also like to thank the patients with thalassaemia and their families who participated in this study. NR 52 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2015 VL 169 IS 6 BP 887 EP 898 DI 10.1111/bjh.13452 PG 12 WC Hematology SC Hematology GA CJ7EN UT WOS:000355657300017 PM 25907665 ER PT J AU Cooper, JM Gadian, DG Jentschke, S Goldman, A Munoz, M Pitts, G Banks, T Chong, WK Hoskote, A Deanfield, J Baldeweg, T de Haan, M Mishkin, M Vargha-Khadem, F AF Cooper, Janine M. Gadian, David G. Jentschke, Sebastian Goldman, Allan Munoz, Monica Pitts, Georgia Banks, Tina Chong, W. Kling Hoskote, Aparna Deanfield, John Baldeweg, Torsten de Haan, Michelle Mishkin, Mortimer Vargha-Khadem, Faraneh TI Neonatal Hypoxia, Hippocampal Atrophy, and Memory Impairment: Evidence of a Causal Sequence SO CEREBRAL CORTEX LA English DT Article DE developmental amnesia; hippocampal volumes; hypoxia ID EXTRACORPOREAL MEMBRANE-OXYGENATION; COLLABORATIVE RANDOMIZED-TRIAL; DEVELOPMENTAL AMNESIA; BRAIN-INJURY; AUTOMATIC SEGMENTATION; COGNITIVE IMPAIRMENT; EVERYDAY MEMORY; FOLLOW-UP; MRI; TIME AB Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. C1 [Cooper, Janine M.; Jentschke, Sebastian; Munoz, Monica; Pitts, Georgia; Baldeweg, Torsten; de Haan, Michelle; Vargha-Khadem, Faraneh] UCL Inst Child Hlth, Dev Cognit Neurosci Unit, London WC1N 1EH, England. [Gadian, David G.; Banks, Tina; Chong, W. Kling] UCL Inst Child Hlth, Imaging & Biophys Unit, London WC1N 1EH, England. [Goldman, Allan; Hoskote, Aparna] UCL Inst Child Hlth, Cardiac Unit, London WC1N 1EH, England. [Deanfield, John] UCL Inst Cardiovasc Sci, London WC1E 6BT, England. [Goldman, Allan; Hoskote, Aparna] Great Ormond St Hosp Sick Children, Cardiac Intens Care, London WC1N 3JH, England. [Banks, Tina; Chong, W. Kling] Great Ormond St Hosp Sick Children, Dept Radiol, London WC1N 3JH, England. [Vargha-Khadem, Faraneh] Great Ormond St Hosp Sick Children, Dept Neuropsychol, London WC1N 3JH, England. [Mishkin, Mortimer] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Cooper, Janine M.] Murdoch Childrens Res Inst, Melbourne, Vic 3052, Australia. [Munoz, Monica] Univ Castilla La Mancha, Albacete 02006, Spain. [Jentschke, Sebastian] Free Univ Berlin, D-14195 Berlin, Germany. RP Vargha-Khadem, F (reprint author), UCL Inst Child Hlth, Dev Cognit Neurosci Unit, 30 Guilford St, London WC1N 1EH, England. EM f.vargha-khadem@ucl.ac.uk RI Munoz-Lopez, Monica/F-3154-2016; OI Munoz Lopez, Monica/0000-0002-5530-2394 FU Medical Research Council [G03000117/65439]; Central and East London Research Network [5177]; National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services; Research Councils UK FX This work was supported by the Medical Research Council (program grant number G03000117/65439); the Central and East London Research Network (5177); and the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services. Funding to pay the Open Access publication charges for this article was provided by Research Councils UK. NR 55 TC 10 Z9 10 U1 2 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JUN PY 2015 VL 25 IS 6 BP 1469 EP 1476 DI 10.1093/cercor/bht332 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CJ7HL UT WOS:000355665300005 PM 24343890 ER PT J AU Torabi-Parizi, P Davey, RT Suffredini, AF Chertow, DS AF Torabi-Parizi, Parizad Davey, Richard T., Jr. Suffredini, Anthony F. Chertow, Daniel S. TI Ethical and Practical Considerations in Providing Critical Care to Patients With Ebola Virus Disease SO CHEST LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; TO-MOUTH RESUSCITATION; PNEUMOCYSTIS-CARINII-PNEUMONIA; INTENSIVE-CARE; IMPROVED OUTCOMES; WEST-AFRICA; AIDS; WORKERS; RELUCTANCE; GUIDELINES AB Infectious disease epidemics in the past have given rise to psychologic and emotional responses among health-care workers (HCWs), stemming from fear of infection during patient care. Early experiences in the AIDS epidemic provide an example where fear of contagion resulted in differential treatment of patients infected with HIV. However, with a deeper understanding of AIDS pathogenesis and treatment, fear and discrimination diminished. Parallels exist between early experiences with AIDS and the present outbreak of Ebola virus disease in West Africa, particularly regarding discussions of medical futility in seriously ill patients. We provide a historical perspective on HCWs' risk of infection during the provision of CPR, discuss physicians' duty to treat in the face of perceived or actual HCW risk, and, finally, present the protocols implemented at the National Institutes of Health to reduce HCW risk while providing lifesaving and life-sustaining care. C1 [Torabi-Parizi, Parizad; Suffredini, Anthony F.; Chertow, Daniel S.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Davey, Richard T., Jr.] NIAID, Clin Res Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Torabi-Parizi, P (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,2C145, Bethesda, MD 20892 USA. EM torabiparizip@cc.nih.gov NR 39 TC 14 Z9 14 U1 0 U2 12 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JUN PY 2015 VL 147 IS 6 BP 1460 EP 1466 DI 10.1378/chest.15-0278 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CJ9QS UT WOS:000355837900025 PM 25764372 ER PT J AU Goh, GBB Pagadala, MR Dasarathy, J Unalp-Arida, A Pai, RK Yerian, L Khiyami, A Sourianarayanane, A Sargent, R Hawkins, C Dasarathy, S McCullough, AJ AF Goh, George Boon-Bee Pagadala, Mangesh R. Dasarathy, Jaividhya Unalp-Arida, Aynur Pai, Rish K. Yerian, Lisa Khiyami, Amer Sourianarayanane, Achuthan Sargent, Ruth Hawkins, Carol Dasarathy, Srinivasan McCullough, Arthur J. TI Age Impacts Ability of Aspartate-Alanine Aminotransferase Ratio to Predict Advanced Fibrosis in Nonalcoholic Fatty Liver Disease SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE NAFLD; Liver transaminases; Age-related changes; Advanced fibrosis ID TRIGLYCERIDE SYNTHESIS; HEPATIC STEATOSIS; SCORING SYSTEM; UNITED-STATES; PREVALENCE; POPULATION; STEATOHEPATITIS; ASSOCIATION; VALIDATION; GLUCOSE AB Background and Aim While histological differences have been reported between pediatric and adult nonalcoholic fatty liver disease (NAFLD), potential age-related changes in serum transaminases and liver histology remain largely unexplored. Our study sought to investigate the clinical and histological characteristics of NAFLD across age. Methods This was a prospective cross-sectional study of 502 biopsy-proven NAFLD patients. Clinical data were evaluated and compared among different age groups; group A (ages 18-44), B (ages 45-64), and C (>= ages 65). Results 34.9, 56.0, and 9.1 % of the cohort were distributed among group A, B, and C, respectively. While the prevalence of nonalcoholic steatohepatitis (NASH) was comparable across age groups, the prevalence of advanced fibrosis increased with age (p = 0.000). Although the mean ALT progressively decreased with age; 87, 64, 56 U/L in group A, B, and C, respectively (p = 0.000), there was no difference in mean AST (p = 0.939) across age. The AST: ALT ratio (AAR) progressively increased from 0.7, 0.9, and 1.1 in group A, B, and C, respectively (p = 0.000). In group C, an AAR >= 1 was found in 74 and 40 % of patients with and without advanced fibrosis. Conclusion With advancing age, ALT levels progressively declined while AST levels remained stable, leading to a higher AAR. Although higher AAR is often used as a surrogate measure of advanced fibrosis, advancing age can also contribute to increased AAR. In fact, an AAR >= 1 was found in significant number of elderly patients without advanced fibrosis. Consequently, an increased AAR may be a function of decreasing ALT with age in addition to progressive fibrosis. C1 [Goh, George Boon-Bee; Pagadala, Mangesh R.; Sourianarayanane, Achuthan; Sargent, Ruth; Dasarathy, Srinivasan; McCullough, Arthur J.] Cleveland Clin Fdn, Dept Gastroenterol, Cleveland, OH 44195 USA. [Goh, George Boon-Bee] Singapore Gen Hosp, Dept Gastroenterol, Singapore, Singapore. [Dasarathy, Jaividhya; Khiyami, Amer; Hawkins, Carol] Metrohlth Med Ctr, Dept Family Med, Cleveland, OH USA. [Unalp-Arida, Aynur] NIDDK, Bethesda, MD 20817 USA. [Pai, Rish K.; Yerian, Lisa] Cleveland Clin Fdn, Dept Pathol, Cleveland, OH 44195 USA. [Dasarathy, Srinivasan; McCullough, Arthur J.] Cleveland Clin Fdn, Dept Pathobiol, Cleveland, OH 44195 USA. RP McCullough, AJ (reprint author), Cleveland Clin Fdn, Dept Gastroenterol, 9500 Euclid Ave,A30, Cleveland, OH 44195 USA. EM george.goh.b.b@sgh.com.sg; pagadam@ccf.org; j.dasarathy@metrohealth.org; aynur.unalp-arida@nih.gov; pair@ccf.org; YERIANL@ccf.org; akhiyami@metrohealth.org; souria.a1@uky.edu; SARGENR@ccf.org; chawkins@metrohealth.org; DASARAS@ccf.org; mcculla@ccf.org FU Singapore Sing Health HMDP; NIH [T32 DK061917]; NIH DK U FX G.B.B.G. was supported by Singapore Sing Health HMDP. M.R.P. was supported by NIH T32 DK061917. S.D., J.D., A.J.M., R.S., C.H. were supported by NIH DK U. NR 42 TC 2 Z9 2 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUN PY 2015 VL 60 IS 6 BP 1825 EP 1831 DI 10.1007/s10620-015-3529-8 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CJ6CM UT WOS:000355580800043 PM 25708897 ER PT J AU Gallardo, VE Varshney, GK Lee, M Bupp, S Xu, LS Shinn, P Crawford, NP Inglese, J Burgess, SM AF Gallardo, Viviana E. Varshney, Gaurav K. Lee, Minnkyong Bupp, Sujata Xu, Lisha Shinn, Paul Crawford, Nigel P. Inglese, James Burgess, Shawn M. TI Phenotype-driven chemical screening in zebrafish for compounds that inhibit collective cell migration identifies multiple pathways potentially involved in metastatic invasion SO DISEASE MODELS & MECHANISMS LA English DT Article DE Drug screening; Metastasis; Orthotopic implantation; Src; Tks5; Zebrafish ID LATERAL-LINE PRIMORDIUM; IN-VIVO; TUMOR-METASTASIS; CANCER; SRC; MORPHOGENESIS; INFLAMMATION; EXPRESSION; KINASES; GROWTH AB In the last decade, high-throughput chemical screening has become the dominant approach for discovering novel compounds with therapeutic properties. Automated screening using in vitro or cultured cell assays have yielded thousands of candidate drugs for a variety of biological targets, but these approaches have not resulted in an increase in drug discovery despite major increases in expenditures. In contrast, phenotype-driven screens have shown a much stronger success rate, which is why we developed an in vivo assay using transgenic zebrafish with a GFP-marked migrating posterior lateral line primordium (PLLp) to identify compounds that influence collective cell migration. We then conducted a high-throughput screen using a compound library of 2160 annotated bioactive synthetic compounds and 800 natural products to identify molecules that block normal PLLp migration. We identified 165 compounds that interfere with primordium migration without overt toxicity in vivo. Selected compounds were confirmed in their migration-blocking activity by using additional assays for cell migration. We then proved the screen to be successful in identifying anti-metastatic compounds active in vivo by performing orthotopic tumor implantation assays in mice. We demonstrated that the Src inhibitor SU6656, identified in our screen, can be used to suppress the metastatic capacity of a highly aggressive mammary tumor cell line. Finally, we used CRISPR/Cas9-targeted mutagenesis in zebrafish to genetically validate predicted targets of compounds. This approach demonstrates that the migrating PLLp in zebrafish can be used for large-scale, highthroughput screening for compounds that inhibit collective cell migration and, potentially, anti-metastatic compounds. C1 [Gallardo, Viviana E.; Varshney, Gaurav K.; Xu, Lisha; Burgess, Shawn M.] NHGRI, Dev Genom Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Minnkyong; Bupp, Sujata; Crawford, Nigel P.; Inglese, James] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Shinn, Paul; Inglese, James] NIH, Dept Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Burgess, SM (reprint author), NHGRI, Dev Genom Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (S.B., N.P.C.). NR 43 TC 8 Z9 8 U1 0 U2 10 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JUN PY 2015 VL 8 IS 6 BP 565 EP 576 DI 10.1242/dmm.018689 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CJ5VD UT WOS:000355559100005 PM 25810455 ER PT J AU Spinelli, E Barnes, AJ Young, S Castaneto, MS Martin, TM Klette, KL Huestis, MA AF Spinelli, Eliani Barnes, Allan J. Young, Sheena Castaneto, Marisol S. Martin, Thomas M. Klette, Kevin L. Huestis, Marilyn A. TI Performance characteristics of an ELISA screening assay for urinary synthetic cannabinoids SO DRUG TESTING AND ANALYSIS LA English DT Article DE immunoassay; synthetic cannabinoids; ELISA ID ENDOCANNABINOID SYSTEM; HERBAL BLENDS; IMMUNOASSAY; PHARMACOLOGY; METABOLITES; MS AB Synthetic cannabinoids are marketed as legal alternatives to cannabis, as routine urine cannabinoid immunoassays do not detect synthetic cannabinoids. Laboratories are challenged to identify these new designer drugs that are widely available and represent a major public health and safety problem. Immunoassay testing offers rapid separation of presumptive positive and negative specimens, prior to more costly and time-consuming chromatographic confirmation. The Neogen SPICE ELISA kit targets JWH-018N-pentanoic acid as a marker for urinary synthetic cannabinoids. Assay performance was evaluated by analyzing 2469 authentic urine samples with the Neogen immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two immunoassay cut-off concentrations, 5 and 10 mu g/L, classified samples as presumptive positive or negative, followed by qualitative LC-MS/MS confirmation for 29 synthetic cannabinoids markers with limits of detection of 0.5-10 mu g/L to determine the assay's sensitivity, specificity and efficacy. Challenges at +/- 25% of each cut-off also were investigated to determine performance around the cut-off and intra- and inter-plate imprecision. The immunoassay was linear from 1 to 250 mu g/L (r(2)=0.992) with intra- and inter-plate imprecision of 5.3% and <9%, respectively. Sensitivity, specificity, and efficiency results with the 5 mu g/L cut-off were 79.9%, 99.7%, and 97.4% and with the 10 mu g/L cut-off 69.3%, 99.8%, and 96.3%, respectively. Cross-reactivity was shown for 18 of 73 synthetic cannabinoids markers evaluated. Good sensitivity, specificity, and efficiency, lack of sample preparation requirements, and rapid semi-automation documented that the Neogen SPICE ELISA kit is a viable method for screening synthetic cannabinoids in urine targeting JWH-018N-pentanoic acid. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Spinelli, Eliani; Barnes, Allan J.; Young, Sheena; Castaneto, Marisol S.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Spinelli, Eliani] Univ Fed Fluminense, CAPES Fdn BEX 1534 12 2, Sch Pharm, Rio De Janeiro, Brazil. [Martin, Thomas M.; Klette, Kevin L.] Personel Risk Reduct, Off Secretary Def Personnel & Readiness, Drug Testing & Program Policy, Washington, DC USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Spinelli, Eliani/0000-0001-5488-2545 FU National Institute on Drug Abuse, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. We also thank Neogen Corporation for providing the controls and assay kits for urine analyses. NR 16 TC 5 Z9 5 U1 4 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JUN PY 2015 VL 7 IS 6 BP 467 EP 474 DI 10.1002/dta.1702 PG 8 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA CJ7LD UT WOS:000355675700003 PM 25167963 ER PT J AU Castaneto, MS Scheidweiler, KB Gandhi, A Wohlfarth, A Klette, KL Martin, TM Huestis, MA AF Castaneto, Marisol S. Scheidweiler, Karl B. Gandhi, Adarsh Wohlfarth, Ariane Klette, Kevin L. Martin, Thomas M. Huestis, Marilyn A. TI Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens SO DRUG TESTING AND ANALYSIS LA English DT Article DE synthetic cannabinoids; immunoassay; LC-MS; MS; urine drug testing ID TANDEM MASS-SPECTROMETRY; HUMAN HEPATOCYTES; LC-MS/MS; METABOLITES; JWH-018; IDENTIFICATION; AM-2201; BLOOD; QUANTIFICATION; VALIDATION AB Synthetic cannabinoid intake is an ongoing health issue worldwide, with new compounds continually emerging, making drug testing complex. Parent synthetic cannabinoids are rarely detected in urine, the most common matrix employed in workplace drug testing. Optimal identification of synthetic cannabinoid markers in authentic urine specimens and correlation of metabolite concentrations and toxicities would improve synthetic cannabinoid result interpretation. We screened 20017 randomly collected US military urine specimens between July 2011 and June 2012 with a synthetic cannabinoid immunoassay yielding 1432 presumptive positive specimens. We analyzed all presumptive positive and 1069 negative specimens with our qualitative synthetic cannabinoid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, which confirmed 290 positive specimens. All 290 positive and 487 randomly selected negative specimens were quantified with the most comprehensive urine quantitative LC-MS/MS method published to date; 290 specimens confirmed positive for 22 metabolites from 11 parent synthetic cannabinoids. The five most predominant metabolites were JWH-018 pentanoic acid (93%), JWH-N-hydroxypentyl (84%), AM2201 N-hydroxypentyl (69%), JWH-073 butanoic acid (69%), and JWH-122N-hydroxypentyl (45%) with 11.1 (0.1-2,434), 5.1 (0.1-1,239), 2.0 (0.1-321), 1.1 (0.1-48.6), and 1.1 (0.1-250) mu g/L median (range) concentrations, respectively. Alkyl hydroxy and carboxy metabolites provided suitable biomarkers for 11 parent synthetic cannabinoids; although hydroxyindoles were also observed. This is by far the largest data set of synthetic cannabinoid metabolites urine concentrations from randomly collected workplace drug testing specimens rather than acute intoxications or driving under the influence of drugs. These data improve the interpretation of synthetic cannabinoid urine test results and suggest suitable urine markers of synthetic cannabinoid intake. This article is a U.S. Government work and is in the public domain in the USA. C1 [Castaneto, Marisol S.; Scheidweiler, Karl B.; Gandhi, Adarsh; Wohlfarth, Ariane; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, NIH, Baltimore, MD 21224 USA. [Castaneto, Marisol S.] Univ Maryland Baltimore, Toxicol Program, Baltimore, MD USA. [Klette, Kevin L.; Martin, Thomas M.] Personnel Risk Reduct, Drug Testing & Program Policy, Off Secretary Def Personnel & Readiness, Washington, DC USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, NIH, 251 Bayview Blvd,BRC 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU DOD Counter Narcotics Program [Y3-DA-1116-01]; National Institute on Drug Abuse, NIH [Y3-DA-1116-01]; Forensic Toxicology Drug Testing Laboratory, Fort Meade, MD FX An Interagency Agreement (Y3-DA-1116-01) between DOD Counter Narcotics Program and Intramural Research Program of the National Institute on Drug Abuse, NIH helped fund this research. Assistance and support of the Forensic Toxicology Drug Testing Laboratory, Fort Meade, MD and Chemistry and Drug Metabolism staff in the conduct of this study are greatly appreciated. NR 57 TC 11 Z9 11 U1 6 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JUN PY 2015 VL 7 IS 6 BP 483 EP 493 DI 10.1002/dta.1709 PG 11 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA CJ7LD UT WOS:000355675700005 PM 25231213 ER PT J AU Lee, D Vandrey, R Mendu, DR Murray, JA Barnes, AJ Huestis, MA AF Lee, Dayong Vandrey, Ryan Mendu, Damodara R. Murray, Jeannie A. Barnes, Allan J. Huestis, Marilyn A. TI Oral fluid cannabinoids in chronic frequent cannabis smokers during ad libitum cannabis smoking SO DRUG TESTING AND ANALYSIS LA English DT Article DE cannabinoid; oral fluid; cannabis; delta-9-tetrahydrocannabinol ID 2-DIMENSIONAL GAS-CHROMATOGRAPHY; RANDOMLY SELECTED DRIVERS; SIMULTANEOUS QUANTIFICATION; PHARMACOKINETIC PROPERTIES; MASS-SPECTROMETRY; DELTA(9)-TETRAHYDROCANNABINOL; MARIJUANA; PLASMA; USERS; DRUGS AB Oral fluid (OF) offers a simple, non-invasive, directly observable sample collection for clinical and forensic drug testing. Given that chronic cannabis smokers often engage in drug administration multiple times daily, evaluating OF cannabinoid pharmacokinetics during ad libitum smoking is important for practical development of analytical methods and informed interpretation of test results. Eleven cannabis smokers resided in a closed research unit for 51days, and underwent four, 5-day oral delta-9-tetrahydrocannabinol (THC) treatments. Each medication period was separated by 9days of ad libitum cannabis smoking from 12:00 to 23:00h daily. Ten OF samples were collected from 9:00-22:00h on each of the last ad libitum smoking days (Study Days 4, 18, 32, and 46). As the number of cannabis cigarettes smoked increased over the study days, OF THC, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH) also increased with a significant effect of time since last smoking (time; range, 0.0-17.4h) and 88% detection rates; concentrations on Day 4 were significantly lower than those on Days 32 and 46 but not Day 18. Within 30min of smoking, median THC, CBN, and THCCOOH concentrations were 689 mu g/L, 116 mu g/L, and 147ng/L, respectively, decreasing to 19.4 mu g/L, 2.4 mu g/L, and 87.6ng/L after 10h. Cannabidiol and 11-hydroxy-THC showed overall lower detection rates of 29 and 8.6%, respectively. Cannabinoid disposition in OF was highly influenced by time and composition of smoked cannabis. Furthermore, cannabinoid OF concentrations increased over ad libitum smoking days, in parallel with increased cannabis self-administration, possibly reflecting development of increased cannabis tolerance. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Lee, Dayong; Mendu, Damodara R.; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Vandrey, Ryan; Murray, Jeannie A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse [R01 DA025044]; National Institute on Drug Abuse, NIH FX This research was funded by grant R01 DA025044 from the National Institute on Drug Abuse and by the Intramural Research Program, National Institute on Drug Abuse, NIH. The funding sources had no role in study design, data collection and analysis, or presentation of results. This study was registered at clinicaltrials.gov (NCT00893074). NR 35 TC 2 Z9 2 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JUN PY 2015 VL 7 IS 6 BP 494 EP 501 DI 10.1002/dta.1718 PG 8 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA CJ7LD UT WOS:000355675700006 PM 25220020 ER PT J AU Walsh, NC Waters, LR Fowler, JA Lin, M Cunningham, CR Brooks, DG Rehg, JE Morse, HC Teitell, MA AF Walsh, Nicole C. Waters, Lynnea R. Fowler, Jessica A. Lin, Mark Cunningham, Cameron R. Brooks, David G. Rehg, Jerold E. Morse, Herbert C., III Teitell, Michael A. TI LKB1 inhibition of NF-kappa B in B cells prevents T follicular helper cell differentiation and germinal center formation SO EMBO REPORTS LA English DT Article DE B cell; T-FH differentiation; germinal center; NF-kappa B ID HEMATOPOIETIC STEM-CELLS; JEGHERS CANCER SYNDROME; TUMOR-SUPPRESSOR LKB1; GENE-EXPRESSION; PROTEIN-KINASE; NUCLEAR-FACTOR; IMMUNE-SYSTEM; ACTIVATION; BCL6; PHOSPHORYLATION AB T-cell-dependent antigenic stimulation drives the differentiation of B cells into antibody-secreting plasma cells and memory B cells, but how B cells regulate this process is unclear. We show that LKB1 expression in B cells maintains B-cell quiescence and prevents the premature formation of germinal centers (GCs). Lkb1-deficient B cells (BKO) undergo spontaneous B-cell activation and secretion of multiple inflammatory cytokines, which leads to splenomegaly caused by an unexpected expansion of T cells. Within this cytokine response, increased IL-6 production results from heightened activation of NF-kappa B, which is suppressed by active LKB1. Secreted IL-6 drives T-cell activation and IL-21 production, promoting T follicular helper (T-FH) cell differentiation and expansion to support a similar to 100-fold increase in steady-state GC B cells. Blockade of IL-6 secretion by BKO B cells inhibits IL-21 expression, a known inducer of T-FH-cell differentiation and expansion. Together, these data reveal cell intrinsic and surprising cell extrinsic roles for LKB1 in B cells that control T-FH-cell differentiation and GC formation, and place LKB1 as a central regulator of T-cell-dependent humoral immunity. C1 [Walsh, Nicole C.; Fowler, Jessica A.; Lin, Mark; Teitell, Michael A.] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90094 USA. [Waters, Lynnea R.; Teitell, Michael A.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. [Cunningham, Cameron R.; Brooks, David G.] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90024 USA. [Cunningham, Cameron R.; Brooks, David G.] Univ Calif Los Angeles, UCLA AIDS Inst, Los Angeles, CA 90024 USA. [Rehg, Jerold E.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD USA. [Teitell, Michael A.] Univ Calif Los Angeles, Calif NanoSyst Inst, Dept Pediat, Broad Stem Cell Res Ctr, Los Angeles, CA USA. [Teitell, Michael A.] Univ Calif Los Angeles, Calif NanoSyst Inst, Broad Stem Cell Res Ctr, Dept Bioengn, Los Angeles, CA USA. [Teitell, Michael A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA USA. RP Teitell, MA (reprint author), Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90094 USA. EM mteitell@mednet.ucla.edu FU NIH [T32CA009120, GM007185, CA90571, CA156674, GM073981, GM114188, CA185189]; ACS grant [LIB-122716]; NIH Intramural Research program, NIAID FX We thank Tammy Phung, Steven Bensinger, and Laura Fahey (UCLA) for assistance and feedback, and Jason Hong and Christopher Pang-Gonzalez (UCLA) for animal colony assistance. FACS was performed at the Broad Stem Cell Research Center FACS Facility and flow cytometry at the UCLA IMED Flow Cytometry Core. This study was supported by NIH grants T32CA009120 (N.C.W.), GM007185 (L.R.W.), CA90571, CA156674, GM073981, GM114188, and CA185189 (M.A.T.), ACS grant LIB-122716 (J.A.F.), and the NIH Intramural Research program, NIAID (H.C.M.). NR 84 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD JUN PY 2015 VL 16 IS 6 BP 753 EP 768 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CJ6MD UT WOS:000355607000013 PM 25916856 ER PT J AU Kurbatova, EV Dalton, T Ershova, J Tupasi, T Caoili, JC Van Der Walt, M Kvasnovsky, C Yagui, M Bayona, J Contreras, C Leimane, V Via, LE Kim, H Akksilp, S Kazennyy, BY Volchenkov, GV Jou, R Kliiman, K Demikhova, OV Cegielski, JP AF Kurbatova, Ekaterina V. Dalton, Tracy Ershova, Julia Tupasi, Thelma Caoili, Janice Campos Van Der Walt, Martie Kvasnovsky, Charlotte Yagui, Martin Bayona, Jaime Contreras, Carmen Leimane, Vaira Via, Laura E. Kim, HeeJin Akksilp, Somsak Kazennyy, Boris Y. Volchenkov, Grigory V. Jou, Ruwen Kliiman, Kai Demikhova, Olga V. Cegielski, J. Peter TI Additional Drug Resistance of Multidrug-Resistant Tuberculosis in Patients in 9 Countries SO EMERGING INFECTIOUS DISEASES LA English DT Article ID TREATMENT OUTCOMES; PNCA MUTATIONS; SURVEILLANCE; METAANALYSIS AB Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line injectable drug would qualify as candidates for a bedaquiline-containing regimen in accordance with published guidelines. Among candidates for the 9-month regimen, standardized drug-susceptibility tests demonstrated susceptibility to a median of 5 (interquartile range 5-6) drugs. Among candidates for bedaquiline, drug-susceptibility tests demonstrated susceptibility to a median of 3 (interquartile range 2-4) drugs; 26% retained susceptibility to <= 2 drugs. These data may assist national TB programs in planning to implement new drugs and drug regimens. C1 [Kurbatova, Ekaterina V.; Dalton, Tracy; Ershova, Julia; Caoili, Janice Campos; Kvasnovsky, Charlotte; Cegielski, J. Peter] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. [Tupasi, Thelma; Caoili, Janice Campos] Trop Dis Fdn, Manila, Philippines. [Van Der Walt, Martie; Kvasnovsky, Charlotte] MRC, Pretoria, South Africa. [Yagui, Martin] Natl Inst Hlth, Lima, Peru. [Bayona, Jaime; Contreras, Carmen] Socios Salud Sucursal Peru, Lima, Peru. [Leimane, Vaira] Riga East Univ Hosp, Ctr TB & Lung Dis, Riga, Latvia. [Via, Laura E.] NIAID, NIH, Bethesda, MD 20892 USA. [Via, Laura E.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Kim, HeeJin] Korean Inst TB, Seoul, South Korea. [Akksilp, Somsak] Minist Publ Hlth, Bangkok, Thailand. [Kazennyy, Boris Y.] Orel Oblast TB Dispensary, Oryol, Russia. [Volchenkov, Grigory V.] Vladimir Oblast TB Dispensary, Vladimir, Russia. [Jou, Ruwen] Taiwan Ctr Dis Control, Taipei, Taiwan. [Kliiman, Kai] Tartu Univ Hosp, Tartu, Estonia. [Demikhova, Olga V.] Russian Acad Med Sci, Moscow, Russia. RP Kurbatova, EV (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop E10, Atlanta, GA 30329 USA. EM ies3@cdc.gov FU US Agency for International Development; CDC; National Institutes of Health's National Institute of Allergy and Infectious Diseases, Division of Intramural Research and South Korea's Center for Disease Control FX This work was supported by the US Agency for International Development; CDC; and, in part, by the National Institutes of Health's National Institute of Allergy and Infectious Diseases, Division of Intramural Research and South Korea's Center for Disease Control support of the sites in South Korea. NR 21 TC 6 Z9 6 U1 0 U2 6 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 JUN PY 2015 VL 21 IS 6 BP 977 EP 983 DI 10.3201/eid2106.141329 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CJ3MA UT WOS:000355386900007 PM 25988299 ER PT J AU Falzarano, D Safronetz, D Prescott, J Marzi, A Feldmann, F Feldmann, H AF Falzarano, Darryl Safronetz, David Prescott, Joseph Marzi, Andrea Feldmann, Friederike Feldmann, Heinz TI Lack of Protection Against Ebola Virus from Chloroquine in Mice and Hamsters SO EMERGING INFECTIOUS DISEASES LA English DT Article ID HEMORRHAGIC-FEVER; CORONAVIRUS; INFECTION; DISEASE; MODEL AB The antimalarial drug chloroquine has been suggested as a treatment for Ebola virus infection. Chloroquine inhibited virus replication in vitro, but only at cytotoxic concentrations. In mouse and hamster models, treatment did not improve survival. Chloroquine is not a promising treatment for Ebola. Efforts should be directed toward other drug classes. C1 [Falzarano, Darryl; Safronetz, David; Prescott, Joseph; Marzi, Andrea; Feldmann, Friederike; Feldmann, Heinz] NIAID, Hamilton, MT USA. RP Feldmann, H (reprint author), NIH, Virol Lab, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 15 TC 6 Z9 6 U1 2 U2 7 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 JUN PY 2015 VL 21 IS 6 BP 1065 EP 1067 DI 10.3201/eid2106.150176 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CJ3MA UT WOS:000355386900025 PM 25988934 ER PT J AU McShane, CM Tapper, C Murray, LJ Landgren, O Bradley, MC Hughes, CM Anderson, LA AF McShane, Charlene M. Tapper, Christopher Murray, Liam J. Landgren, Ola Bradley, Marie C. Hughes, Carmel M. Anderson, Lesley A. TI Oral statin use associated with reduced risk of monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based nested case-control study SO EUROPEAN JOURNAL OF CANCER CARE LA English DT Meeting Abstract C1 [McShane, Charlene M.; Tapper, Christopher; Murray, Liam J.; Anderson, Lesley A.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT7 1NN, Antrim, North Ireland. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Bradley, Marie C.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Hughes, Carmel M.] Queens Univ Belfast, Sch Pharm, Belfast BT7 1NN, Antrim, North Ireland. 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 0961-5423 EI 1365-2354 J9 EUR J CANCER CARE JI Eur. J. Cancer Care PD JUN PY 2015 VL 24 SU 1 SI SI MA 0-01 BP 1 EP 1 DI 10.1111/ecc.12329 PG 1 WC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation SC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation GA CJ8FW UT WOS:000355736600002 ER PT J AU Liu, Q Li, ZZ Gao, JL Wan, WZ Ganesan, S McDermott, DH Murphy, PM AF Liu, Qian Li, Zhanzhuo Gao, Ji-Liang Wan, Wuzhou Ganesan, Sundar McDermott, David H. Murphy, Philip M. TI CXCR4 antagonist AMD3100 redistributes leukocytes from primary immune organs to secondary immune organs, lung, and blood in mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE AMD3100; CXCR4; Cell trafficking; Lymphoid organs; Leukocytes; Mouse ID CHEMOKINE RECEPTOR CXCR4; HUMAN HEMATOPOIETIC STEM; REGULATORY T-CELLS; BONE-MARROW; RAPID MOBILIZATION; WHIM SYNDROME; NEUTROPHIL MOBILIZATION; STROMAL CELLS; PLERIXAFOR; EXPRESSION AB AMD3100 (plerixafor), is a specific CXCR4 antagonist approved by the FDA for mobilizing hematopoietic stem cells from bone marrow to blood for transplantation in cancer. AMD3100 also mobilizes most mature leukocyte subsets to blood; however, their source and trafficking potential have not been fully delineated. Here, we show that a single injection of AMD3100 10 mg/kg into C57Bl/6 mice rapidly mobilizes (peak approximate to 2.5 h) the same leukocyte subsets to blood as in humans. Using this model, we found that AMD3100 mobilization of neutrophils, lymphocytes, and monocytes to blood is not reduced by splenectomy or by blockade of lymphocyte egress from lymph node with FTY720, but is coupled to (i) reduced content of each of these cell types in the bone marrow; (ii) reduced T-cell numbers in thymuses; (iii) increased lymphocytes in lymph nodes; and (iv) increased neutrophil and monocyte content in the lung. Direct intrathymic labeling showed that AMD3100 selectively mobilizes naive thymic CD4(+) and CD8(+) T cells to blood. Finally, AMD3100-induced neutrophil mobilization to blood did not reduce neutrophil trafficking to thioglycollate-inflamed peritoneum. Thus, AMD3100 redistributes lymphocytes, monocytes, and neutrophils from primary immune organs to secondary immune organs, peripheral tissues, and blood, without compromising neutrophil trafficking to inflamed sites. C1 [Liu, Qian; Li, Zhanzhuo; Gao, Ji-Liang; Wan, Wuzhou; McDermott, David H.; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Ganesan, Sundar] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Room 11N113,9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov OI McDermott, David/0000-0001-6978-0867 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. We thank Dr. Michail S. Lionakis and Dr. Estefania Claudio for providing us the lung tissue digestion and perfusion protocol. NR 51 TC 3 Z9 3 U1 1 U2 4 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 JUN PY 2015 VL 45 IS 6 BP 1855 EP 1867 DI 10.1002/eji.201445245 PG 13 WC Immunology SC Immunology GA CJ9QE UT WOS:000355836500027 PM 25801950 ER PT J AU Hendershot, CS Wardell, JD Strang, NM Markovich, MSD Claus, ED Ramchandani, VA AF Hendershot, Christian S. Wardell, Jeffrey D. Strang, Nicole M. Markovich, Mike S. D. Claus, Eric D. Ramchandani, Vijay A. TI Application of an Alcohol Clamp Paradigm to Examine Inhibitory Control, Subjective Responses, and Acute Tolerance in Late Adolescence SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE adolescent; alcohol sensitivity; attention-deficit hyperactivity disorder; impulsivity; intravenous alcohol ID FAMILY-HISTORY; USE DISORDERS; INCREASED SENSITIVITY; HIGH-RISK; DRINKING; IMPAIRMENT; MODEL; INTOXICATION; DEPENDENCE; DRINKERS AB Individual differences in acute alcohol effects on cognitive control and subjective responses-and acute tolerance to these effects-are implicated in the risk for heavy drinking and alcohol-related harms. Few studies have examined these effects in drinkers under age 21. Additionally, studies of acute tolerance typically involve bolus oral alcohol administration, such that estimates of tolerance are confounded with blood alcohol concentration (BAC) limb. The current study examined cognitive control and subjective responses in young heavy drinkers (n = 88; M = 19.8 years old, SD = 0.8) during a single-session alcohol clamp protocol. Participants completed an intravenous alcohol session comprising an ascending limb (0 to 80 mg% in 20 min) and a BAC plateau (80 mg% for 80 min). Serial assessments included a cued go/no-go task and measures of stimulation, sedation, and craving. Relevant individual difference factors (attention-deficit hyperactivity disorder [ADHD] symptoms and sensation seeking) were examined as moderators. Multilevel modeling demonstrated that response inhibition worsened following initial rise in BAC and showed increasing impairment during the BAC plateau. ADHD symptoms and sensation seeking moderated this effect. Significant within-person associations between stimulation and craving were evident on the ascending limb only. Participants with higher ADHD symptoms reported steeper increases in stimulation during the ascending limb. These findings provide initial information about subjective and behavioral responses during pseudoconstant BAC, and potential moderators of these outcomes, in late adolescence. Additional studies with placebo-controlled designs are necessary to confirm these findings. C1 [Hendershot, Christian S.; Wardell, Jeffrey D.; Strang, Nicole M.] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON M6J 1H4, Canada. [Hendershot, Christian S.] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. [Hendershot, Christian S.; Markovich, Mike S. D.] Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. [Claus, Eric D.] Mind Res Network, Albuquerque, NM USA. [Claus, Eric D.] Lovelace Biomed & Environm Res Inst, Albuquerque, NM USA. [Ramchandani, Vijay A.] NIAAA, Sect Human Psychopharmacol, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Hendershot, CS (reprint author), Ctr Addict & Mental Hlth, 100 Stokes St, Toronto, ON M6J 1H4, Canada. EM christian.hendershot@utoronto.ca RI Hendershot, Christian/C-1638-2009; OI Hendershot, Christian/0000-0002-5328-2035 FU ABMRF/The Foundation for Alcohol Research; Canadian Institutes of Health Research [260418, 288905/307742]; Ontario Mental Health Foundation; Canada Foundation for Innovation; NIAAA Division of Intramural Clinical and Biological Research; NIH [R21AA020304]; Indiana Alcohol Research Center [NIH P60 AA007611] FX This study was supported by a grant from ABMRF/The Foundation for Alcohol Research (Christian S. Hendershot). The funding agency had no role in the study other than financial support. The authors also acknowledge support from the Canadian Institutes of Health Research (Grants 260418, 288905/307742), the Ontario Mental Health Foundation, and the Canada Foundation for Innovation (Christian S. Hendershot), the NIAAA Division of Intramural Clinical and Biological Research (Vijay A. Ramchandani), and NIH R21AA020304 (Eric D. Claus, Christian S. Hendershot). The authors thank Sean O'Connor and Victor Vitvitskiy at the Indiana Alcohol Research Center (NIH P60 AA007611) for software support. The authors also express appreciation to Dr. Ariel Graff, Vanessa Garofalo, and Matthew McPhee for their assistance with data collection. All authors contributed significantly to the manuscript and all authors have read and approved the final manuscript. NR 64 TC 4 Z9 4 U1 1 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 EI 1936-2293 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD JUN PY 2015 VL 23 IS 3 BP 147 EP 158 DI 10.1037/pha0000017 PG 12 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA CK1BK UT WOS:000355940200002 PM 26053322 ER PT J AU Morgan, JT Kwon, HS Wood, JA Borjesson, DL Tomarev, SI Murphy, CJ Russell, P AF Morgan, Joshua T. Kwon, Heung Sun Wood, Joshua A. Borjesson, Dori L. Tomarev, Stanislav I. Murphy, Christopher J. Russell, Paul TI Thermally labile components of aqueous humor potently induce osteogenic potential in adipose-derived mesenchymal stem cells SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE Aqueous humor; Mesenchymal stem cells; Osteogenic potential; Myocilin; Alkaline phosphatase ID HUMAN TRABECULAR MESHWORK; OPEN-ANGLE GLAUCOMA; TISSUE GROWTH-FACTOR; THERAPY POSITION STATEMENT; UMBILICAL-CORD BLOOD; MATRIX GLA PROTEIN; STROMAL CELLS; BONE-MARROW; INTERNATIONAL-SOCIETY; RAT CALVARIA AB Adipose-derived mesenchymal stem cells (ASCs) hold promise for use in cell-based therapies. Their intrinsic anti-inflammatory properties are potentially useful for treatments of inflammatory conditions such as uveitis, while their ability to differentiate along multiple cell lineages suggests use in regenerating damaged or degenerated tissue. However, how ASCs will respond to the intraocular environment is poorly studied. We have recently reported that aqueous humor (AH), the fluid that nourishes the anterior segment of the eye, potently increases alkaline phosphatase (ALP) activity of ASCs, indicating osteogenic differentiation. Here, we expand on our previous findings to better define the nature of this response. To this end, we cultured ASCs in the presence of 0, 5, 10, and 20% AH and assayed them for ALP activity. We found ALP activity correlates with increasing AH concentrations from 5 to 20%, and that longer treatments result in increased ALP activity. By using serum free media and pretreating AH with dextran-coated charcoal, we found that serum and charcoal-adsorbable AH components augment but are not required for this response. Further, by heat-treating the AH, we established that thermally labile components are required for the osteogenic response. Finally, we showed myocilin, a protein present in AH, could induce ALP activity in ASCs. However, this was to a lesser extent than untreated 5% AH, and myocilin could only partially rescue the effect after heat treatment, documenting there were additional thermally labile constituents of AH involved in the osteogenic response. Our work adds to the understanding of the induction of ALP in ASCs following exposure to AH, providing important insight in how ASCs will be influenced by the ocular environment. In conclusion, increased osteogenic potential upon exposure to represents a potential challenge to developing ASC cell-based therapies directed at the eye. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Morgan, Joshua T.; Murphy, Christopher J.; Russell, Paul] Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA 95616 USA. [Kwon, Heung Sun; Tomarev, Stanislav I.] NEI, Sect Retinal Gangl Cell Biol, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Wood, Joshua A.; Borjesson, Dori L.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Murphy, Christopher J.] Univ Calif Davis, Sch Med, Dept Ophthalmol & Vis Sci, Davis, CA 95616 USA. RP Russell, P (reprint author), Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, 1 Shields Ave, Davis, CA 95616 USA. EM prussell@ucdavis.edu FU National Institutes of Health [R01EY019475, R01EY019970]; Research to Prevent Blindness; Intramural Research Program of the National Eye Institute, National Institutes of Health FX This work was funded by grants from the National Institutes of Health R01EY019475 and R01EY019970, and an unrestricted grant from Research to Prevent Blindness, and the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 79 TC 1 Z9 1 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD JUN PY 2015 VL 135 BP 127 EP 133 DI 10.1016/j.exer.2015.02.018 PG 7 WC Ophthalmology SC Ophthalmology GA CJ8RC UT WOS:000355770200014 PM 25720657 ER PT J AU Devine, K Mumford, SL Goldman, KN Hodes-Wertz, B Druckenmiller, S Propst, AM Noyes, N AF Devine, Kate Mumford, Sunni L. Goldman, Kara N. Hodes-Wertz, Brooke Druckenmiller, Sarah Propst, Anthony M. Noyes, Nicole TI Baby budgeting: oocyte cryopreservation in women delaying reproduction can reduce cost per live birth SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med DE Oocyte cryopreservation; vitrification; fertility preservation; cost analysis; ART ID ASSISTED REPRODUCTION; DECISION-ANALYSIS; AGE; FERTILITY; VITRIFICATION; EFFICIENCY; FRESH; SPAN AB Objective: To determine whether oocyte cryopreservation for deferred reproduction is cost effective per live birth using a model constructed from observed clinical practice. Design: Decision-tree mathematical model with sensitivity analyses. Setting: Not applicable. Patient(s): A simulated cohort of women wishing to delay childbearing until age 40 years. Intervention(s): Not applicable. Main Outcome Measure(s): Cost per live birth. Result(s): Our primary model predicted that oocyte cryopreservation at age 35 years by women planning to defer pregnancy attempts until age 40 years would decrease cost per live birth from $ 55,060 to $ 39,946 (and increase the odds of live birth from 42% to 62% by the end of the model), indicating that oocyte cryopreservation is a cost-effective strategy relative to forgoing it. If fresh autologous assisted reproductive technology (ART) was added at age 40 years, before thawing oocytes, 74% obtained a live birth, and cost per live birth increased to $ 61,887. Separate sensitivity analyses demonstrated that oocyte cryopreservation remained cost effective as long as performed before age 38 years, and more than 49% of those women not obtaining a spontaneously conceived live birth returned to thaw oocytes. Conclusion(s): In women who plan to delay childbearing until age 40 years, oocyte cryopreservation before 38 years of age reduces the cost to obtain a live birth. (C) 2015 by American Society for Reproductive Medicine. C1 [Devine, Kate] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Goldman, Kara N.; Hodes-Wertz, Brooke; Druckenmiller, Sarah; Noyes, Nicole] NYU, Sch Med, New York, NY USA. [Propst, Anthony M.] Texas Fertil Ctr, Austin, TX USA. RP Devine, K (reprint author), 10 Ctr Dr,MSC 1109,Room 1-3140, Bethesda, MD 20892 USA. EM kate.devine@nih.gov OI Goldman, Kara/0000-0002-5455-627X; Hodes-Wertz, Brooke/0000-0001-8766-6216 FU Intramural NIH HHS [Z99 HD999999] NR 30 TC 11 Z9 11 U1 2 U2 9 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 JUN PY 2015 VL 103 IS 6 BP 1446 EP U105 DI 10.1016/j.fertnstert.2015.02.029 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CJ5TM UT WOS:000355552600016 PM 25813281 ER PT J AU Devine, K Connell, MT Richter, KS Ramirez, CI Levens, ED DeCherney, AH Stillman, RJ Widra, EA AF Devine, Kate Connell, Matthew T. Richter, Kevin S. Ramirez, Christina I. Levens, Eric D. DeCherney, Alan H. Stillman, Robert J. Widra, Eric A. TI Single vitrified blastocyst transfer maximizes liveborn children per embryo while minimizing preterm birth SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med DE Frozen embryo transfer; low birth weight; preterm birth; single embryo transfer; vitrification ID IN-VITRO FERTILIZATION; ASSISTED REPRODUCTIVE TECHNOLOGY; ELECTIVE SINGLE; INFERTILITY TRIAL; UNITED-STATES; CRYOPRESERVATION; CYCLES; WEIGHT; WOMEN; RATES AB Objective: To compare live-birth rates, blastocyst to live-birth efficiency, gestational age, and birth weights in a large cohort of patients undergoing single versus double thawed blastocyst transfer. Design: Retrospective cohort study. Setting: Assisted reproduction technology (ART) practice. Patient(s): All autologous frozen blastocyst transfers (FBT) of one or two vitrified-warmed blastocysts from January 2009 through April 2012. Intervention(s): Single or double FBT. Main Outcome Measure(s): Live birth, blastocyst to live-birth efficiency, preterm birth, low birth weight. Result(s): Only supernumerary blastocysts with good morphology (grade BB or better) were vitrified, and 1,696 FBTs were analyzed. No differences were observed in patient age, rate of embryo progression, or postthaw blastomere survival. Double FBT yielded a higher live birth per transfer, but 33% of births from double FBT were twins versus only 0.6% of single FBT. Double FBT was associated with statistically significant increases in preterm birth and low birth weight, the latter of which was statistically significant even when the analysis was limited to singletons. Of the blastocysts transferred via single FBT, 38% resulted in a liveborn child versus only 34% with double FBT. This suggests that two single FBTs would result in more liveborn children with significantly fewer preterm births when compared with double FBT. Conclusion(s): Single FBT greatly decreased multiple and preterm birth risk while providing excellent live-birth rates. Patients should be counseled that a greater overall number of live born children per couple can be expected when thawed blastocysts are transferred one at a time. (C) 2015 by American Society for Reproductive Medicine. C1 [Devine, Kate; Connell, Matthew T.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Rockville, MD USA. [Devine, Kate; Richter, Kevin S.; Levens, Eric D.; Stillman, Robert J.; Widra, Eric A.] Shady Grove Fertil Reprod Sci Ctr, Washington, DC USA. [Devine, Kate; Richter, Kevin S.; Levens, Eric D.; Stillman, Robert J.; Widra, Eric A.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Ramirez, Christina I.] Walter Reed Natl Mil Med Ctr, Dept Obstet & Gynecol, Bethesda, MD USA. RP Devine, K (reprint author), Shady Grove Fertil, 2021 K St NW 701, Washington, DC 20006 USA. EM kate.devine@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 40 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2015 VL 103 IS 6 BP 1454 EP U113 DI 10.1016/j.fertnstert.2015.02.032 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CJ5TM UT WOS:000355552600017 PM 25813283 ER PT J AU Louis, GMB Druschel, C Bell, E Stern, JE Luke, B McLain, A Sundaram, R Yeung, E AF Louis, Germaine M. Buck Druschel, Charlotte Bell, Erin Stern, Judy E. Luke, Barbara McLain, Alexander Sundaram, Rajeshwari Yeung, Edwina TI Use of assisted reproductive technology treatment as reported by mothers in comparison with registry data: the Upstate KIDS Study SO FERTILITY AND STERILITY LA English DT Article DE Assisted reproductive technologies; infertility; maternal report; sensitivity; validity ID IN-VITRO FERTILIZATION; ASSESSMENT MONITORING-SYSTEM; BIRTH CERTIFICATE; INFERTILITY TREATMENT; PERINATAL OUTCOMES; MASSACHUSETTS; COHORT; METAANALYSIS; INFORMATION; CONCEPTION AB Objective: To assess the validity of maternally reported assisted reproductive technologies (ART) use and to identify predictors of reporting errors. Design: Linkage study. Setting: Not applicable. Patient(s): A total of 5,034 (27%) mothers enrolled, from whom 4,886 (97%) self-reported information about use of infertility treatment, including ART, for the index birth. Intervention(s): None. Main Outcome Measure(s): Four measures of validity (sensitivity, specificity, positive and negative predictive values) and use of net reclassification improvement (NRI) methods to identify predictors associated with concordant/discordant maternal reporting. Result(s): The Upstate New York Infant Development Screening Program (Update KIDS Study) was linked with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) using a defined algorithmfor 2008-2010. The sensitivity, specificity, positive and negative predictive values were high (0.93, 0.99, 0.80, and 1.00, respectively). The validity of maternal report was high, reflecting few differences by participant characteristics except for maternal age dichotomized at 29 years as identified with NRI methods. Conclusion(s): Maternally reported ART is valid, with little variation across various characteristics. No strong predictors of discordant reporting were found, supporting the utility of population-based research with SART CORS linkage. (C) 2015 by American Society for Reproductive Medicine. C1 [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Druschel, Charlotte] SUNY Albany, New York State Dept Hlth, Albany, NY 12222 USA. [Bell, Erin] SUNY Albany, Dept Environm Hlth Sci & Epidemiol, Albany, NY 12222 USA. [Stern, Judy E.] Geisel Sch Med Dartmouth, Dept Obstet & Gynecol, Hanover, NH USA. [Luke, Barbara] Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, E Lansing, MI 48824 USA. [McLain, Alexander] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Yeung, Edwina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Rockville, MD 20852 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 20852 USA. EM louisg@mail.nih.gov OI Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU National Institutes of Health [R01HD064595, R01HD067270, R01CA151973]; American Society for Reproductive Medicine; Society for Assisted Reproductive Technology; Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NICHD) [HHSN267200700019C, HHSN275201200005C] FX G.M.B.L. has nothing to disclose. C.D. has nothing to disclose. E.B. has nothing to disclose. J.E.S. has received grants from the National Institutes of Health (R01HD064595 and R01HD067270) and the American Society for Reproductive Medicine outside the submitted work. B.L. has received personal fees from the Society for Assisted Reproductive Technology and grants from the National Institutes of Health (R01CA151973, R01HD064595, and R01HD067270) outside the submitted work. A.M. has nothing to disclose. R.S. has nothing to disclose. E.Y. has nothing to disclose.; Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NICHD contracts HHSN267200700019C; HHSN275201200005C). NR 24 TC 5 Z9 5 U1 0 U2 5 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 JUN PY 2015 VL 103 IS 6 BP 1461 EP 1468 DI 10.1016/j.fertnstert.2015.02.033 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CJ5TM UT WOS:000355552600018 ER PT J AU Hill, MJ Royster, GD Healy, MW Richter, KS Levy, G DeCherney, AH Levens, ED Suthar, G Widra, E Levy, MJ AF Hill, Micah J. Royster, Greene Donald Healy, Mae Wu Richter, Kevin S. Levy, Gary DeCherney, Alan H. Levens, Eric D. Suthar, Geeta Widra, Eric Levy, Michael J. TI Are good patient and embryo characteristics protective against the negative effect of elevated progesterone level on the day of oocyte maturation? SO FERTILITY AND STERILITY LA English DT Article DE Elevated progesterone; premature luteinization; implantation; IVF ID IN-VITRO FERTILIZATION; HUMAN CHORIONIC-GONADOTROPIN; INTRACYTOPLASMIC SPERM INJECTION; FOLLICLE-STIMULATING-HORMONE; PREMATURE LUTEINIZATION; OVARIAN STIMULATION; SERUM PROGESTERONE; PREGNANCY RATES; ENDOMETRIAL RECEPTIVITY; LIVE BIRTH AB Objective: To evaluate if an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration is associated with a decrease in live-birth rate in patients with a good prognosis. Design: Retrospective cohort study. Setting: Large, private, assisted reproductive technology (ART) practice. Patient(s): One thousand six hundred twenty fresh autologous ART cycles. Intervention(s): None. Main Outcome Measure(s): Live-birth rate. Result(s): A total of 934 blastocyst and 686 cleavage-stage embryo transfer (ET) cycles were evaluated. Serum P levels were not associated with markers of oocyte or embryo quality, including fertilization, embryo stage at transfer, and embryos available for cryopreservation. Patient age, stage of ET, embryo quality, the number of embryos transferred, and P level on the day of hCG administration were all significantly associated with live birth. Higher P levels were associated with decreased odds of live birth for cleavage- and blastocyst-stage embryos, poor-fair and good-quality embryos, and poor-and high-responder patients. The nonsignificance of interaction tests of P levels with embryo stage, embryo quality, patient age, and ovarian response indicated that the relationship between P level and live birth was similar regardless of these factors. Conclusion(s): An elevated serum P level on the day of hCG administration was negatively associated with live birth, even in ETs with a good prognosis. (C) 2015 by American Society for Reproductive Medicine. C1 [Hill, Micah J.; Royster, Greene Donald; Healy, Mae Wu; Richter, Kevin S.; Levy, Gary; Levens, Eric D.; Suthar, Geeta; Widra, Eric; Levy, Michael J.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Hill, Micah J.; Royster, Greene Donald; Healy, Mae Wu; Levy, Gary; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Hill, MJ (reprint author), 10 Ctr Dr, Bethesda, MD 20876 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 Intramural Research Program of 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 32 TC 12 Z9 13 U1 1 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 JUN PY 2015 VL 103 IS 6 BP 1477 EP U145 DI 10.1016/j.fertnstert.2015.02.038 PG 13 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CJ5TM UT WOS:000355552600020 PM 25881880 ER PT J AU Bolnick, JM Kilburn, BA Bolnick, AD Diamond, MP Singh, M Hertz, M Dai, J Armant, DR AF Bolnick, Jay M. Kilburn, Brian A. Bolnick, Alan D. Diamond, Michael P. Singh, Manvinder Hertz, Michael Dai, Jing Armant, D. Randall TI Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3 ',5 '-cyclic monophosphate signaling SO FERTILITY AND STERILITY LA English DT Article DE Trophoblast invasion; phosphodiesterase-5 inhibitor; nitric oxide; guanosine 3 ',5 '-cyclic monophosphate; integrins ID ENDOTHELIAL PROGENITOR CELLS; IN-VITRO; PREECLAMPTIC PREGNANCIES; PLACENTAL ISCHEMIA; TYROSINE KINASE-1; GROWTH-FACTOR; CYCLIC-GMP; HLA-G; EXPRESSION; INHIBITOR AB Objective: To determine the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on trophoblast invasiveness. Design: Laboratory investigation. Setting: Academic medical center. Patient(s): Placental tissues discarded after first-trimester terminations were obtained from patients with informed consent. Intervention(s): A cell line, HTR-8/SVneo, established from first-trimester cytotrophoblast, and villous explants, was treated with or without sildenafil, guanosine 3',5'-cyclic monophosphate (cGMP) analog, cGMP inhibitor, or L-NAME (N-G-nitro-L-arginine methyl ester hydrochloride) and cultured on fibronectin or Matrigel. Integrins alpha 6 beta 4 and alpha 1 beta 1 were detected by immunocytochemistry. Main Outcome Measure(s): Trophoblast outgrowth from villous tips, cytotrophoblast cell invasion, and integrin immunostaining were assessed in cytotrophoblast and explant cultures. Result(s): Integrin expression in trophoblast cells ex vivo switched from alpha 6 to alpha 1, and invasiveness increased, when exposed to sildenafil or cGMP agonist. Either cGMP antagonist or L-NAME blocked integrin switching and invasion induced by sildenafil. Elevation of nitric oxide pharmacologically induced invasion, but not when cGMP antagonist was present. Conclusion(s): Sildenafil altered trophoblast phenotype through a process dependent on nitric oxide availability and cGMP accumulation. In addition to its vasoactivity, sildenafil directly stimulates trophoblast extravillous differentiation, which would be favorable for implantation and reduce risk for adverse pregnancy outcomes. (C) 2015 by American Society for Reproductive Medicine. C1 [Bolnick, Jay M.; Kilburn, Brian A.; Bolnick, Alan D.; Singh, Manvinder; Hertz, Michael; Dai, Jing; Armant, D. Randall] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Armant, DR (reprint author), Wayne State Univ, Mott Ctr Human Growth & Dev, 275 East Hancock St, Detroit, MI 48201 USA. EM D.Armant@Wayne.edu OI Diamond, Michael/0000-0001-6353-4489; Armant, D. Randall/0000-0001-5904-9325 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [HD071408]; W.K. Kellogg Foundation FX This research was supported in part by the Intramural Research Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health grant HD071408, and the W.K. Kellogg Foundation. NR 58 TC 2 Z9 3 U1 1 U2 6 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 JUN PY 2015 VL 103 IS 6 BP 1587 EP U285 DI 10.1016/j.fertnstert.2015.02.025 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CJ5TM UT WOS:000355552600034 PM 25813289 ER PT J AU Basudhar, D Cheng, RC Bharadwaj, G Ridnour, LA Wink, DA Miranda, KM AF Basudhar, Debashree Cheng, Robert C. Bharadwaj, Gaurav Ridnour, Lisa A. Wink, David A. Miranda, Katrina M. TI Chemotherapeutic potential of diazeniumdiolate-based aspirin prodrugs in breast cancer SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Nitroxyl; Nitric oxide; NONOate; Diazeniumdiolate; IPA/NO; DEA/NO; NSAID; Aspirin; Anti-inflammatory; Anticancer ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NITRIC-OXIDE SYNTHASE; TRIOXODINITRATE ANGELIS SALT; DETERRENT AGENT CYANAMIDE; TUMOR ANGIOGENESIS; POLY(ADP-RIBOSE) POLYMERASE; NITROXYL HNO; IN-VIVO; SODIUM TRIOXODINITRATE; POOR SURVIVAL AB Diazeniumdiolate-based aspirin prodrugs have previously been shown to retain the anti-inflammatory properties of aspirin while protecting against the common side effect of stomach ulceration. Initial analysis of two new prodrugs of aspirin that also release either nitroxyl (HNO) or nitric oxide (NO) demonstrated increased cytotoxicity toward human lung carcinoma cells compared to either aspirin or the parent nitrogen oxide donor. In addition, cytotoxicity was significantly lower in endothelial cells, suggesting cancer-specific sensitivity. To assess the chemotherapeutic potential of these new prodrugs in treatment of breast cancer, we studied their effect both in cultured cells and in a nude mouse model. Both prodrugs reduced growth of breast adenocarcinoma cells more effectively than the parent compounds while not being appreciably cytotoxic in a related nontumorigenic cell line (MCF-10A). The HNO donor also was more cytotoxic than the related NO donor. The basis for the observed specificity was investigated in terms of impact on metabolism, DNA damage and repair, apoptosis, angiogenesis and metastasis. The results suggest a significant pharmacological potential for treatment of breast cancer. (C) 2015 Elsevier Inc. All rights reserved. C1 [Basudhar, Debashree; Bharadwaj, Gaurav; Miranda, Katrina M.] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA. [Cheng, Robert C.; Ridnour, Lisa A.; Wink, David A.] NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Miranda, KM (reprint author), Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA. EM kmiranda@email.arizona.edu FU National Institutes of Health [R01-GM076247]; Intramural Research Program of the National Institutes of Health, National Cancer Institute; Center for Cancer Research FX This work is supported in part by a National Institutes of Health grant (R01-GM076247 to K.M.M.) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research (D.A.W.). NR 148 TC 3 Z9 3 U1 2 U2 17 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 JUN PY 2015 VL 83 BP 101 EP 114 DI 10.1016/j.freeradbiomed.2015.01.029 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CJ6BI UT WOS:000355577600010 PM 25659932 ER PT J AU van 't Erve, TJ Lih, FB Kadiiska, MB Deterding, LJ Eling, TE Mason, RP AF van 't Erve, Thomas J. Lih, Fred B. Kadiiska, Maria B. Deterding, Leesa J. Eling, Thomas E. Mason, Ronald P. TI Reinterpreting the best biomarker of oxidative stress: The 8-iso-PGF(2 alpha)/PGF(2 alpha), ratio distinguishes chemical from enzymatic lipid peroxidation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE F-2-isoprostanes; Oxidative stress; Inflammation; Biomarkers; Lipid peroxidation ID 8-EPI-PROSTAGLANDIN F-2 ALPHA; IN-VIVO; ENDOTHELIAL EXPRESSION; ISCHEMIA-REPERFUSION; DEPENDENT FORMATION; MASS-SPECTROMETRY; GENERATION; INJURY; F-2-ISOPROSTANES; ISOPROSTANE AB The biomarker 8-iso-prostaglandin F-2 alpha (8-iso-PGF(2 alpha)) is regarded as the gold standard for detection of excessive chemical lipid peroxidation in humans. However, biosynthesis of 8-iso-PGF(2 alpha) via enzymatic lipid peroxidation by prostaglandin-endoperoxide synthases (PGHSs), which are significantly induced in inflammation, could lead to incorrect biomarker interpretation. To resolve the ambiguity with this biomarker, the ratio of 8-iso-PGF(2 alpha) to prostaglandin F-2 alpha (PGF(2 alpha)) is established as a quantitative measure to distinguish enzymatic from chemical lipid peroxidation in vitro, in animal models, and in humans. Using this method, we find that chemical lipid peroxidation contributes only 3% to the total 8-iso-PGF(2 alpha) in the plasma of rats. In contrast, the 8-iso-PGF(2 alpha) levels in plasma of human males are generated > 99% by chemical lipid peroxidation. This establishes the potential for an alternate pathway of biomarker synthesis, and draws into question the source of increases in 8-iso-PGF(2 alpha) seen in many human diseases. In conclusion, increases in 8-iso-PGF(2 alpha) do not necessarily reflect increases in oxidative stress: therefore, past studies using 8-iso-PGF(2 alpha) as a marker of oxidative stress may have been misinterpreted. The 8-isoPGF(2 alpha)/PGF(2 alpha) ratio can be used to distinguish biomarker synthesis pathways and thus confirm the potential change in oxidative stress in the myriad of disease and chemical exposures known to induce 8-iso-PGFF(2 alpha). Published by Elsevier Inc. C1 [van 't Erve, Thomas J.; Kadiiska, Maria B.; Mason, Ronald P.] NIEHS, Immun Inflammat & Dis Lab, Res Triangle Pk, NC 27709 USA. [Lih, Fred B.; Deterding, Leesa J.] NIEHS, Epigenet & Stem Cell Biol Lab, Res Triangle Pk, NC 27709 USA. [Eling, Thomas E.] NIEHS, Emeritus, Res Triangle Pk, NC 27709 USA. RP van 't Erve, TJ (reprint author), NIEHS, Immun Inflammat & Dis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM thomas.vanterve@nih.gov OI van 't Erve, Thomas/0000-0002-3260-6627 FU National Institutes of Health; National Institute of Environmental Health Sciences FX The authors gratefully acknowledge Dr. Jason Williams and Dr. Stephanie London for their review of this manuscript and Sandra Chambers for the literature search. We thank the staff of the NIEHS Clinical Research Unit for their help in obtaining human plasma samples. We thank Jean Corbett, Dr. Ann Motten, and Mary Mason for their editorial expertise. This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 31 TC 10 Z9 10 U1 0 U2 6 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 JUN PY 2015 VL 83 BP 245 EP 251 DI 10.1016/j.freeradbiomed.2015.03.004 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CJ6BI UT WOS:000355577600024 PM 25772010 ER PT J AU Chang, CQ Tingle, SR Filipski, KK Khoury, MJ Lam, TK Schully, SD Ioannidis, JPA AF Chang, Christine Q. Tingle, Sharna R. Filipski, Kelly K. Khoury, Muin J. Lam, Tram Kim Schully, Sheri D. Ioannidis, John P. A. TI An overview of recommendations and translational milestones for genomic tests in cancer SO GENETICS IN MEDICINE LA English DT Review DE cancer; genomics; genetic testing; recommendations and guidelines; translational research ID PERSONALIZED MEDICINE; PROGNOSTIC MARKERS AB Purpose: To understand the translational trajectory of genomic tests in cancer screening, diagnosis, prognosis, and treatment, we reviewed tests that have been assessed by recommendation and guideline developers. Methods: For each test, we marked translational milestones by determining when the genomic association with cancer was first discovered and studied in patients, and when a health application for a specified clinical use was successfully demonstrated and approved or cleared by the US Food and Drug Administration. To identify recommendations and guidelines, we reviewed the websites of cancer, genomic, and general guideline developers and professional organizations. We searched the in vitro diagnostics database of the US Food and Drug Administration for information, and we searched PubMed for translational milestones. Milestones were examined against type of recommendation, Food and Drug Administration approval or clearance, disease rarity, and test purpose. Results: Of the 45 tests we identified, 9 received strong recommendations for their usage in clinical settings, 14 received positive but moderate recommendations, and 22 were not currently recommended. For 18 tests, two or more different sources had issued recommendations, with 67% concordance. Only five tests had Food and Drug Administration approval, and an additional five had clearance. The median time from discovery to recommendation statement was 14.7 years. Conclusion: In general, there were no associations found between translational trajectory and recommendation category. C1 [Chang, Christine Q.; Tingle, Sharna R.; Filipski, Kelly K.; Khoury, Muin J.; Lam, Tram Kim; Schully, Sheri D.; Ioannidis, John P. A.] NCI, Epidemiol & Genom Res Program, Rockville, MD 20852 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Gen, Atlanta, GA USA. [Ioannidis, John P. A.] Stanford Univ, Stanford Prevent Res Ctr, Sch Med, Dept Med, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Humanities & Sci, Dept Stat, Stanford, CA 94305 USA. RP Chang, CQ (reprint author), NCI, Epidemiol & Genom Res Program, Rockville, MD 20852 USA. EM christine.chang2@nih.gov OI Chang, Christine/0000-0002-4624-898X FU Intramural CDC HHS [CC999999] NR 30 TC 1 Z9 1 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JUN PY 2015 VL 17 IS 6 BP 431 EP 440 DI 10.1038/gim.2014.133 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CJ5WS UT WOS:000355564200001 PM 25341115 ER PT J AU Wang, Y Liu, G Caggana, M Kennedy, J Zimmerman, R Oyeku, SO Werner, EM Grant, AM Green, NS Grosse, SD AF Wang, Ying Liu, Gang Caggana, Michele Kennedy, Joseph Zimmerman, Regina Oyeku, Suzette O. Werner, Ellen M. Grant, Althea M. Green, Nancy S. Grosse, Scott D. TI Mortality of New York children with sickle cell disease identified through newborn screening SO GENETICS IN MEDICINE LA English DT Article DE long-term follow-up; maternal race/ethnicity; mortality; newborn screening; sickle cell disease ID TERM-FOLLOW-UP; UNITED-STATES; BIRTH OUTCOMES; 1ST DECADE; ANEMIA; HYDROXYUREA; LIFE; US; ADOLESCENTS; DISORDERS AB Purpose: Long-term follow-up of newborn screening for conditions such as sickle cell disease can be conducted using linkages to population-based data. We sought to estimate childhood sickle cell disease mortality and risk factors among a statewide birth cohort with sickle cell disease identified through newborn screening. Methods: Children with sickle cell disease identified by newborn screening and born to New York residents in 2000-2008 were matched to birth and death certificates. Mortality rates were calculated (using numbers of deaths and observed person-years at risk) and compared with mortality rates for all New York children by maternal race/ethnicity. Stratified analyses were conducted to examine associations between selected factors and mortality. Results: Among 1,911 infants with sickle cell disease matched to birth certificates, 21 deaths were identified. All-cause mortality following diagnosis was 3.8 per 1,000 person-years in the first 2 years of life and 1.0 per 1,000 person-years at ages 2-9 years. The mortality rate was significantly lower among children of foreign-born mothers and was significantly higher among preterm infants with low birth weight. The mortality rates were not significantly higher for infants after 28 days with sickle cell disease than for all New York births, but they were 2.7-8.4 times higher for children 1 through 9 years old with homozygous sickle cell disease than for those of all non-Hispanic black or Hispanic children born to New York residents. Conclusion: Estimated mortality risk in children with homozygous sickle cell disease remains elevated even after adjustment for maternal race/ethnicity. These results provide evidence regarding the current burden of child mortality among children with sickle cell disease despite newborn screening. C1 [Wang, Ying; Liu, Gang; Caggana, Michele] SUNY Albany, Sch Publ Hlth, Albany, NY 12222 USA. [Wang, Ying] New York State Dept Hlth, Div Data Management & Res, Off Primary Care & Hlth Management Syst, Albany, NY USA. [Caggana, Michele] New York State Dept Hlth, Wadsworth Ctr, Newborn Screening Program, Albany, NY USA. [Zimmerman, Regina] New York City Dept Hlth & Mental Hyg, Off Vital Stat, New York, NY USA. [Oyeku, Suzette O.] Childrens Hosp Montefiore, Albert Einstein Coll Med, Dept Pediat, New York, NY USA. [Werner, Ellen M.] NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Grant, Althea M.; Grosse, Scott D.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Div Blood Disorders, Atlanta, GA USA. [Green, Nancy S.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY USA. RP Wang, Y (reprint author), SUNY Albany, Sch Publ Hlth, Albany, NY 12222 USA. EM wxy01@health.state.ny.us OI Green, Nancy/0000-0002-9877-1561 FU US Centers for Disease Control and Prevention; National Heart, Lung and Blood Institute [U50DD000722] FX This project was supported by the US Centers for Disease Control and Prevention and the National Heart, Lung and Blood Institute (grant U50DD000722). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 40 TC 2 Z9 3 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JUN PY 2015 VL 17 IS 6 BP 452 EP 459 DI 10.1038/gim.2014.123 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA CJ5WS UT WOS:000355564200004 PM 25255366 ER PT J AU Butrick, M Kelly, S Peshkin, BN Luta, G Nusbaum, R Hooker, GW Graves, K Feeley, L Isaacs, C Valdimarsdottir, HB Jandorf, L DeMarco, T Wood, M McKinnon, W Garber, J McCormick, SR Schwartz, MD AF Butrick, Morgan Kelly, Scott Peshkin, Beth N. Luta, George Nusbaum, Rachel Hooker, Gillian W. Graves, Kristi Feeley, Lisa Isaacs, Claudine Valdimarsdottir, Heiddis B. Jandorf, Lina DeMarco, Tiffani Wood, Marie McKinnon, Wendy Garber, Judy McCormick, Shelley R. Schwartz, Marc D. TI Disparities in uptake of BRCA1/2 genetic testing in a randomized trial of telephone counseling SO GENETICS IN MEDICINE LA English DT Article DE cancer; genetic counseling; genetic testing; psychosocial predictors; telephone counseling ID BREAST-CANCER SUSCEPTIBILITY; HEREDITARY BREAST; OVARIAN-CANCER; RACIAL-DIFFERENCES; HIGH-RISK; WOMEN; COMMUNICATION; VALIDATION; QUALITY; PATIENT AB Purpose: As genetic counseling and testing become more fully integrated into clinical care, alternative delivery models are increasingly prominent. This study examines predictors of genetic testing for hereditary breast/ovarian cancer among high-risk women in a randomized trial of in-person versus telephone-based genetic counseling. Methods: Methods include multivariable logistic regression and interaction analyses. Results: Of the 669 participants, 600 completed counseling and 523 received test results. As previously reported, participants randomized to telephone counseling were significantly less likely to be tested. In intention-to-treat analyses, completion of counseling and testing was associated with: race/ethnicity (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.20-3.20), perceived stress (OR = 0.89, 95% CI: 0.81-0.98), knowledge (OR = 1.12, 95% CI: 1.02-1.23), and randomization group (OR = 1.48, 95% CI: 1.01-2.16). Further, race/ ethnicity moderated the association between randomization group and testing; minority women receiving telephone counseling were least likely to complete testing. Conclusion: Evidence for logistical and communication-based explanations for this interaction is presented. The overall increased access made possible with telephone genetic counseling should be considered in light of the possibility that this may also lead to lower rates of testing among high-risk minority women. Additional care should be taken to assess and address potential barriers when services are delivered by telephone. C1 [Butrick, Morgan] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kelly, Scott; Peshkin, Beth N.; Nusbaum, Rachel; Graves, Kristi; Feeley, Lisa; Isaacs, Claudine; DeMarco, Tiffani; Schwartz, Marc D.] Georgetown Univ, Dept Oncol, Canc Prevent & Control Program, Washington, DC 20057 USA. [Kelly, Scott; Peshkin, Beth N.; Nusbaum, Rachel; Graves, Kristi; Feeley, Lisa; Isaacs, Claudine; DeMarco, Tiffani; Schwartz, Marc D.] Georgetown Univ, Fisher Ctr Familial Canc Res, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Luta, George] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC USA. [Hooker, Gillian W.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Valdimarsdottir, Heiddis B.; Jandorf, Lina] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Wood, Marie; McKinnon, Wendy] Univ Vermont, Coll Med, Vermont Canc Ctr, Familial Canc Program, Burlington, VT USA. [Garber, Judy; McCormick, Shelley R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA 02115 USA. RP Schwartz, MD (reprint author), Georgetown Univ, Dept Oncol, Canc Prevent & Control Program, Washington, DC 20057 USA. EM schwartm@georgetown.edu RI Kelly, Scott/D-3195-2013; OI Kelly, Scott/0000-0002-0375-1040; Luta, George/0000-0001-9013-2207; Luta, George/0000-0002-4035-7632 FU National Cancer Institute [R01 CA108933, P30 CA051008]; Jess and Mildred Fisher Center for Familial Cancer Research FX Grant support was received from the National Cancer Institute (grants R01 CA108933 and P30 CA051008) and the Jess and Mildred Fisher Center for Familial Cancer Research. 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 40 TC 9 Z9 9 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JUN PY 2015 VL 17 IS 6 BP 467 EP 475 DI 10.1038/gim.2014.125 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CJ5WS UT WOS:000355564200006 PM 25232856 ER PT J AU Stavreva, DA Coulon, A Baek, S Sung, MH John, S Stixova, L Tesikova, M Hakim, O Miranda, T Hawkins, M Stamatoyannopoulos, JA Chow, CC Hager, GL AF Stavreva, Diana A. Coulon, Antoine Baek, Songjoon Sung, Myong-Hee John, Sam Stixova, Lenka Tesikova, Martina Hakim, Ofir Miranda, Tina Hawkins, Mary Stamatoyannopoulos, John A. Chow, Carson C. Hager, Gordon L. TI Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing SO GENOME RESEARCH LA English DT Article ID NEUTRAL LIPID DROPLETS; DNASE-I; HYPERSENSITIVE SITES; REGULATORY ELEMENTS; GLOBIN CHROMATIN; RECEPTOR BINDING; CHIP-SEQ; TRANSCRIPTION; STRESS; CELLS AB Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within +/- 50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings. C1 [Stavreva, Diana A.; Baek, Songjoon; Sung, Myong-Hee; Miranda, Tina; Hawkins, Mary; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Coulon, Antoine; Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [John, Sam] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Stixova, Lenka] Acad Sci Czech Republic, Inst Biophys, Dept Mol Cytol & Cytometry, Brno 61265, Czech Republic. [Tesikova, Martina] Univ Oslo, Dept Biosci, N-0316 Oslo, Norway. [Hakim, Ofir] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel. [Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM stavrevd@mail.nih.gov; hagerg@exchange.nih.gov RI Coulon, Antoine/A-9006-2012 FU Center for Cancer Research; National Institute of Diabetes and Digestive and Kidney Diseases; federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; OPVK project [CZ.1.07/2.3.00/30.0030]; 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, Center for Cancer Research, and National Institute of Diabetes and Digestive and Kidney Diseases. This project was also 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 U.S. Government. We acknowledge the assistance of Tatiana Karpova, LRBGE Fluorescence Imaging Facility. The work of L.S. was supported by OPVK project CZ.1.07/2.3.00/30.0030. NR 55 TC 13 Z9 13 U1 1 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD JUN PY 2015 VL 25 IS 6 BP 845 EP 857 DI 10.1101/gr.184168.114 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA CJ5XF UT WOS:000355565900007 PM 25677181 ER PT J AU Kim, J Park, HS Damiano, DL AF Kim, Jonghyun Park, Hyung-Soon Damiano, Diane L. TI An Interactive Treadmill Under a Novel Control Scheme for Simulating Overground Walking by Reducing Anomalous Force SO IEEE-ASME TRANSACTIONS ON MECHATRONICS LA English DT Article DE Anomalous force (AF); locomotor training; rehabilitation; simulating overground walking (OW); treadmill control ID GAIT REHABILITATION; SPEED; INJURY; STROKE; SYSTEM AB Since the purpose of treadmill-based locomotor training is to transfer lower extremity coordinative skill to overground walking (OW), it needs to simulate OW as closely as possible for optimal skill transfer. Typical treadmill walking at a preset constant speed is different from realistic overground walking because it is less engaging and more automatic. As a remedy for the limitation, this paper investigates a novel treadmill control scheme that allows users to change walking speed freely. It further simulates natural walking by reducing anomalous force (AF) due to acceleration of the treadmill belt. Adding an attenuator in the scheme effectively diminishes the AF when changing walking speed. The proposed scheme, which requires real-time measurement of pelvic and swing foot motion, was developed for a treadmill with a typical belt length (1.5 m). A clinical test was conducted with nine healthy subjects in order to quantitatively evaluate the proposed scheme by comparing it with the two existing control schemes in the literature. C1 [Kim, Jonghyun; Park, Hyung-Soon] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Park, HS (reprint author), Korea Adv Inst Sci & Technol, Dept Mech Engn, Taejon 305701, South Korea. EM jhkim@dgist.ac.kr; hyungspark@kaist.ac.kr; damianod@cc.nih.gov RI Park, Hyung-Soon/B-3334-2010; Damiano, Diane/B-3338-2010 OI Park, Hyung-Soon/0000-0003-4274-7420; Damiano, Diane/0000-0002-2770-5356 FU National Institutes of Health, Clinical Center [90-CC-0168]; DGIST R&D Program of the Ministry of Education, Science, and Technology of Korea [11-BD-0402] FX This work was supported in part by the intramural research program of the National Institutes of Health, Clinical Center (protocol number 90-CC-0168) and in part by the DGIST R&D Program of the Ministry of Education, Science, and Technology of Korea (11-BD-0402). (Corresponding author: Hyung-Soon Park.) NR 21 TC 2 Z9 2 U1 0 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1083-4435 EI 1941-014X J9 IEEE-ASME T MECH JI IEEE-ASME Trans. Mechatron. PD JUN PY 2015 VL 20 IS 3 BP 1491 EP 1496 DI 10.1109/TMECH.2014.2341039 PG 6 WC Automation & Control Systems; Engineering, Manufacturing; Engineering, Electrical & Electronic; Engineering, Mechanical SC Automation & Control Systems; Engineering GA CJ3VT UT WOS:000355413000047 ER PT J AU Burke, JG Lich, KH Neal, JW Meissner, HI Yonas, M Mabry, PL AF Burke, Jessica G. Lich, Kristen Hassmiller Neal, Jennifer Watling Meissner, Helen I. Yonas, Michael Mabry, Patricia L. TI Enhancing Dissemination and Implementation Research Using Systems Science Methods SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Dissemination; Implementation; Systems science; System dynamics; Agent-based modeling; Network analysis ID NETWORK ANALYSIS; PUBLIC-HEALTH; SIMULATION; MODEL; INTERVENTIONS; POLICY AB Dissemination and implementation (D&I) research seeks to understand and overcome barriers to adoption of behavioral interventions that address complex problems, specifically interventions that arise from multiple interacting influences crossing socio-ecological levels. It is often difficult for research to accurately represent and address the complexities of the real world, and traditional methodological approaches are generally inadequate for this task. Systems science methods, expressly designed to study complex systems, can be effectively employed for an improved understanding about dissemination and implementation of evidence-based interventions. The aims of this study were to understand the complex factors influencing successful D&I of programs in community settings and to identify D&I challenges imposed by system complexity. Case examples of three systems science methods-system dynamics modeling, agent-based modeling, and network analysis-are used to illustrate how each method can be used to address D&I challenges. The case studies feature relevant behavioral topical areas: chronic disease prevention, community violence prevention, and educational intervention. To emphasize consistency with D&I priorities, the discussion of the value of each method is framed around the elements of the established Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. Systems science methods can help researchers, public health decision makers, and program implementers to understand the complex factors influencing successful D&I of programs in community settings and to identify D&I challenges imposed by system complexity. C1 [Burke, Jessica G.; Yonas, Michael] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Lich, Kristen Hassmiller] Univ N Carolina, Chapel Hill, NC 27599 USA. [Neal, Jennifer Watling] Michigan State Univ, E Lansing, MI 48824 USA. [Meissner, Helen I.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Burke, JG (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM jgburke@pitt.edu; klich@unc.edu; jneal@msu.edu; meissneh@mail.nih.gov; myonas24@gmail.com; mabryp@od.nih.gov FU National Institute Of General Medical Sciences of the National Institutes of Health [U54 GM088491] FX Diane R. Orenstein, we would like to recognize and sincerely thank you for your help conceptualizing the manuscript and for the feedback on multiple drafts. We would also like to acknowledge and thank the following people for their contributions to the projects presented: John Grefenstette, Richard Garland, Shawn Brown, Jeffrey Borrebach, and Donald Burke (agent-based modeling) and Patricia Farrell, Marvin McKinney, Giannina Fehler-Cabral, Patrick Janulis, Gabriela Saenz, and staff at the five PAS elementary schools (network analysis). The agent based modeling research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number U54 GM088491. NR 39 TC 7 Z9 7 U1 6 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD JUN PY 2015 VL 22 IS 3 SI SI BP 283 EP 291 DI 10.1007/s12529-014-9417-3 PG 9 WC Psychology, Clinical SC Psychology GA CJ2UR UT WOS:000355340700002 PM 24852184 ER PT J AU Hu, YZ Salmeron, BJ Gu, H Stein, EA Yang, YH AF Hu, Yuzheng Salmeron, Betty Jo Gu, Hong Stein, Elliot A. Yang, Yihong TI Impaired Functional Connectivity Within and Between Frontostriatal Circuits and Its Association With Compulsive Drug Use and Trait Impulsivity in Cocaine Addiction SO JAMA PSYCHIATRY LA English DT Article ID ANTERIOR CINGULATE CORTEX; DORSAL STRIATUM; PREFRONTAL CORTEX; DECISION-MAKING; BASAL GANGLIA; SEEKING; DEPENDENCE; DISORDER; HYPOACTIVITY; PERFORMANCE AB IMPORTANCE Converging evidence has long identified both impulsivity and compulsivity as key psychological constructs in drug addiction. Although dysregulated striatal-cortical network interactions have been identified in cocaine addiction, the association between these brain networks and addiction is poorly understood. OBJECTIVES To test the hypothesis that cocaine addiction is associated with disturbances in striatal-cortical communication as captured by resting-state functional connectivity (rsFC), measured from coherent spontaneous fluctuations in the blood oxygenation level-dependent functional magnetic resonance imaging signal, and to explore the relationships between striatal rsFC, trait impulsivity, and uncontrolled drug use in cocaine addiction. DESIGN, SETTING, AND PARTICIPANTS A case-control, cross-sectional study was conducted at the National Institute on Drug Abuse Intramural Research Program outpatient magnetic resonance imaging facility. Data used in the present study were collected between December 8, 2005, and September 30, 2011. Participants included 56 non-treatment-seeking cocaine users (CUs) (52 with cocaine dependence and 3 with cocaine abuse) and 56 healthy individuals serving as controls (HCs) matched on age, sex, years of education, race, estimated intelligence, and smoking status. MAIN OUTCOMES AND MEASURES Voxelwise statistical parametric analysis testing the rsFC strength differences between CUs and HCs in brain regions functionally connected to 6 striatal subregions defined a priori. RESULTS Increased rsFC strength was observed predominantly in striatal-frontal circuits; decreased rsFC was found between the striatum and cingulate, striatal, temporal, hippocampal/amygdalar, and insular regions in the CU group compared with the HCs. Increased striatal-dorsal lateral prefrontal cortex connectivity strength was positively correlated with the amount of recent cocaine use (uncorrected P < .046) and elevated trait impulsivity in the CUs (uncorrected P < .012), and an index reflecting the balance between striatal-dorsal anterior cingulate cortex and striatal-anterior prefrontal/orbitofrontal cortex circuits was significantly associated with loss of control over cocaine use (corrected P < .012). CONCLUSIONS AND RELEVANCE Cocaine addiction is associated with disturbed rsFC in several specific striatal-cortical circuits. Specifically, compulsive cocaine use, a defining characteristic of dependence, was associated with a balance of increased striatal-anterior prefrontal/orbitofrontal and decreased striatal-dorsal anterior cingulate connectivity; trait impulsivity, both a risk factor for and a consequence of cocaine use, was associated with increased dorsal striatal-dorsal lateral prefrontal cortex connectivity uniquely in CUs. These findings provide new insights toward the neurobiological mechanisms of addiction and suggest potential novel therapeutic targets for treatment. C1 [Hu, Yuzheng; Salmeron, Betty Jo; Gu, Hong; Stein, Elliot A.; Yang, Yihong] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Yang, YH (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, 251 Bayview Blvd,Ste 200, Baltimore, MD 21224 USA. EM yihongyang@intra.nida.nih.gov RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 FU Intramural Research Program of the National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 63 TC 20 Z9 21 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUN PY 2015 VL 72 IS 6 BP 584 EP 592 DI 10.1001/jamapsychiatry.2015.1 PG 9 WC Psychiatry SC Psychiatry GA CJ9FH UT WOS:000355807400009 PM 25853901 ER PT J AU Olfson, M King, M Schoenbaum, M AF Olfson, Mark King, Marissa Schoenbaum, Michael TI The Popularity of Benzodiazepines, Their Advantages, and Inadequate Pharmacological Alternatives Reply SO JAMA PSYCHIATRY LA English DT Letter ID METAANALYSIS C1 [Olfson, Mark] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [King, Marissa] Yale Univ, Sch Management, New Haven, CT USA. [Schoenbaum, Michael] NIMH, Off Director, NIH, Bethesda, MD 20892 USA. RP Olfson, M (reprint author), Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10027 USA. EM mo49@columbia.edu NR 6 TC 0 Z9 0 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUN PY 2015 VL 72 IS 6 BP 624 EP 624 DI 10.1001/jamapsychiatry.2015.24 PG 1 WC Psychiatry SC Psychiatry GA CJ9FH UT WOS:000355807400017 PM 25830609 ER PT J AU Strickland, M Stephens, T Liu, J Tjandra, N AF Strickland, Madeleine Stephens, Thomas Liu, Jian Tjandra, Nico TI Exploiting image registration for automated resonance assignment in NMR SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Automation; Backbone assignment; Fast Fourier transform; Cross-correlation; FFT ID NOE ASSIGNMENT; BACKBONE RESONANCES; BINDING DOMAIN; PROTEIN; SPECTROSCOPY; SPECTRA; ALGORITHM; N-15; C-13; H-1 AB Analysis of protein NMR data involves the assignment of resonance peaks in a number of multidimensional data sets. To establish resonance assignment a three-dimensional search is used to match a pair of common variables, such as chemical shifts of the same spin system, in different NMR spectra. We show that by displaying the variables to be compared in two-dimensional plots the process can be simplified. Moreover, by utilizing a fast Fourier transform cross-correlation algorithm, more common to the field of image registration or pattern matching, we can automate this process. Here, we use sequential NMR backbone assignment as an example to show that the combination of correlation plots and segmented pattern matching establishes fast backbone assignment in fifteen proteins of varying sizes. For example, the 265-residue RalBP1 protein was 95.4 % correctly assigned in 10 s. The same concept can be applied to any multidimensional NMR data set where analysis comprises the comparison of two variables. This modular and robust approach offers high efficiency with excellent computational scalability and could be easily incorporated into existing assignment software. C1 [Strickland, Madeleine; Stephens, Thomas; Liu, Jian; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 50,Room 3503, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov OI Strickland, Madeleine/0000-0001-8160-070X FU NIH, National Heart, Lung, and Blood Institute FX This work was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. Our software is available free of charge by contacting Nico Tjandra (tjandran@nhlbi.nih.gov). NR 43 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUN PY 2015 VL 62 IS 2 BP 143 EP 156 DI 10.1007/s10858-015-9926-7 PG 14 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA CJ6TM UT WOS:000355626800003 PM 25828257 ER PT J AU Wu, P Bandettini, PA Harper, RM Handwerker, DA AF Wu, Paula Bandettini, Peter A. Harper, Ronald M. Handwerker, Daniel A. TI Effects of thoracic pressure changes on MRI signals in the brain SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE breath hold; cerebral blood flow; functional MRI; hypercapnia; Valsalva ID VALSALVA MANEUVER; FUNCTIONAL MRI; BLOOD-VOLUME; BOLD FMRI; CORTEX; TASK; NORMALIZATION; VARIABILITY; HYPERCAPNIA; METABOLISM AB Cerebrovascular stressors, such as breath holding or CO2 inhalation, cause global magnetic resonance imaging (MRI) signal changes. In this study, we show that intrathoracic pressure changes cause rapid MRI signal alterations that have similar spatial patterns to the changes associated with breath holding or CO2 inhalation. Nine subjects performed the Valsalva maneuver during functional MRI data collection. Expiratory pressures ranged from 10 to 40 mm Hg. Breath holds ending on either inhalation or exhalation were also collected. The maximal and minimal functional MRI (fMRI) signal scaled with thoracic pressure load, and the overall amplitude of responses to the Valsalva varied, depending on brain tissue. Additionally, a Valsalva effort as short as 5 seconds yielded signal changes similar in spatial distribution and magnitude to a 20-second breath hold, suggesting potential applications of the Valsalva maneuver for calibrated fMRI experiments. C1 [Wu, Paula; Bandettini, Peter A.; Handwerker, Daniel A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20814 USA. [Bandettini, Peter A.] NIMH, Funct MRI Facil, Bethesda, MD 20814 USA. [Harper, Ronald M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Harper, Ronald M.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. RP Handwerker, DA (reprint author), NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, 10 Ctr Dr,Room 1D80,MSC1148, Bethesda, MD 20814 USA. EM handwerkerd@mail.nih.gov FU NIMH at NIH [ZIAMH002783] FX This research was supported by the NIMH Intramural Research Program at NIH: ZIAMH002783. The study was approved under NIH Combined Neuroscience Institutional Review Board protocol #93-M-0170 (ClinicalTrials.gov identifier: NCT00001360). NR 26 TC 3 Z9 3 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 JUN PY 2015 VL 35 IS 6 BP 1024 EP 1032 DI 10.1038/jcbfm.2015.20 PG 9 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA CJ6AO UT WOS:000355575600017 PM 25712496 ER PT J AU Wilson, RP Ives, ML Rao, G Lau, A Payne, K Kobayashi, M Arkwright, PD Peake, J Wong, M Adelstein, S Smart, JM French, MA Fulcher, DA Picard, C Bustamante, J Boisson-Dupuis, S Gray, P Stepensky, P Warnatz, K Freeman, AF Rossjohn, J McCluskey, J Holland, SM Casanova, JL Uzel, G Ma, CS Tangye, SG Deenick, EK AF Wilson, Robert P. Ives, Megan L. Rao, Geetha Lau, Anthony Payne, Kathryn Kobayashi, Masao Arkwright, Peter D. Peake, Jane Wong, Melanie Adelstein, Stephen Smart, Joanne M. French, Martyn A. Fulcher, David A. Picard, Capucine Bustamante, Jacinta Boisson-Dupuis, Stephanie Gray, Paul Stepensky, Polina Warnatz, Klaus Freeman, Alexandra F. Rossjohn, Jamie McCluskey, James Holland, Steven M. Casanova, Jean-Laurent Uzel, Gulbu Ma, Cindy S. Tangye, Stuart G. Deenick, Elissa K. TI STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HYPER-IGE SYNDROME; ROR-GAMMA-T; EFFECTOR FUNCTIONS; CLINICAL-FEATURES; MAIT CELLS; MUTATIONS; DOMINANT; RECEPTOR; DIFFERENTIATION; DEFICIENCY AB Unconventional T cells such as gamma delta T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not gamma delta T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor ROR gamma t. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFN gamma and TNF The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers. C1 [Wilson, Robert P.; Lau, Anthony] Univ Bath, Bath BA2 7AY, Avon, England. [Wilson, Robert P.; Ives, Megan L.; Rao, Geetha; Lau, Anthony; Payne, Kathryn; Ma, Cindy S.; Tangye, Stuart G.; Deenick, Elissa K.] Garvan Inst Med Res, Immunol Div, Sydney, NSW 2010, Australia. [Ives, Megan L.; Ma, Cindy S.; Tangye, Stuart G.; Deenick, Elissa K.] Univ New S Wales, St Vincents Clin Sch, Sydney, NSW 2052, Australia. [Gray, Paul] Univ New S Wales, Sch Womens & Childrens Hlth, Sydney, NSW 2052, Australia. [Kobayashi, Masao] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Pediat, Hiroshima 7398511, Japan. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Manchester M13 9WL, Lancs, England. [Peake, Jane] Royal Childrens Hosp, Dept Paediat & Child Hlth, Brisbane, Qld 4006, Australia. [Wong, Melanie] Childrens Hosp, Dept Allergy & Immunol, Westmead, NSW 2145, Australia. [Adelstein, Stephen] Royal Prince Alfred Hosp, Dept Clin Immunol, Camperdown, NSW 2050, Australia. [Smart, Joanne M.] Royal Childrens Hosp Melbourne, Dept Allergy & Immunol, Parkville, Vic 3052, Australia. [French, Martyn A.] Royal Perth Hosp, Dept Clin Immunol, Perth, WA 6000, Australia. [French, Martyn A.] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA 6009, Australia. [Fulcher, David A.] Westmead Hosp, Inst Clin Pathol & Med Res, Dept Immunol, Westmead, NSW 2006, Australia. [Picard, Capucine; Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Necker Hosp Sick Children, Lab Human Genet Infect Dis, Necker Branch, French Inst Hlth & Med Res INSERM,U1163, F-75015 Paris, France. [Casanova, Jean-Laurent] Necker Hosp Sick Children, Pediat Hematol & Immunol Unit, F-75015 Paris, France. [Picard, Capucine; Bustamante, Jacinta] Hop Necker Enfants Malad, AP HP, Study Ctr Primary Immunodeficiencies, F-75015 Paris, France. [Picard, Capucine; Bustamante, Jacinta; Casanova, Jean-Laurent] Paris Descartes Univ, Imagine Inst, F-75015 Paris, France. [Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA. [Stepensky, Polina] Hebrew Univ Jerusalem, Med Ctr, Hadassah Med Ctr, Dept Pediat Hematol Oncol & Bone Marrow, IL-91120 Jerusalem, Israel. [Warnatz, Klaus] Univ Freiburg, Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, D-79106 Freiburg, Germany. [Freeman, Alexandra F.; Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Rossjohn, Jamie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Rossjohn, Jamie] Monash Univ, Ctr Excellence Adv Mol Imaging, Australian Res Council ARC, Clayton, Vic 3800, Australia. [Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [McCluskey, James] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic 3000, Australia. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY 10065 USA. RP Deenick, EK (reprint author), Garvan Inst Med Res, Immunol Div, Sydney, NSW 2010, Australia. EM s.tangye@garvan.org.au; e.deenick@garvan.org.au RI Peake, Jane/B-4488-2011; Adelstein, Stephen/I-7936-2016; McCluskey, James/A-1291-2007 OI Deenick, Elissa/0000-0002-9271-0004; Lau, Anthony/0000-0002-7338-7176; Arkwright, Peter/0000-0002-7411-5375; Rossjohn, Jamie/0000-0002-2020-7522; Adelstein, Stephen/0000-0001-7221-6298; McCluskey, James/0000-0002-8597-815X FU National Health and Medical Research Council (NHMRC) of Australia [1016953, 1066694, 1027400]; Rockefeller University Center for 541 Clinical and Translational Science [5UL1RR024143]; Career Development Fellowship [1008820]; NHMRC of Australia [1042925] FX This work was funded by project and program grants from the National Health and Medical Research Council (NHMRC) of Australia (1016953, 1066694, and 1027400 to E.K. Deenick and S.G. Tangye) and the Rockefeller University Center for 541 Clinical and Translational Science (5UL1RR024143 to J.-L. Casanova). C.S. Ma is a recipient of a Career Development Fellowship (1008820), and S.G. Tangye is a recipient of a Principal Research Fellowship (1042925) from the NHMRC of Australia. NR 43 TC 13 Z9 14 U1 2 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUN 1 PY 2015 VL 212 IS 6 BP 855 EP 864 DI 10.1084/jem.20141992 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CJ5YF UT WOS:000355569300003 PM 25941256 ER PT J AU Kim, ML Chae, JJ Park, YH De Nardo, D Stirzaker, RA Ko, HJ Tye, H Cengia, L DiRago, L Metcalf, D Roberts, AW Kastner, DL Lew, AM Lyras, D Kile, BT Croker, BA Masters, SL AF Kim, Man Lyang Chae, Jae Jin Park, Yong Hwan De Nardo, Dominic Stirzaker, Roslynn A. Ko, Hyun-Ja Tye, Hazel Cengia, Louise DiRago, Ladina Metcalf, Donald Roberts, Andrew W. Kastner, Daniel L. Lew, Andrew M. Lyras, Dena Kile, Benjamin T. Croker, Ben A. Masters, Seth L. TI Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1 beta SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID FAMILIAL MEDITERRANEAN FEVER; DISRUPT MICROFILAMENT ORGANIZATION; GAMMA-INDUCING FACTOR; ENDOTOXIC-SHOCK; MICE DEFICIENT; PROTEIN ASC; T-CELLS; ACTIVATION; CASPASE-1; INTERLEUKIN-1-BETA AB Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1 beta production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1 beta, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease. C1 [Kim, Man Lyang; De Nardo, Dominic; Tye, Hazel; Masters, Seth L.] Walter & Eliza Hall Inst Med Res, Div Inflammat, Parkville, Vic 3052, Australia. [Stirzaker, Roslynn A.; Cengia, Louise; DiRago, Ladina; Metcalf, Donald; Roberts, Andrew W.] Walter & Eliza Hall Inst Med Res, Div Canc & Hematol, Parkville, Vic 3052, Australia. [Ko, Hyun-Ja; Lew, Andrew M.] Walter & Eliza Hall Inst Med Res, Div Immunol, Parkville, Vic 3052, Australia. [Kile, Benjamin T.] Walter & Eliza Hall Inst Med Res, ACRF Chem Biol Div, Parkville, Vic 3052, Australia. [Chae, Jae Jin; Park, Yong Hwan; Kastner, Daniel L.] NHGRI, Inflammatory Dis Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, Bethesda, MD 20892 USA. [Lyras, Dena] Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia. [Croker, Ben A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Kim, Man Lyang; De Nardo, Dominic; Metcalf, Donald; Roberts, Andrew W.; Lew, Andrew M.; Kile, Benjamin T.; Masters, Seth L.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. RP Masters, SL (reprint author), Walter & Eliza Hall Inst Med Res, Div Inflammat, Parkville, Vic 3052, Australia. EM masters@wehi.edu.au RI Kile, Benjamin/F-6593-2011; Roberts, Andrew/C-6736-2012 OI Kile, Benjamin/0000-0002-8836-8947; Roberts, Andrew/0000-0002-7341-5720 FU National Institutes of Health [1008131, 1043414, 1016647, 1037321, 1R56AI103352-01A1]; National Health and Medical Research Council [361646]; Victorian Endowment for Science Knowledge and Innovation; Australian Research Council; Sylvia and Charles Viertel Charitable Foundation; Cancer Council of Victoria; Australian Cancer Research Foundation; Australian Phenomics Network FX This work was supported by project grants (1008131 and 1043414), program grants (1016647 and 1037321), fellowships (to B.T. Kile, B.A. Croker, A.M. Lew, and S.L. Masters), a National Institutes of Health grant (1R56AI103352-01A1; to B.A. Croker), and an Independent Research Institutes Infrastructure Support Scheme grant (361646) from the National Health and Medical Research Council; fellowships from the Victorian Endowment for Science Knowledge and Innovation (to S.L. Masters), the Australian Research Council (to B.A. Croker and B.T. Kile), the Sylvia and Charles Viertel Charitable Foundation (to B.T. Kile), and the Cancer Council of Victoria (to D. Metcalf); the Australian Cancer Research Foundation, the Australian Phenomics Network, and a Victorian State Government Operational Infrastructure Support grant. NR 54 TC 18 Z9 18 U1 3 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUN 1 PY 2015 VL 212 IS 6 BP 927 EP 938 DI 10.1084/jem.20142384 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CJ5YF UT WOS:000355569300009 PM 26008898 ER PT J AU Sidhu, R Jiang, H Farhat, NY Carrillo-Carrasco, N Woolery, M Ottinger, E Porter, FD Schaffer, JE Ory, DS Jiang, XT AF Sidhu, Rohini Jiang, Hui Farhat, Nicole Y. Carrillo-Carrasco, Nuria Woolery, Myra Ottinger, Elizabeth Porter, Forbes D. Schaffer, Jean E. Ory, Daniel S. Jiang, Xuntian TI A validated LC-MS/MS assay for quantification of 24(S)-hydroxycholesterol in plasma and cerebrospinal fluid SO JOURNAL OF LIPID RESEARCH LA English DT Article DE two-dimensional liquid chromatography-tandem mass spectrometry; validation; Niemann-Pick C1 disease; 2-hydroxypropyl-beta-cyclodextrin ID TANDEM MASS-SPECTROMETRY; 2-DIMENSIONAL LIQUID-CHROMATOGRAPHY; BRAIN CHOLESTEROL-METABOLISM; ALZHEIMERS-DISEASE; MULTIPLE-SCLEROSIS; 24S-HYDROXYCHOLESTEROL REFLECT; 24S-AND 27-HYDROXYCHOLESTEROL; QUANTITATIVE-ANALYSIS; HUNTINGTONS-DISEASE; OXIDATION-PRODUCTS AB 24(S)-hydroxycholesterol [24(S)-HC] is a cholesterol metabolite that is formed almost exclusively in the brain. The concentrations of 24(S)-HC in cerebrospinal fluid (CSF) and/or plasma might be a sensitive marker of altered cholesterol metabolism in the CNS. A highly sensitive 2D-LC-MS/MS assay was developed for the quantification of 24(S)-HC in human plasma and CSF. In the development of an assay for 24(S)-HC in CSF, significant nonspecific binding of 24(S)-HC was observed and resolved with the addition of 2.5% 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) into CSF samples. The sample preparation consists of liquid-liquid extraction with methyl-tert-butyl ether and derivatization with nicotinic acid. Good linearity was observed in a range from 1 to 200 ng/ml and from 0.025 to 5 ng/ml, for plasma and CSF, respectively. Acceptable precision and accuracy were obtained for concentrations over the calibration curve ranges. Stability of 24(S)-HC was reported under a variety of storage conditions. This method has been successfully applied to support a National Institutes of Health-sponsored clinical trial of HP-beta-CD in Niemann-Pick type C1 patients, in which 24(S)-HC is used as a pharmacodynamic biomarker. C1 [Sidhu, Rohini; Jiang, Hui; Schaffer, Jean E.; Ory, Daniel S.; Jiang, Xuntian] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. [Farhat, Nicole Y.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Woolery, Myra] NIH, Dept Nursing, Bethesda, MD 20892 USA. [Carrillo-Carrasco, Nuria] Natl Ctr Adv Translat Sci, Therapeut Rare & Neglected Dis, NIH, Rockville, MD 20850 USA. [Ottinger, Elizabeth] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Rockville, MD 20850 USA. RP Jiang, XT (reprint author), Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. EM xjiang@wustl.edu RI Carrillo-Carrasco, Nuria/B-9034-2009; Sidhu, Rohini/G-3547-2012 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808; FU Bench-to-Bedside Program; Office of Rare Diseases Research; Therapies for Rare and Neglected Diseases (TRND) Program in the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH); National Institutes of Health [1ZIAHD008824-07]; Dana's Angels Research Trust FX This work was supported by the Bench-to-Bedside Program, the Office of Rare Diseases Research, the Therapies for Rare and Neglected Diseases (TRND) Program in the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH), and National Institutes of Health Grant 1ZIAHD008824-07 (F.D.P.). Additional support was provided by a grant from Dana's Angels Research Trust (D.S.O). Quantification of 24(S)-HC was performed in the Metabolomics Facility at Washington University (P30 DK020579). NR 66 TC 5 Z9 5 U1 2 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD JUN PY 2015 VL 56 IS 6 BP 1222 EP 1233 DI 10.1194/jlr.D058487 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ5MR UT WOS:000355532400013 PM 25866316 ER PT J AU Wallace, GL Eisenberg, IW Robustelli, B Dankner, N Kenworthy, L Giedd, JN Martin, A AF Wallace, Gregory L. Eisenberg, Ian W. Robustelli, Briana Dankner, Nathan Kenworthy, Lauren Giedd, Jay N. Martin, Alex TI Longitudinal Cortical Development During Adolescence and Young Adulthood in Autism Spectrum Disorder: Increased Cortical Thinning but Comparable Surface Area Changes SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE autism; longitudinal; cortical thickness; surface area; executive function ID HUMAN CEREBRAL-CORTEX; DIAGNOSTIC INTERVIEW; EXECUTIVE FUNCTION; BRAIN; THICKNESS; CHILDHOOD; MRI; AGE; CHILDREN; ANATOMY AB Objective: Prior reports suggest that autism spectrum disorder (ASD) is associated with atypically excessive early brain growth. Recent cross-sectional studies suggest that later cortical development during adolescence/adulthood might also be aberrant, although longitudinal designs are required to evaluate atypical growth trajectories. The present study sought to examine longitudinal changes in cortical thickness and surface area among adolescents and young adults with ASD. Method: Two high-resolution anatomic magnetic resonance imaging scans approximately 2 years apart were acquired from 17 adolescents with ASD and 18 typically developing (TD) adolescents, matched on age (range = 14-24 years), IQ, sex ratio, and handedness (70 scans total). The Free Surfer image analysis suite was used to quantify longitudinal changes in cortical thickness and surface area. Results: Accelerated cortical thinning for the ASD group as compared to the TD group was found in 2 areas in the left hemisphere, the posterior portion of ventral temporal cortex and superior parietal cortex (cluster corrected p <.01). For ventral temporal cortex, cortical thinning was associated with everyday executive function impairments, and thinner cortex at time 2 was correlated with ASD social symptoms. Differences in surface area changes were not detected. Conclusion: The present longitudinal study extends prior cross-sectional research by demonstrating increased cortical thinning (in portions of temporal and parietal cortex) but comparable surface area growth rates in participants with ASD compared to TD controls during adolescence and into young adulthood. These findings provide further evidence for atypical cortical development beyond the early years in ASD, marked by increased cortical thinning in late adolescence/young adulthood. C1 [Wallace, Gregory L.; Eisenberg, Ian W.; Robustelli, Briana; Dankner, Nathan; Kenworthy, Lauren; Martin, Alex] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Wallace, Gregory L.] George Washington Univ, Washington, DC 20052 USA. [Giedd, Jay N.] NIMH, Child Psychiat Branch, Rockville, MD USA. RP Wallace, GL (reprint author), George Washington Univ, Dept Speech & Hearing Sci, 2115 G St NW,Room 201, Washington, DC 20052 USA. EM gwallac1@gwu.edu RI Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 FU Intramural Research Program at NIMH, National Institutes of Health (NIH) [1-ZIA-MH002920-05] FX This work was supported by the Intramural Research Program at NIMH, National Institutes of Health (NIH) under grant number 1-ZIA-MH002920-05. Ethics approval for this study was granted by the NIH Combined Neuroscience Institutional Review Board under protocol number 10-M-0027. NR 40 TC 11 Z9 11 U1 6 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUN PY 2015 VL 54 IS 6 BP 464 EP 469 DI 10.1016/j.jaac.2015.03.007 PG 6 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CJ8VZ UT WOS:000355782900006 PM 26004661 ER PT J AU Kopp, JB Winkler, CA Zhao, XC Radeva, MK Gassman, JJ D'Agati, VD Nast, CC Wei, CL Reiser, J Guay-Woodford, LM Pollak, MR Hildebrandt, F Moxey-Mims, M Gipson, DS Trachtman, H Friedman, AL Kaskel, FJ AF Kopp, Jeffrey B. Winkler, Cheryl A. Zhao, Xiongce Radeva, Milena K. Gassman, Jennifer J. D'Agati, Vivette D. Nast, Cynthia C. Wei, Changli Reiser, Jochen Guay-Woodford, Lisa M. Pollak, Martin R. Hildebrandt, Friedhelm Moxey-Mims, Marva Gipson, Debbie S. Trachtman, Howard Friedman, Aaron L. Kaskel, Frederick J. CA FSGS-CT Study Consortium TI Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HIV-ASSOCIATED NEPHROPATHY; VARIANTS ASSOCIATE; AFRICAN-AMERICANS; GENE VARIANTS; ADULTS AB Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone. C1 [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Biostat Core, NIH, Bethesda, MD 20892 USA. [Moxey-Mims, Marva] NIDDK, Div Kidney Urol & Hematol, NIH, Bethesda, MD 20892 USA. [Winkler, Cheryl A.] Leidos Biomed Res Inc, Basic Res Lab, Ctr Canc Res, NCI,Frederick Natl Lab, Frederick, MD USA. [Radeva, Milena K.; Gassman, Jennifer J.] Cleveland Clin, Dept Quantitat Heath Sci, Cleveland, OH 44106 USA. [D'Agati, Vivette D.] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA. [Nast, Cynthia C.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Wei, Changli; Reiser, Jochen] Rush Univ, Dept Med, Med Ctr, Chicago, IL 60612 USA. [Guay-Woodford, Lisa M.] Childrens Natl Hlth Syst, Ctr Translat Sci, Washington, DC USA. [Pollak, Martin R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Hildebrandt, Friedhelm] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Gipson, Debbie S.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Trachtman, Howard] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Friedman, Aaron L.] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. [Kaskel, Frederick J.] Albert Einstein Coll Med, Childrens Hosp Montefiore, Bronx, NY 10467 USA. RP Kopp, JB (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Trachtman, Howard/0000-0001-7447-9489 FU NIDDK; National Cancer Institute (NCI); NCI, NIH [HHSN26120080001E]; NIH, NCI, Center for Cancer Research FX The FSGS Clinical Trial was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), and this work was supported by the NIDDK and National Cancer Institute (NCI) Intramural Research Programs. This project has been funded in whole or part with federal funds from NCI, NIH Contract HHSN26120080001E. This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 16 TC 22 Z9 23 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2015 VL 26 IS 6 BP 1443 EP 1448 DI 10.1681/ASN.2013111242 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA CJ3LS UT WOS:000355386100022 PM 25573908 ER PT J AU Allen, KB Horvath, K AF Allen, Keith B. Horvath, Keith TI AORTIC FILTRATION SYSTEM'S IMPACT ON PREVENTING ADVERSE CLINICAL EVENTS SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Letter ID INTRAAORTIC FILTER; CAPTURE C1 [Allen, Keith B.] Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64110 USA. [Horvath, Keith] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. RP Allen, KB (reprint author), Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64110 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JUN PY 2015 VL 149 IS 6 BP 1674 EP 1675 DI 10.1016/j.jtcvs.2015.01.029 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CJ8HI UT WOS:000355740400066 PM 26060007 ER PT J AU Koblin, BA Grant, S Frye, V Superak, H Sanchez, B Lucy, D Dunbar, D Graham, P Madenwald, T Escamilia, G Swann, E Morgan, C Novak, RM Frank, I AF Koblin, Beryl A. Grant, Shannon Frye, Victoria Superak, Hillary Sanchez, Brittany Lucy, Debbie Dunbar, Debora Graham, Parrie Madenwald, Tamra Escamilia, Gina Swann, Edith Morgan, Cecilia Novak, Richard M. Frank, Ian CA HVTN 906 Study Team TI HIV Sexual Risk and Syndemics among Women in Three Urban Areas in the United States: Analysis from HVTN 906 SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE Women; HIV; Syndemics; Sexual risk ID INTIMATE PARTNER VIOLENCE; NEW-YORK-CITY; SUBSTANCE-ABUSE; SOCIAL-CONTEXT; AFRICAN-AMERICANS; LOW-INCOME; DEPRESSION; INFECTION; HIV/AIDS; INTERVENTIONS AB Limited data are available on the longitudinal occurrence of syndemic factors among women at risk for HIV infection in the USA and how these factors relate to sexual risk over time. HVTN 906 was a longitudinal study enrolling 799 HIV-uninfected women in three cities. Assessments were done at baseline, 6, 12, and 18 months to assess syndemic factors (low education, low income, unemployment, lack of health insurance, housing instability, substance use, heavy alcohol use, partner violence, incarceration) and sexual risk outcomes. For each sexual risk outcome, a GEE model was fit with syndemic factors or syndemic score (defined as sum of binary syndemics, ranging from 0 to 9), visit, study site, age and race/ethnicity as predictors to examine the multivariable association between syndemic factors and outcomes over time. Odds of unprotected sex while drunk or high were significantly higher when women reported lack of health insurance, substance and heavy alcohol use and partner violence. Housing instability, substance and heavy alcohol use, partner violence and recent incarceration were associated with higher odds of having multiple sexual partners. Odds of sex exchange were significantly higher in the presence of unemployment, housing instability, low education, lack of health insurance, substance and heavy alcohol use, partner violence and incarceration. Housing instability, substance and heavy alcohol use, and partner violence were significantly associated with higher odds of unprotected anal sex. Odds of having a recent STI were significantly higher when women reported housing instability and partner violence. There were significantly higher odds of the reporting of any risk outcomes during follow-up with higher syndemic score. This study highlights a group of women experiencing multiple poor social and health outcomes who need to be the focus of comprehensive interventions. C1 [Koblin, Beryl A.; Lucy, Debbie] New York Blood Ctr, Lab Infect Dis Prevent, New York, NY 10065 USA. [Grant, Shannon; Superak, Hillary; Sanchez, Brittany; Madenwald, Tamra; Escamilia, Gina; Morgan, Cecilia] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Frye, Victoria] New York Blood Ctr, Lab Social & Behav Sci, New York, NY 10065 USA. [Dunbar, Debora; Frank, Ian] Univ Penn, HIV Prevent Div, Philadelphia, PA 19104 USA. [Graham, Parrie; Novak, Richard M.] Univ Illinois, Infect Dis Sect, Chicago, IL USA. [Swann, Edith] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Frank, Ian] Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. RP Koblin, BA (reprint author), New York Blood Ctr, Lab Infect Dis Prevent, 310 E 67th St, New York, NY 10065 USA. EM bkoblin@nybloodcenter.org FU Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health [1UM1AI068614, 1UM1A1069470, 1UM1A1069554, 1UM1A1069534, 1UM1AI068635, P30AI045008] FX The HVTN 906 study team would like to thank the study participants, community advisory board members, and the study site staff for their commitment to this study. This research was funded by the Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health, grants 1UM1AI068614, 1UM1A1069470, 1UM1A1069554, 1UM1A1069534, 1UM1AI068635 and P30AI045008. NR 32 TC 5 Z9 5 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 EI 1468-2869 J9 J URBAN HEALTH JI J. Urban Health PD JUN PY 2015 VL 92 IS 3 BP 572 EP 583 DI 10.1007/s11524-015-9944-5 PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CJ6SR UT WOS:000355624400013 PM 25743100 ER PT J AU Arock, M Sotlar, K Akin, C Broesby-Olsen, S Hoermann, G Escribano, L Kristensen, TK Kluin-Nelemans, HC Hermine, O Dubreuil, P Sperr, WR Hartmann, K Gotlib, J Cross, NCP Haferlach, T Garcia-Montero, A Orfao, A Schwaab, J Triggiani, M Horny, HP Metcalfe, DD Reiter, A Valent, P AF Arock, M. Sotlar, K. Akin, C. Broesby-Olsen, S. Hoermann, G. Escribano, L. Kristensen, T. K. Kluin-Nelemans, H. C. Hermine, O. Dubreuil, P. Sperr, W. R. Hartmann, K. Gotlib, J. Cross, N. C. P. Haferlach, T. Garcia-Montero, A. Orfao, A. Schwaab, J. Triggiani, M. Horny, H-P Metcalfe, D. D. Reiter, A. Valent, P. TI KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis SO LEUKEMIA LA English DT Review ID CHRONIC MYELOMONOCYTIC LEUKEMIA; FAMILIAL CUTANEOUS MASTOCYTOSIS; INDOLENT SYSTEMIC MASTOCYTOSIS; POLYMERASE-CHAIN-REACTION; PROTOONCOGENE C-KIT; OF-THE-LITERATURE; D816V MUTATION; TYROSINE KINASE; PEDIATRIC MASTOCYTOSIS; MYELOGENOUS LEUKEMIA AB Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutations in patients with mastocytosis at diagnosis and during follow-up with sufficient precision and sensitivity in daily practice. In addition, we provide recommendations for sampling and storage of diagnostic material as well as a robust diagnostic algorithm. Using highly sensitive assays, KIT D816V can be detected in peripheral blood leukocytes from most patients with systemic mastocytosis (SM) that is a major step forward in screening and SM diagnosis. In addition, the KIT D816V allele burden can be followed quantitatively during the natural course or during therapy. Our recommendations should greatly facilitate diagnostic and follow-up investigations in SM in daily practice as well as in clinical trials. In addition, the new tools and algorithms proposed should lead to a more effective screen, early diagnosis of SM and help to avoid unnecessary referrals. C1 [Arock, M.] Ecole Normale Super, LBPA CNRS UMR8113, Mol Oncol & Pharmacol, Cachan, France. [Arock, M.] Grp Hosp Pitie Salpetriere, Hematol Lab, Paris, France. [Sotlar, K.; Horny, H-P] Univ Munich, Inst Pathol, Munich, Germany. [Akin, C.] Harvard Univ, Sch Med, Dept Med Brigham & Womens Hosp, Div Allergy & Immunol, Boston, MA USA. [Broesby-Olsen, S.] Odense Univ Hosp, Dept Dermatol & Allergy Ctr, DK-5000 Odense, Denmark. [Hoermann, G.] Med Univ Vienna, Dept Lab Med, Vienna, Austria. [Escribano, L.; Garcia-Montero, A.; Orfao, A.] Univ Salamanca, IBSAL, Serv Cent Citometria, Ctr Invest Canc,IBMCC,CSIC USAL, E-37008 Salamanca, Spain. [Escribano, L.; Garcia-Montero, A.; Orfao, A.] Univ Salamanca, Dept Med, E-37008 Salamanca, Spain. [Kristensen, T. K.] Odense Univ Hosp, Dept Pathol, DK-5000 Odense, Denmark. [Kluin-Nelemans, H. C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands. [Hermine, O.] Paris Descartes Univ, Fac Med, Dept Clin Hematol, Paris, France. [Hermine, O.] Paris Descartes Univ, AP HP Necker Enfants Malades, Paris, France. [Dubreuil, P.] CRCM, Inserm U1068, Signaling Hematopoiesis & Mech Oncogenesis, Marseille, France. [Dubreuil, P.] Inst J Paoli I Calmettes, F-13009 Marseille, France. [Dubreuil, P.] Aix Marseille Univ, UM 105, Marseille, France. [Dubreuil, P.] CNRS, CRCM, UMR7258, Marseille, France. [Sperr, W. R.; Valent, P.] Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, Vienna, Austria. [Hartmann, K.] Univ Cologne, Dept Dermatol, D-50931 Cologne, Germany. [Gotlib, J.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, MD USA. [Cross, N. C. P.] Wessex Reg Genet Lab, Salisbury, England. [Cross, N. C. P.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Haferlach, T.] Munich Leukemia Lab, Munich, Germany. [Schwaab, J.] Med Univ Mannheim, Med Clin, Hematol & Oncol, Mannheim, Germany. [Triggiani, M.] Univ Salerno, Div Clin Immunol & Allergy, I-84100 Salerno, Italy. [Metcalfe, D. D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Arock, M (reprint author), Ecole Normale Super, LBPA CNRS UMR8113, Mol Oncol & Pharmacol, Cachan, France. EM arock@ens-cachan.fr RI Cross, Nicholas/B-4817-2009; Hoermann, Gregor/B-8832-2016; Hartmann, Karin/N-4865-2015; OI Cross, Nicholas/0000-0001-5481-2555; Hoermann, Gregor/0000-0002-7374-4380; Hartmann, Karin/0000-0002-4595-8226; Akin, Cem/0000-0001-6301-4520 FU Fondation de France; La Ligue Nationale Contre le Cancer (equipe labellisee); Ministry of Economy and Competitivity, Madrid, Spain, (FEDER) [RD12/0036/0048, PI11/02399]; Fundacion Ramon Areces, Madrid, Spain [CIVP16A1806]; Division of Intramural Research, NIAID; Austrian Science Funds (FWF) [SFB F4611, SFB F4704-B20]; INCa; Instituto de Salud Carlos III FX We were unable to cite all the original papers because of reference limits and apologize for not citing all relevant original papers. M Arock is supported by Fondation de France; P Dubreuil is supported by La Ligue Nationale Contre le Cancer (equipe labellisee) and INCa; A Garcia-Montero and A Orfao are supported by grants from the Instituto de Salud Carlos III, Ministry of Economy and Competitivity, Madrid, Spain (Grant Numbers RD12/0036/0048 and PI11/02399, FEDER) and from Fundacion Ramon Areces, Madrid, Spain (Grant Number CIVP16A1806); DD Metcalfe is supported in part by the Division of Intramural Research, NIAID; P Valent is supported by Austrian Science Funds (FWF) Project SFB F4611 and SFB F4704-B20. NR 97 TC 24 Z9 24 U1 1 U2 6 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 JUN PY 2015 VL 29 IS 6 BP 1223 EP 1232 DI 10.1038/leu.2015.24 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA CJ6PE UT WOS:000355615000001 PM 25650093 ER PT J AU Purdue, MP Lan, Q Kemp, TJ Hildesheim, A Weinstein, SJ Hofmann, JN Virtamo, J Albanes, D Pinto, LA Rothman, N AF Purdue, M. P. Lan, Q. Kemp, T. J. Hildesheim, A. Weinstein, S. J. Hofmann, J. N. Virtamo, J. Albanes, D. Pinto, L. A. Rothman, N. TI Elevated serum sCD23 and sCD30 up to two decades prior to diagnosis associated with increased risk of non-Hodgkin lymphoma SO LEUKEMIA LA English DT Letter ID B-CELL ACTIVATION; SOLUBLE CD30; MARKERS; IMMUNE; CD23; CYTOKINES C1 [Purdue, M. P.; Lan, Q.; Hildesheim, A.; Weinstein, S. J.; Hofmann, J. N.; Albanes, D.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Purdue, M. P.] Ontario Inst Canc Res, Toronto, ON, Canada. [Kemp, T. J.; Pinto, L. A.] Leidos Biomed Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM mark.purdue@ontariohealthstudy.ca RI Hildesheim, Allan/B-9760-2015; Purdue, Mark/C-9228-2016 OI Hildesheim, Allan/0000-0003-0257-2363; Purdue, Mark/0000-0003-1177-3108 FU Intramural NIH HHS NR 15 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 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JUN PY 2015 VL 29 IS 6 BP 1429 EP 1431 DI 10.1038/leu.2015.2 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA CJ6PE UT WOS:000355615000022 PM 25567136 ER PT J AU Sun, B Wang, Y Kota, K Shi, YR Motlak, S Makambi, K Loffredo, CA Shields, PG Yang, Q Harris, CC Zheng, YL AF Sun, Bing Wang, Ying Kota, Krishna Shi, Yaru Motlak, Salaam Makambi, Kepher Loffredo, Christopher A. Shields, Peter G. Yang, Qin Harris, Curtis C. Zheng, Yun-Ling TI Telomere length variation: A potential new telomere biomarker for lung cancer risk SO LUNG CANCER LA English DT Article DE Lung cancer; Telomere length variation; Telomere length; Blood-based biomarker; Risk prediction; Telomere dysfunction ID HEMATOPOIETIC STEM-CELLS; OXIDATIVE STRESS; DYSKERATOSIS-CONGENITA; CHROMOSOME STABILITY; HUMAN FIBROBLASTS; DNA-DAMAGE; DYSFUNCTION; SENESCENCE; MICE; AGE AB Objectives: In this report the associations between telomere length variation (TLV), mean telomere length in blood lymphocytes and lung cancer risk were examined. Materials and methods: The study design is case-control. Cases (N = 191) were patients newly diagnosed with histologically confirmed non-small cell lung cancer. Controls (N = 207) were healthy individuals recruited from the same counties as cases and matched to cases on age and gender. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and lung cancer risk. Results: Telomere length variation across all chromosomal ends was significantly associated with lung cancer risk; adjusted odds ratios 4.67 [95% confidence interval (CI): 1.46-14.9] and 0.46 (95% CI: 025-0.84) for younger (age <= 60) and older (age >60) individuals, respectively. TLV and mean telomere length jointly affected lung cancer risk: when comparing individuals with short telomere length and high TLV to those with long telomere length and low TLV, adjusted odd ratios were 8.21 (95% Cl: 1.71-39.5) and 0.33 (95% CI: 0.15-0.72) for younger and older individuals, respectively. Conclusions: TLV in blood lymphocytes is significantly associated with lung cancer risk and the associations were modulated by age. TLV in combination with mean telomere length might be useful in identifying high risk population for lung cancer computerized tomography screening. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Sun, Bing; Wang, Ying; Kota, Krishna; Shi, Yaru; Motlak, Salaam; Makambi, Kepher; Loffredo, Christopher A.; Zheng, Yun-Ling] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, Washington, DC 20057 USA. [Makambi, Kepher; Loffredo, Christopher A.] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC 20057 USA. [Shields, Peter G.] Ohio State Univ, Wexner Med Ctr, James Canc Hosp, Columbus, OH 43220 USA. [Yang, Qin] Washington Univ, Sch Med, Dept Radiat Oncol, Div Canc Biol, St Louis, MO USA. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zheng, YL (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, 3970 Reservoir Rd NW,Res Bldg,Room W201, Washington, DC 20057 USA. EM yz37@georgetown.edu FU National Cancer Institute of the National Institutes of Health [R01CA132996]; Susan G. Komen for the Cure [KG100283] FX We thank Donna Perlmutter, Bonnie Cooper, Terrence Clemmons, Carolynn Harris, Laura Hall and Dawn Tucker for recruiting study subjects, and Betty Williams for data coding and editing. We thank John Cottrell and Zhipeng Yu for processing and handling the samples and Audrey Salabes for examining medical records. We thank Scarlett Sun and Michael Xu for their assistance in telomere length measurement. Research in YLZ's laboratory is supported by grants from the National Cancer Institute of the National Institutes of Health (R01CA132996)and Susan G. Komen for the Cure (KG100283). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 50 TC 4 Z9 4 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD JUN PY 2015 VL 88 IS 3 BP 297 EP 303 DI 10.1016/j.lungcan.2015.03.011 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CJ7WU UT WOS:000355711900009 PM 25840848 ER PT J AU Lam, C Golas, GA Davids, M Huizing, M Kane, MS Krasnewich, DM Malicdan, MCV Adams, DR Markello, TC Zein, WM Gropman, AL Lodish, MB Stratakis, CA Maric, I Rosenzweig, SD Baker, EH Ferreira, CR Danylchuk, NR Kahler, S Garnica, AD Schaefer, GB Boerkoel, CF Gahl, WA Wolfe, LA AF Lam, Christina Golas, Gretchen A. Davids, Mariska Huizing, Marjan Kane, Megan S. Krasnewich, Donna M. Malicdan, May Christine V. Adams, David R. Markello, Thomas C. Zein, Wadih M. Gropman, Andrea L. Lodish, Maya B. Stratakis, Constantine A. Maric, Irina Rosenzweig, Sergio D. Baker, Eva H. Ferreira, Carlos R. Danylchuk, Noelle R. Kahler, Stephen Garnica, Adolfo D. Schaefer, G. Bradley Boerkoel, Cornelius F. Gahl, William A. Wolfe, Lynne A. TI Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE PIGT-CDG; Congenital disorder of glycosylation; Glycosylphosphatidylinositol anchor; Phenotype; Flow cytometry; Exome ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; HYPOTONIA-SEIZURES SYNDROME; MENTAL-RETARDATION SYNDROME; INTELLECTUAL DISABILITY; UNDIAGNOSED DISEASES; GERMLINE MUTATION; GPI; HYPERPHOSPHATASIA; PROTEINS; DEFICIENCY AB PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6 years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C > T encoding a previously described missense variant Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders. (C) 2015 Published by Elsevier Inc. C1 [Lam, Christina; Ferreira, Carlos R.] NHGRI, Med Genet & Genom Med Training Program, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Golas, Gretchen A.; Davids, Mariska; Kane, Megan S.; Adams, David R.; Gropman, Andrea L.; Gahl, William A.; Wolfe, Lynne A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Golas, Gretchen A.; Davids, Mariska; Kane, Megan S.; Malicdan, May Christine V.; Adams, David R.; Markello, Thomas C.; Boerkoel, Cornelius F.; Gahl, William A.; Wolfe, Lynne A.] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20892 USA. [Huizing, Marjan; Malicdan, May Christine V.; Adams, David R.; Markello, Thomas C.; Gahl, William A.] NHGRI, Human Biochem Genet Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Krasnewich, Donna M.] NHGRI, Div Genet & Dev Biol, NIH, Bethesda, MD 20892 USA. [Zein, Wadih M.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Lodish, Maya B.] NICHD, Heritable Disorders Branch, NIH, Bethesda, MD USA. [Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [Maric, Irina] NIH, Hematol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.] NIH, Serv Immunol, Ctr Clin, Bethesda, MD 20892 USA. [Baker, Eva H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Danylchuk, Noelle R.; Kahler, Stephen; Garnica, Adolfo D.; Schaefer, G. Bradley] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Danylchuk, Noelle R.; Kahler, Stephen; Garnica, Adolfo D.; Schaefer, G. Bradley] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. RP Lam, C (reprint author), NHGRI, NIH, Bldg 10,Room 5D38, Bethesda, MD 20892 USA. EM lamct@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA FX We would like to thank the family for participating in this study. We appreciate the expert laboratory assistance of Carla Ciccone, the Magnetic Resonance technologists who scanned the patients (Mastaneh Owhadi and Bonita Damaska), and Dr. F.D. Porter for the use of his patients as a reference group. This study was supported by the by the Common Fund, Office of the Director and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. NR 37 TC 2 Z9 2 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN-JUL PY 2015 VL 115 IS 2-3 BP 128 EP 140 DI 10.1016/j.ymgme.2015.04.007 PG 13 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CK0KH UT WOS:000355893600010 PM 25943031 ER PT J AU Grasso, CS Tang, YJ Truffaux, N Berlow, NE Liu, LN Debily, MA Quist, MJ Davis, LE Huang, EC Woo, PJ Ponnuswami, A Chen, S Johung, TB Sun, WC Kogiso, M Dui, YC Qi, L Huang, YL Hutt-Cabezas, M Warrenm, KE Le Dret, L Meltzerm, PS Mao, H Quezado, M van Vuurden, DG Abraham, J Fouladi, M Svalina, MN Wang, N Hawkins, C Nazarian, J Alonso, MM Raabe, EH Hulleman, E Spellman, PT Li, XN Keller, C Pal, R Grill, J Monje, M AF Grasso, Catherine S. Tang, Yujie Truffaux, Nathalene Berlow, Noah E. Liu, Lining Debily, Marie-Anne Quist, Michael J. Davis, Lara E. Huang, Elaine C. Woo, Pamelyn J. Ponnuswami, Anitha Chen, Spenser Johung, Tessa B. Sun, Wenchao Kogiso, Mari Dui, Yuchen Qi, Lin Huang, Yulun Huett-Cabezas, Marianne Warrenm, Katherine E. Le Dret, Ludivine Meltzerm, Paul S. Mao, Hua Quezado, Martha van Vuurden, Dannis G. Abraham, Jinu Fouladi, Maryam Svalina, Matthew N. Wang, Nicholas Hawkins, Cynthia Nazarian, Javad Alonso, Marta M. Raabe, Eric H. Hulleman, Esther Spellman, Paul T. Li, Xiao-Nan Keller, Charles Pal, Ranadip Grill, Jacques Monje, Michelle TI Functionally defined therapeutic targets in diffuse intrinsic pontine glioma SO NATURE MEDICINE LA English DT Article ID BRAIN-STEM; PEDIATRIC GLIOBLASTOMA; GENE-EXPRESSION; HISTONE H3.3; MUTATIONS; INHIBITION; SUBGROUPS; PRC2; CELL AB Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG. C1 [Grasso, Catherine S.; Quist, Michael J.; Wang, Nicholas; Spellman, Paul T.] Oregon Hlth & Sci Univ, Ctr Spatial Syst Biomed, Dept Mol & Med Genet, Portland, OR 97201 USA. [Grasso, Catherine S.; Tang, Yujie; Liu, Lining; Woo, Pamelyn J.; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa B.; Sun, Wenchao; Monje, Michelle] Stanford Univ, Dept Neurol, Stanford, CA 94305 USA. [Tang, Yujie; Liu, Lining; Woo, Pamelyn J.; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa B.; Monje, Michelle] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Tang, Yujie; Liu, Lining; Woo, Pamelyn J.; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa B.; Monje, Michelle] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Tang, Yujie; Liu, Lining; Woo, Pamelyn J.; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa B.; Monje, Michelle] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Truffaux, Nathalene; Le Dret, Ludivine; Grill, Jacques] Univ Paris Sud, CNRS, Gustave Roussy, UMR 8203, Villejuif, France. [Berlow, Noah E.; Pal, Ranadip] Texas Tech Univ, Elect & Comp Engn, Lubbock, TX 79409 USA. [Debily, Marie-Anne; Davis, Lara E.] Univ Evry Val dEssone, Dept Biol, Evry, France. [Huang, Elaine C.; Abraham, Jinu; Keller, Charles] Oregon Hlth & Sci Univ, Dept Pediat, Pape Family Pediat Res Inst, Pediat Canc Biol Program, Portland, OR 97201 USA. [Kogiso, Mari; Dui, Yuchen; Qi, Lin; Mao, Hua; Li, Xiao-Nan] Baylor Coll Med, Texas Childrens Canc Ctr, Mol Neurooncol Lab, Houston, TX 77030 USA. [Huett-Cabezas, Marianne; Raabe, Eric H.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Huett-Cabezas, Marianne; Warrenm, Katherine E.; Quezado, Martha; Raabe, Eric H.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Meltzerm, Paul S.] NCI, Bethesda, MD 20892 USA. [van Vuurden, Dannis G.; Hulleman, Esther] Vrije Univ Amsterdam, Med Ctr, Dept Pediat Oncol & Hematol, Amsterdam, Netherlands. [van Vuurden, Dannis G.; Hulleman, Esther] Vrije Univ Amsterdam, Med Ctr, Neuroncol Res Grp Canc Ctr Amsterdam, Amsterdam, Netherlands. [Fouladi, Maryam] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Cincinnati, OH 45229 USA. [Svalina, Matthew N.; Keller, Charles] Childrens Canc Therapy Dev Inst, Ft Collins, CO USA. [Hawkins, Cynthia] Univ Toronto, Dept Pediat Lab Med, Toronto, ON, Canada. [Hawkins, Cynthia] Univ Toronto, Hosp Sick Children, Labatt Brain Tumor Res Ctr, Toronto, ON M5G 1X8, Canada. [Nazarian, Javad] Childrens Natl Hlth Syst, Ctr Res Inst, Washington, DC USA. [Alonso, Marta M.] Univ Hosp Navarra, Dept Oncol, Pamplona, Spain. [Grill, Jacques] Univ Paris Sud, Inst Gustave Roussy, Dept Cancerol Enfant & Adolescent, Villejuif, France. [Grill, Jacques] Parke Davis Res Unit, Inst Gustave Roussy, Dept Cancerol Enfant & Adolescent, Villejuif, France. RP Monje, M (reprint author), Stanford Univ, Dept Neurol, Stanford, CA 94305 USA. EM charles@cc-TDI.org; mmonje@stanford.edu OI Van Vuurden, Dannis/0000-0002-1364-9007 FU Lyla Nsouli Foundation; Children's Oncology Group (COG) Central Nervous System Committee; DIPG Collaborative (The Cure Starts Now Foundation); DIPG Collaborative (Reflections of Grace Foundation); DIPG Collaborative (Smiles for Sophie Foundation); DIPG Collaborative (Cancer-Free Kids Foundation); DIPG Collaborative (Carly's Crusade Foundation); DIPG Collaborative (Jeffrey Thomas Hayden Foundation); DIPG Collaborative (Soar with Grace Foundation); Accelerate Brain Cancer Cures Foundation (ABC2); CureSearch for Childhood Cancer; Team Julian Foundation; COG Chair's Grant [5UOCA098543]; US National Institutes of Health [K08NS070926]; Alex's Lemonade Stand Foundation; McKenna Claire Foundation; Connor Johnson Memorial Fund; Dylan Jewett Memorial Fund; Elizabeth Stein Memorial Fund; Dylan Frick Memorial Fund; Abigail Jensen Memorial Fund; Zoey Ganesh Memorial Fund; Wayland Villars DIPG Foundation; Jennifer Kranz Memorial Fund; Unravel Pediatric Cancer; Virginia & D.K. Ludwig Fund for Cancer Research; Price Family Charitable Fund; Matthew Larson Foundation; Godfrey Family Fund in Memory of Fiona Penelope; Child Health Research Institute at Stanford; Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases; Etoile de Martin; Fondation Lemos; Le Defi de Fortunee; Scott Carter Foundation; Semmy Foundation; US Department of Defense; National Science Foundation [CCF0953366]; Marie Curie grant [IRG270459]; Spanish Ministry of Health [PI13/0125]; St. Baldrick's Foundation; Iron Matt Foundation FX We thank the many children and families who selflessly contributed to this study through tissue donations obtained from surgery or autopsy, and A. Gajjar for his guidance and vision throughout this study. We also thank D. Hargrave, J. Olson and S. Leary for selection of V.2 chemical screen agents. We are grateful for the critical questions and comments by S. Cheetham and N. Nsouli. We also acknowledge important comments by another DIPG Preclinical Consortium member, O. Becher. We thank G. Grant for assistance in developing rodent CED techniques. We thank R. Hashizume and C.D. James (Northwestern University) for use of the SF7761 DIPG cell line. Short-read sequencing was performed by the OHSU Massively Parallel Sequencing Shared Resource. This research is supported by the Lyla Nsouli Foundation, the Children's Oncology Group (COG) Central Nervous System Committee, the DIPG Collaborative (The Cure Starts Now Foundation, Reflections of Grace Foundation, Smiles for Sophie Foundation, Cancer-Free Kids Foundation, Carly's Crusade Foundation, Jeffrey Thomas Hayden Foundation, Soar with Grace Foundation), the Accelerate Brain Cancer Cures Foundation (ABC2), CureSearch for Childhood Cancer, the Team Julian Foundation and the COG Chair's Grant (5UOCA098543). Additional funding support was provided by US National Institutes of Health grant K08NS070926 (to M.M.), Alex's Lemonade Stand Foundation (to M.M. and Y.T.), the McKenna Claire Foundation, the Connor Johnson Memorial Fund, the Dylan Jewett Memorial Fund, the Elizabeth Stein Memorial Fund, the Dylan Frick Memorial Fund, the Abigail Jensen Memorial Fund, the Zoey Ganesh Memorial Fund, the Wayland Villars DIPG Foundation, the Jennifer Kranz Memorial Fund, Unravel Pediatric Cancer, the Virginia & D.K. Ludwig Fund for Cancer Research, the Price Family Charitable Fund, the Matthew Larson Foundation, the Godfrey Family Fund in Memory of Fiona Penelope, the Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases (all to M.M.), Etoile de Martin (to J.G. and N.T.), Fondation Lemos and Le Defi de Fortunee (to J.G.), the Scott Carter Foundation (to N.E.B.), the Semmy Foundation (to D.G.v.V. and E.H.), the US Department of Defense (to X.-N.L.), National Science Foundation grant CCF0953366 (to R.P.), Marie Curie grant IRG270459 (to M.M.A.); the Spanish Ministry of Health grant PI13/0125 (to M.M.A.), and the St. Baldrick's Foundation and Iron Matt Foundation (both to E.R. and M.H.-C.). NR 19 TC 38 Z9 39 U1 7 U2 27 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 JUN PY 2015 VL 21 IS 6 BP 555 EP 559 DI 10.1038/nm.3855 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CJ8UF UT WOS:000355778300010 PM 25939062 ER PT J AU Long, AH Haso, WM Shern, JF Wanhainen, KM Murgai, M Ingaramo, M Smith, JP Walker, AJ Kohler, ME Venkateshwara, VR Kaplan, RN Patterson, GH Fry, TJ Orentas, RJ Mackall, CL AF Long, Adrienne H. Haso, Waleed M. Shern, Jack F. Wanhainen, Kelsey M. Murgai, Meera Ingaramo, Maria Smith, Jillian P. Walker, Alec J. Kohler, M. Eric Venkateshwara, Vikas R. Kaplan, Rosandra N. Patterson, George H. Fry, Terry J. Orentas, Rimas J. Mackall, Crystal L. TI 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors SO NATURE MEDICINE LA English DT Article ID CHRONIC VIRAL-INFECTION; ANTITUMOR-ACTIVITY; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; ENHANCED SURVIVAL; CLINICAL-TRIAL; CD28; PERSISTENCE; CANCER; MEMORY AB Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We show that tonic CAR CD3-zeta, phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy. Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials. C1 [Long, Adrienne H.; Haso, Waleed M.; Shern, Jack F.; Wanhainen, Kelsey M.; Murgai, Meera; Smith, Jillian P.; Walker, Alec J.; Kohler, M. Eric; Venkateshwara, Vikas R.; Kaplan, Rosandra N.; Fry, Terry J.; Orentas, Rimas J.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Long, Adrienne H.] Northwestern Univ, Feinberg Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA. [Wanhainen, Kelsey M.] Colgate Univ, Dept Biol, Hamilton, NY 13346 USA. [Ingaramo, Maria; Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD USA. [Kohler, M. Eric] Johns Hopkins Univ Hosp, Dept Pediat, Baltimore, MD 21287 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov OI Wanhainen, Kelsey/0000-0001-8666-0584 FU NIH, NCI; NIH, National Institute of Biomedical Imaging and Bioengineering (NIBIB) [ZIA BC 011073, ZIA BC 011565, ZIA BC 011332, ZIA EB 000071-06]; Stand Up To Cancer - St. Baldrick's - NCI Pediatric Dream Team Translational Cancer Research Grant FX We kindly thank S. Gottschalk (Texas Children's Hospital) for providing sequences for the 14g2a scFv and IgG1 CH2CH3; J. Kochenderfer (National Cancer Institute, NCI, US National Institutes of Health, NIH) for the H3 MSGV-FMC63-28z retroviral vector producer line; S. Grupp (Children's Hospital of Philadelphia) for the NALM6-GL cell line; R. Morgan (BlueBird Bio, previously NCI, NIH) for the MSGV-139-28z and MSGV-4D5-28BBz vectors; and C. June (University of Pennsylvania) for sequences to the 4-1BB CAR endodomain. We also thank L. Cooper (M.D. Anderson) for providing the 136.20.1, FMC63 anti-idiotype antibody; the Biological Research Branch of NCI for providing the 1A7, 14g2a anti-idiotype antibody; the Clinical Support Laboratory of the Frederick National Laboratory for Cancer Research (FNLCR) for assisting in MesoScale cytokine release assays; and the Laboratory of Molecular Technology (LMT) Microarray Group of FNLCR for assisting in microarray assays. We thank N. Restifo and M. Roederer for careful review of this manuscript. This work was supported by the Intramural Research Program of the NIH, including the NCI and the National Institute of Biomedical Imaging and Bioengineering (NIBIB): ZIA BC 011073 (A.H.L., K.M.W., J.P.S., A.J.W., M.E.K., V.R.V., R.J.O. and C.L.M); ZIA BC 011565 (W.M.H. and T.J.F.); ZIA BC 011332 (M.M. and R.N.K.); and ZIA EB 000071-06 (M.I. and G.H.P.) This research was also supported by a Stand Up To Cancer - St. Baldrick's - NCI Pediatric Dream Team Translational Cancer Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. NR 56 TC 71 Z9 74 U1 4 U2 37 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 JUN PY 2015 VL 21 IS 6 BP 581 EP 590 DI 10.1038/nm.3838 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CJ8UF UT WOS:000355778300014 PM 25939063 ER PT J AU Gutmanas, A Adams, PD Bardiaux, B Berman, HM Case, DA Fogh, RH Guntert, P Hendrickx, PMS Herrmann, T Kleywegt, GJ Kobayashi, N Lange, OF Markley, JL Montelione, GT Nilges, M Ragan, TJ Schwieters, CD Tejero, R Ulrich, EL Velankar, S Vranken-, WF Wedell, JR Westbrook, J Wishart, DS Vuister, GW AF Gutmanas, Aleksandras Adams, Paul D. Bardiaux, Benjamin Berman, Helen M. Case, David A. Fogh, Rasmus H. Guentert, Peter Hendrickx, Pieter M. S. Herrmann, Torsten Kleywegt, Gerard J. Kobayashi, Naohiro Lange, Oliver F. Markley, John L. Montelione, Gaetano T. Nilges, Michael Ragan, Timothy J. Schwieters, Charles D. Tejero, Roberto Ulrich, Eldon L. Velankar, Sameer Vranken-, Wim F. Wedell, Jonathan R. Westbrook, John Wishart, David S. Vuister, Geerten W. TI NMR Exchange Format: a unified and open standard for representation of NMR restraint data SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Letter ID PROTEIN DATA-BANK; WWPDB; FILE C1 [Gutmanas, Aleksandras; Hendrickx, Pieter M. S.; Kleywegt, Gerard J.; Velankar, Sameer] European Bioinformat Inst, European Mol Biol Lab, Protein Data Bank Europe, Cambridge, England. [Adams, Paul D.] Lawrence Berkeley Lab, Phys Biosci Div, Berkeley, CA USA. [Bardiaux, Benjamin; Nilges, Michael] Inst Pasteur, Unite Bioinformat Struct, Dept Biol Struct & Chim, Paris, France. [Bardiaux, Benjamin; Nilges, Michael] CNRS, Unite Mixte Rech 3528, Paris, France. [Berman, Helen M.; Case, David A.; Westbrook, John] Rutgers State Univ, Ctr Integrat Prote Res, Dept Chem & Chem Biol, Piscataway, NJ USA. [Fogh, Rasmus H.; Ragan, Timothy J.; Vuister, Geerten W.] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. [Guentert, Peter] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, Inst Biophys Chem, D-60054 Frankfurt, Germany. [Guentert, Peter] Tokyo Metropolitan Univ, Grad Sch Sci & Engn, Tokyo 158, Japan. [Guentert, Peter] ETH, Phys Chem, Zurich, Switzerland. [Herrmann, Torsten] Ecole Normale Super Lyon, Ctr Resonance Magnet Nucl Tres Hauts Champs, Villeurbanne, France. [Herrmann, Torsten] CNRS, Unite Mixte Rech 5280, Inst Sci Analyt, Villeurbanne, France. [Kobayashi, Naohiro] Osaka Univ, Inst Prot Res, Osaka, Japan. [Lange, Oliver F.] Tech Univ Munich, Biomol NMR, Munich Ctr Integrated Prot Sci, Dept Chem, Garching, Germany. [Markley, John L.; Ulrich, Eldon L.] Univ Wisconsin, Dept Biochem, Madison, WI 53705 USA. [Montelione, Gaetano T.] Rutgers State Univ, Dept Mol Biol & Biochem, Ctr Adv Biotechnol & Med, Piscataway, NJ USA. [Montelione, Gaetano T.] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Biochem & Mol Biol, Piscataway, NJ 08854 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Tejero, Roberto] Univ Valencia, Dept Quim Fis, Valencia, Spain. [Vranken-, Wim F.] Vlaams Inst Biotechnol, Struct Biol Res Ctr, Brussels, Belgium. [Vranken-, Wim F.] Vrije Univ Brussel, Struct Biol Brussels, Brussels, Belgium. [Vranken-, Wim F.] Univ Libre Bruxelles, Vrije Univ Brussel, Interuniv Inst Bioinformat Brussels, Brussels, Belgium. [Wishart, David S.] Univ Alberta, Dept Comp Sci, Edmonton, AB, Canada. [Wishart, David S.] Univ Alberta, Dept Biol Sci, Edmonton, AB, Canada. RP Vuister, GW (reprint author), Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. EM gutmanas@ebi.ac.uk; gv29@le.ac.uk RI Nilges, Michael/E-4803-2011; Herrmann, Torsten/B-9978-2008; Adams, Paul/A-1977-2013; Tejero Toquero, Roberto/F-5104-2016; Vranken, Wim/J-5051-2016; Guntert, Peter/L-5577-2013; Fachbereich14, Dekanat/C-8553-2015 OI Nilges, Michael/0000-0002-1451-8092; Wishart, David S/0000-0002-3207-2434; Herrmann, Torsten/0000-0003-2115-4781; Adams, Paul/0000-0001-9333-8219; Tejero Toquero, Roberto/0000-0003-2504-5988; Vranken, Wim/0000-0001-7470-4324; Guntert, Peter/0000-0002-2911-7574; FU Biotechnology and Biological Sciences Research Council [BB/E005071/1, BB/J007471, BB/J007897/1, BB/K021249/1]; Intramural NIH HHS; Medical Research Council [MR/L000555/1]; NIGMS NIH HHS [P01 GM063210, R01 GM109046, R01GM109046]; NLM NIH HHS [P41 LM005799, P41LM05799]; Wellcome Trust [088944] NR 9 TC 2 Z9 2 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2015 VL 22 IS 6 BP 433 EP 434 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CJ6RI UT WOS:000355620600001 PM 26036565 ER PT J AU Xiao, YL Ma, BY McElheny, D Parthasarathy, S Long, F Hoshi, M Nussinov, R Ishii, Y AF Xiao, Yiling Ma, Buyong McElheny, Dan Parthasarathy, Sudhakar Long, Fei Hoshi, Minako Nussinov, Ruth Ishii, Yoshitaka TI A beta(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; BETA-SHEET STRUCTURES; A-BETA; EXPERIMENTAL CONSTRAINTS; PROTEIN BACKBONE; ROTATING SOLIDS; CHEMICAL-SHIFTS; MODEL; POLYMORPHISM AB Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid beta(A beta(1-42)), rather than of the more abundant A beta(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded A beta(1-42) have remained elusive. Here we present the atomic model of an A beta(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-beta-sheet segments that differ from reported structures of A beta(1-40) fibrils. Remarkably, A beta(1-40) is incompatible with the triple-beta-motif, because seeding with A beta(1-42) fibrils does not promote conversion of monomeric A beta(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in A beta(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes A beta(1-40). The results provide insight into the A beta(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease. C1 [Xiao, Yiling; McElheny, Dan; Parthasarathy, Sudhakar; Long, Fei; Ishii, Yoshitaka] Univ Illinois, Dept Chem, Chicago, IL 60607 USA. [Ma, Buyong; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res, Frederick, MD 21701 USA. [Hoshi, Minako] Inst Biomed Res & Innovat, Kobe, Hyogo, Japan. [Hoshi, Minako] Kyoto Univ, Dept Anat & Dev Biol, Grad Sch Med, Kyoto, Japan. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Ishii, Yoshitaka] Univ Illinois, Struct Biol Ctr, Chicago, IL USA. RP Ishii, Y (reprint author), Univ Illinois, Dept Chem, Chicago, IL 60607 USA. EM yishii@uic.edu RI Ishii, Yoshitaka/F-4558-2014; Ma, Buyong/F-9491-2011 OI Ishii, Yoshitaka/0000-0002-7724-6469; Ma, Buyong/0000-0002-7383-719X FU US National Institutes of Health (NIH) RO1 program [GM 098033]; Alzheimer's Association Investigator-Initiated Research Grant (IIRG) [08-91256]; federal funds from the Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research FX This work was supported primarily by the US National Institutes of Health (NIH) RO1 program (GM 098033) and by an Alzheimer's Association Investigator-Initiated Research Grant (IIRG) (08-91256) to Y.I. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E, to B.M. and R.N. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research, to B.M. and R.N. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. MD simulations to generate initial structural models were performed at the high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH (http://biowulf.nih.gov/). Y.I. is grateful to S. Chimon, C. Jones and N. Wickramasinghe for their initial efforts in the preparation of A beta(1-42) fibrils at the University of Illinois at Chicago. NR 57 TC 82 Z9 84 U1 18 U2 118 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2015 VL 22 IS 6 BP 499 EP U97 DI 10.1038/nsmb.2991 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CJ6RI UT WOS:000355620600013 PM 25938662 ER PT J AU van Sloten, TT Protogerou, AD Henry, RMA Schram, MT Launer, LJ Stehouwer, CDA AF van Sloten, Thomas T. Protogerou, Athanase D. Henry, Ronald M. A. Schram, Miranda T. Launer, Lenore J. Stehouwer, Coen D. A. TI Association between arterial stiffness, cerebral small vessel disease and cognitive impairment: A systematic review and meta-analysis SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Arterial stiffness; Cerebral small vessel disease; White matter hyperintensities; Cerebral microbleeds; Cerebral infarcts; Cognitive impairment; Dementia; Meta-analysis; Systematic review ID PULSE-WAVE VELOCITY; WHITE-MATTER HYPERINTENSITIES; COMMUNITY-DWELLING POPULATION; HIGH BLOOD-PRESSURE; ALZHEIMERS-DISEASE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; HYPERTENSIVE PATIENTS; STROKE PATIENTS; ROTTERDAM SCAN AB Arterial stiffness may be a cause of cerebral small vessel disease and cognitive impairment. We therefore performed a systematic review and meta-analysis of studies on the association between stiffness, cerebral small vessel disease and cognitive impairment. For the associations between stiffness (i.e. carotid-femoral pulse wave velocity (cfPWV), brachial-ankle PVVV (baPWV), carotid stiffness and pulse pressure) on the one hand and cerebral small vessel disease and cognitive impairment on the other, we identified 23 (n = 15,666/20 cross-sectional; 1 longitudinal; 2 combined cross-sectional/longitudinal) and 41 studies (n= 57,671/26 cross-sectional; 11 longitudinal; 4 combined cross-sectional/longitudinal), respectively. Pooled analyses of cross-sectional studies showed that greater stiffness was associated with markers of cerebral small vessel disease with odds ratios, per +1 SD, of 1.29-1.32 (P<.001). Studies on cognitive impairment could not be pooled due to large heterogeneity. Some (but not all) studies showed an association between greater stiffness and cognitive impairment, and the strength of this association was relatively weak. The present study supports the hypothesis that greater arterial stiffness is a contributor to microvascular brain disease. (C) 2015 Elsevier Ltd. All rights reserved. C1 [van Sloten, Thomas T.; Protogerou, Athanase D.; Henry, Ronald M. A.; Schram, Miranda T.; Stehouwer, Coen D. A.] Maastricht Univ, Med Ctr, Cardiovasc Res Inst Maastricht, Dept Med, NL-6229 HX Maastricht, Netherlands. [van Sloten, Thomas T.] Maastricht Univ, Med Ctr, Sch Nutr Toxicol & Metab, NL-6229 HX Maastricht, Netherlands. [Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Stehouwer, CDA (reprint author), Maastricht Univ, Med Ctr, Dept Med, Prof Debyelaan 25, NL-6229 HX Maastricht, Netherlands. EM cda.stehouwer@mumc.nl OI Schram, Miranda/0000-0003-0515-4124; Protogerou, Athanase/0000-0002-3825-532X FU European Union [299086] FX Dr. Protogerou has received funding from the European Union Seventh Framework Programme ([FP7/2009-2013]) under grand agreement No. 299086. NR 81 TC 19 Z9 19 U1 7 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD JUN PY 2015 VL 53 BP 121 EP 130 DI 10.1016/j.neubiorev.2015.03.011 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CJ2ZJ UT WOS:000355352900007 PM 25827412 ER PT J AU Hoffman, L Bann, C Higgins, R Vohr, B AF Hoffman, Laurie Bann, Carla Higgins, Rosemary Vohr, Betty CA Eunice Kennedy Shriver Natl Inst C TI Developmental Outcomes of Extremely Preterm Infants Born to Adolescent Mothers SO PEDIATRICS LA English DT Article ID BIRTH-WEIGHT INFANTS; CHILD-DEVELOPMENT; LOW-INCOME; PREDICTORS; PSYCHOPATHOLOGY; INTERVENTION; GRANDMOTHER; TEENAGE; DELAY AB BACKGROUND AND OBJECTIVES: Extremely preterm infants and infants born to adolescent mothers are at risk for adverse developmental. The objectives were to evaluate development and behavior outcomes of extremely low birth weight (ELBW) infants born to adolescent mothers <20 compared with adult mothers >= 20 years and to identify socioeconomic risk factors that affect outcomes. METHODS: Retrospective cohort analysis of 211 infants >27 weeks of adolescent mothers and 1723 infants of adult mothers at Neonatal Research Network centers from 2008 to 2011. Groups were compared and regression models were run to predict 18- to 22-month adverse outcomes. Primary outcomes were Bayley-III scores, neurodevelopmental impairment, and Brief Infant Toddler Social Emotional Assessment problem scores (BITSEA/P) >= 75th percentile. RESULTS: Adolescent mothers were more often single, Hispanic, less educated, and had public insurance. By 18 to 22 months, their children had significantly increased rates of having lived >= 3 places (21% vs 9%), state supervision (7% vs 3%), rehospitalization (56% vs 46%), and BITSEA/P >= 75th percentile (50% vs 32%) and nonsignificant Bayley-III language scores,85 (56% vs 49%, P=.07). In regression analysis, children of adolescent mothers were more likely to have BITSEA/P >= 75th percentile (relative risk 1.50, 95% confidence interval 1.08-2.07). Living >= 3 places and nonwhite race were predictors of adverse behavior. State supervision was an independent predictor of each Bayley-III composite,70 and neurodevelopmental impairment. CONCLUSIONS: ELBW infants of adolescent mothers experience high social and environmental risks that are associated with adverse behavior outcomes. These findings inform the need for comprehensive follow-up, coordinated care services, and behavior interventions for ELBW infants of adolescent mothers. C1 [Hoffman, Laurie; Vohr, Betty] Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI 02908 USA. [Bann, Carla] RTI Int, Stat & Epidemiol, Res Triangle Pk, NC USA. [Higgins, Rosemary] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Hoffman, L (reprint author), Brown Univ, Women & Infants Hosp, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. EM lhoffman@wihri.org FU National Institutes of Health (NIH) FX Eunice Kennedy Shriver National Institute of Child Health and Human Development Research Network. Funded by the National Institutes of Health (NIH). NR 30 TC 1 Z9 1 U1 4 U2 9 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 JUN PY 2015 VL 135 IS 6 BP 1082 EP 1092 DI 10.1542/peds.2014-3880 PG 11 WC Pediatrics SC Pediatrics GA CJ5UR UT WOS:000355557400047 PM 25963007 ER PT J AU Watson, NF Badr, MS Belenky, G Bliwise, DL Buxton, OM Buysse, D Dinges, DF Gangwisch, J Grandner, MA Kushida, C Malhotra, RK Martin, JL Patel, SR Quan, SF Tasali, E Twery, M Croft, JB Maher, E Barrett, JA Thomas, SM Heald, JL AF Watson, Nathaniel F. Badr, M. Safwan Belenky, Gregory Bliwise, Donald L. Buxton, Orfeu M. Buysse, Daniel Dinges, David F. Gangwisch, James Grandner, Michael A. Kushida, Clete Malhotra, Raman K. Martin, Jennifer L. Patel, Sanjay R. Quan, Stuart F. Tasali, Esra Twery, Michael Croft, Janet B. Maher, Elise Barrett, Jerome A. Thomas, Sherene M. Heald, Jonathan L. TI Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society SO SLEEP LA English DT Editorial Material AB Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine. C1 Univ Washington, Seattle, WA 98195 USA. [Badr, M. Safwan] Wayne State Univ, Detroit, MI USA. [Belenky, Gregory] Washington State Univ, Spokane, WA USA. [Bliwise, Donald L.] Emory Univ, Atlanta, GA 30322 USA. [Buxton, Orfeu M.] Penn State Univ, University Pk, PA 16802 USA. [Buysse, Daniel] Univ Pittsburgh, Pittsburgh, PA USA. [Dinges, David F.; Grandner, Michael A.] Univ Penn, Philadelphia, PA 19104 USA. [Gangwisch, James] Columbia Univ, New York, NY USA. [Kushida, Clete] Stanford Univ, Stanford, CA 94305 USA. [Malhotra, Raman K.] St Louis Univ, St Louis, MO 63103 USA. [Martin, Jennifer L.] Univ Calif Los Angeles, Los Angeles, CA USA. [Patel, Sanjay R.; Quan, Stuart F.] Harvard Univ, Sch Med, Boston, MA USA. [Tasali, Esra] Univ Chicago, Chicago, IL 60637 USA. [Twery, Michael] NHLBI, NIH, Bethesda, MD 20892 USA. [Croft, Janet B.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Maher, Elise] Sleep Disorders Inst, New York, NY USA. [Barrett, Jerome A.; Thomas, Sherene M.; Heald, Jonathan L.] Amer Acad Sleep Med, Darien, IL USA. RP Watson, NF (reprint author), 2510 Frontage Rd, Darien, IL 60561 USA. EM research@aasmnet.org OI Patel, Sanjay/0000-0002-9142-5172 FU NCATS NIH HHS [UL1 TR000430]; NCCDPHP CDC HHS [1U50DP004930-01] NR 3 TC 42 Z9 43 U1 4 U2 9 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD JUN 1 PY 2015 VL 38 IS 6 BP 843 EP 844 AR PII sp-00231-15 DI 10.5665/sleep.4716 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CJ6PY UT WOS:000355617000001 PM 26039963 ER PT J AU Williams, RM Puetz, TW Giza, CC Broglio, SP AF Williams, Richelle M. Puetz, Tim W. Giza, Christopher C. Broglio, Steven P. TI Concussion Recovery Time Among High School and Collegiate Athletes: A Systematic Review and Meta-Analysis SO SPORTS MEDICINE LA English DT Review ID SPORT-RELATED CONCUSSION; TRAUMATIC BRAIN-INJURY; MILD HEAD-INJURY; FOOTBALL PLAYERS; NEUROCOGNITIVE PERFORMANCE; NEUROPSYCHOLOGICAL DEFICITS; INTERNATIONAL-CONFERENCE; CONSENSUS STATEMENT; NCAA CONCUSSION; SOCCER PLAYERS AB Background Concussion diagnosis and management is made through the clinical exam using assessment tools that include self-report symptomatology, postural control, and cognitive evaluations. The specific timing of concussion resolution varies between individuals. However, despite a lack of research in concussion recovery, it is widely accepted that the majority of young adults will recover in 7-10 days, with youth athletes taking longer. Objectives The purpose of this review is to directly compare the recovery duration among high school and collegiate athletes on symptom reports and cognitive assessments following concussion. Data Sources Data were collected from a literature search comprising high school or college athletes only. This included studies (n = 6) that reported symptom or cognitive performance recovery to the exact day. Results High school athletes self-reported symptom recovery at 15 days compared with 6 days in collegiate athletes. Both college and high school athletes showed cognitive recovery at similar rates of 5 and 7 days. Limitations This review only included articles that were directly related to concussed high school or college athletes. Additionally, athletes in the high school and college setting typically receive a battery of neurocognitive tests that may not be as sensitive or as comprehensive as a full neuropsychological exam. Conclusion The review finds that neurocognitive recovery rates are similar among high school and college athletes, while symptom reporting shows longer recovery time points in high school than in college. Implications of Key Findings An individualized and stepwise concussion management plan is important for proper concussion recovery regardless of age. C1 [Williams, Richelle M.] Univ Michigan, Dept Kinesiol, Ann Arbor, MI 48109 USA. [Puetz, Tim W.] NIH, Off Director, Ctr Clin, Bethesda, MD 20892 USA. [Giza, Christopher C.] Univ Calif Los Angeles, Dept Pediat, Mattel Childrens Hosp, Los Angeles, CA 90024 USA. [Giza, Christopher C.] Univ Calif Los Angeles, Dept Neurosurg, Mattel Childrens Hosp, Los Angeles, CA USA. [Broglio, Steven P.] Univ Michigan, Sch Kinesiol, Univ Michigan Injury Ctr, Ann Arbor, MI 48109 USA. RP Broglio, SP (reprint author), Univ Michigan, Dept Kinesiol, Ann Arbor, MI 48109 USA. EM broglio@umich.edu RI Meijer, Anna/K-5118-2016 FU Department of Defense; Joseph Drown Foundation; National Collegiate Athletic Association (NCAA); National Institutes of Health (NIH); Today's and Tomorrow's Children Fund; University of California, Los Angeles (UCLA) Brain Injury Research Center (BIRC), UCLA Steve Tisch BrainSPORT FX Dr. Giza is supported by the Department of Defense, the Joseph Drown Foundation, the National Collegiate Athletic Association (NCAA), the National Institutes of Health (NIH), Today's and Tomorrow's Children Fund, University of California, Los Angeles (UCLA) Brain Injury Research Center (BIRC), UCLA Steve Tisch BrainSPORT. NR 68 TC 12 Z9 12 U1 2 U2 29 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0112-1642 EI 1179-2035 J9 SPORTS MED JI Sports Med. PD JUN PY 2015 VL 45 IS 6 BP 893 EP 903 DI 10.1007/s40279-015-0325-8 PG 11 WC Sport Sciences SC Sport Sciences GA CJ6KP UT WOS:000355603000009 PM 25820456 ER PT J AU Yin, F Cai, JF Zen, W Wei, YH Zhou, W Yuan, F Singh, SR Wei, YY AF Yin, Feng Cai, Junfeng Zen, Wen Wei, Yanhui Zhou, Wei Yuan, Feng Singh, Shree Ram Wei, Yiyong TI Cartilage Regeneration of Adipose-Derived Stem Cells in the TGF-beta 1-Immobilized PLGA-Gelatin Scaffold SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE Chondrogenesis; Adipose-derived stem cells; PLGA; Gelatin microspheres; Transforming growth factor-beta 1 ID CHONDROGENIC DIFFERENTIATION; STROMAL CELLS; HYBRID SCAFFOLD; IN-VITRO; TISSUE; MICROSPHERES; ASSAY; VIVO AB Articular cartilage has restricted self-regenerative capacity; therefore, treatment of cartilage lesions is a great challenge in the field of orthopedics. In the present study, we evaluate the enhancing effect of a transforming growth factor-beta 1 (TGF-beta 1)-immobilized scaffold, fabricated by incorporating TGF-beta 1-loaded gelatin microspheres into PLGA framework, on the differentiation of adipose-derived stem cells (ASCs) into chondrocytes. Significant increase in cell proliferation was observed in the TGF-beta 1-immobilized PLGA-gelatin scaffold, as compared with the ASC-seeded non-TGF-beta 1-immobilized PLGA-gelatin scaffold. When chondrogenic differentiation of ASCs was evaluated for both constructs, sulfated glycosaminoglycan (sGAG) content was significantly higher in the TGF-beta 1-immobilized scaffold. This study showed that ASCs containing the TGF-beta 1-immobilized scaffold better promoted cartilage regeneration in defective articular cartilage, which is assessed by histological observation. Based on the above results, we conclude that TGF-beta 1-immobilized PLGA-gelatin scaffold seeded with ASCs considerably enhances the quality of the tissue-engineered cartilage, therefore, advancing the field of cartilage tissue engineering. C1 [Yin, Feng; Cai, Junfeng; Zen, Wen; Wei, Yanhui; Zhou, Wei; Yuan, Feng] Tongji Univ, Sch Med, Shanghai East Hosp, Dept Joint & Bone Dis, Shanghai 200120, Peoples R China. [Singh, Shree Ram] NCI, Basic Res Lab, Stem Cell Regulat & Anim Aging Sect, Frederick, MD 21702 USA. [Wei, Yiyong] Jiao Tong Univ, Sch Med, Shanghai 200025, Peoples R China. RP Singh, SR (reprint author), NCI, Basic Res Lab, Stem Cell Regulat & Anim Aging Sect, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov; weiyiyong1232@163.com RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU Intramural NIH HHS [Z99 CA999999] NR 28 TC 8 Z9 8 U1 4 U2 28 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 EI 1558-6804 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD JUN PY 2015 VL 11 IS 3 BP 453 EP 459 DI 10.1007/s12015-014-9561-9 PG 7 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CJ7FZ UT WOS:000355661300008 PM 25267436 ER PT J AU Kelloff, GJ Sigman, CC Scher, HI AF Kelloff, Gary J. Sigman, Caroline C. Scher, Howard I. TI Biomarker development in the context of urologic cancers SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Biomarker; Analytical validation; Biomarker qualification; Prostate cancer biomarkers; Bladder cancer biomarkers; Clinical utility; Circulating tumor cells (CTCs) ID SURROGATE END-POINTS; REFRACTORY PROSTATE-CANCER; CIRCULATING TUMOR-CELLS; QUALITY-OF-LIFE; BLADDER-CANCER; DRUG DEVELOPMENT; CLINICAL-TRIALS; CHEMOTHERAPY; SURVIVAL; MITOXANTRONE AB Background: The Food and Drug Administration (FDA) has called for the use of analytically validated biomarkers that have strong evidence of being fit for purpose to identify patients likely to respond and to evaluate the patient response to a therapy, potential toxicity, and drug resistance. This article discusses development and application of these biomarkers in the context of urologic cancers specifically in cancers of the prostate and urinary bladder. Methods: The FDA has defined four specific categories for contexts of biomarker use: prognostic, predictive, response-indicator, and efficacy-response (surrogate endpoints). Prognostic and predictive biomarkers include pretreatment characteristics of the patient and the tumor. Response-indicator and efficacy response biomarkers occur after treatment and show the effects of treatment on biomarkers. Efficacy response biomarkers show changes associated with clinical benefit and can be surrogates for clinical endpoints leading to drug approvals. Results: Well-structured development plans are required to satisfy rigorous criteria that must be met to qualify biomarkers for specific contexts of use in drug development and patient management. A description of the extensive effort applied to the validation and qualification of circulating tumor cells in castration resistant prostate cancer is described as an example of the potential utility of biomarkers in urological cancers. Conclusions: Many potential biomarkers have been identified in prostate and urinary bladder cancers, but few have sufficient demonstration of analytical and clinical validity to meet FDA standards for use in clinical settings. Circulating tumor cell (CTC) assays are particularly promising candidates for informative new biomarkers to measure disease before and after treatment. New technologies are providing opportunities for high definition, more informative analysis. Statistical and computational methodologies to describe assay results are also rapidly evolving. These advances will lead to better diagnosis, earlier indications of treatment response and failure, and better definition of patient cohorts that will respond to a specific treatment. (C) 2015 Elsevier Inc. All rights reserved. C1 [Kelloff, Gary J.] NCI, Div Canc Treatment & Diag, NIH, Rockville, MD USA. [Sigman, Caroline C.] CCS Associates, Mountain View, CA 94043 USA. [Scher, Howard I.] Mem Sloan Kettering Canc Ctr, Genitourinary Oncol Serv, Dept Med, New York, NY 10021 USA. [Scher, Howard I.] Weill Cornell Med Coll, Dept Med, New York, NY USA. RP Sigman, CC (reprint author), CCS Associates, Mountain View, CA 94043 USA. EM csigman@ccsainc.com RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU NCI NIH HHS [P50 CA092629] NR 50 TC 7 Z9 7 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUN PY 2015 VL 33 IS 6 BP 295 EP 301 DI 10.1016/j.urolonc.2015.01.007 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CJ8XF UT WOS:000355786100007 PM 25746942 ER PT J AU Cai, T Hirai, H Xu, HY Notkins, AL AF Cai, Tao Hirai, Hiroki Xu, Huanyu Notkins, Abner L. TI The minimal promoter region of the dense-core vesicle protein IA-2: transcriptional regulation by CREB SO ACTA DIABETOLOGICA LA English DT Article DE Dense-core vesicle; Insulin; IA-2; Promoter; PKA pathway; CREB-binding site ID DEPENDENT DIABETES-MELLITUS; INSULIN SECRETORY RESPONSES; PANCREATIC BETA-CELLS; TYROSINE-PHOSPHATASE; TRANSMEMBRANE PROTEIN; GENE-EXPRESSION; GLUCOSE; AUTOANTIGEN; SEQUENCE; ISLETS AB IA-2 is a transmembrane protein found in the dense-core vesicles (DCV) of neuroendocrine cells and one of the major autoantigens in type 1 diabetes. DCV are involved in the secretion of hormones (e.g., insulin) and neurotransmitters. Stimulation of pancreatic beta cells with glucose upregulates the expression of IA-2 and an increase in IA-2 results in an increase in the number of DCV. Little is known, however, about the promoter region of IA-2 or the transcriptional factors that regulate the expression of this gene. In the present study, we constructed eight deletion fragments from the upstream region of the IA-2 transcription start site and linked them to a luciferase reporter. By this approach, we have identified a short bp region (-216 to +115) that has strong promoter activity. We also identified a transcription factor, cAMP responsive element-binding protein (CREB), which binds to two CREB-related binding sites located in this region. The binding of CREB to these sites enhanced IA-2 transcription by more than fivefold. We confirmed these findings by site-directed mutagenesis, chromatin immunoprecipitation assays and RNAi inhibition. Based on these findings, we conclude that the PKA pathway is a critical, but not the exclusive signaling pathway involved in IA-2 gene expression. C1 [Cai, Tao; Hirai, Hiroki; Xu, Huanyu; Notkins, Abner L.] NIDCR, Expt Med Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), NIDCR, Expt Med Sect, Lab Sensory Biol, NIH, B30 Rm106, Bethesda, MD 20892 USA. EM tcai@mail.nih.gov; anotkins@mail.nih.gov FU Intramural Research Program of the NIH FX We thank Dr. Raju Gottumukkala for his comments and Charles Wohlenberg for technical help. This research was supported by the Intramural Research Program of the NIH. NR 29 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 0940-5429 EI 1432-5233 J9 ACTA DIABETOL JI Acta Diabetol. PD JUN PY 2015 VL 52 IS 3 BP 573 EP 580 DI 10.1007/s00592-014-0689-5 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CJ1HB UT WOS:000355233500017 PM 25528004 ER PT J AU Scadding, GW Eifan, AO Lao-Araya, M Penagos, M Poon, SY Steveling, E Yan, R Switzer, A Phippard, D Togias, A Shamji, MH Durham, SR AF Scadding, G. W. Eifan, A. O. Lao-Araya, M. Penagos, M. Poon, S. Y. Steveling, E. Yan, R. Switzer, A. Phippard, D. Togias, A. Shamji, M. H. Durham, S. R. TI Effect of grass pollen immunotherapy on clinical and local immune response to nasal allergen challenge SO ALLERGY LA English DT Article DE allergic rhinitis; chemokine; cytokine; Th2; tryptase ID CONTROLLED-TRIAL; LAVAGE FLUID; TIME-COURSE; RHINITIS; SECRETIONS; MEDIATORS; CYTOKINES; CELLS; PROVOCATION; EXPOSURE AB RationaleNasal allergen provocations may be useful in investigating the pathophysiology of allergic rhinitis and effects of treatments. ObjectiveTo use grass pollen nasal allergen challenge (NAC) to investigate the effects of allergen immunotherapy in a cross-sectional study. MethodsWe studied nasal and cutaneous responses in untreated subjects with seasonal grass-pollen allergic rhinitis (n=14) compared with immunotherapy-treated allergics (n=14), plus a nonatopic control group (n=14). Volunteers underwent a standardized NAC with 2000biological units of timothy grass allergen (equivalent to 1.3g major allergen, Phl p5). Nasal fluid was collected and analysed by ImmunoCAP and multiplex assays. Clinical response was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Cutaneous response was measured by intradermal allergen injection. Retrospective seasonal symptom questionnaires were also completed. ResultsImmunotherapy-treated patients had lower symptom scores (P=0.04) and higher PNIF (P=0.02) after challenge than untreated allergics. They had reduced early (P=0.0007) and late (P<0.0001) skin responses, and lower retrospective seasonal symptom scores (P<0.0001). Compared to untreated allergics, immunotherapy-treated patients had reduced nasal fluid concentrations of IL-4, IL-9 and eotaxin (all P<0.05, 8h level and/or area under the curve comparison), and trends for reduced IL-13 (P=0.07, area under the curve) and early-phase tryptase levels (P=0.06). ConclusionsNasal allergen challenge is sensitive in the detection of clinical and biological effects of allergen immunotherapy and may be a useful surrogate marker of treatment efficacy in future studies. C1 [Scadding, G. W.; Eifan, A. O.; Lao-Araya, M.; Penagos, M.; Poon, S. Y.; Steveling, E.; Yan, R.; Switzer, A.; Shamji, M. H.; Durham, S. R.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Allergy & Clin Immunol, London SW7 2AZ, England. [Phippard, D.] Immune Tolerance Network, Bethesda, MD USA. [Togias, A.] NIAID, Bethesda, MD 20892 USA. RP Durham, SR (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Allergy & Clin Immunol, Sir Alexander Fleming Bldg, London SW7 2AZ, England. EM s.durham@imperial.ac.uk OI Eifan, Aarif/0000-0003-4098-4211 FU Imperial College Wellcome Trust Clinical PhD Fellow Programme [097881/Z/11/Z]; ALK-Abello, Denmark; Immune Tolerance Network (NIH) [N01 AI15416]; National Institute of Allergy and Infectious Diseases, USA FX This research was funded by an Imperial College Wellcome Trust Clinical PhD Fellow Programme, awarded to Guy W. Scadding (reference: 097881/Z/11/Z), and by a research grant from ALK-Abello, Denmark. Stephen R. Durham and Mohamed H. Shamji were part-funded by the Immune Tolerance Network (NIH Contract # N01 AI15416), an international clinical research consortium headquartered at the Benaroya Research Institute, Seattle, Washington, and supported by the National Institute of Allergy and Infectious Diseases, USA. NR 30 TC 14 Z9 14 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 EI 1398-9995 J9 ALLERGY JI Allergy PD JUN PY 2015 VL 70 IS 6 BP 689 EP 696 DI 10.1111/all.12608 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA CJ1LR UT WOS:000355245600010 PM 25773990 ER PT J AU Trehan, A Brady, JM Maduro, V Bone, WP Huang, Y Golas, GA Kane, MS Lee, PR Thurm, A Gropman, AL Paul, SM Vezina, G Markello, TC Gahl, WA Boerkoel, CF Tifft, CJ AF Trehan, Aditi Brady, Jacqueline M. Maduro, Valerie Bone, William P. Huang, Yan Golas, Gretchen A. Kane, Megan S. Lee, Paul R. Thurm, Audrey Gropman, Andrea L. Paul, Scott M. Vezina, Gilbert Markello, Thomas C. Gahl, William A. Boerkoel, Cornelius F. Tifft, Cynthia J. TI MED23-associated intellectual disability in a non-consanguineous family SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE intellectual disability (ID); MED23; mediator complex; whole exome sequencing (WES) ID MUTATION; MED12; GENE AB Intellectual disability (ID) is a heterogeneous condition arising from a variety of environmental and genetic factors. Among these causes are defects in transcriptional regulators. Herein, we report on two brothers in a nonconsanguineous family with novel compound heterozygous, disease-segregating mutations (NM_015979.3: [3656A>G];[4006C>T], NP_057063.2: [H1219R];[R1336X]) in MED23. This gene encodes a subunit of the Mediator complex that modulates the expression of RNA polymerase II-dependent genes. These brothers, who had profound ID, spasticity, congenital heart disease, brain abnormalities, and atypical electroencephalography, represent the first case of MED23-associated ID in a non-consanguineous family. They also expand upon the clinical features previously reported for mutations in this gene. (c) 2015 Wiley Periodicals, Inc. C1 [Trehan, Aditi; Brady, Jacqueline M.; Maduro, Valerie; Bone, William P.; Huang, Yan; Golas, Gretchen A.; Gropman, Andrea L.; Gahl, William A.; Tifft, Cynthia J.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Trehan, Aditi; Brady, Jacqueline M.; Maduro, Valerie; Bone, William P.; Huang, Yan; Golas, Gretchen A.; Kane, Megan S.; Markello, Thomas C.; Gahl, William A.; Boerkoel, Cornelius F.; Tifft, Cynthia J.] NIH Off Rare Dis Res, NIH Undiagnosed Dis Program, Bethesda, MD USA. [Trehan, Aditi; Brady, Jacqueline M.; Maduro, Valerie; Bone, William P.; Huang, Yan; Golas, Gretchen A.; Kane, Megan S.; Markello, Thomas C.; Gahl, William A.; Boerkoel, Cornelius F.; Tifft, Cynthia J.] NHGRI, Bethesda, MD 20892 USA. [Lee, Paul R.] NINDS, NIH, Bethesda, MD 20892 USA. [Thurm, Audrey] NIMH, Pediat & Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Gropman, Andrea L.; Vezina, Gilbert] George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Washington, DC 20052 USA. [Paul, Scott M.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Tifft, CJ (reprint author), NHGRI, Off Clin Director, NIH, Bldg 10 CRC3-2551 MSC 1205,10 Ctr Dr, Bethesda, MD 20892 USA. EM cynthiat@mail.nih.gov NR 17 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUN PY 2015 VL 167 IS 6 BP 1374 EP 1380 DI 10.1002/ajmg.a.37047 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA CJ1WV UT WOS:000355276700031 PM 25845469 ER PT J AU Allen-Daniels, MJ Serrano, MG Pflugner, LP Fettweis, JM Prestosa, MA Koparde, VN Brooks, JP Strauss, JF Romero, R Chaiworapongsa, T Eschenbach, DA Buck, GA Jefferson, KK AF Allen-Daniels, Matthew Josiah Serrano, Myrna G. Pflugner, Lindsey P. Fettweis, Jennifer M. Prestosa, Melissa A. Koparde, Vishal N. Brooks, J. Paul Strauss, Jerome F., III Romero, Roberto Chaiworapongsa, Tinnakorn Eschenbach, David A. Buck, Gregory A. Jefferson, Kimberly K. TI Identification of a gene in Mycoplasma hominis associated with preterm birth and microbial burden in intraamniotic infection SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE chorioamnionitis; genital mycoplasmas; genome sequencing; microbial invasion of the amniotic cavity; pathogenicity ID AMNIOTIC-FLUID INFECTION; ABNORMAL VAGINAL FLORA; ADVERSE PREGNANCY OUTCOMES; BACTERIAL VAGINOSIS; UREAPLASMA-UREALYTICUM; PREMATURE LABOR; INTACT MEMBRANES; INTRAUTERINE INFECTION; PERIODONTAL-DISEASE; PRELABOR RUPTURE AB OBJECTIVE: Microbial invasion of the amniotic cavity is associated with spontaneous preterm labor and adverse pregnancy outcome, and Mycoplasma hominis often is present. However, the pathogenic process by which Mycoplasma hominis invades the amniotic cavity and gestational tissues, often resulting in chorioamnionitis and preterm birth, remains unknown. We hypothesized that strains of Mycoplasma hominis vary genetically with regards to their potential to invade and colonize the amniotic cavity and placenta. STUDY DESIGN: We sequenced the entire genomes of 2 amniotic fluid isolates and a placental isolate of Mycoplasma hominis from pregnancies that resulted in preterm births and compared them with the previously sequenced genome of the type strain PG21. We identified genes that were specific to the amniotic fluid/placental isolates. We then determined the microbial burden and the presence of these genes in another set of subjects from whom samples of amniotic fluid had been collected and were positive for Mycoplasma hominis. RESULTS: We identified 2 genes that encode surface-located membrane proteins (Lmp1 and Lmp-like) in the sequenced amniotic fluid/placental isolates that were truncated severely in PG21. We also identified, for the first time, a microbial gene of unknown function that is referred to in this study as gene of interest C that was associated significantly with bacterial burden in amniotic fluid and the risk of preterm delivery in patients with preterm labor. CONCLUSION: A gene in Mycoplasma hominis was identified that is associated significantly with colonization and/or infection of the upper reproductive tract during pregnancy and with preterm birth. C1 [Allen-Daniels, Matthew Josiah; Pflugner, Lindsey P.; Fettweis, Jennifer M.; Prestosa, Melissa A.; Buck, Gregory A.; Jefferson, Kimberly K.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Sch Med, Richmond, VA 23298 USA. [Brooks, J. Paul] Virginia Commonwealth Univ, Sch Med, Dept Stat Sci & Operat Res, Richmond, VA 23298 USA. [Strauss, Jerome F., III] Virginia Commonwealth Univ, Sch Med, Dept Obstet & Gynecol, Richmond, VA 23298 USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Perinatal Res & Obstet, Perinatol Res Branch, NIH, Bethesda, MD USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Eschenbach, David A.] Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. RP Jefferson, KK (reprint author), Virginia Commonwealth Univ, Dept Microbiol & Immunol, Sch Med, Richmond, VA 23298 USA. EM kkjefferson@vcu.edu OI Koparde, Vishal/0000-0001-8978-8495 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Department of Health and Human Services; National Institutes of Health grant "A Multi-'omic Analysis of the Vaginal Microbiome during Pregnancy" [4UH3AI083263, P60 MD002256, U54 DE023786, AI 31871] FX Supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, and National Institutes of Health grant numbers 4UH3AI083263, P60 MD002256, U54 DE023786 "A Multi-'omic Analysis of the Vaginal Microbiome during Pregnancy," and AI 31871. NR 85 TC 2 Z9 2 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2015 VL 212 IS 6 AR 779.e1 DI 10.1016/j.ajog.2015.01.032 PG 13 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CJ1RN UT WOS:000355262000021 PM 25637842 ER PT J AU Grigg, ME Dubey, JP Nussenblatt, RB AF Grigg, Michael E. Dubey, Jitender P. Nussenblatt, Robert B. TI Ocular Toxoplasmosis: Lessons From Brazil SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Editorial Material ID GLOBAL REASSESSMENT; MEMORIAL-LECTURE; SOUTHERN BRAZIL; GONDII; RETINOCHOROIDITIS; INFECTION; DISEASE; RECURRENCES; ANTIGENS; BLOOD C1 [Grigg, Michael E.] NIAID, Parasit Dis Lab, Mol Parasitol Sect, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Dubey, Jitender P.] USDA, Beltsville Agr Res Ctr, Beltsville, MD 20705 USA. RP Grigg, ME (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room B1-06, Bethesda, MD 20892 USA. EM griggm@niaid.nih.gov FU Intramural NIH HHS [ZIA AI001017-09] NR 29 TC 11 Z9 11 U1 1 U2 5 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 JUN PY 2015 VL 159 IS 6 BP 999 EP 1001 DI 10.1016/j.ajo.2015.04.005 PG 3 WC Ophthalmology SC Ophthalmology GA CI9DL UT WOS:000355070500001 PM 25956461 ER PT J AU Castaneto, MS Barnes, AJ Concheiro, M Klette, KL Martin, TA Huestis, MA AF Castaneto, Marisol S. Barnes, Allan J. Concheiro, Marta Klette, Kevin L. Martin, Thomas A. Huestis, Marilyn A. TI Biochip array technology immunoassay performance and quantitative confirmation of designer piperazines for urine workplace drug testing SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Piperazines; BZP; HRMS; Biochip; Novel psychoactive substances ID N-BENZYLPIPERAZINE BZP; SYNTHETIC CANNABINOIDS; ABUSE; 1-BENZYLPIPERAZINE; METABOLISM; TRAZODONE; 1-(3-TRIFLUOROMETHYLPHENYL)-PIPERAZINE; SPECTROMETRY; TFMPP; MS AB Designer piperazines are emerging novel psychoactive substances (NPS) with few high-throughput screening methods for their identification. We evaluated a biochip array technology (BAT) immunoassay for phenylpiperazines (PNP) and benzylpiperazines (BZP) and analyzed 20,017 randomly collected urine workplace specimens. Immunoassay performance at recommended cutoffs was evaluated for PNPI (5 mu g/L), PNPII (7.5 mu g/L), and BZP (5 mu g/L) antibodies. Eight hundred forty positive and 206 randomly selected presumptive negative specimens were confirmed by liquid chromatography high-resolution mass spectrometry (LC-HRMS). Assay limits of detection for PNPI, PNPII, and BZP were 2.9, 6.3, and 2.1 mu g/L, respectively. Calibration curves were linear (R (2) > 0.99) with upper limits of 42 mu g/L for PNPI/PNII and 100 mu g/L for BZP. Quality control samples demonstrated imprecision < 19.3 %CV and accuracies 86.0-94.5 % of target. There were no interferences from 106 non-piperazine substances. Seventy-eight of 840 presumptive positive specimens (9.3 %) were LC-HRMS positive, with 72 positive for 1-(3-chlorophenyl)piperazine (mCPP), a designer piperazine and antidepressant trazodone metabolite. Of 206 presumptive negative specimens, one confirmed positive for mCPP (3.3 mu g/L) and one for BZP (3.6 mu g/L). BAT specificity (21.1 to 91.4 %) and efficiency (27.0 to 91.6 %) increased, and sensitivity slightly decreased (97.5 to 93.8 %) with optimized cutoffs of 25 mu g/L PNPI, 42 mu g/L PNPI, and 100 mu g/L BZP. A high-throughput screening method is needed to identify piperazine NPS. We evaluated performance of the Randox BAT immunoassay to identify urinary piperazines and documented improved performance when antibody cutoffs were raised. In addition, in randomized workplace urine specimens, all but two positive specimens contained mCPP and/or trazodone, most likely from legitimate medical prescriptions. C1 [Castaneto, Marisol S.; Barnes, Allan J.; Concheiro, Marta; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Castaneto, Marisol S.] Univ Maryland, Baltimore Sch Med, Toxicol Program, Baltimore, MD 20742 USA. [Klette, Kevin L.; Martin, Thomas A.] Off Secretary Def Personnel & Readiness, Drug Testing & Program Policy, Personnel Risk Reduct, Washington, DC USA. [Concheiro, Marta] CUNY John Jay Coll Criminal Justice, Dept Sci, New York, NY 10019 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU DOD Counter Narcotics Program [Y3-DA-1116-01]; Intramural Research Program of the National Institute on Drug Abuse, NIH; Forensic Toxicology Drug Testing Laboratory, Fort Meade, MD; Chemistry and Drug Metabolism FX An Interagency Agreement (Y3-DA-1116-01) between DOD Counter Narcotics Program and Intramural Research Program of the National Institute on Drug Abuse, NIH helped fund this research. Assistance and support of the Forensic Toxicology Drug Testing Laboratory, Fort Meade, MD and Chemistry and Drug Metabolism staff in the conduct of this study are greatly appreciated. NR 25 TC 4 Z9 4 U1 1 U2 9 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 JUN PY 2015 VL 407 IS 16 BP 4639 EP 4648 DI 10.1007/s00216-015-8660-z PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CJ0FZ UT WOS:000355152500013 PM 25903022 ER PT J AU Flores, KF Robledo, CA Hwang, BS Leishear, K Grantz, KL Mendola, P AF Flores, Katrina F. Robledo, Candace A. Hwang, Beom Seuk Leishear, Kira Grantz, Katherine Laughon Mendola, Pauline TI Does maternal asthma contribute to racial/ethnic disparities in obstetrical and neonatal complications? SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Asthma; Pregnancy; Infant; Ethnic groups; Health disparities ID BLACK WOMENS HEALTH; PERINATAL OUTCOMES; PRETERM BIRTH; RACIAL-DISCRIMINATION; DEPRESSIVE SYMPTOMS; ETHNIC DISPARITIES; AFRICAN-AMERICAN; INFANT-MORTALITY; PREGNANT-WOMEN; UNITED-STATES AB Purpose: To examine whether maternal asthma contributes to racial/ethnic differences in obstetrical and neonatal complications. Methods: Data on white (n = 110,603), black (n = 50,284), and Hispanic (n = 38,831) singleton deliveries came from the Consortium on Safe Labor. Multilevel logistic regression models, with an interaction term for asthma and race/ethnicity, estimated Within-group adjusted odds ratios (aORs) for gestational diabetes, gestational hypertension, pre-eclampsia, placental abruption, premature rupture of membranes, preterm delivery, maternal hemorrhage, neonatal intensive care unit admissions, small for gestational age, apnea, respiratory distress syndrome, transient tachypnea of the newborn, anemia, and hyperbilirubinemia after adjustment for clinical and demographic confounders. Nonasthmatics of the same racial/ethnic group were the reference group. Results: Compared with nonasthmatics, white asthmatics had increased odds of pre-eclampsia (aOR, 1.28; 95% confidence interval [CI], 1.15-1.43) and maternal hemorrhage (aOR, 1.14; 95% Cl, 1.04-1.23). White and Hispanic infants were more likely to have neonatal intensive care unit admissions (aOR, 1.19; 95% Cl, 1.11-1.28; aOR, 1.16; 95% Cl, 1.02-1.32, respectively) and be small for gestational age (aOR, 1.11; 95% Cl, 1.02-1.20; aOR, 1.26; 95% Cl, 1.10-1.44, respectively), and Hispanic infants were more likely to have apnea (aOR, 1.32; 95% Cl, 1.02-1.69). Conclusions: Maternal asthma did not affect most obstetrical and neonatal complication risks within racial/ethnic groups. Despite their increased risk for both asthma and many complications, our findings for black women were null. Asthma did not contribute to racial/ethnic disparities in complications. Published by Elsevier Inc. C1 [Flores, Katrina F.; Robledo, Candace A.; Grantz, Katherine Laughon; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Hwang, Beom Seuk] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Leishear, Kira] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Off Pharmacovigilance & Epidemiol,Ctr Drug Evalua, Silver Spring, MD USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B03F, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Intramural Research Program of the NIH, NICHD [HHSN267200603425C] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The data included in this article were obtained from the Consortium on Safe Labor, supported by the Intramural Research Program of the NIH, NICHD, through contract number HHSN267200603425C. NR 41 TC 0 Z9 0 U1 1 U2 7 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 JUN PY 2015 VL 25 IS 6 BP 392 EP 397 DI 10.1016/j.annepidem.2015.01.011 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI8KM UT WOS:000355021200002 PM 25724829 ER PT J AU Hughes, JP Haley, DF Frew, PM Golin, CE Adimora, AA Kuo, I Justman, J Soto-Torres, L Wang, J Hodder, S AF Hughes, James P. Haley, Danielle F. Frew, Paula M. Golin, Carol E. Adimora, Adaora A. Kuo, Irene Justman, Jessica Soto-Torres, Lydia Wang, Jing Hodder, Sally TI Regression to the mean and changes in risk behavior following study enrollment in a cohort of US women at risk for HIV SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE HIV; Risk behavior; Statistical model; Logistic regression ID ACQUISITION; TRIAL AB Purpose: Reductions in risk behaviors are common following enrollment in human immunodeficiency virus (HIV) prevention studies. We develop methods to quantify the proportion of change in risk behaviors that can be attributed to regression to the mean versus study participation and other factors. Methods: A novel model that incorporates both regression to the mean and study participation effects is developed for binary measures. The model is used to estimate the proportion of change in the prevalence of "unprotected sex in the past 6 months" that can be attributed to study participation versus regression to the mean in a longitudinal cohort of women at risk for HIV infection who were recruited from ten U.S. communities with high rates of HIV and poverty. HIV risk behaviors were evaluated using audio computer-assisted self-interviews at baseline and every 6 months for up to 12 months. Results: The prevalence of "unprotected sex in the past 6 months" declined from 96% at baseline to 77% at 12 months. However, this change could be almost completely explained by regression to the mean. Conclusions: Analyses that examine changes over time in cohorts selected for high- or low- risk behaviors should account for regression to the mean effects. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hughes, James P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Hughes, James P.; Wang, Jing] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Haley, Danielle F.; Frew, Paula M.] Emory Univ, Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. [Haley, Danielle F.] Family Hlth Int FHI360, Durham, NC USA. [Frew, Paula M.] Emory Univ, Sch Med, Div Infect Dis, Dept Med, Atlanta, GA 30322 USA. [Golin, Carol E.; Adimora, Adaora A.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Golin, Carol E.; Adimora, Adaora A.] Univ N Carolina, Gillings Sch Publ Hlth, Chapel Hill, NC USA. [Kuo, Irene] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. [Justman, Jessica] Columbia Univ, ICAP Columbia, Dept Epidemiol, New York, NY USA. [Justman, Jessica] Columbia Univ, ICAP Columbia, Dept Med, New York, NY USA. [Soto-Torres, Lydia] NIAID, Bethesda, MD 20892 USA. [Hodder, Sally] W Virginia Univ, Clin & Translat Sci Inst, Morgantown, WV 26506 USA. RP Hughes, JP (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM jphughes@uw.edu FU National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; National Institute of Mental Health [UM1 AI068617] FX This study was sponsored by the National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse and National Institute of Mental Health under cooperative agreement UM1 AI068617. NR 15 TC 1 Z9 1 U1 0 U2 4 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 JUN PY 2015 VL 25 IS 6 BP 439 EP 444 DI 10.1016/j.annepidem.2015.03.013 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI8KM UT WOS:000355021200009 PM 25883065 ER PT J AU Brownson, RC Samet, JM Chavez, GF Davies, MM Galea, S Hiatt, RA Hornung, CA Khoury, MJ Koo, D Mays, VM Remington, P Yarber, L AF Brownson, Ross C. Samet, Jonathan M. Chavez, Gilbert F. Davies, Megan M. Galea, Sandro Hiatt, Robert A. Hornung, Carlton A. Khoury, Muin J. Koo, Denise Mays, Vickie M. Remington, Patrick Yarber, Laura TI Charting a future for epidemiologic training SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Epidemiology; Genomics; Globalization; Medicine; Public health; Translational research ID PUBLIC-HEALTH; TRANSLATIONAL RESEARCH; CANCER-EPIDEMIOLOGY; POPULATION HEALTH; BIG DATA; 21ST-CENTURY; OPPORTUNITIES; COMPETENCES; SCIENCE; GLOBALIZATION AB Purpose: To identify macro-level trends that are changing the needs of epidemiologic research and practice and to develop and disseminate a set of competencies and recommendations for epidemiologic training that will be responsive to these changing needs. Methods: There were three stages to the project: (1) assembling of a working group of senior epidemiologists from multiple sectors, (2) identifying relevant literature, and (3) conducting key informant interviews with 15 experienced epidemiologists. Results: Twelve macro trends were identified along with associated actions for the field and educational competencies. The macro trends include the following: (1) "Big Data" or informatics, (2) the changing health communication environment, (3) the Affordable Care Act or health care system reform, (4) shifting demographics, (5) globalization, (6) emerging high-throughput technologies (omics), (7) a greater focus on accountability, (8) privacy changes, (9) a greater focus on "upstream" causes of disease, (10) the emergence of translational sciences, (11) the growing centrality of team and transdisciplinary science, and (12) the evolving funding environment. Conclusions: Addressing these issues through curricular change is needed to allow the field of epidemiology to more fully reach and sustain its full potential to benefit population health and remain a scientific discipline that makes critical contributions toward ensuring clinical, social, and population health. (C) 2015 Elsevier Inc. All rights reserved. C1 [Brownson, Ross C.] Washington Univ, Brown Sch, Prevent Res Ctr St Louis, St Louis, MO 63130 USA. [Brownson, Ross C.] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO 63130 USA. [Brownson, Ross C.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63130 USA. [Samet, Jonathan M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Chavez, Gilbert F.] Calif Dept Publ Hlth, Ctr Infect Dis, Sacramento, CA USA. [Davies, Megan M.] North Carolina Dept Hlth & Human Serv, Div Publ Hlth, Raleigh, NC USA. [Davies, Megan M.] Council State & Terr Epidemiologists, Atlanta, GA USA. [Galea, Sandro] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Hiatt, Robert A.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Hornung, Carlton A.] Univ Louisville, Sch Med, Dept Med, Louisville, KY 40292 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Koo, Denise] Ctr Dis Control & Prevent, Off Publ Hlth Sci Serv, Atlanta, GA USA. [Mays, Vickie M.] Univ Calif Los Angeles, Dept Psychol, Fielding Sch Publ Hlth, Los Angeles, CA 90024 USA. [Mays, Vickie M.] Univ Calif Los Angeles, BRITE Ctr Sci Res & Policy, Los Angeles, CA USA. [Mays, Vickie M.] Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Remington, Patrick] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53706 USA. [Yarber, Laura] St Louis Univ, Coll Publ Hlth & Social Justice, Prevent Res Ctr St Louis, St Louis, MO 63103 USA. RP Brownson, RC (reprint author), Washington Univ, Brown Sch, Prevent Res Ctr St Louis, 621 N Skinker Blvd, St Louis, MO 63130 USA. EM rbrownson@wustl.edu FU Intramural CDC HHS [CC999999]; NCCDPHP CDC HHS [U48 DP000060]; NCI NIH HHS [P50 CA095815]; NIDDK NIH HHS [P30 DK092950]; NIMHD NIH HHS [P60 MD006923] NR 58 TC 6 Z9 6 U1 1 U2 13 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 JUN PY 2015 VL 25 IS 6 BP 458 EP 465 DI 10.1016/j.annepidem.2015.03.002 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI8KM UT WOS:000355021200012 PM 25976024 ER PT J AU Ward, MM Guthrie, LC Alba, MI AF Ward, Michael M. Guthrie, Lori C. Alba, Maria I. TI Measures of Arthritis Activity Associated With Patient-Reported Improvement in Rheumatoid Arthritis When Assessed Prospectively Versus Retrospectively SO ARTHRITIS CARE & RESEARCH LA English DT Article ID PATIENTS GLOBAL ASSESSMENT; DISEASE-ACTIVITY; GENERAL HEALTH; ASSESSMENTS; PHYSICIAN; INSTRUMENTS AB ObjectiveThe patient global assessment (PGA) is intended to provide an integrated summary of all symptoms of arthritis, but it is not clear which disease features most impact patients' assessments of changes in their overall status. We investigated what aspects of rheumatoid arthritis (RA) activity correlated best with prospectively measured changes in the PGA and with patients' retrospective judgments of improvement. MethodsWe studied 250 patients with active RA in a prospective longitudinal study. Disease activity measures were collected before and after treatment escalation. Prospectively measured changes in PGA and patients' judgments of improvement or worsening at the followup visit were tested for correlations with changes in patient-reported measures of symptoms and functioning, joint counts, and laboratory tests. ResultsPatients improved during the study, with the meanSD PGA decreasing from 55.6 +/- 25.2 to 37.6 +/- 24.0. At the followup visit, 167 patients (66.8%) reported improvement in overall arthritis status. Changes in pain severity, stiffness severity, and fatigue were the only significant correlates of changes in PGA. In contrast, changes in the Health Assessment Questionnaire, tender joint count or Disease Activity Score in 28 joints (DAS28), and stiffness severity were associated with retrospective judgments of improvement. ConclusionProspectively measured changes in PGA in RA were related solely to other patient-reported measures, but patients' retrospective judgments of improvement were related to functional limitations, tender joint count, and DAS28. Patients' subjective judgments of improvement reflect aspects of RA different from the PGA and may be a simple complementary measure of treatment efficacy. C1 [Ward, Michael M.; Guthrie, Lori C.; Alba, Maria I.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMS, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH FX Supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 16 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JUN PY 2015 VL 67 IS 6 BP 776 EP 781 DI 10.1002/acr.22509 PG 6 WC Rheumatology SC Rheumatology GA CJ2QQ UT WOS:000355330000005 PM 25370806 ER PT J AU Miloslavsky, EM Specks, U Merkel, PA Seo, P Spiera, R Langford, CA Hoffman, GS Kallenberg, CGM St Clair, EW Tchao, NK Ding, L Ikle, D Villareal, M Lim, N Brunetta, P Fervenza, FC Monach, PA Stone, JH AF Miloslavsky, E. M. Specks, U. Merkel, P. A. Seo, P. Spiera, R. Langford, C. A. Hoffman, G. S. Kallenberg, C. G. M. St Clair, E. W. Tchao, N. K. Ding, L. Ikle, D. Villareal, M. Lim, N. Brunetta, P. Fervenza, F. C. Monach, P. A. Stone, J. H. CA Rituximab Anca-Associated Vasculit TI Outcomes of Nonsevere Relapses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Treated With Glucocorticoids SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID ANCA-ASSOCIATED VASCULITIS; DAILY ORAL CYCLOPHOSPHAMIDE; WEGENERS-GRANULOMATOSIS; RANDOMIZED-TRIAL; MAINTENANCE THERAPY; REMISSION; METHOTREXATE; INDUCTION; RITUXIMAB; AZATHIOPRINE AB Objective. Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. Methods. RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. Results. Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P<0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P<0.01). Conclusion. Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients. C1 [Miloslavsky, E. M.; Stone, J. H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Specks, U.; Fervenza, F. C.] Mayo Clin, Rochester, MN USA. [Merkel, P. A.] Univ Penn, Philadelphia, PA 19104 USA. [Seo, P.] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, R.] Hosp Special Surg, New York, NY 10021 USA. [Langford, C. A.; Hoffman, G. S.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Kallenberg, C. G. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [St Clair, E. W.] Duke Univ, Med Ctr, Durham, NC USA. [Tchao, N. K.] Immune Tolerance Network, San Francisco, CA USA. [Ding, L.] NIAID, NIH, Bethesda, MD 20892 USA. [Ikle, D.; Villareal, M.] Rho, Chapel Hill, NC USA. [Lim, N.] Immune Tolerance Network, Bethesda, MD USA. [Brunetta, P.] Genentech Inc, San Francisco, CA 94080 USA. [Monach, P. A.] Boston Univ, Boston, MA 02215 USA. [Monach, P. A.] Boston Med Ctr, Boston, MA USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, Yawkey 2C,55 Fruit St, Boston, MA 02114 USA. EM jhstone@partners.org FU Immune Tolerance Network (NIH) [N01-AI-15416, ITN021AI]; National Institute of Allergy and Infectious Diseases, NIH; Juvenile Diabetes Research Foundation; Genentech; Biogen Idec; NIH (Mayo Clinic: National Center for Research Resources Clinical and Translational Science award) [1-UL1-RR-024150-01]; NIH (Johns Hopkins University: National Center for Research Resources Clinical and Translational Science) [UL1-RR-025005, K23-AR-052820, K24-AR-049185]; NIH (Boston University: National Center for Research Resources Clinical and Translational Science) [UL1-RR-025771, M01-RR-00533, K24-AR-02224]; NIH (Cleveland Clinic: National Center for Advancing Translational Sciences) [UL1-TR-000439]; Arthritis Foundation; ChemoCentryx; GlaxoSmithKline; Eli Lilly; MedImmune FX The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was performed with the support of the Immune Tolerance Network (NIH contract N01-AI-15416, protocol number ITN021AI), an international clinical research consortium headquartered at the University of California San Francisco and supported by the National Institute of Allergy and Infectious Diseases, NIH, and the Juvenile Diabetes Research Foundation. Genentech and Biogen Idec provided the study medication and partial funding for the RAVE trial. At the Mayo Clinic, Johns Hopkins University, Boston University, and the Cleveland Clinic, the RAVE trial was supported by the NIH (Mayo Clinic: National Center for Research Resources Clinical and Translational Science award 1-UL1-RR-024150-01; Johns Hopkins University: National Center for Research Resources Clinical and Translational Science award UL1-RR-025005 and career development awards K23-AR-052820 to Dr. Seo and K24-AR-049185 to Dr. Stone; Boston University: National Center for Research Resources Clinical and Translational Science award UL1-RR-025771, grant M01-RR-00533, and career development award K24-AR-02224 to Dr. Merkel; Cleveland Clinic: National Center for Advancing Translational Sciences grant UL1-TR-000439). The RAVE trial at Boston University was also supported by the Arthritis Foundation (Investigator Award to Dr. Monach).; Dr. Miloslavsky has received consulting fees, speaking fees, and/or honoraria (less than $10,000) and research funding from Genentech. Dr. Specks has received consulting fees, speaking fees, and/or honoraria from Genentech (less than $10,000). Dr. Kallenberg has received consulting fees from ChemoCentryx, GlaxoSmithKline, Eli Lilly, and MedImmune (less than $10,000 each). Dr. Brunetta owns stock or stock options in Genentech. Dr. Monach has received consulting fees, speaking fees, and/or honoraria (less than $10,000) from Genentech. Dr. Stone has received consulting fees, speaking fees, and/or honoraria from Genentech (less than $10,000). NR 27 TC 11 Z9 11 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JUN PY 2015 VL 67 IS 6 BP 1629 EP 1636 DI 10.1002/art.39104 PG 8 WC Rheumatology SC Rheumatology GA CJ2QA UT WOS:000355328400026 PM 25776953 ER PT J AU Kupfer, D Cuthbert, B AF Kupfer, D. Cuthbert, B. TI The future of diagnosis in the bipolar spectrum SO BIPOLAR DISORDERS LA English DT Meeting Abstract C1 [Kupfer, D.] Univ Pittsburgh, Sch Med, Psychiat, Pittsburgh, PA USA. [Cuthbert, B.] NIMH, RDoC Unit, 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 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2015 VL 17 SU 1 SI SI BP 8 EP 8 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CJ2TS UT WOS:000355338100004 ER PT J AU Merikangas, K Cui, L Lameira, D Zipunnikov, V Lamers, F Swendsen, J AF Merikangas, K. Cui, L. Lameira, D. Zipunnikov, V. Lamers, F. Swendsen, J. TI Targets for intervention in mood disorders: evidence from objective measures of activity, mood, energy and sleep SO BIPOLAR DISORDERS LA English DT Meeting Abstract C1 [Merikangas, K.; Cui, L.; Lameira, D.] NIMH, Bethesda, MD 20892 USA. [Zipunnikov, V.] Johns Hopkins Univ, Sch Hlth, Baltimore, MD 21218 USA. [Lamers, F.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Swendsen, J.] Univ Bordeaux, Bordeaux, France. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2015 VL 17 SU 1 SI SI BP 34 EP 34 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CJ2TS UT WOS:000355338100083 ER PT J AU Preisig, M Vandeleur, CL Strippoli, MPF Castelao, E Gholam-Rezaee, M Merikangas, KR Marquet, P Aubry, JM AF Preisig, M. Vandeleur, C. L. Strippoli, M. P. F. Castelao, E. Gholam-Rezaee, M. Merikangas, K. R. Marquet, P. Aubry, J. M. TI The specificity of mania and early age of onset in high risk youth: a 10 year prospective study SO BIPOLAR DISORDERS LA English DT Meeting Abstract C1 [Preisig, M.; Vandeleur, C. L.; Strippoli, M. P. F.; Castelao, E.; Gholam-Rezaee, M.; Marquet, P.] Univ Lausanne Hosp, Dept Psychiat, Lausanne, Switzerland. [Merikangas, K. R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Aubry, J. M.] Univ Hosp Geneva, Dept Mental Hlth & Psychiat, Geneva, Switzerland. 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 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2015 VL 17 SU 1 SI SI BP 34 EP 34 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CJ2TS UT WOS:000355338100084 ER PT J AU Miller, S Suppes, T Mintz, J Hellemann, G Frye, M McElroy, S Nolen, W Kupka, R Leverich, G Grunze, H Altshuler, L Keck, P Post, R AF Miller, S. Suppes, T. Mintz, J. Hellemann, G. Frye, M. McElroy, S. Nolen, W. Kupka, R. Leverich, G. Grunze, H. Altshuler, L. Keck, P. Post, R. TI Mixed depression in bipolar disorder: prevalence rate and clinical correlates during naturalistic follow up SO BIPOLAR DISORDERS LA English DT Meeting Abstract C1 [Miller, S.; Suppes, T.] VA Palo Alto Hlth Care Syst, Stanford, CA USA. [Miller, S.; Suppes, T.] Stanford Univ, Med Ctr, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Mintz, J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Hellemann, G.; Altshuler, L.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Frye, M.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [McElroy, S.; Keck, P.] Lindner Ctr HOPE, Cincinnati, OH USA. [Nolen, W.] Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Kupka, R.] Altrecht Inst Mental Hlth Care, Altrecht, Netherlands. [Kupka, R.] Univ Med Ctr, Altrecht, Netherlands. [Leverich, G.] NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Grunze, H.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Post, R.] George Washington Sch Med, Washington, DC USA. RI Mintz, Jim/N-7385-2014 OI Mintz, Jim/0000-0002-8299-5851 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 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2015 VL 17 SU 1 SI SI BP 35 EP 35 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CJ2TS UT WOS:000355338100086 ER PT J AU Lederman, RJ O'Neill, WW Greenbaum, AB AF Lederman, Robert J. O'Neill, William W. Greenbaum, Adam B. TI Transcaval access for TAVR across a polyester aortic graft SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE structural heart disease; transcatheter aortic valve implantation; caval-aortic fenestrated graft; vascular access and closure; extra-anatomic procedures ID IN-SITU FENESTRATION; REPLACEMENT; DURABILITY; PUNCTURE AB Transcaval access to the aorta allows transcatheter aortic valve replacement in patients without other good access options. The resulting aorto-caval fistula is closed with a nitinol cardiac occluder device. There is no experience traversing a synthetic aortic graft to perform transcaval access and closure. We describe a patient who underwent successful traversal of a polyester aortic graft using radiofrequency energy applied from the tip of a guidewire, to allow retrograde transcatheter aortic valve replacement from a femoral vein, along with details of our technique. The patient did well and was discharged home after 3 days. There was residual aorto-caval fistulous flow immediately after implantation of a polyester-seeded nitinol muscular ventricular septal defect occluder device, but this fistula spontaneously occluded within one month. (c) 2015 Wiley Periodicals, Inc. C1 [Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [O'Neill, William W.; Greenbaum, Adam B.] Inst Struct Heart Dis, Div Cardiol, Henry Ford Hlth Syst, Detroit, MI USA. RP Lederman, RJ (reprint author), NHLBI, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. EM lederman@nih.gov OI lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health [Z01-HL006040]; Institute for Structural Heart Disease, Division of Cardiology, Henry Ford Health System FX Supported by the Division of Intramural Research (Z01-HL006040), National Heart Lung and Blood Institute, National Institutes of Health (RJL), and the Institute for Structural Heart Disease, Division of Cardiology, Henry Ford Health System (ABG, WWO). Drs. Lederman and Greenbaum are inventors on patent applications for devices for caval-aortic access that have been assigned to their employers, NIH and Henry Ford Hospital, respectively. NR 9 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUN PY 2015 VL 85 IS 7 BP 1270 EP 1273 DI 10.1002/ccd.25781 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CI8DU UT WOS:000355000100034 PM 25510917 ER PT J AU Sacks, DB Kricka, LJ AF Sacks, David B. Kricka, Larry J. TI Plasmonic Chip Tackles Type 1 Diabetes Diagnosis SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Kricka, Larry J.] Univ Penn, Dept Pathol & Lab Med, Med Ctr, Philadelphia, PA USA. RP Kricka, LJ (reprint author), Hosp Univ Penn, Dept Pathol & Lab Med, 3400 Spruce St, Philadelphia, PA 19104 USA. EM kricka@mail.med.upenn.edu OI Sacks, David/0000-0003-3100-0735 FU Intramural NIH HHS NR 5 TC 0 Z9 0 U1 0 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 JUN PY 2015 VL 61 IS 6 BP 794 EP 796 DI 10.1373/clinchem.2014.233346 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CJ1SW UT WOS:000355265800003 PM 25655270 ER PT J AU Hartman, RL Brown, TL Milavetz, G Spurgin, A Gorelick, DA Gaffney, G Huestis, MA AF Hartman, Rebecca L. Brown, Timothy L. Milavetz, Gary Spurgin, Andrew Gorelick, David A. Gaffney, Gary Huestis, Marilyn A. TI Controlled Cannabis Vaporizer Administration: Blood and Plasma Cannabinoids with and without Alcohol SO CLINICAL CHEMISTRY LA English DT Article ID CONTROLLED SMOKED CANNABIS; WHOLE-BLOOD; DELTA(9)-TETRAHYDROCANNABINOL THC; MARIJUANA SMOKING; HUMAN VOLUNTEERS; HEAVY; USERS; PHARMACOKINETICS; PERFORMANCE; ETHANOL AB BACKGROUND: Increased medical and legal cannabis intake is accompanied by greater use of cannabis vaporization and more cases of driving under the influence of cannabis. Although simultaneous Delta(9)-tetrahydrocannabinol (THC) and alcohol use is frequent, potential pharmacokinetic interactions are poorly understood. Here we studied blood and plasma vaporized cannabinoid disposition, with and without simultaneous oral low-dose alcohol. METHODS: Thirty-two adult cannabis smokers (>= 1 time/3 months, <= 3 days/week) drank placebo or lowdose alcohol (target approximately 0.065% peak breath-alcohol concentration) 10 min before inhaling 500 mg placebo, low-dose (2.9%) THC, or high-dose (6.7%) THC vaporized cannabis (6 within-individual alcoholcannabis combinations). Blood and plasma were obtained before and up to 8.3 h after ingestion. RESULTS: Nineteen participants completed all sessions. Median (range) maximum blood concentrations (C-max) for low and high THC doses (no alcohol) were 32.7 (11.4-66.2) and 42.2 (15.2-137) mu g/L THC, respectively, and 2.8 (0-9.1) and 5.0 (0-14.2) mu g/L 11-OHTHC. With alcohol, low and high dose Cmax values were 35.3 (13.0-71.4) and 67.5 (18.1-210) mu g/L THC and 3.7 (1.4-6.0) and 6.0 (0 -23.3) mu g/L 11-OH-THC, significantly higher than without alcohol. With a THC detection cutoff of >= 1 mu g/L, >= 16.7% of participants remained positive 8.3 h postdose, whereas <= 21.1% were positive by 2.3 h with a cutoff of >= 5 mu g/L. CONCLUSIONS: Vaporization is an effective THC delivery route. The significantly higher blood THC and 11-OHTHC Cmax values with alcohol possibly explain increased performance impairment observed from cannabisalcohol combinations. Chosen driving-related THC cutoffs should be considered carefully to best reflect performance impairment windows. Our results will help facilitate forensic interpretation and inform the debate on drugged driving legislation. (C) 2015 American Association for Clinical Chemistry C1 [Hartman, Rebecca L.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD USA. [Hartman, Rebecca L.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Brown, Timothy L.] Univ Iowa, Natl Adv Driving Simulator, Iowa City, IA USA. [Milavetz, Gary; Spurgin, Andrew] Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA. [Gaffney, Gary] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Gorelick, David A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), Biomed Res Ctr, Suite 200,Rm 05A-721,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU NIDA; US Office of National Drug Control Policy; National Highway Traffic Safety Administration; NIH FX R.L. Hartman, D.A. Gorelick, and M.A. Huestis, Intramural Research Program, NIDA, NIH and interagency agreements between NIDA and the US Office of National Drug Control Policy and the National Highway Traffic Safety Administration; materials transfer agreements between NIDA and Storz & Bickel, who provided Volcano vaporizer devices/equipment for this study. T.L. Brown, G. Milavetz, A. Spurgin, and G. Gaffney, contract between National Highway Traffic Safety Administration and the University of Iowa. NR 40 TC 12 Z9 12 U1 1 U2 15 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 JUN PY 2015 VL 61 IS 6 BP 850 EP 869 DI 10.1373/clinchem.2015.238287 PG 20 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CJ1SW UT WOS:000355265800012 PM 26019183 ER PT J AU Berg, AH Powe, CE Evans, MK Wenger, J Ortiz, G Zonderman, AB Suntharalingam, P Lucchesi, K Powe, NR Karumanchi, SA Thadhani, RI AF Berg, Anders H. Powe, Camille E. Evans, Michele K. Wenger, Julia Ortiz, Guillermo Zonderman, Alan B. Suntharalingam, Pirianthini Lucchesi, Kathryn Powe, Neil R. Karumanchi, S. Ananth Thadhani, Ravi I. TI 24,25-Dihydroxyvitamin D-3 and Vitamin D Status of Community-Dwelling Black and White Americans SO CLINICAL CHEMISTRY LA English DT Article ID BONE-MINERAL DENSITY; D-BINDING PROTEIN; CHRONIC KIDNEY-DISEASE; 25-HYDROXYVITAMIN D; D SUPPLEMENTATION; D DEFICIENCY; SERUM 25-HYDROXYVITAMIN-D; HIP-FRACTURES; ELDERLY-WOMEN; RISK AB BACKGROUND: 24,25-Dihydroxyvitamin D[24,25(OH)(2)D] is a metabolite of 25-hydroxyvitamin D (25D). Blacks frequently have low total 25D without manifestations of vitamin D deficiency, suggesting that total serum 25D may incorrectly reflect vitamin Dstatus in different racial groups. The ratio of serum 24,25(OH)(2)D to 25D [vitamin D metabolite ratio (VMR)] represents a new candidate biomarker for vitamin D status. METHODS: We measured 24,25(OH)(2)D-3 and 25D(3) by mass spectrometry in a random community cohort of black (n = 212) and white (n = 164) Americans to evaluate VMR as a marker for vitamin D status. We measured parathyroid hormone concentrations by immunoassay to compare VMR and 25D(3) against a physiological indicator of vitamin D deficiency. RESULTS: Serum 24,25(OH)(2)D-3 strongly correlated with 25D3 in both black and white study participants (r = 0.90, P < 0.001 and r = 0.86, P < 0.001 respectively). Blacks had lower mean 25D3 than whites [17.0 (7.8) vs 27.5 (11.3) ng/mL; 42.4 (19.5) vs 68.6 (28.2) nmol/L, P < 0.001] and lower mean 24,25(OH)(2)D-3 [2.1 (1.3) vs 3.6 (2.0) ng/mL; 5.1 (3.1) vs 8.7 (4.8) nmol/L, P < 0.001]. In contrast to total 25D(3) concentrations, mean VMR values were similar in blacks and whites [11.9 (4.0) vs 12.5 (3.4), P = 0.16, respectively] and were negatively correlated with parathyroid hormone concentrations in both races (r(s) = -0.26, P = 0.001, and r(s) = -0.25, P < 0.001, respectively). CONCLUSIONS: Our results provide further evidence that measurement of total 25D for assessment of vitamin D status in patients of African descent deserves reevaluation and suggest that alternative measures such as VMR should be considered. (C) 2015 American Association for Clinical Chemistry C1 [Berg, Anders H.; Suntharalingam, Pirianthini] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Berg, Anders H.; Suntharalingam, Pirianthini] Harvard Univ, Sch Med, Boston, MA USA. [Powe, Camille E.] Massachusetts Gen Hosp, Div Endocrinol, Boston, MA 02215 USA. [Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Wenger, Julia; Ortiz, Guillermo; Lucchesi, Kathryn; Thadhani, Ravi I.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02215 USA. [Powe, Neil R.] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Powe, Neil R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02115 USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Berg, AH (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave YA309, Boston, MA 02115 USA. EM ahberg@bidmc.harvard.edu; rthadhani@mgh.harvard.edu FU National Institute on Aging Intramural Research Program at NIH [ZIA AG000513]; National Institutes of Health [K08 HL121801, K24 DK094872, R01 DK094486]; Howard Hughes Medical Institute FX National Institute on Aging Intramural Research Program at NIH, project #ZIA AG000513; A.H. Berg, K08 HL121801 from the National Institutes of Health; A. Karumanchi, Howard Hughes Medical Institute; R.I. Thadhani, K24 DK094872 and R01 DK094486 from the National Institutes of Health. Expert Testimony: None declared. NR 37 TC 15 Z9 16 U1 0 U2 2 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 JUN PY 2015 VL 61 IS 6 BP 877 EP 884 DI 10.1373/clinchem.2015.240051 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CJ1SW UT WOS:000355265800014 PM 25922442 ER PT J AU Panlilio, LV Goldberg, SR Justinova, Z AF Panlilio, L. V. Goldberg, S. R. Justinova, Z. TI Cannabinoid Abuse and Addiction: Clinical and Preclinical Findings SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID SUBSTANCE USE DISORDERS; SQUIRREL-MONKEYS; SYNTHETIC CANNABINOIDS; DELTA(9)-TETRAHYDROCANNABINOL THC; MARIJUANA WITHDRAWAL; REINFORCING EFFICACY; SEEKING BEHAVIOR; RECEPTOR AGONIST; CONTROLLED-TRIAL; ADENOSINE A(2A) AB Cannabinoid abuse disorders represent a widespread public health issue, but there are no approved medications for their treatment. This review describes efforts to understand the mechanisms of cannabinoid abuse and its adverse effects, to identify molecular targets for pharmacotherapy, and to evaluate potential treatments in human volunteers and animal models of cannabinoid reward, withdrawal, and relapse. C1 [Panlilio, L. V.; Goldberg, S. R.; Justinova, Z.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Justinova, Z (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. EM zjustino@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, the Department of Health and Human Services FX We dedicate this article to the memory of Steven R. Goldberg (1941-2014), whose passion for cannabinoid research was an inspiration to us. Preparation of this manuscript was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, the Department of Health and Human Services. NR 75 TC 9 Z9 10 U1 2 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUN PY 2015 VL 97 IS 6 BP 616 EP 627 DI 10.1002/cpt.118 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI9ZU UT WOS:000355131400019 PM 25788435 ER PT J AU Hymel, R Jones, GC Simone, CB AF Hymel, Rockne Jones, Guy C. Simone, Charles B., II TI Whole pelvic intensity-modulated radiotherapy for gynecological malignancies: A review of the literature SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE IMRT; Radiation therapy; Endometrial; Cervical; Gynecologic ID LOCALIZED PROSTATE-CANCER; RADIATION-THERAPY; CERVICAL-CANCER; UTERINE CERVIX; ENDOMETRIAL CANCER; ADJUVANT TREATMENT; ONCOLOGY-GROUP; ORGAN MOTION; BONE-MARROW; CARCINOMA AB Radiation therapy has long played a major role in the treatment of gynecological malignancies. There is increasing interest in the utility of intensity-modulated radiotherapy (IMRT) and its application to treat gynecological malignancies. Herein, we review the state-of-the-art use of IMRT for gynecological malignancies and report how it is being used alone as well as in combination with chemotherapy in both the adjuvant and definitive settings. Based on dosimetric and clinical evidence, IMRT can reduce gastrointestinal, genitourinary, and hematological toxicities compared with 3D-conformal radiotherapy for gynecologic malignancies. We discuss how these attributes of IMRT may lead to improvements in disease outcomes by allowing for dose escalation of radiation therapy, intensification of chemotherapy, and limiting toxicity-related treatment breaks. Currently accruing trials investigating pelvic IMRT for cervical and endometrial cancers are discussed. Published by Elsevier Ireland Ltd. C1 [Hymel, Rockne] Louisiana State Univ, Hlth Sci Ctr, Sch Med, New Orleans, LA 70112 USA. [Jones, Guy C.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Simone, Charles B., II] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Jones, GC (reprint author), NCI, Ctr Canc Res, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC 1682,Bldg 10 CRC Room B2-3561, Bethesda, MD 20892 USA. EM rhyme1@lsuhsc.edu; guy.jones@nih.gov; charles.simone@uphs.upenn.edu FU Intramural NIH HHS [Z99 CA999999] NR 34 TC 1 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 EI 1879-0461 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD JUN PY 2015 VL 94 IS 3 BP 371 EP 379 DI 10.1016/j.critrevonc.2014.12.015 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA CJ3FS UT WOS:000355369400011 PM 25600840 ER PT J AU Fascelli, M George, AK Frye, T Turkbey, B Choyke, PL Pinto, PA AF Fascelli, Michele George, Arvin K. Frye, Thomas Turkbey, Baris Choyke, Peter L. Pinto, Peter A. TI The Role of MRI in Active Surveillance for Prostate Cancer SO CURRENT UROLOGY REPORTS LA English DT Article DE Active surveillance; Prostate cancer; Multiparametric MRI; Outcomes; Cancer detection ID TRANSRECTAL ULTRASOUND BIOPSY; RESONANCE-IMAGING PREDICT; MULTIPARAMETRIC MRI; FUSION BIOPSY; FOLLOW-UP; RADICAL PROSTATECTOMY; 3 TESLA; MEN; RISK; ANTIGEN AB Approximately one in seven American men will be diagnosed with prostate cancer during his lifetime, and at least 50 % of newly diagnosed patients will present with low-risk disease. In the last decade, the decision-making paradigm for management has shifted due to high rates of disease detection and overtreatment, attributed to prostate-specific antigen screening, with more men deferring definitive treatment for active surveillance. The advent of multiparametric magnetic resonance imaging (MP-MRI) and MRI/transrectal ultrasound-guided fusion-guided prostate biopsy has refined the process of diagnosis, identifying patients with clinically-significant cancer and larger disease burden who would most likely benefit from intervention. In parallel, the utilization of MP-MRI in the surveillance of low-grade, low-volume disease is on the rise, reflecting support in a growing body of literature. The aim of this review is to appraise and summarize the data evaluating the role of magnetic resonance imaging in active surveillance for prostate cancer. C1 [Fascelli, Michele; George, Arvin K.; Frye, Thomas; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, MSC 1210,10 Ctr Dr, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov FU NIH FX The National Institutes of Health (NIH) Medical Research Scholars Program is a public-private partnernship supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. NR 56 TC 16 Z9 16 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2737 J9 CURR UROL REP JI Curr. Urol. Rep. PD JUN PY 2015 VL 16 IS 6 AR 42 DI 10.1007/s11934-015-0507-9 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CJ2VW UT WOS:000355343800009 PM 26017850 ER PT J AU Cunningham, TJ Kumar, S Yamaguchi, TP Duester, G AF Cunningham, Thomas J. Kumar, Sandeep Yamaguchi, Terry P. Duester, Gregg TI Wnt8a and Wnt3a cooperate in the axial stem cell niche to promote mammalian body axis extension SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Wnt8a; Wnt3a; body axis extension; somitogenesis; Fgf8; retinoic acid; Rdh10; mouse ID POSTERIOR NEURAL PLATE; RETINOIC ACID CONTROLS; MOUSE EMBRYO; MESODERM FORMATION; LIMB DEVELOPMENT; GENE ACTIVATION; SEGMENTATION; FGF; ELONGATION; GROWTH AB Background: Vertebrate body axis extension occurs in a head-to-tail direction from a caudal progenitor zone that responds to interacting signals. Wnt/-catenin signaling is critical for generation of paraxial mesoderm, somite formation, and maintenance of the axial stem cell pool. Body axis extension requires Wnt8a in lower vertebrates, but in mammals Wnt3a is required, although the anterior trunk develops in the absence of Wnt3a. Results: We examined mouse Wnt8a(-/-) and Wnt3a(-/-) single and double mutants to explore whether mammalian Wnt8a contributes to body axis extension and to determine whether a posterior growth function for Wnt8a is conserved throughout the vertebrate lineage. We find that caudal Wnt8a is expressed only during early somite stages and is required for normal development of the anterior trunk in the absence of Wnt3a. During this time, we show that Wnt8a and Wnt3a cooperate to maintain Fgf8 expression and prevent premature Sox2 up-regulation in the axial stem cell niche, critical for posterior growth. Similar to Fgf8, Wnt8a requires retinoic acid (RA) signaling to restrict its caudal expression boundary and possesses an upstream RA response element that binds RA receptors. Conclusions: These findings provide new insight into interaction of caudal Wnt-FGF-RA signals required for body axis extension. Developmental Dynamics 244:797-807, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Cunningham, Thomas J.; Kumar, Sandeep; Duester, Gregg] Sanford Burnham Med Res Inst, Dev Aging & Regenerat Program, La Jolla, CA 92037 USA. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21701 USA. RP Duester, G (reprint author), Sanford Burnham Med Res Inst, Dev & Aging Program, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM duester@sanfordburnham.org OI Cunningham, Thomas/0000-0002-4751-3140 FU NIH [GM062848] FX Grant sponsor: NIH; Grant number: GM062848 NR 62 TC 6 Z9 7 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 EI 1097-0177 J9 DEV DYNAM JI Dev. Dyn. PD JUN PY 2015 VL 244 IS 6 BP 797 EP 807 DI 10.1002/dvdy.24275 PG 11 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA CJ1DY UT WOS:000355223500008 PM 25809880 ER PT J AU Willette, AA Modanlo, N Kapogiannis, D AF Willette, Auriel A. Modanlo, Nina Kapogiannis, Dimitrios CA Alzheimer's Dis Neuroimaging TI Insulin Resistance Predicts Medial Temporal Hypermetabolism in Mild Cognitive Impairment Conversion to Alzheimer Disease SO DIABETES LA English DT Article ID NEUROIMAGING INITIATIVE ADNI; GLUCOSE-METABOLISM; MEMORY IMPAIRMENT; COMPOSITE SCORE; FDG-PET; BRAIN; DECLINE; PROGRESSION; DEMENTIA; ADULTS AB Alzheimer disease (AD) is characterized by progressive hypometabolism on [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. Peripheral insulin resistance (IR) increases AD risk. No studies have examined associations between FDG metabolism and IR in mild cognitive impairment (MCI) and AD, as well as MCI conversion to AD. We studied 26 cognitively normal (CN), 194 MCI (39 MCI-progressors, 148 MCI-stable, 2 years after baseline), and 60 AD subjects with baseline FDG-PET from the Alzheimer's Disease Neuroimaging Initiative. Mean FDG metabolism was derived for AD-vulnerable regions of interest (ROIs), including lateral parietal and posteromedial cortices, medial temporal lobe (MTL), hippocampus, and ventral prefrontal cortices (vPFC), as well as postcentral gyrus and global cerebrum control regions. The homeostasis model assessment of IR (HOMA-IR) was used to measure IR. For AD, higher HOMA-IR predicted lower FDG in all ROIs. For MCI-progressors, higher NOMA-Ill predicted higher FDG in the MTL and hippocampus. Control regions showed no associations. Higher HOMA-IR predicted hypermetabolism in MCI-progressors and hypometabolism in AD in medial temporal regions. Future longitudinal studies should examine the pathophysiologic significance of the shift from MTL hyper- to hypometabolism associated with IR. C1 [Willette, Auriel A.; Kapogiannis, Dimitrios] NIA, Neurosci Lab, Baltimore, MD 21224 USA. [Modanlo, Nina] Johns Hopkins Univ, Baltimore, MD USA. RP Kapogiannis, D (reprint author), NIA, Neurosci Lab, Baltimore, MD 21224 USA. EM kapogiannisd@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; ADNI (National Institutes of Health) [U01-AG-024904]; Department of Defense ADNI [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; Northern California Institute for Research and Education FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Data collection and sharing for this project were funded by the ADNI (National Institutes of Health Grant U01-AG-024904) and Department of Defense ADNI (award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private-sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 47 TC 15 Z9 15 U1 0 U2 7 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 JUN PY 2015 VL 64 IS 6 BP 1933 EP 1940 DI 10.2337/db14-1507 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CJ3GH UT WOS:000355370900011 PM 25576061 ER PT J AU Gennery, AR Holland, SM AF Gennery, Andrew R. Holland, Steven M. TI Primary immunodeficiencies: not just paediatric diseases SO EUROPEAN RESPIRATORY JOURNAL LA English DT Editorial Material ID CHRONIC GRANULOMATOUS-DISEASE; STEM-CELL TRANSPLANTATION; HEMATOPOIETIC ALLOGRAFT; MULTICENTER; INFECTIONS; CHILDREN C1 [Gennery, Andrew R.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Gennery, AR (reprint author), Great North Childrens Hosp, Old Childrens Outpatients, Paediat Immunol Dept, Queen Victoria Rd, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. EM andrew.gennery@ncl.ac.uk NR 17 TC 1 Z9 1 U1 0 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JUN PY 2015 VL 45 IS 6 BP 1521 EP 1523 DI 10.1183/09031936.00020215 PG 3 WC Respiratory System SC Respiratory System GA CJ2QN UT WOS:000355329700002 PM 26028614 ER PT J AU Gonzalez, FJ Fang, ZZ Ma, XC AF Gonzalez, Frank J. Fang, Zhong-Ze Ma, Xiaochao TI Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE CYP; CYP3A4; genetically modified mice; metabolomics; pregnane X receptor; UPLC-ESI-QTOFMS; xenobiotics ID HUMAN DRUG-METABOLISM; PREGNANE-X-RECEPTOR; INHIBITOR RITONAVIR ABT-538; HUMANIZED MOUSE MODELS; HEPATOCYTE-LIKE CELLS; MS-BASED METABOLOMICS; INDUCED LIVER-DISEASE; PPARA-NULL MOUSE; LITHOCHOLIC ACID; IN-VITRO AB Introduction: The study of xenobiotic metabolism and toxicity has been greatly aided by the use of genetically modified mouse models and metabolomics. Areas covered: Gene knockout mice can be used to determine the enzymes responsible for the metabolism of xenobiotics in vivo and to examine the mechanisms of xenobiotic-induced toxicity. Humanized mouse models are especially important because there exist marked species differences in the xenobiotic-metabolizing enzymes and the nuclear receptors that regulate these enzymes. Humanized mice expressing CYPs and nuclear receptors including the pregnane X receptor, the major regulator of xenobiotic metabolism and transport were produced. With genetically modified mouse models, metabolomics can determine the metabolic map of many xenobiotics with a level of sensitivity that allows the discovery of even minor metabolites. This technology can be used for determining the mechanism of xenobiotic toxicity and to find early biomarkers for toxicity. Expert opinion: Metabolomics and genetically modified mouse models can be used for the study of xenobiotic metabolism and toxicity by: i) comparison of the metabolomics profiles between wild-type and genetically modified mice, and searching for genotype-dependent endogenous metabolites; ii) searching for and elucidating metabolites derived from xenobiotics; and iii) discovery of specific alterations of endogenous compounds induced by xenobiotics-induced toxicity. C1 [Gonzalez, Frank J.; Fang, Zhong-Ze] NCI, NIH, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA. [Fang, Zhong-Ze] Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, Tianjin 300070, Peoples R China. [Ma, Xiaochao] Univ Pittsburgh, Sch Pharm, Ctr Pharmacogenet, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. RP Gonzalez, FJ (reprint author), NCI, NIH, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU National Cancer Institute Intramural Research Program; National Institute of Diabetes and Digestive and Kidney Diseases [DK090305]; National Institute of Allergy and Infectious Diseases [AI095425] FX The authors were supported in part by the National Cancer Institute Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases [DK090305] and the National Institute of Allergy and Infectious Diseases [AI095425]. 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 100 TC 5 Z9 5 U1 4 U2 16 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1742-5255 EI 1744-7607 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD JUN PY 2015 VL 11 IS 6 BP 869 EP 881 DI 10.1517/17425255.2015.1032245 PG 13 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA CI7NQ UT WOS:000354950800003 PM 25836352 ER PT J AU Craig, MT McBain, CJ AF Craig, Michael T. McBain, Chris J. TI Navigating the circuitry of the brain's GPS system: Future challenges for neurophysiologists SO HIPPOCAMPUS LA English DT Article DE interneurons; hippocampus; oscillations ID MEDIAL ENTORHINAL CORTEX; FREELY-MOVING RATS; GAMMA-FREQUENCY OSCILLATIONS; PERSISTENT CORTICAL ACTIVITY; HIPPOCAMPAL PYRAMIDAL CELLS; THETA-PHASE PRECESSION; GABA-B RECEPTORS; UNIT-ACTIVITY; GRID CELLS; IN-VITRO AB The discovery of the brain's navigation system creates a compelling challenge for neurophysiologists: how do we map the circuitry of a system that can only be definitively identified in awake, behaving animals? Do grid and border cells in the entorhinal cortex correspond to the two classes of principal cell found there, stellate and pyramidal cells? In the hippocampus, does the diversity seen in pyramidal cell subtypes have functional correlates in the place cell system? How do interneurons regulate the activity of spatially tuned principal cells in the hippocampal and entorhinal circuits? Here, we discuss recent literature relating the cellular circuitry of these circuits to in vivo studies of the brain's navigation system, and the role that interneurons have in regulating the activity of principal cells in these circuits. We propose that studying in vitro models of neuronal oscillations in the entorhinal cortex and hippocampus can provide useful insights for bridging the gap in understanding that exists in relating in vivo and behavioral studies to circuit function at the cellular level. (c) 2015 Wiley Periodicals, Inc. C1 [Craig, Michael T.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD USA. RP McBain, CJ (reprint author), NICHD, Program Dev Neurobiol, NIH, Bethesda, MD 20814 USA. EM mcbainc@mail.nih.gov RI Craig, Michael/E-7070-2011 OI Craig, Michael/0000-0001-8481-6709 FU NICHD Intramural Award FX Grant sponsor: NICHD Intramural Award. NR 81 TC 1 Z9 1 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD JUN PY 2015 VL 25 IS 6 SI SI BP 736 EP 743 DI 10.1002/hipo.22456 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CJ1FR UT WOS:000355228700011 PM 25786788 ER PT J AU Gierach, GL Patel, DA Falk, RT Pfeiffer, RM Geller, BM Vacek, PM Weaver, DL Chicoine, RE Shepherd, JA Mahmoudzadeh, AP Wang, J Fan, B Herschorn, SD Xu, X Veenstra, T Fuhrman, B Sherman, ME Brinton, LA AF Gierach, Gretchen L. Patel, Deesha A. Falk, Roni T. Pfeiffer, Ruth M. Geller, Berta M. Vacek, Pamela M. Weaver, Donald L. Chicoine, Rachael E. Shepherd, John A. Mahmoudzadeh, Amir Pasha Wang, Jeff Fan, Bo Herschorn, Sally D. Xu, Xia Veenstra, Timothy Fuhrman, Barbara Sherman, Mark E. Brinton, Louise A. TI Relationship of Serum Estrogens and Metabolites with Area and Volume Mammographic Densities SO HORMONES & CANCER LA English DT Article ID BREAST-CANCER RISK; TANDEM MASS-SPECTROMETRY; CIRCULATING SEX-HORMONES; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; ASSAY REPRODUCIBILITY; PARENCHYMAL PATTERNS; URINARY ESTROGENS; ASSOCIATION; STEROIDS AB Elevated mammographic density is a breast cancer risk factor, which has a suggestive, but unproven, relationship with increased exposure to sex steroid hormones. We examined associations of serum estrogens and estrogen metabolites with area and novel volume mammographic density measures among 187 women, ages 40-65, undergoing diagnostic breast biopsies at an academic facility in Vermont. Serum parent estrogens, estrone and estradiol, and their 2-, 4-, and 16-hydroxylated metabolites were measured using liquid chromatography-tandem mass spectrometry. Area mammographic density was measured in the breast contralateral to the biopsy using thresholding software; volume mammographic density was quantified using a density phantom. Linear regression was used to estimate associations of estrogens with mammographic densities, adjusted for age and body mass index, and stratified by menopausal status and menstrual cycle phase. Weak, positive associations between estrogens, estrogen metabolites, and mammographic density were observed, primarily among postmenopausal women. Among premenopausal luteal phase women, the 16-pathway metabolite estriol was associated with percent area (p=0.04) and volume (p=0.05) mammographic densities and absolute area (p=0.02) and volume (p=0.05) densities. Among postmenopausal women, levels of total estrogens, the sum of parent estrogens, and 2-, 4- and 16-hydroxylation pathway metabolites were positively associated with area density measures (percent: p=0.03, p=0.04, p=0.01, p=0.02, p=0.07; absolute: p=0.02, p=0.02, p=0.01, p=0.02, p=0.03, respectively) but not volume density measures. Our data suggest that serum estrogen profiles are weak determinants of mammographic density and that analysis of different density metrics may provide complementary information about relationships of estrogen exposure to breast tissue composition. C1 [Gierach, Gretchen L.; Patel, Deesha A.; Falk, Roni T.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Geller, Berta M.; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.; Herschorn, Sally D.] Univ Vermont, Burlington, VT USA. [Shepherd, John A.; Mahmoudzadeh, Amir Pasha; Wang, Jeff; Fan, Bo] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Xu, Xia; Veenstra, Timothy] Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Canc Res Technol Program, Leidos Biomed Res Inc, Frederick, MD USA. [Fuhrman, Barbara] Univ Arkansas Med Sci, Dept Epidemiol, Fay W Boozman Coll Publ Hlth, Little Rock, AR 72205 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Gierach, GL (reprint author), 9609 Med Ctr Dr,Rm 7-E108, Bethesda, MD 20892 USA. EM gierachg@mail.nih.gov; deesha.patel@nih.gov; falkr@exchange.nih.gov; pfeiffer@mail.nih.gov; berta.geller@uvm.edu; pvacek@uvm.edu; Donald.Weaver@uvm.edu; rchicoin@uvm.edu; John.Shepherd@ucsf.edu; AmirPasha.Mahmoudzadeh@ucsf.edu; jeff.wing.wang.walla.walla@gmail.com; bo.fan@ucsf.edu; sally.herschorn@uvmhealth.org; xuxi@mail.nih.gov; tveenstra@c2ndiagnostics.com; BJFuhrman@uams.edu; shermanm@exchange.nih.gov; brintonl@exchange.nih.gov RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016; OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522; Fuhrman, Barbara/0000-0002-1777-9888 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute; National Cancer Institute [HHSN261200800001E, U01CA70013, 1R21CA157254]; Breast Cancer Research Stamp Funds from the National Cancer Institute; National Center for Research Resources [M01 RR000109] FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Cancer Institute federal funds awarded under Contract No. HHSN261200800001E to SAIC-Frederick, Inc. Breast Cancer Research Stamp Funds and cooperative agreement U01CA70013 (B.M. Geller, P.M. Vacek, D.L. Weaver, R.E. Chicoine, S.D. Herschorn) and 1R21CA157254 (J.A. Shepherd, B. Fan, A.P. Mahmoudzadeh) from the National Cancer Institute funded some of the data collection and image analysis for this study. Grant number M01 RR000109 from the National Center for Research Resources funded the blood processing at the University of Vermont's General Clinical Research Center. 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 52 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD JUN PY 2015 VL 6 IS 2-3 BP 107 EP 119 DI 10.1007/s12672-015-0216-3 PG 13 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA CJ0BT UT WOS:000355138100005 PM 25757805 ER PT J AU Imani, F Zhuang, B Tahmasebi, A Kwak, JT Xu, S Agarwal, H Bharat, S Uniyal, N Turkbey, IB Choyke, P Pinto, P Wood, B Moradi, M Mousavi, P Abolmaesumi, P AF Imani, Farhad Zhuang, Bo Tahmasebi, Amir Kwak, Jin Tae Xu, Sheng Agarwal, Harsh Bharat, Shyam Uniyal, Nishant Turkbey, Ismail Baris Choyke, Peter Pinto, Peter Wood, Bradford Moradi, Mehdi Mousavi, Parvin Abolmaesumi, Purang TI Augmenting MRI-transrectal ultrasound-guided prostate biopsy with temporal ultrasound data: a clinical feasibility study SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article; Proceedings Paper CT 6th International Conference on Information Processing in Computer-Assisted Interventions (IPCAI) CY JUN 24, 2015 CL Barcelona, SPAIN DE Temporal ultrasound data; Cancer diagnosis; Prostate cancer ID REAL-TIME ELASTOGRAPHY; CANCER-DETECTION; FUSION; DIAGNOSIS; GUIDANCE AB In recent years, fusion of multi-parametric MRI (mp-MRI) with transrectal ultrasound (TRUS)-guided biopsy has enabled targeted prostate biopsy with improved cancer yield. Target identification is solely based on information from mp-MRI, which is subsequently transferred to the subject coordinates through an image registration approach. mp-MRI has shown to be highly sensitive to detect higher-grade prostate cancer, but suffers from a high rate of false positives for lower-grade cancer, leading to unnecessary biopsies. This paper utilizes a machine-learning framework to further improve the sensitivity of targeted biopsy through analyzing temporal ultrasound data backscattered from the prostate tissue. Temporal ultrasound data were acquired during targeted fusion prostate biopsy from suspicious cancer foci identified in mp-MRI. Several spectral features, representing the signature of backscattered signal from the tissue, were extracted from the temporal ultrasound data. A supervised support vector machine classification model was trained to relate the features to the result of histopathology analysis of biopsy cores obtained from cancer foci. The model was used to predict the label of biopsy cores for mp-MRI-identified targets in an independent group of subjects. Training of the classier was performed on data obtained from 35 biopsy cores. A fivefold cross-validation strategy was utilized to examine the consistency of the selected features from temporal ultrasound data, where we achieved the classification accuracy and area under receiver operating characteristic curve of 94 % and 0.98, respectively. Subsequently, an independent group of 25 biopsy cores was used for validation of the model, in which mp-MRI had identified suspicious cancer foci. Using the trained model, we predicted the tissue pathology using temporal ultrasound data: 16 out of 17 benign cores, as well as all three higher-grade cancer cores, were correctly identified. The results show that temporal analysis of ultrasound data is potentially an effective approach to complement mp-MRI-TRUS-guided prostate cancer biopsy, specially to reduce the number of unnecessary biopsies and to reliably identify higher-grade cancers. C1 [Imani, Farhad; Zhuang, Bo; Uniyal, Nishant; Moradi, Mehdi; Abolmaesumi, Purang] Univ British Columbia, Dept Elect & Comp Engn, Vancouver, BC V6T 1Z4, Canada. [Tahmasebi, Amir; Agarwal, Harsh; Bharat, Shyam] Philips Res North Amer, Briarcliff Manor, NY USA. [Kwak, Jin Tae; Xu, Sheng; Turkbey, Ismail Baris; Choyke, Peter; Pinto, Peter; Wood, Bradford] NIH, Bethesda, MD 20892 USA. [Mousavi, Parvin] Queens Univ, Sch Comp, Kingston, ON, Canada. RP Imani, F (reprint author), Univ British Columbia, Dept Elect & Comp Engn, Vancouver, BC V6T 1Z4, Canada. EM farhadi@ece.ubc.ca FU Natural Sciences and Engineering Research Council of Canada (NSERC); Canadian Institutes of Health Research (CIHR) FX The authors would like to acknowledge the help of Jochen Kruecker and Pingkun Yan for assisting with the experiments. This work was supported in part by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canadian Institutes of Health Research (CIHR). NR 30 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD JUN PY 2015 VL 10 IS 6 SI SI BP 727 EP 735 DI 10.1007/s11548-015-1184-3 PG 9 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA CJ3ZF UT WOS:000355422800006 PM 25843948 ER PT J AU Bharmal, N Kaplan, RM Shapiro, MF Mangione, CM Kagawa-Singer, M Wong, MD McCarthy, WJ AF Bharmal, Nazleen Kaplan, Robert M. Shapiro, Martin F. Mangione, Carol M. Kagawa-Singer, Marjorie Wong, Mitchell D. McCarthy, William J. TI The Association of Duration of Residence in the United States with Cardiovascular Disease Risk Factors Among South Asian Immigrants SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Asian Americans; Immigrants; Acculturation; Cardiovascular disease; Risk factors; United States ID BODY-MASS INDEX; CORONARY-HEART-DISEASE; SELF-REPORT MEASURES; METABOLIC SYNDROME; PHYSICAL-ACTIVITY; MYOCARDIAL-INFARCTION; DIABETES-MELLITUS; HEALTH BEHAVIORS; ARTERY-DISEASE; ETHNIC-GROUPS AB South Asians are disproportionately impacted by cardiovascular disease (CVD). Our objective was to examine the association between duration of residence in the US and CVD risk factors among South Asian adult immigrants. Multivariate logistic regression analyses using pooled data from the 2005, 2007, 2009 California Health Interview Surveys. Duration of residence in the US < 15 years was significantly associated with overweight/obese BMI (OR 0.59; 95 % CI 0.35, 0.98 for 5 to < 10 years), daily consumption of 5+ servings of fruits/vegetables (OR 0.37; 95 % CI 0.15, 0.94 for 10 to < 15 years), and sedentary lifestyle (OR 2.11; 95 % CI 1.17, 3.81 for 10 to < 15 years) compared with duration of residence a parts per thousand yen15 years after adjusting for illness burden, healthcare access, and socio-demographic characteristics. Duration of residence was not significantly associated with other CVD risk factors. Duration of residence is an important correlate of overweight/obesity and other risk factors among South Asian immigrants. C1 [Bharmal, Nazleen; Shapiro, Martin F.; Mangione, Carol M.; Wong, Mitchell D.] Univ Calif Los Angeles, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Kaplan, Robert M.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Kagawa-Singer, Marjorie] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA USA. [McCarthy, William J.] Univ Calif Los Angeles, Dept Psychol, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA 90024 USA. [McCarthy, William J.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. RP Bharmal, N (reprint author), Univ Calif Los Angeles, Dept Med, Div Gen Internal Med & Hlth Serv Res, 911 Broxton Ave,Room 203, Los Angeles, CA 90095 USA. EM nbharmal@mednet.ucla.edu RI Dey, Kamalesh/E-6568-2017; OI Wong, Mitchell/0000-0002-4800-8410 FU Division of General Internal Medicine and Health Services Research; American Heart Association-Pharmaceutical Roundtable Spina Outcomes Center at the University of California, Los Angeles [0875133 N]; NHLBI [1P50HL105188-6094] FX The authors thank Gerardo Moreno, MD, MSHS and Keith C. Norris, MD, FACP for their review of manuscript drafts. NB was supported by the Division of General Internal Medicine and Health Services Research and the American Heart Association-Pharmaceutical Roundtable Spina Outcomes Center (0875133 N) fellowship at the University of California, Los Angeles. WJM was supported by the NHLBI - 1P50HL105188-6094. No funding source had any role in the study design, analysis, interpretation of data, writing of the manuscript, or decision to submit the article for publication. NR 77 TC 5 Z9 5 U1 0 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD JUN PY 2015 VL 17 IS 3 BP 781 EP 790 DI 10.1007/s10903-013-9973-7 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CJ1OX UT WOS:000355254500020 PM 24380928 ER PT J AU Bai, RL Cloninger, A Czaja, W Sasser, PJ AF Bai, Ruiliang Cloninger, Alexander Czaja, Wojciech Sasser, Peter J. TI Efficient 2D MRI relaxometry using compressed sensing SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Relaxation; 2D relaxometry; Compressed sensing; MRI; Inverse Laplace transform; Exchange; Rician noise ID CROSS-CORRELATION RELAXOMETRY; TIME-CORRELATION RELAXOMETRY; MULTIDIMENSIONAL NMR; EXCHANGE SPECTROSCOPY; T-2 DISTRIBUTION; 1ST KIND; IN-VIVO; DIFFUSION; RELAXATION; INVERSION AB Potential applications of 2D relaxation spectrum NMR and MRI to characterize complex water dynamics (e.g., compartmental exchange) in biology and other disciplines have increased in recent years. However, the large amount of data and long MR acquisition times required for conventional 2D MR relaxometry limits its applicability for in vivo preclinical and clinical MRI. We present a new MR pipeline for 2D relaxometry that incorporates compressed sensing (CS) as a means to vastly reduce the amount of 2D relaxation data needed for material and tissue characterization without compromising data quality. Unlike the conventional CS reconstruction in the Fourier space (k-space), the proposed CS algorithm is directly applied onto the Laplace space (the joint 2D relaxation data) without compressing k-space to reduce the amount of data required for 2D relaxation spectra. This framework is validated using synthetic data, with NMR data acquired in a well-characterized urea/water phantom, and on fixed porcine spinal cord tissue. The quality of the CS-reconstructed spectra was comparable to that of the conventional 2D relaxation spectra, as assessed using global correlation, local contrast between peaks, peak amplitude and relaxation parameters, etc. This result brings this important type of contrast closer to being realized in preclinical, clinical, and other applications. (C) 2015 Published by Elsevier Inc. C1 [Bai, Ruiliang; Sasser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. [Bai, Ruiliang] Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20740 USA. [Cloninger, Alexander] Yale Univ, Program Appl Math, New Haven, CT 06511 USA. [Czaja, Wojciech] Univ Maryland, Dept Math, Norbert Wiener Ctr, College Pk, MD 20742 USA. RP Sasser, PJ (reprint author), NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. EM pjbasser@helix.nih.gov FU Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; National Science Foundation [DMS-1402254] FX This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Alexander Cloninger is supported by the National Science Foundation under Award No. DMS-1402254. Thanks to Mrs. Joni Taylor, Mr. T.J. Hunt, and Mr. R.R. Clevenger from the ASR Core, NHLBI, for obtaining the spinal cord specimens and Ms. L. Salak for editing the manuscript. We are also grateful to our colleagues Dr. Y. Gao for help preparing the urea/water phantom and Dr. M.E. Komlosh and Dr. E. Hutchinson for assistance with MRI experiment. NR 49 TC 4 Z9 4 U1 4 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD JUN PY 2015 VL 255 BP 88 EP 99 DI 10.1016/j.jmr.2015.04.002 PG 12 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA CJ3LU UT WOS:000355386300011 PM 25917134 ER PT J AU Oldfield, EH Merrill, MJ AF Oldfield, Edward H. Merrill, Marsha J. TI Apoplexy of pituitary adenomas: the perfect storm SO JOURNAL OF NEUROSURGERY LA English DT Article DE pituitary adenoma; pituitary apoplexy; pituitary surgery ID POSITRON-EMISSION-TOMOGRAPHY; PRECIPITATING FACTORS; INTRASELLAR PRESSURE; CLINICAL-FEATURES; TISSUE PRESSURE; TUMOR APOPLEXY; ANGIOGENESIS; PET; MANAGEMENT; HYPERPROLACTINEMIA AB OBJECT Pituitary adenomas occasionally undergo infarction, apoplexy, which often destroys much of the tumor. It is well known that apoplexy can be precipitated by several acute factors, including cardiac surgery, other types of surgery, trauma, insulin infusion, and stimulation with administration of hypothalamic releasing factors. METHODS The prior focus on mechanisms underlying pituitary apoplexy has been on these acute events. Less attention has been given to the endogenous features of pituitary tumors that make them susceptible to spontaneous infarction, despite that most pituitary apoplexy occurs in the absence of a recognized precipitating event. The authors examine intrinsic features of pituitary adenomas that render them vulnerable to apoplexy-features such as high metabolic demand, paucity of angiogenesis, and sparse vascularity, qualities that have previously not been linked with apoplexy-and argue that it is these features of adenomas that underlie their susceptibility to spontaneous infarction. The sensitivity of freshly cultured pituitary adenomas to hypoglycemia is assessed. RESULTS Adenomas have high metabolic demand, limited angiogenesis, and reduced vessel density compared with the normal gland. Pituitary adenoma cells do not survive in the presence of reduced or absent concentrations of glucose. CONCLUSIONS The authors propose that the frequent ischemic infarction of pituitary adenomas is the product of intrinsic features of these tumors. These endogenous qualities create a tenuous balance between high metabolic demand and marginal tissue perfusion. Thus, the tumor is vulnerable to spontaneous infarction or to acute ischemia by any event that acutely alters the balance between tumor perfusion and tumor metabolism, events such as acute systemic hypotension, abruptly decreased supply of nutrients, hypoglycemia with insulin administration, or increase in the tumor's metabolic demand due to administration of hypothalamic releasing factors. It may be possible to take advantage of these intrinsic features of pituitary adenomas by using aspects of this vulnerability for development of new approaches for treatment. C1 [Oldfield, Edward H.] Univ Virginia, Dept Neurol Surg, Hlth Sci Ctr, Charlottesville, VA 22908 USA. [Oldfield, Edward H.; Merrill, Marsha J.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), Univ Virginia, Dept Neurol Surg, POB 800212, Charlottesville, VA 22908 USA. EM eho4u@virginia.edu NR 47 TC 5 Z9 5 U1 2 U2 8 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD JUN PY 2015 VL 122 IS 6 BP 1444 EP 1449 DI 10.3171/2014.10.JNS141720 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CI8OK UT WOS:000355031400028 PM 25859802 ER PT J AU Saftlas, AF Spracklen, CN Ryckman, KK Stockdale, CK Penrose, K Ault, K Rubenstein, LM Pinto, LA AF Saftlas, Audrey F. Spracklen, Cassandra N. Ryckman, Kelli K. Stockdale, Colleen K. Penrose, Kerri Ault, Kevin Rubenstein, Linda M. Pinto, Ligia A. TI Influence of a loop electrosurgical excision procedure (LEEP) on levels of cytokines in cervical secretions SO JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Loop electrosurgical excision procedure (LEEP); Cervical intraepithelial neoplasia (CIN); Cervical secretions; Cytokines ID HUMAN-PAPILLOMAVIRUS INFECTION; INTRAEPITHELIAL NEOPLASIA; INFLAMMATION MARKERS; IMMUNE-RESPONSES; IFN-GAMMA; RISK; HPV; WOMEN; CLEARANCE; CANCER AB Over the past decade, there has been heightened interest in determining if there is an increased risk of adverse reproductive outcomes among women who had a loop electrosurgical excision procedure (LEEP) to remove cervical intraepithelial neoplasia (CIN). The objective of this exploratory study was to determine if the treatment of CIN with a LEEP is associated with changes in cervical soluble immune markers. Cervical cytokine concentrations were measured in women treated with LEEP and a control group of women who had colposcopy only and did not undergo LEEP. Cytokines were examined in cervical secretions collected in Merocel (R) sponges at study entry and at 6-month follow-up. Cytokines were measured using a Luminex 18-plex cytokine bead assay. The mean cytokine levels were not significantly changed from baseline to follow-up in either group, with the exception of TNF-alpha, which decreased among women who underwent a LEEP. When the mean levels of cytokines of the treated and untreated groups at baseline or follow-up were compared, cytokine levels tended to be lower in the treated group (particularly IFN-gamma, IL-6, IL-8, and MCP-1). Findings from adjusted repeated measures analyses revealed no differences between the two groups with regard to changes in cytokine levels overtime. Overall, women undergoing a LEEP showed few changes in the cervical microenvironment relative to untreated women. Future studies with additional cervical environment markers and larger sample sizes are needed to determine if a LEEP is associated with dysregulation of the cervical microenvironment. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Saftlas, Audrey F.; Ryckman, Kelli K.; Rubenstein, Linda M.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. [Spracklen, Cassandra N.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Stockdale, Colleen K.] Univ Iowa, Carver Coll Med, Dept Obstet & Gynecol, Iowa City, IA 51214 USA. [Penrose, Kerri] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. [Ault, Kevin] Univ Kansas, Med Ctr, Dept Obstet & Gynecol, Kansas City, KS 66160 USA. [Pinto, Ligia A.] Leidos Biomed Res Inc, Human Papillomavirus Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Saftlas, AF (reprint author), Univ Iowa, Coll Publ Hlth, Dept Epidemiol, 145 Riverside Dr,S427 CPHB, Iowa City, IA 52242 USA. EM audrey-saftlas@uiowa.edu; cnspracklen@unc.edu; kelli-ryckman@uiowa.edu; colleen-stockdale@uiowa.edu; kjp43@pitt.edu; kault2@kumc.edu; linda-rubenstein@uiowa.edu; pintol@mail.nih.gov FU National Institute of Allergy and Infectious Diseases [R21-AI06811]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the National Institute of Allergy and Infectious Diseases (R21-AI06811).; This project has been funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract no. HHSN261200800001E. The content of this paper does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 23 TC 0 Z9 0 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-0378 J9 J REPROD IMMUNOL JI J. Reprod. Immunol. PD JUN PY 2015 VL 109 BP 74 EP 83 DI 10.1016/j.jri.2015.01.002 PG 10 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA CJ3DW UT WOS:000355364600011 PM 25721621 ER PT J AU Collard, RM Comijs, HC Naarding, P Penninx, BW Milaneschi, Y Ferrucci, L Voshaar, RCO AF Collard, Rose M. Comijs, Hannie C. Naarding, Paul Penninx, Brenda W. Milaneschi, Yuri Ferrucci, Luigi Voshaar, Richard C. Oude TI Frailty as a Predictor of the Incidence and Course of Depressed Mood SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Depression; frailty; older persons; InCHIANTI ID DWELLING OLDER PERSONS; LATE-LIFE DEPRESSION; COMMUNITY; ASSOCIATION; DISABILITY; PROGNOSIS; INCHIANTI; HEALTH; ADULTS; AGE AB Background: Late-life depression and physical frailty are supposed to be reciprocally associated, however, longitudinal studies are lacking. Objectives: This study examines whether physical frailty predicts a higher incidence of depression, as well as a less favorable course of depression. Methods: A population-based cohort study of 888 people aged 65 years and over with follow-up measures at 3, 6, and 9 years. Cox proportional hazards models adjusted for age, sex, education, smoking, alcohol usage, and global cognitive functioning were applied to calculate the incidence of depressed mood in those nondepressed at baseline (n = 699) and remission in those with depressed mood at baseline (n = 189). Depressed mood onset or remission was defined as crossing the cut-off score of 20 points on the Center for Epidemiological Studies-Depression Scale combined with a relevant change in this score. Physical frailty was based on the presence of >= 3 out of 5 components (ie, weight loss, weakness, slowness, exhaustion, and low physical activity level). Results: A total of 214 out of 699 (30.6%) nondepressed persons developed depressed mood during follow-up. Physical frailty predicted the onset of depressed mood with a hazard rate of 1.26 (95% confidence interval 1.09e1.45, P = .002). Of the 189 persons with depressed mood at baseline, 96 (50.8%) experienced remission during follow-up. Remission was less likely in the presence of a higher level of physical frailty (hazard rate = 0.72, 95% confidence interval 0.58-0.91, P = .005). Conclusions: Because physical frailty predicts both the onset and course of late-life depressed mood, physical frailty should receive more attention in mental health care planning for older persons as well as its interference with treatment. Future studies into the pathophysiological mechanisms may guide the development of new treatment opportunities for these vulnerable patients. (C) 2015 AMDA - The Society for Post-Acute and Long-Term Care Medicine. C1 [Collard, Rose M.; Voshaar, Richard C. Oude] Radboud Univ Nijmegen Med Ctr, Dept Psychiat, NL-6500 HB Nijmegen, Netherlands. [Collard, Rose M.] Nijmegen Mental Hlth Ctr, Pro Persona, Nijmegen, Netherlands. [Comijs, Hannie C.; Penninx, Brenda W.; Milaneschi, Yuri] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Comijs, Hannie C.; Penninx, Brenda W.; Milaneschi, Yuri] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, GGZinGeest, Amsterdam, Netherlands. [Naarding, Paul] GGNet, Dept Old Age Psychiat, Apeldoorn, Netherlands. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Voshaar, Richard C. Oude] Univ Groningen, Univ Med Ctr Groningen, Univ Ctr Psychiat, Groningen, Netherlands. [Voshaar, Richard C. Oude] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol Emot Regulat, Groningen, Netherlands. RP Collard, RM (reprint author), Radboud Univ Nijmegen Med Ctr, Dept Psychiat, Hp 966,Postbus 9101, NL-6500 HB Nijmegen, Netherlands. EM rose.collard@radboudumc.nl FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging, Bethesda, Maryland [236 MD 916413, 236 MD 821336]; US National Institute on Aging [N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002] FX The original InCHIANTI study baseline (1998-2000) was supported by the Italian Ministry of Health (ICS110.1/RF97.71) and in part by the U.S. National Institute on Aging, Bethesda, Maryland (contracts 236 MD 916413 and 236 MD 821336). The InCHIANTI follow-up 1 (2001-2003) was funded by the US National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI follow-up 2 and 3 studies (2004-2010) were financed by the US National Institute on Aging (Contract N01-AG-5-0002). NR 46 TC 3 Z9 3 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD JUN 1 PY 2015 VL 16 IS 6 BP 509 EP 514 DI 10.1016/j.jamda.2015.01.088 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CJ0AQ UT WOS:000355134100011 PM 25737263 ER PT J AU Polley, MYC YLeung, SC Gao, D Mastropasqua, MG Zabaglo, LA Bartlett, JMS McShane, LM Enos, RA Badve, SS Bane, AL Borgquist, S Fineberg, S Lin, MG Gown, AM Grabau, D Gutierrez, C Hugh, JC Moriya, T Ohi, Y Osborne, CK Penault-Llorca, FM Piper, T Porter, PL Sakatani, T Salgado, R Starczynski, J Laenkholm, AV Viale, G Dowsett, M Hayes, DF Nielsen, TO AF Polley, Mei-Yin C. YLeung, Samuel C. Gao, Dongxia Mastropasqua, Mauro G. Zabaglo, Lila A. Bartlett, John M. S. McShane, Lisa M. Enos, Rebecca A. Badve, Sunil S. Bane, Anita L. Borgquist, Signe Fineberg, Susan Lin, Ming-Gang Gown, Allen M. Grabau, Dorthe Gutierrez, Carolina Hugh, Judith C. Moriya, Takuya Ohi, Yasuyo Osborne, C. Kent Penault-Llorca, Frederique M. Piper, Tammy Porter, Peggy L. Sakatani, Takashi Salgado, Roberto Starczynski, Jane Laenkholm, Anne-Vibeke Viale, Giuseppe Dowsett, Mitch Hayes, Daniel F. Nielsen, Torsten O. CA Int Ki67 Breast Canc Working Grp North American Breast Canc Grp BIG TI An international study to increase concordance in Ki67 scoring SO MODERN PATHOLOGY LA English DT Article ID PRACTICE GUIDELINE UPDATE; BREAST-CANCER HIGHLIGHTS; AMERICAN SOCIETY; CLINICAL ONCOLOGY/COLLEGE; EXPERT CONSENSUS; PRIMARY THERAPY; RECOMMENDATIONS; INDEX; ESTROGEN; WOMEN AB Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation >= 0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes. C1 [Polley, Mei-Yin C.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [YLeung, Samuel C.; Gao, Dongxia; Nielsen, Torsten O.] Univ British Columbia, Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Mastropasqua, Mauro G.] European Inst Oncol, Div Pathol, Milan, Italy. [Mastropasqua, Mauro G.] European Inst Oncol, Lab Med, Milan, Italy. [Zabaglo, Lila A.; McShane, Lisa M.] Breakthrough Breast Canc Res Ctr, Inst Canc Res, London, England. [Bartlett, John M. S.] Ontario Inst Canc Res, Transformat Pathol, Toronto, ON, Canada. [Enos, Rebecca A.] Emmes Corp, Rockville, MD USA. [Badve, Sunil S.] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Bane, Anita L.] McMaster Univ, Juravinski Hosp, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Bane, Anita L.] McMaster Univ, Ctr Canc, Hamilton, ON, Canada. [Borgquist, Signe; Grabau, Dorthe] Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden. [Fineberg, Susan] Montefiore Med Ctr, Bronx, NY 10467 USA. [Fineberg, Susan] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Lin, Ming-Gang; Porter, Peggy L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Gown, Allen M.] PhenoPath Labs, Seattle, WA USA. [Gutierrez, Carolina; Osborne, C. Kent] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Gutierrez, Carolina; Osborne, C. Kent] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Hugh, Judith C.] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB T6G 2M7, Canada. [Moriya, Takuya] Kawasaki Med Univ, Dept Pathol, Kurashiki, Okayama, Japan. [Ohi, Yasuyo] Hakuaikai Sagara Hosp, Dept Pathol, Kagoshima, Japan. [Penault-Llorca, Frederique M.] Ctr Jean Perrin, Dept Pathol, Clermont Ferrand, France. [Penault-Llorca, Frederique M.] Univ Auvergne, Clermont Ferrand, France. [Piper, Tammy] Western Gen Hosp, Edinburgh Canc Res Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. [Sakatani, Takashi] Jichi Med Univ, Dept Pathol, Shimotsuke, Tochigi, Japan. [Salgado, Roberto] Inst Jules Bordet, B-1000 Brussels, Belgium. [Starczynski, Jane] Natl Hlth Serv, Birmingham Heart England, Birmingham, W Midlands, England. [Laenkholm, Anne-Vibeke] Slagelse Hosp, Slagelse, Denmark. [Viale, Giuseppe] European Inst Oncol, Div Pathol, Milan, Italy. [Viale, Giuseppe] European Inst Oncol, Lab Med, Milan, Italy. [Viale, Giuseppe] Univ Milan, Milan, Italy. [Dowsett, Mitch] Royal Marsden Hosp, Acad Dept Biochem, London SW3 6JJ, England. [Hayes, Daniel F.] Univ Michigan, Breast Oncol Program, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Nielsen, TO (reprint author), Univ British Columbia, Pathol & Lab Med, Anat Pathol, Vancouver Hosp & Hlth Sci Ctr, JP 1401,855 W 12th Ave,, Vancouver, BC V5Z 1M9, Canada. EM torsten@mail.ubc.ca FU Breast Cancer Research Foundation; Breakthrough Breast Cancer; National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital; Government of Ontario FX This work was supported by the Breast Cancer Research Foundation. Additional funding for the UK laboratories was received from Breakthrough Breast Cancer and the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. Funding for the Ontario Institute for Cancer Research is provided by the Government of Ontario. Judith Hugh is the Lilian McCullough Chair in Breast Cancer Surgery Research and the CBCF Prairies/NWT Chapter. We are grateful to the Breast International Group and North American Breast Cancer Group (BIG-NABCG) collaboration, including the leadership of Dr Nancy Davidson, Dr Martine Piccart, and Dr Larry Norton, and for the support of the Breast Cancer Research Foundation. NR 21 TC 44 Z9 46 U1 1 U2 9 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 JUN PY 2015 VL 28 IS 6 BP 778 EP 786 DI 10.1038/modpathol.2015.38 PG 9 WC Pathology SC Pathology GA CJ1ZW UT WOS:000355284800004 PM 25698062 ER PT J AU Papathomas, TG Oudijk, L Persu, A Gill, AJ van Nederveen, F Tischler, AS Tissier, F Volante, M Matias-Guiu, X Smid, M Favier, J Rapizzi, E Libe, R Curras-Freixes, M Aydin, S Huynh, T Lichtenauer, U van Berkel, A Canu, L Domingues, R Clifton-Bligh, RJ Bialas, M Vikkula, M Baretton, G Papotti, M Nesi, G Badoual, C Pacak, K Eisenhofer, G Timmers, HJ Beuschlein, F Bertherat, J Mannelli, M Robledo, M Gimenez-Roqueplo, AP Dinjens, WNM Korpershoek, E de Krijger, RR AF Papathomas, Thomas G. Oudijk, Lindsey Persu, Alexandre Gill, Anthony J. van Nederveen, Francien Tischler, Arthur S. Tissier, Frederique Volante, Marco Matias-Guiu, Xavier Smid, Marcel Favier, Judith Rapizzi, Elena Libe, Rosella Curras-Freixes, Maria Aydin, Selda Huynh, Thanh Lichtenauer, Urs van Berkel, Anouk Canu, Letizia Domingues, Rita Clifton-Bligh, Roderick J. Bialas, Magdalena Vikkula, Miikka Baretton, Gustavo Papotti, Mauro Nesi, Gabriella Badoual, Cecile Pacak, Karel Eisenhofer, Graeme Timmers, Henri J. Beuschlein, Felix Bertherat, Jerome Mannelli, Massimo Robledo, Mercedes Gimenez-Roqueplo, Anne-Paule Dinjens, Winand N. M. Korpershoek, Esther de Krijger, Ronald R. TI SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T) SO MODERN PATHOLOGY LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; SUCCINATE-DEHYDROGENASE DEFICIENCY; RENAL-CARCINOMA; SDHA MUTATIONS; CARNEY TRIAD; HEREDITARY PHEOCHROMOCYTOMA; GERMLINE MUTATIONS; GENE-MUTATIONS; IDENTIFICATION; INACTIVATION AB Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB kappa= 0.7338; SDHA kappa = 0.6707) or a three-tiered classification approach (SDHB kappa = 0.6543; SDHA kappa = 0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (similar to 90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (similar to 16%) VHL-mutated, as well as 1 of 21 (similar to 5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable. C1 [Papathomas, Thomas G.] Kings Coll Hosp London, Dept Histopathol, London, England. [Papathomas, Thomas G.; Oudijk, Lindsey; Dinjens, Winand N. M.; Korpershoek, Esther; de Krijger, Ronald R.] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands. [Persu, Alexandre] Catholic Univ Louvain, Clin Univ Saint Luc, Pole Cardiovasc Res, Inst Rech Expt & Clin, B-1200 Brussels, Belgium. [Persu, Alexandre] Catholic Univ Louvain, Clin Univ Saint Luc, Div Cardiol, B-1200 Brussels, Belgium. [Gill, Anthony J.] Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW 2065, Australia. [Gill, Anthony J.] Univ Sydney, Kolling Inst Med Res, Canc Diag & Pathol Res Grp, Sydney, NSW 2006, Australia. [van Nederveen, Francien] PAL Dordrecht, Lab Pathol, Dordrecht, Netherlands. [Tischler, Arthur S.] Tufts Univ, Dept Pathol, Tufts Med Ctr, Sch Med, Boston, MA 02111 USA. [Tischler, Arthur S.] Tufts Univ, Lab Med, Tufts Med Ctr, Sch Med, Boston, MA 02111 USA. [Tissier, Frederique] Univ Paris 05, Inst Natl Sante & Rech Med U1016, Inst Cochin,Ctr Natl Rech Sci UMR8104, Sorbonne Paris Cite,Rare Adrenal Canc Network COM, Paris, France. [Tissier, Frederique] Univ Paris 06, Hop Pitie Salpetriere, Dept Pathol, Paris, France. [Volante, Marco; Papotti, Mauro] Univ Turin, San Luigi Hosp, Dept Oncol, Turin, Italy. [Matias-Guiu, Xavier] Univ Lleida, IRBLLEIDA, Hosp Univ Arnau Vilanova, Dept Pathol & Mol Genet, Lleida, Spain. [Matias-Guiu, Xavier] Univ Lleida, IRBLLEIDA, Hosp Univ Arnau Vilanova, Res Lab, Lleida, Spain. [Smid, Marcel] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands. [Favier, Judith; Badoual, Cecile; Gimenez-Roqueplo, Anne-Paule] Hop Europeen Georges Pompidou, Inserm UMR970, Paris Ctr Rech Cardiovasc PARCC, Paris, France. [Favier, Judith; Badoual, Cecile; Gimenez-Roqueplo, Anne-Paule] Univ Paris 05, Sorbonne Paris Cite, Fac Med, Paris, France. [Rapizzi, Elena; Canu, Letizia; Mannelli, Massimo] Univ Florence, Endocrinol Unit, Dept Expt & Clin Biomed Sci, Florence, Italy. [Curras-Freixes, Maria; Beuschlein, Felix; Robledo, Mercedes] Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Madrid, Spain. [Aydin, Selda] Catholic Univ Louvain, Clin Univ Saint Luc, Dept Pathol, Inst Rech Expt & Clin, B-1200 Brussels, Belgium. [Huynh, Thanh; Pacak, Karel] NIH, Program Reprod & Adult Endocrinol, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Lichtenauer, Urs] Klinikum Univ Munchen, Endocrine Res Unit, Med Klin & Poliklinik 4, Munich, Germany. [van Berkel, Anouk; Timmers, Henri J.] Radboud Univ Nijmegen Med Ctr, Endocrinol Sect, Dept Internal Med, Nijmegen, Netherlands. [Domingues, Rita] Inst Portugues Oncol Francisco Gentil, UIPM, Lisbon, Portugal. [Clifton-Bligh, Roderick J.] Univ Sydney, Royal N Shore Hosp, Kolling Inst Med Res, Canc Genet, Sydney, NSW 2006, Australia. [Bialas, Magdalena] Jagiellonian Univ, Coll Med, Dept Pathomorphol, Krakow, Poland. [Vikkula, Miikka] Catholic Univ Louvain, Duve Inst, Lab Human Mol Genet, B-1200 Brussels, Belgium. [Baretton, Gustavo] Tech Univ Dresden, Dept Pathol, D-01062 Dresden, Germany. [Nesi, Gabriella] Univ Florence, Div Pathol Anat, Florence, Italy. [Badoual, Cecile] AP HP, Hop Europeen Georges Pompidou, Serv Anat Pathol, Paris, France. [Eisenhofer, Graeme] Tech Univ Dresden, Univ Hosp, Inst Clin Chem, D-01062 Dresden, Germany. [Eisenhofer, Graeme] Tech Univ Dresden, Univ Hosp, Lab Med, D-01062 Dresden, Germany. [Eisenhofer, Graeme] Tech Univ Dresden, Univ Hosp, Dept Med 3, D-01062 Dresden, Germany. [Bertherat, Jerome] Univ Paris 05, Inst Cochin, CNRS, INSERM U1016,UMR8104, Paris, France. [Bertherat, Jerome] Hop Cochin, Assistance Publ Hop Paris, Referral Ctr Rare Adrenal Dis, Dept Endocrinol, Paris, France. [Mannelli, Massimo] ITT, Florence, Italy. [Robledo, Mercedes] Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain. [de Krijger, Ronald R.] Reinier Graaf Hosp, Dept Pathol, Delft, Netherlands. [de Krijger, Ronald R.] Univ Med Ctr Utrecht, Princess Maxima Ctr Pediat Oncol, Dept Pathol, Utrecht, Netherlands. RP Papathomas, TG (reprint author), Kings Coll Hosp London, Dept Histopathol, Denmark Hill, London, England. EM t.papathomas@erasmusmc.nl RI matias-guiu, xavier/C-3039-2009; Robledo, Mercedes/O-2230-2013; canu, letizia/E-7718-2017; OI matias-guiu, xavier/0000-0002-7201-6605; Robledo, Mercedes/0000-0001-6256-5902; canu, letizia/0000-0003-4995-8108; Vikkula, Miikka/0000-0002-6236-338X; Mannelli, Massimo/0000-0002-8001-9857; Domingues, Rita/0000-0001-7130-3795 FU Seventh Framework Programme (FP7) (ENS@T-Cancer) [259735]; Fonds de la Recherche Scientifique Medicale (FRSM) [3.4.587.08 F] FX This study was supported by the Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259735 (ENS@T-Cancer). Genetic analysis of the Belgian subset was partly supported by the Fonds de la Recherche Scientifique Medicale (FRSM) convention number 3.4.587.08 F (to AP). AP, SA, and MV acknowledge the contribution of N Lannoy, A Mendola, and L Evenepoel (Clin. Univ. St-Luc/UCL) for genetic analysis and F Severino (Clin. Univ. St-Luc) for maintenance of the database. Besides Professor A Mourin (Clin. Univ. St-Luc/UCL), they are also grateful to all pathologists who contributed tumor samples: Professors M Delos and B Weynand and Drs M-C Nollevaux and C Fervaille (Cl. Un. De Mont-Godinne, UCL); Drs N Detrembleur, N Bletard, and I Scagnol (CHU Sart-Tilman, Ulg); Drs E Laterre and G Beniuga (IPG Gosselies); Professor H De Raeve and Dr W Jeuris (OLV, Aalst); Dr V Duwel (Ziekenhuis KLINA); Drs A Janssen and S Talpe Clniques du Sud-Luxembourg, Arlon); Drs C Robrechts and J Bekaert (Imelda Ziekenhuis); Dr R Duttmann (CHU Brugmann); Dr N de Saint-Aubain (Institut Bordet); and Drs R Achten and K Wouters (Jessa Ziekenhuis). MM, ER, LC, and GN acknowledge the contribution of Dr T Ercolino for the genetic analysis of the Italian (Florence) samples. GE and GB acknowledge the contribution of Drs C Pamporaki, R Darr, S Richter, and J Brutting for data collection of the German (Dresden) samples. We thank J Shukla (Erasmus MC Cancer Institute) for her valuable technical assistance as well as Drs M Versasky and M Gomez Morales (Hospital Universitario San Cecilio) for providing one SDHD-mutated HNPGL sample. NR 79 TC 14 Z9 14 U1 1 U2 5 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 JUN PY 2015 VL 28 IS 6 BP 807 EP 821 DI 10.1038/modpathol.2015.41 PG 15 WC Pathology SC Pathology GA CJ1ZW UT WOS:000355284800007 PM 25720320 ER PT J AU Lyda, TA Joshi, MB Andersen, JF Kelada, AY Owings, JP Bates, PA Dwyer, DM AF Lyda, Todd A. Joshi, Manju B. Andersen, John F. Kelada, Andrew Y. Owings, Joshua P. Bates, Paul A. Dwyer, Dennis M. TI A unique, highly conserved secretory invertase is differentially expressed by promastigote developmental forms of all species of the human pathogen, Leishmania SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE Leishmania; Protozoan pathogen; Human parasite; Invertase; Secretory enzyme ID ACID-PHOSPHATASE; DONOVANI PROMASTIGOTES; GLUCOSE-TRANSPORTER; BIOCHEMICAL-CHARACTERIZATION; FUNCTIONAL DOMAINS; MEMBRANE-PROTEINS; GENE; INFECTION; NUCLEASE; SUCRASE AB Leishmania are protozoan pathogens of humans that exist as extracellular promastigotes in the gut of their sand fly vectors and as obligate intracellular amastigotes within phagolysosomes of infected macrophages. Between infectious blood meal feeds, sand flies take plant juice meals that contain sucrose and store these sugars in their crop. Such sugars are regurgitated into the sand fly anterior midgut where they impact the developing promastigote parasite population. In this report we showed that promastigotes of all Leishmania species secreted an invertase/sucrase enzyme during their growth in vitro. In contrast, neither L. donovani nor L. mexicana amastigotes possessed any detectable invertase activity. Importantly, no released/secreted invertase activity was detected in culture supernatants from either Trypanosoma brucei or Trypanosoma cruzi. Using HPLC, the L. donovani secretory invertase was isolated and subjected to amino acid sequencing. Subsequently, we used a molecular approach to identify the LdINV and LmexINV genes encoding the similar to 72 kDa invertases produced by these organisms. Interestingly, we identified high fidelity LdINV-like homologs in the genomes of all Leishmania sp. but none were present in either T. brucei or T. cruzi. Northern blot and RT-PCR analyses showed that these genes were developmentally/differentially expressed in promastigotes but not amastigotes of these parasites. Homologous transfection studies demonstrated that these genes in fact encoded the functional secretory invertases produced by these parasites. Cumulatively, our results suggest that these secretory enzymes play critical roles in the survival/growth/development and transmission of all Leishmania parasites within their sand fly vector hosts. C1 [Joshi, Manju B.; Kelada, Andrew Y.; Owings, Joshua P.; Dwyer, Dennis M.] NIAID, Cell Biol Sect, Parasit Dis Lab, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Bates, Paul A.] Univ Lancaster, Fac Hlth & Med, Div Biomed & Life Sci, Lancaster LA1 4YQ, England. RP Lyda, TA (reprint author), 105 Collings St BRC 216, Clemson, SC 29634 USA. EM todd.a.lyda@gmail.com OI Bates, Paul/0000-0001-6861-5421 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Intramural Research Training Award Post-doctoral Fellowship from the NIAID, NIH; Oak Ridge Institute for Science and Education (ORISE), Research Specialist Program at NIH; Postbaccalaureate Intramural Research Training Awards from the NIAID, NIH FX This research was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). Dr. Todd Lyda was supported by an Intramural Research Training Award Post-doctoral Fellowship from the NIAID, NIH. Dr. Manju Joshi was supported by an appointment through the Oak Ridge Institute for Science and Education (ORISE), Research Specialist Program at NIH. The program is administered by ORISE through an inter-agency agreement between the US Department of Energy and the NIH. Mr. Andrew Y. Kelada and Mr. Joshua P. Owings were supported by Postbaccalaureate Intramural Research Training Awards from the NIAID, NIH. We thank Dr. Greg Matlashewski, Department of Microbiology and Immunology McGill University, Montreal, CA for providing the pKSNEO leishmanial expression vector; Dr. Buddy Ullman, Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, OR for providing the L. donovani cosmid library used in this study. NR 46 TC 3 Z9 3 U1 1 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 EI 1573-4919 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD JUN PY 2015 VL 404 IS 1-2 BP 53 EP 77 DI 10.1007/s11010-015-2366-6 PG 25 WC Cell Biology SC Cell Biology GA CJ4DE UT WOS:000355433900008 PM 25763714 ER PT J AU Mishra, PK Guo, JS Dittman, LE Haase, J Yeh, E Bloom, K Basrai, MA AF Mishra, Prashant K. Guo, Jiasheng Dittman, Lauren E. Haase, Julian Yeh, Elaine Bloom, Kerry Basrai, Munira A. TI Pat1 protects centromere-specific histone H3 variant Cse4 from Psh1-mediated ubiquitination SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; CHROMOSOME SEGREGATION; CENP-A; ECTOPIC LOCALIZATION; N-TERMINUS; KINETOCHORE; CHROMATIN; DNA; SCM3 AB Evolutionarily conserved histone H3 variant Cse4 and its homologues are essential components of specialized centromere (CEN)-specific nucleosomes and serve as an epigenetic mark for CEN identity and propagation. Cse4 is a critical determinant for the structure and function of the kinetochore and is required to ensure faithful chromosome segregation. The kinetochore protein Pat1 regulates the levels and spatial distribution of Cse4 at centromeres. Deletion of PAT1 results in altered structure of CEN chromatin and chromosome segregation errors. In this study, we show that Pat1 protects CEN-associated Cse4 from ubiquitination in order to maintain proper structure and function of the kinetochore in budding yeast. PAT1-deletion strains exhibit increased ubiquitination of Cse4 and faster turnover of Cse4 at kinetochores. Psh1, a Cse4-specific E3-ubiquitin ligase, interacts with Pat1 in vivo and contributes to the increased ubiquitination of Cse4 in pat1 Delta strains. Consistent with a role of Psh1 in ubiquitination of Cse4, transient induction of PSH1 in a wildtype strain resulted in phenotypes similar to a pat1. strain, including a reduction in CEN-associated Cse4, increased Cse4 ubiquitination, defects in spatial distribution of Cse4 at kinetochores, and altered structure of CEN chromatin. Pat1 interacts with Scm3 and is required for its maintenance at kinetochores. In conclusion, our studies provide novel insights into mechanisms by which Pat1 affects the structure of CEN chromatin and protects Cse4 from Psh1-mediated ubiquitination for faithful chromosome segregation. C1 [Mishra, Prashant K.; Dittman, Lauren E.; Basrai, Munira A.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Guo, Jiasheng; Haase, Julian; Yeh, Elaine; Bloom, Kerry] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. RP Basrai, MA (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM basraim@mail.nih.gov OI Bloom, Kerry/0000-0002-3457-004X FU National Cancer Institute, National Institutes of Health; National Institute of Health [R37 GM32238] FX We thank Jennifer Gerton, Sue Biggins, Roy Parker, Michael Lichten, and Richard Baker for reagents, Kathy McKinnon of the National Cancer Institute Vaccine Branch FACS Core for assistance with FACS, Wei-Chun Au for assistance with the ubiquitin pull-down assay, and members of the Basrai laboratory for discussions. Support for P.K.M., L.E.D., and M.A.B. was provided by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Support for J.G., J.H., E.Y., and K.B. was derived from National Institute of Health Grant R37 GM32238 to K.B. NR 57 TC 3 Z9 3 U1 0 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN 1 PY 2015 VL 26 IS 11 BP 2067 EP 2079 DI 10.1091/mbc.E14-08-1335 PG 13 WC Cell Biology SC Cell Biology GA CJ1LP UT WOS:000355245400009 PM 25833709 ER PT J AU Iglesias-Bartolome, R Torres, D Marone, R Feng, XD Martin, D Simaan, M Chen, M Weinstein, LS Taylor, SS Molinolo, AA Gutkind, JS AF Iglesias-Bartolome, Ramiro Torres, Daniela Marone, Romina Feng, Xiaodong Martin, Daniel Simaan, May Chen, Min Weinstein, Lee S. Taylor, Susan S. Molinolo, Alfredo A. Gutkind, J. Silvio TI Inactivation of a G alpha(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis SO NATURE CELL BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; HEDGEHOG SIGNALING PATHWAY; MOUSE EPIDERMIS; YAP PATHWAY; CANCER; DIFFERENTIATION; PROLIFERATION; KINASE; MERLIN; ALPHA AB Genomic alterations in GNAS, the gene coding for the G alpha(s) heterotrimeric G protein, are associated with a large number of human diseases. Here, we explored the role of G alpha(s) on stem cell fate decisions by using the mouse epidermis as a model system. Conditional epidermal deletion of Gnas or repression of PKA signalling caused a remarkable expansion of the stem cell compartment, resulting in rapid basal-cell carcinoma formation. In contrast, inducible expression of active G alpha(s) in the epidermis caused hair follicle stem cell exhaustion and hair loss. Mechanistically, we found that G alpha(s)-PKA disruption promotes the cell autonomous Sonic Hedgehog pathway stimulation and Hippo signalling inhibition, resulting in the non-canonical activation of GLI and YAP1. Our study highlights an important tumour suppressive function of G alpha(s)-PKA, limiting the proliferation of epithelial stem cells and maintaining proper hair follicle homeostasis. These findings could have broad implications in multiple pathophysiological conditions, including cancer. C1 [Iglesias-Bartolome, Ramiro; Torres, Daniela; Marone, Romina; Feng, Xiaodong; Martin, Daniel; Simaan, May; Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Chen, Min; Weinstein, Lee S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Taylor, Susan S.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Taylor, Susan S.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov FU Intramural Research Program at the National Institutes of Health, National Institute of Dental and Craniofacial Research; Swiss National Science Foundation (Advanced Postdoc Mobility fellowship, SNF); Margarete und Walter Lichtenstein Stiftung; [DK54441] FX This work was supported by the Intramural Research Program at the National Institutes of Health, National Institute of Dental and Craniofacial Research. R.M. was supported by grants from the Swiss National Science Foundation (Advanced Postdoc Mobility fellowship, SNF) and the Margarete und Walter Lichtenstein Stiftung. S.S.T. was supported by grant DK54441. NR 64 TC 18 Z9 18 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUN PY 2015 VL 17 IS 6 BP 793 EP + DI 10.1038/ncb3164 PG 24 WC Cell Biology SC Cell Biology GA CJ1XD UT WOS:000355277500011 PM 25961504 ER PT J AU Moriarity, BS Otto, GM Rahrmann, EP Rathe, SK Wolf, NK Weg, MT Manlove, LA Larue, RS Temiz, NA Molyneux, SD Choi, K Holly, KJ Sarver, AL Scott, MC Forster, CL Modiano, JF Khanna, C Hewitt, SM Khokha, R Yang, Y Gorlick, R Dyer, MA Largaespada, DA AF Moriarity, Branden S. Otto, George M. Rahrmann, Eric P. Rathe, Susan K. Wolf, Natalie K. Weg, Madison T. Manlove, Luke A. LaRue, Rebecca S. Temiz, Nuri A. Molyneux, Sam D. Choi, Kwangmin Holly, Kevin J. Sarver, Aaron L. Scott, Milcah C. Forster, Colleen L. Modiano, Jaime F. Khanna, Chand Hewitt, Stephen M. Khokha, Rama Yang, Yi Gorlick, Richard Dyer, Michael A. Largaespada, David A. TI A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis SO NATURE GENETICS LA English DT Article ID NERVE SHEATH TUMOR; POOR-PROGNOSIS; HEPATOCELLULAR-CARCINOMA; NEUROFIBROMATOSIS TYPE-1; CELL-PROLIFERATION; OSTEOGENIC-SARCOMA; COLORECTAL-CANCER; PROSTATE-CANCER; COPY NUMBER; EXPRESSION AB Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. C1 [Moriarity, Branden S.; Otto, George M.; Rahrmann, Eric P.; Largaespada, David A.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Moriarity, Branden S.; Otto, George M.; Rahrmann, Eric P.; Largaespada, David A.] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN USA. [Moriarity, Branden S.; Otto, George M.; Rahrmann, Eric P.; Largaespada, David A.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Otto, George M.; Rahrmann, Eric P.; Wolf, Natalie K.; Weg, Madison T.; Manlove, Luke A.; Holly, Kevin J.; Largaespada, David A.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA. [LaRue, Rebecca S.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Molyneux, Sam D.; Khokha, Rama] Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. [Choi, Kwangmin] Cincinnati Childrens Hosp Med Ctr, Cincinnati Childrens Hosp Res Fdn, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Scott, Milcah C.; Modiano, Jaime F.] Univ Minnesota, Dept Vet Clin Sci, St Paul, MN 55108 USA. [Forster, Colleen L.] Univ Minnesota, Acad Hlth Ctr, BioNet, Minneapolis, MN USA. [Modiano, Jaime F.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, TARP, Pathol Lab, Bethesda, MD 20892 USA. [Yang, Yi] Peking Univ, Peoples Hosp, Musculoskeletal Tumor Ctr, Dept Orthoped Surg, Beijing 100871, Peoples R China. [Gorlick, Richard] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Gorlick, Richard] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10467 USA. [Dyer, Michael A.] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. RP Largaespada, DA (reprint author), Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. EM larga002@umn.edu OI Hewitt, Stephen/0000-0001-8283-1788; Modiano, Jaime/0000-0001-6398-7648 FU US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Musculoskeletal Training Grant [AR050938]; Sobiech Osteosarcoma Fund Award; Children's Cancer Research Fund; American Cancer Center Research Professor Grant [123939]; National Cancer Institute grant [R01 CA113636]; comprehensive Masonic Cancer Center (US National Institutes of Health grant) [P30 CA077598] FX B.S.M. was funded by US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Musculoskeletal Training Grant AR050938. This research was funded by the Sobiech Osteosarcoma Fund Award, the Children's Cancer Research Fund, an American Cancer Center Research Professor Grant (123939) and National Cancer Institute grant R01 CA113636 (to D.A.L.). We extend our thanks to the University of Minnesota resources involved in our project. The University of Minnesota Genomics Center provided services for RNA sequencing, oligonudeotide preparation and Sanger sequencing. The Minnesota Supercomputing Institute maintains the Galaxy software platform, as well as provides data management services and training. The cytogenetic analyses were performed in the Cytogenomics Shared Resource at the University of Minnesota with support from the comprehensive Masonic Cancer Center (US National Institutes of Health grant P30 CA077598). NR 80 TC 41 Z9 41 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2015 VL 47 IS 6 BP 615 EP 624 DI 10.1038/ng.3293 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CJ3LW UT WOS:000355386500012 PM 25961939 ER PT J AU Li, AH Morrison, AC Kovar, C Cupples, LA Brody, JA Polfus, LM Yu, B Metcalf, G Muzny, D Veeraraghavan, N Liu, XM Lumley, T Mosley, TH Gibbs, RA Boerwinkle, E AF Li, Alexander H. Morrison, Alanna C. Kovar, Christie Cupples, L. Adrienne Brody, Jennifer A. Polfus, Linda M. Yu, Bing Metcalf, Ginger Muzny, Donna Veeraraghavan, Narayanan Liu, Xiaoming Lumley, Thomas Mosley, Thomas H. Gibbs, Richard A. Boerwinkle, Eric TI Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease SO NATURE GENETICS LA English DT Article ID GENES; PREDICTIONS; MUTATIONS; DATABASE; DBNSFP AB A typical human exome harbors dozens of loss-of-function (LOF) variants(1), which can lower disease risk factor levels and affect drug efficacy(2). We hypothesized that LOF variants are enriched in genes influencing risk factor levels and the onset of common chronic diseases, such as cardiovascular disease and diabetes. To test this hypothesis, we sequenced the exomes of 8,554 individuals and analyzed the effects of predicted LOF variants on 20 chronic disease risk factor phenotypes. Analysis of this sample as discovery and replication strata of equal size verified two relationships in well-studied genes (PCSK9 and APOC3) and identified eight new loci. Previously unknown relationships included elevated fasting glucose in carriers of heterozygous LOF variation in TXNDC5, which encodes a biomarker for type 1 diabetes progression, and apparent recessive effects of C1QTNF8 on serum magnesium levels. These data demonstrate the utility of functional-variant annotation within a large sample of deeply phenotyped individuals for gene discovery. C1 [Li, Alexander H.; Morrison, Alanna C.; Polfus, Linda M.; Yu, Bing; Liu, Xiaoming; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Kovar, Christie; Metcalf, Ginger; Muzny, Donna; Veeraraghavan, Narayanan; Gibbs, Richard A.; Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Cupples, L. Adrienne] NHLBI Framingham Heart Study, Framingham, MA USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Brody, Jennifer A.; Lumley, Thomas] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med Geriatr, Jackson, MS 39216 USA. RP Boerwinkle, E (reprint author), Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. EM eric.boerwinkle@uth.tmc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institutes of Health through the American Recovery and Reinvestment Act of 2009 (AREA) [5RC2HL102419]; Baylor College of Medicine Human Genome Sequencing Center [U54 HG003273] FX The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C). We thank the staff and participants of the ARIC study for their important contributions. Funding support for "Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium" was provided by the National Institutes of Health through the American Recovery and Reinvestment Act of 2009 (AREA) (5RC2HL102419). Sequencing was carried out at the Baylor College of Medicine Human Genome Sequencing Center (U54 HG003273). NR 16 TC 12 Z9 12 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUN PY 2015 VL 47 IS 6 BP 640 EP 642 DI 10.1038/ng.3270 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA CJ3LW UT WOS:000355386500015 PM 25915599 ER PT J AU Viswanathan, S Williams, ME Bloss, EB Stasevich, TJ Speer, CM Nern, A Pfeiffer, BD Hooks, BM Li, WP English, BP Tian, T Henry, GL Macklin, JJ Patel, R Gerfen, CR Zhuang, XW Wang, YL Rubin, GM Looger, LL AF Viswanathan, Sarada Williams, Megan E. Bloss, Erik B. Stasevich, Timothy J. Speer, Colenso M. Nern, Aljoscha Pfeiffer, Barret D. Hooks, Bryan M. Li, Wei-Ping English, Brian P. Tian, Teresa Henry, Gilbert L. Macklin, John J. Patel, Ronak Gerfen, Charles R. Zhuang, Xiaowei Wang, Yalin Rubin, Gerald M. Looger, Loren L. TI High-performance probes for light and electron microscopy SO NATURE METHODS LA English DT Article ID GREEN FLUORESCENT PROTEIN; LIVING CELLS; DIFFUSION-COEFFICIENTS; MONOCLONAL-ANTIBODIES; ARRAY TOMOGRAPHY; MAMMALIAN-CELLS; NEURAL CIRCUITS; GENE-TRANSFER; DROSOPHILA; SYSTEM AB We describe an engineered family of highly antigenic molecules based on GFP-like fluorescent proteins. These molecules contain numerous copies of peptide epitopes and simultaneously bind IgG antibodies at each location. These 'spaghetti monster' fluorescent proteins (smFPs) distributed well in neurons, notably into small dendrites, spines and axons. smFP immunolabeling localized weakly expressed proteins not well resolved with traditional epitope tags. By varying epitope and scaffold, we generated a diverse family of mutually orthogonal antigens. In cultured neurons and mouse and fly brains, smFP probes allowed robust, orthogonal multicolor visualization of proteins, cell populations and neuropil. smFP variants complement existing tracers and greatly increase the number of simultaneous imaging channels, and they performed well in advanced preparations such as array tomography, super-resolution fluorescence imaging and electron microscopy. In living cells, the probes improved single-molecule image tracking and increased yield for RNA-seq. These probes facilitate new experiments in connectomics, transcriptomics and protein localization. C1 [Viswanathan, Sarada; Bloss, Erik B.; Stasevich, Timothy J.; Nern, Aljoscha; Pfeiffer, Barret D.; Hooks, Bryan M.; Li, Wei-Ping; English, Brian P.; Tian, Teresa; Henry, Gilbert L.; Macklin, John J.; Patel, Ronak; Wang, Yalin; Rubin, Gerald M.; Looger, Loren L.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Williams, Megan E.] Univ Utah, Dept Neurobiol & Anat, Salt Lake City, UT USA. [Speer, Colenso M.; Zhuang, Xiaowei] Harvard Univ, Howard Hughes Med Inst, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Hooks, Bryan M.; Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Zhuang, Xiaowei] Harvard Univ, Howard Hughes Med Inst, Dept Phys, Cambridge, MA 02138 USA. RP Looger, LL (reprint author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. EM loogerl@janelia.hhmi.org RI English, Brian/O-8156-2016; OI English, Brian/0000-0002-4037-6294; Williams, Megan/0000-0002-5461-4126; Rubin, Gerald/0000-0001-8762-8703 FU Howard Hughes Medical Institute FX We thank the Cell Culture, Vivarium, Fly Facility, Histology, Electron Microscopy, Media and Molecular Biology Shared Resources, and the Fly Light Project Team, at Janelia. N. Betley, A. Hantman, J. Colonell, J.-C. Rah, S. Sengupta, M. Baird and G. Tervo provided helpful discussions. H. Su and H. Kimura helped with reagents, B. Karsh assisted with image alignment for immunoEM and AT, and H. Rouault helped with statistical analysis. Members of the Looger lab and M. Jefferies provided helpful feedback during the project. A. Hantman and K. Ritola (Janelia) provided the mTagBFP2 virus. This work was supported by the Howard Hughes Medical Institute. NR 70 TC 22 Z9 22 U1 13 U2 81 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 JUN PY 2015 VL 12 IS 6 BP 568 EP + DI 10.1038/nmeth.3365 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CJ1MQ UT WOS:000355248100028 PM 25915120 ER PT J AU Garfield, AS Li, C Madara, JC Shah, BP Webber, E Steger, JS Campbell, JN Gavrilova, O Lee, CE Olson, DP Elmquist, JK Tannous, BA Krashes, MJ Lowell, BB AF Garfield, Alastair S. Li, Chia Madara, Joseph C. Shah, Bhavik P. Webber, Emily Steger, Jennifer S. Campbell, John N. Gavrilova, Oksana Lee, Charlotte E. Olson, David P. Elmquist, Joel K. Tannous, Bakhos A. Krashes, Michael J. Lowell, Bradford B. TI A neural basis for melanocortin-4 receptor-regulated appetite SO NATURE NEUROSCIENCE LA English DT Article ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; MELANOCYTE-STIMULATING HORMONE; PROTEIN-COUPLED RECEPTORS; AGOUTI-RELATED PROTEIN; PARABRACHIAL NUCLEUS; FEEDING-BEHAVIOR; AGRP NEURONS; RNA-SEQ; LATERAL HYPOTHALAMUS; FRAMESHIFT MUTATION AB Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVHMC4R neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVHMC4R -> lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVHMC4R -> LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development. C1 [Garfield, Alastair S.; Madara, Joseph C.; Shah, Bhavik P.; Steger, Jennifer S.; Campbell, John N.; Olson, David P.; Lowell, Bradford B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab,Dept Med, Boston, MA 02215 USA. [Garfield, Alastair S.] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland. [Li, Chia; Webber, Emily; Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Li, Chia; Webber, Emily; Krashes, Michael J.] NIDA, NIH, Baltimore, MD USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core, NIH, Bethesda, MD 20892 USA. [Lee, Charlotte E.; Elmquist, Joel K.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hypothalam Res, Dallas, TX 75390 USA. [Tannous, Bakhos A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Lowell, Bradford B.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. RP Lowell, BB (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab,Dept Med, Boston, MA 02215 USA. EM agarfiel@staffmail.ed.ac.uk; michael.krashes@nih.gov; blowell@bidmc.harvard.edu FU Boston Area Diabetes Endocrinology Research Center [BADERC P30 DK057521]; University of Edinburgh; US National Institutes of Health [R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, F32 DK089710, K08 DK071561, R01 DK088423, R37 DK0053301]; US National Institutes of Health (BNORC Transgenic Core) [P30 DK046200]; US National Institutes of Health (BADERC Transgenic Core) [P30 DK057521]; American Heart Association [14POST20100011]; viral vector production core [P30 NS045776]; American Diabetes Association; NIH, NIDDK [DK075087, DK075088] FX The authors gratefully acknowledge the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Mouse Metabolism Core for technical support, V. Petkova and the Beth Israel Deaconess Medical Center Molecular Medicine Core Facility for assistance with quantitative PCR and sample preparation, and D. Morse for the production of the rabies virus. Sequencing and initial data processing were performed at Massachusetts General Hospital's Next-Gen Sequencing Core. Sequencing was supported in part by funding from the Boston Area Diabetes Endocrinology Research Center (BADERC P30 DK057521). This work was supported by the University of Edinburgh Chancellor's Fellowship (A.S.G.); US National Institutes of Health grants to B.B.L. (R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, BNORC Transgenic Core P30 DK046200, BADERC Transgenic Core P30 DK057521), to M.J.K. (F32 DK089710), to D.P.O. (K08 DK071561) and to J.K.E. (R01 DK088423 and R37 DK0053301); American Heart Association Postdoctoral Fellowship 14POST20100011 to J.N.C.; viral vector production core P30 NS045776 to B.A.T.; and an American Diabetes Association Mentor-Based Fellowship to B.P.S. and B.B.L. This research was supported, in part, by the Intramural Research Program of the NIH, NIDDK (DK075087, DK075088). NR 63 TC 50 Z9 50 U1 3 U2 26 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 JUN PY 2015 VL 18 IS 6 BP 863 EP U299 DI 10.1038/nn.4011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CJ1CB UT WOS:000355218300014 PM 25915476 ER PT J AU Long, MT Pedley, A Massaro, JM Hoffmann, U Esliger, DW Vasan, RS Fox, CS Murabito, JM AF Long, Michelle T. Pedley, Alison Massaro, Joseph M. Hoffmann, Udo Esliger, Dale W. Vasan, Ramachandran S. Fox, Caroline S. Murabito, Joanne M. TI Hepatic steatosis is associated with lower levels of physical activity measured via accelerometry SO OBESITY LA English DT Article ID FATTY LIVER-DISEASE; ALL-CAUSE MORTALITY; UNITED-STATES; RISK-FACTORS; WEIGHT-LOSS; INSULIN SENSITIVITY; EXERCISE; ADULTS; POPULATION; HEALTH AB ObjectivePrior studies on the association of physical activity (PA) and nonalcoholic fatty liver disease are limited by reliance on subjective measures of PA. We examined the association between objectively measured PA and hepatic steatosis defined by computed tomography (CT). MethodsWe conducted a cross-sectional study of 1,060 Framingham Heart Study participants who participated in the Multidetector CT 2 substudy and who underwent assessment of PA via accelerometry. Hepatic steatosis was estimated by liver attenuation, as measured by CT. We explored the relationship between liver attenuation and PA using multivariable regression models. ResultsIn multivariable-adjusted models, we observed an inverse association between PA and liver attenuation. Each 30 minutes/day increase in moderate to vigorous PA (MVPA) was associated with a reduced odds of hepatic steatosis (OR = 0.62, P < 0.001). This association was attenuated and no longer statistically significant after adjustment for body mass index (BMI) (OR = 0.77, P = 0.05) or visceral adipose tissue (VAT) (OR = 0.83, P = 0.18). Participants who met the national PA recommendations of engaging in 150 minutes/week of MVPA had the lowest odds of hepatic steatosis, even after adjusting for BMI (OR = 0.63, P = 0.007) or VAT (OR = 0.67, P = 0.03). ConclusionsThere is an inverse association between PA and hepatic steatosis. Participants who met the national PA guidelines had the lowest prevalence of hepatic steatosis. C1 [Long, Michelle T.] Boston Univ, Sch Med, Boston Med Ctr, Div Gastroenterol, Boston, MA 02118 USA. [Long, Michelle T.; Pedley, Alison; Massaro, Joseph M.; Vasan, Ramachandran S.; Fox, Caroline S.; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Esliger, Dale W.] Univ Loughborough, Sch Sport Exercise & Hlth Sci, Loughborough, Leics, England. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Murabito, JM (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. EM murabito@bu.edu OI Long, Michelle/0000-0001-6131-3981; Ramachandran, Vasan/0000-0001-7357-5970 FU Boston University School of Medicine; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Division of Intramural Research of the National Heart, Lung, and Blood Institute; NIH [1RO1-AG-047645]; Boston University Clinical and Translational Science Institute [UL1-TR000157] FX This work was supported by the Boston University School of Medicine, the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195), and the Division of Intramural Research of the National Heart, Lung, and Blood Institute. We received additional support from the NIH grant 1RO1-AG-047645. Dr. Long is supported in part by the Boston University Clinical and Translational Science Institute (grant UL1-TR000157). NR 39 TC 4 Z9 4 U1 0 U2 2 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 JUN PY 2015 VL 23 IS 6 BP 1259 EP 1266 DI 10.1002/oby.21058 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CJ0FG UT WOS:000355150300019 PM 25959049 ER PT J AU Kwilas, AR Gameiro, SR Kim, PS Malamas, AS Hodge, JW AF Kwilas, Anna R. Gameiro, Sofia R. Kim, Peter S. Malamas, Anthony S. Hodge, James W. TI Improving clinical benefit for prostate cancer patients through the combination of androgen deprivation and immunotherapy SO ONCOIMMUNOLOGY LA English DT Editorial Material DE Androgen-deprivation therapy; cancer immunotherapy; enzalutamide; immunogenic modulation; therapeutic cancer vaccine ID THERAPY; SURVIVAL; VACCINE; CELLS AB Androgen-deprivation therapy (ADT) induces prostate cancer immunogenic modulation (IM) by reducing human tumor cell expression of anti-apoptotic genes thus facilitating increased sensitivity to immune-mediated lysis. Through its stimulation of IM, ADT has been shown to synergize with active immunotherapy thereby significantly improving overall survival in a mouse model of prostate cancer. C1 [Kwilas, Anna R.; Gameiro, Sofia R.; Kim, Peter S.; Malamas, Anthony S.; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jh241d@nih.gov NR 10 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD JUN PY 2015 VL 4 IS 6 DI 10.1080/2162402X.2015.1009303 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA CJ0XK UT WOS:000355203300023 ER PT J AU Arora, NK Hesse, BW Clauser, SB AF Arora, Neeraj K. Hesse, Bradford W. Clauser, Steven B. TI Walking in the Shoes of Patients, Not Just in Their Genes: A Patient-Centered Approach to Genomic Medicine SO PATIENT-PATIENT CENTERED OUTCOMES RESEARCH LA English DT Article ID BREAST-CANCER-TREATMENT; HEALTH-CARE; SYMPTOM MANAGEMENT; COLORECTAL-CANCER; SURVEILLANCE; PREVENTION; DECISIONS; IMPACT; ASSAY; RISK AB Genomic technologies are increasing the precision with which clinicians can assess an individual patient's risk for developing diseases and identify which patients are likely to benefit from specific treatments. Also advocating for a shift away from a one-size-fits-all approach is the growing emphasis on "patient-centered" care. Using examples from breast cancer, we make a case for why, in order to optimize patient health outcomes, genomic medicine will need to be practiced within a patient-centered framework. We present a six-function conceptual framework for patient-centered care and discuss findings from a national survey evaluating the patient-centeredness of care delivered in the USA. C1 [Arora, Neeraj K.; Hesse, Bradford W.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Clauser, Steven B.] Patient Ctr Outcomes Res Inst, Washington, DC USA. RP Arora, NK (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 9609 Med Ctr Dr,3E514,MSC 9762, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 NR 46 TC 6 Z9 6 U1 4 U2 8 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1178-1653 EI 1178-1661 J9 PATIENT JI Patient PD JUN PY 2015 VL 8 IS 3 BP 239 EP 245 DI 10.1007/s40271-014-0089-5 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CJ0WD UT WOS:000355199000001 PM 25300612 ER PT J AU Chuang, GY Zhang, BS Mckee, K O'Dell, S Do Kwon, Y Zhou, TQ Blinn, J Lloyd, K Parks, R Von Holle, T Ko, SY Kong, WP Pegu, A Wang, KY Baruah, K Crispin, M Mascola, JR Moody, MA Haynes, BF Georgiev, IS Kwong, PD AF Chuang, Gwo-Yu Zhang, Baoshan McKee, Krisha O'Dell, Sijy Kwon, Young Do Zhou, Tongqing Blinn, Julie Lloyd, Krissey Parks, Robert Von Holle, Tarra Ko, Sung-Youl Kong, Wing-Pui Pegu, Amarendra Wang, Keyun Baruah, Kavitha Crispin, Max Mascola, John R. Moody, M. Anthony Haynes, Barton F. Georgiev, Ivelin S. Kwong, Peter D. TI Eliminating antibody polyreactivity through addition of N-linked glycosylation SO PROTEIN SCIENCE LA English DT Article DE polyreactivity; antibody engineering; bioinformatics; broadly neutralizing antibody; glycan engineering ID NEUTRALIZING HIV-1 ANTIBODY; SIDE-CHAIN CONFORMATIONS; THERAPEUTIC ANTIBODIES; MONOCLONAL-ANTIBODY; B-CELLS; IMPROVES PROTECTION; CD4-BINDING SITE; STRUCTURAL BASIS; VARIABLE-REGION; RATIONAL DESIGN AB Antibody polyreactivity can be an obstacle to translating a candidate antibody into a clinical product. Standard tests such as antibody binding to cardiolipin, HEp-2 cells, or nuclear antigens provide measures of polyreactivity, but its causes and the means to resolve are often unclear. Here we present a method for eliminating antibody polyreactivity through the computational design and genetic addition of N-linked glycosylation near known sites of polyreactivity. We used the HIV-1-neutralizing antibody, VRC07, as a test case, since efforts to increase VRC07 potency at three spatially distinct sites resulted in enhanced polyreactivity. The addition of N-linked glycans proximal to the polyreactivity-enhancing mutations at each of the spatially distinct sites resulted in reduced antibody polyreactivity as measured by (i) anti-cardiolipin ELISA, (ii) Luminex AtheNA Multi-Lyte ANA binding, and (iii) HEp-2 cell staining. The reduced polyreactivity trended with increased antibody concentration over time in mice, but not with improved overall protein stability as measured by differential scanning calorimetry. Moreover, glycan proximity to the site of polyreactivity appeared to be a critical factor. The results provide evidence that antibody polyreactivity can result from local, rather than global, features of an antibody and that addition of N-linked glycosylation can be an effective approach to reducing antibody polyreactivity. C1 [Chuang, Gwo-Yu; Zhang, Baoshan; McKee, Krisha; O'Dell, Sijy; Kwon, Young Do; Zhou, Tongqing; Ko, Sung-Youl; Kong, Wing-Pui; Pegu, Amarendra; Wang, Keyun; Mascola, John R.; Georgiev, Ivelin S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Blinn, Julie; Lloyd, Krissey; Parks, Robert; Von Holle, Tarra; Moody, M. Anthony; Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Med Ctr, Durham, NC 10302 USA. [Baruah, Kavitha; Crispin, Max] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program of the Vaccine Research Center, NIAID; Office of AIDS Research, NIH FX Grant sponsor: Intramural Research Program of the Vaccine Research Center, NIAID, and the Office of AIDS Research, NIH. NR 40 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUN PY 2015 VL 24 IS 6 BP 1019 EP 1030 DI 10.1002/pro.2682 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ0FM UT WOS:000355151200011 PM 25800131 ER PT J AU Khan, I Tang, E Arany, P AF Khan, Imran Tang, Elieza Arany, Praveen TI Molecular pathway of near-infrared laser phototoxicity involves ATF-4 orchestrated ER stress SO SCIENTIFIC REPORTS LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ACTIVATING TRANSCRIPTION FACTOR-4; BIPHASIC DOSE-RESPONSE; LEVEL LIGHT THERAPY; ENDOPLASMIC-RETICULUM; OXIDATIVE STRESS; IN-VITRO; CELLS; IRRADIATION; NEURONS AB High power lasers are used extensively in medicine while lower power applications are popular for optical imaging, optogenetics, skin rejuvenation and a therapeutic modality termed photobiomodulation (PBM). This study addresses the therapeutic dose limits, biological safety and molecular pathway of near-infrared (NIR) laser phototoxicity. Increased erythema and tissue damage were noted in mice skin and cytotoxicity in cell cultures at phototoxic laser doses involving generation of reactive oxygen species (ROS) coupled with a rise in surface temperature(>45 degrees C). NIR laser phototoxicity results from Activating Transcription Factor-4 (ATF-4) mediated endoplasmic reticulum stress and autophagy. Neutralizations of heat or ROS and overexpressing ATF-4 were noted to rescue NIR laser phototoxicity. Further, NIR laser mediated phototoxicity was noted to be non-genotoxic and non-mutagenic. This study outlines the mechanism of NIR laser phototoxicity and the utility of monitoring surface temperature and ATF4 expression as potential biomarkers to develop safe and effective clinical applications. C1 [Khan, Imran; Tang, Elieza; Arany, Praveen] Natl Inst Dent & Craniofacial Res, Cell Regulat & Control Unit, NIH, Bethesda, MD 20892 USA. RP Arany, P (reprint author), Natl Inst Dent & Craniofacial Res, Cell Regulat & Control Unit, NIH, Bethesda, MD 20892 USA. EM praveenarany@gmail.com FU Intramural research program of National Institute of Dental and Craniofacial Research, National Institutes of Health FX We would like to thank Abhinav Seetharaman, Suneetha Gottumukkala, Monica Ashok and Karl Engel for help with experiments. We thank Silvio Gutkind, Kathy Carbone, Pamela Kearney, Lauren Davidson, Matthew Starost, Murali Cherukuri, Sushil Rane and Lalage Wakefield for critical inputs in these studies. This work was supported by the Intramural research program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 57 TC 8 Z9 8 U1 3 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 1 PY 2015 VL 5 AR 10581 DI 10.1038/srep10581 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ6JC UT WOS:000355599100001 PM 26030745 ER PT J AU Feigin, VL Krishnamurthi, R Bhattacharjee, R Parmar, P Theadom, A Hussein, T Purohit, M Hume, P Abbott, M Rush, E Kasabov, N Crezee, I Frielick, S Barker-Collo, S Barber, PA Arroll, B Poulton, R Ratnasabathy, Y Tobias, M Cabral, N Martins, SCO Furtado, LETA Lindsay, P Saposnik, G Giroud, M Bejot, Y Hacke, W Mehndiratta, MM Pandian, JD Gupta, S Padma, V Mandal, DK Kokubo, Y Ibrahim, NM Sahathevan, R Fu, H Wang, WZ Liu, L Hou, ZG Goncalves, AF Correia, M Varakin, Y Kravchenko, M Piradov, M Saadah, M Thrift, AG Cadilhac, D Davis, S Donnan, G Lopez, AD Hankey, GJ Maujean, A Kendall, E Brainin, M Abd-Allah, F Bornstein, NM Caso, V Marquez-Romero, JM Akinyemi, RO Bin Dhim, NF Norrving, B Sindi, S Kivipelto, M Mendis, S Ikram, MA Hofman, A Mirza, SS Rothwell, PM Sandercock, P Shakir, R Sacco, RL Culebras, A Roth, GA Moradi-Lakeh, M Murray, C Narayan, V Mensah, GA Wiebers, D Moran, AE AF Feigin, Valery L. Krishnamurthi, Rita Bhattacharjee, Rohit Parmar, Priya Theadom, Alice Hussein, Tasleem Purohit, Mitali Hume, Patria Abbott, Max Rush, Elaine Kasabov, Nikola Crezee, Ineke Frielick, Stanley Barker-Collo, Suzanne Barber, P. Alan Arroll, Bruce Poulton, Richie Ratnasabathy, Yogini Tobias, Martin Cabral, Norberto Martins, Sheila C. O. Furtado, Luis E. T. A. Lindsay, Patrice Saposnik, Gustavo Giroud, Maurice Bejot, Yannick Hacke, Werner Mehndiratta, Man Mohan Pandian, Jeyaraj Durai Gupta, Sanjeev Padma, Vasantha Mandal, Dipes Kumar Kokubo, Yoshihiro Ibrahim, Norlinah Mohamed Sahathevan, Ramesh Fu, Hua Wang, Wenzhi Liu, Liping Hou, Zeng-Guang Goncalves, Antonio Freire Correia, Manuel Varakin, Yury Kravchenko, Michael Piradov, Michael Saadah, Mohammed Thrift, Amanda G. Cadilhac, Dominique Davis, Stephen Donnan, Geoffrey Lopez, Alan D. Hankey, Graeme J. Maujean, Annick Kendall, Elizabeth Brainin, Michael Abd-Allah, Foad Bornstein, Natan M. Caso, Valeria Manuel Marquez-Romero, Juan Akinyemi, Rufus O. Bin Dhim, Nasser F. Norrving, Bo Sindi, Shireen Kivipelto, Miia Mendis, Shanthi Ikram, M. Arfan Hofman, Albert Mirza, Saira Saeed Rothwell, Peter M. Sandercock, Peter Shakir, Raad Sacco, Ralph L. Culebras, Antonio Roth, Gregory A. Moradi-Lakeh, Maziar Murray, Christopher Narayan, Venkat Mensah, George A. Wiebers, David Moran, Andrew E. CA RIBURST Study Collaboration Writin TI New Strategy to Reduce the Global Burden of Stroke SO STROKE LA English DT Review DE prevention and control; stroke ID RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR-DISEASE; RISK-FACTORS; SMARTPHONE APPLICATION; SYSTEMATIC ANALYSIS; NONCOMMUNICABLE DISEASES; PRIMARY PREVENTION; PUBLIC AWARENESS; ISCHEMIC-STROKE; 21 REGIONS C1 [Feigin, Valery L.; Krishnamurthi, Rita; Bhattacharjee, Rohit; Parmar, Priya; Theadom, Alice] Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Sch Publ Hlth & Psychosocial Studies, Auckland 1142, New Zealand. [Hume, Patria; Abbott, Max; Rush, Elaine] Auckland Univ Technol, Fac Hlth & Environm Sci, Auckland 1142, New Zealand. [Hussein, Tasleem] Auckland Univ Technol, Informat Technol, Auckland 1142, New Zealand. [Purohit, Mitali] Auckland Univ Technol, Res & Innovat Off, Auckland 1142, New Zealand. [Kasabov, Nikola] Auckland Univ Technol, Knowledge Engn & Discovery Res Inst, Auckland 1142, New Zealand. [Crezee, Ineke] Auckland Univ Technol, Translat & Interpreting Dept, Auckland 1142, New Zealand. [Frielick, Stanley] Auckland Univ Technol, Ctr Learing & Teaching, Auckland 1142, New Zealand. [Barker-Collo, Suzanne] Univ Auckland, Sch Psychol, Auckland 1, New Zealand. [Barber, P. Alan] Univ Auckland, Dept Neurol, Auckland 1, New Zealand. [Arroll, Bruce] Univ Auckland, Sch Publ Hlth, Auckland 1, New Zealand. [Poulton, Richie] Univ Otago, Dept Prevent & Social Med, Dunedin, New Zealand. [Ratnasabathy, Yogini] Older People Care, Waitemata DHB, Auckland, New Zealand. [Tobias, Martin] Minist Hlth, Hlth Intelligence, Wellington, New Zealand. [Cabral, Norberto] Univ Regiao Joinville, Joinville Stroke Register, Joinville, Brazil. [Martins, Sheila C. O.] Hosp Clin Porto Alegre, Hosp Moinhos Vento, Minist Hlth, Porto Alegre, RS, Brazil. [Furtado, Luis E. T. A.] Univ Fed Ceara, Dept Neurol, Sobral Ceara, Brazil. [Lindsay, Patrice] Stroke Fdn Canada, Ottawa, ON, Canada. [Saposnik, Gustavo] Univ Toronto, Dept Med & Hlth Policy, Management & Evaluat, Toronto, ON, Canada. [Giroud, Maurice; Bejot, Yannick] Univ Burgundy, Univ Hosp & Med Sch Dijon, Dijon Stroke Registry, EA4184, Dijon, France. [Hacke, Werner] Heidelberg Univ, Dept Neurol, Heidelberg, Germany. [Mehndiratta, Man Mohan] Janakpuri Super Special Hosp, New Delhi, India. [Pandian, Jeyaraj Durai] Christian Med Coll & Hosp, Dept Neurol, Ludhiana, Punjab, India. [Gupta, Sanjeev] Banarsidas Chandiwala Inst Physiotherapy, New Delhi, India. [Padma, Vasantha] All India Inst Med Sci, New Delhi, India. [Mandal, Dipes Kumar] Stroke Fdn Bengal, Kolkata, W Bengal, India. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Osaka, Japan. [Ibrahim, Norlinah Mohamed; Sahathevan, Ramesh] UKM Med Ctr, Kuala Lumpur, Malaysia. [Fu, Hua] Fudan Univ, Sch Publ Hlth, Shanghai 200433, Peoples R China. [Wang, Wenzhi] Beijing Neurosurg Inst, Beijing, Peoples R China. [Liu, Liping] Capital Med Univ, Beijing, Peoples R China. [Hou, Zeng-Guang] Inst Automat, Beijing, Peoples R China. [Goncalves, Antonio Freire] Univ Hosp Coimbra, Coimbra, Portugal. [Correia, Manuel] Hosp Santo Antoni, Serv Neurol, Oporto, Portugal. [Varakin, Yury; Kravchenko, Michael; Piradov, Michael] Res Ctr Neurol, Moscow, Russia. [Saadah, Mohammed] Univ Emirates, Abu Dhabi, U Arab Emirates. [Thrift, Amanda G.; Cadilhac, Dominique] Monash Univ, Dept Med, Clayton, Vic, Australia. [Davis, Stephen] Univ Melbourne, Royal Melbourne Hosp, Parkville, Vic 3052, Australia. [Donnan, Geoffrey] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia. [Lopez, Alan D.] Univ Melbourne, Publ Hlth, Parkville, Vic 3052, Australia. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Brainin, Michael] Danube Univ, Ctr Clin Neurosci, Vienna, Austria. [Abd-Allah, Foad] Cairo Univ, Cairo, Egypt. [Bornstein, Natan M.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Neurol, IL-69978 Tel Aviv, Israel. [Caso, Valeria] Stroke Unit, Perugia, Italy. [Manuel Marquez-Romero, Juan] IMSS Aguascalientes, HGZ 2, Aguascalientes, Mexico. [Akinyemi, Rufus O.] Fed Med Ctr Abeokuta, Abeokuta, Nigeria. [Bin Dhim, Nasser F.] Saudi Elect Univ, Hlth Informat Dept, Riyadh, Saudi Arabia. [Norrving, Bo] Lund Univ, Dept Neurol, Lund, Sweden. [Sindi, Shireen] Karolinska Inst, Dept Epidemiol, Stockholm, Sweden. [Kivipelto, Miia] Karolinska Inst, Aging Res Ctr, Ctr Alzheimer Res, Stockholm, Sweden. [Mendis, Shanthi] WHO, Noncommun Dis, CH-1211 Geneva, Switzerland. [Ikram, M. Arfan; Hofman, Albert; Mirza, Saira Saeed] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Neurosci, Oxford, England. [Sandercock, Peter] Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. [Shakir, Raad] Imperial Coll NHS Trust, Dept Neurol, London, England. [Sacco, Ralph L.] Univ Miami, Miller Sch Med, Dept Neurol, Coral Gables, FL 33124 USA. [Culebras, Antonio] SUNY Upstate Med Univ, Dept Neurol, Syracuse, NY 13210 USA. [Roth, Gregory A.] Univ Washington, Dept Med, Div Cardiol, Seattle, WA 98195 USA. [Roth, Gregory A.; Moradi-Lakeh, Maziar; Murray, Christopher] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Narayan, Venkat] Emory Univ, Atlanta, GA 30322 USA. [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bethesda, MD 20892 USA. [Wiebers, David] Mayo Clin, Dept Neurol, Rochester, MN USA. [Moran, Andrew E.] Columbia Univ, Med Ctr, Div Gen Med, New York, NY 10027 USA. RP Feigin, VL (reprint author), Auckland Univ Technol, Fac Hlth & Environm Sci, Sch Publ Hlth & Psychosocial Studies, Natl Inst Stroke & Appl Neurosci, AUT North Shore Campus,AA254,90 Akoranga Dr, Auckland 1142, New Zealand. EM valery.feigin@aut.ac.nz RI Hankey, Graeme /H-4968-2014; Crezee, Ineke/B-4876-2016; Piradov, Mikhail/B-4407-2012; Thrift, Amanda/I-6251-2012; Kravchenko, Michael/B-2596-2012; Varakin, Yuriy/C-8634-2012; OI Hankey, Graeme /0000-0002-6044-7328; Crezee, Ineke/0000-0001-6354-1136; Theadom, Alice/0000-0003-0351-6216; Kendall, Elizabeth/0000-0003-2399-1460; Piradov, Mikhail/0000-0002-6055-8335; Thrift, Amanda/0000-0001-8533-4170; Kravchenko, Michael/0000-0001-5187-5518; Piradov, Michael/0000-0002-6338-0392; BinDhim, Nasser F/0000-0001-8117-1044; Donnan, Geoffrey/0000-0001-6324-3403; Barber, P Alan/0000-0003-2469-9023; Sindi, Shireen/0000-0002-3786-0552; Hume, Patria/0000-0003-1847-8128; Cadilhac, Dominique/0000-0001-8162-682X; Moradi-Lakeh, Maziar/0000-0001-7381-5305 FU Auckland University of Technology, Research and Innovation Office, Faculty of Health and Environmental Sciences, Centre for Learning and Teaching; Kiwi Innovation Network Limited, Waikato Mail Centre, Hamilton, New Zealand; Auckland University of Technology Enterprises Ltd at Auckland University of Technology, Auckland, New Zealand FX This study was supported by Auckland University of Technology, Research and Innovation Office, Faculty of Health and Environmental Sciences, Centre for Learning and Teaching and Auckland University of Technology Enterprises Ltd at Auckland University of Technology, Auckland 1142, New Zealand and Kiwi Innovation Network Limited, Waikato Mail Centre, Hamilton, New Zealand. NR 60 TC 14 Z9 15 U1 10 U2 25 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 JUN PY 2015 VL 46 IS 6 BP 1740 EP + DI 10.1161/STROKEAHA.115.008222 PG 10 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CI7KI UT WOS:000354941800066 PM 25882050 ER PT J AU Pahigiannis, K Mott, M Koroshetz, W AF Pahigiannis, Katherine Mott, Meghan Koroshetz, Walter TI Hypertension and Brain Health: Setting Limits National Institute of Neurological Disorders and Stroke Organizational Update SO STROKE LA English DT Editorial Material DE cognitive impairment; dementia; hypertension; stroke ID GUIDELINES C1 [Pahigiannis, Katherine; Mott, Meghan; Koroshetz, Walter] NINDS, NIH, Bethesda, MD 20892 USA. RP Koroshetz, W (reprint author), NINDS, NIH, Bldg 31,Room 8A52,31 Ctr Dr,MSC 2540, Bethesda, MD 20892 USA. EM koroshetzw@mail.nih.gov NR 4 TC 1 Z9 1 U1 0 U2 4 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 JUN PY 2015 VL 46 IS 6 BP E147 EP E148 DI 10.1161/STROKEAHA.115.008763 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CI7KI UT WOS:000354941800006 PM 25922505 ER PT J AU Bousquet, J Anto, JM Berkouk, K Gergen, P Antunes, JP Auge, P Camuzat, T Bringer, J Mercier, J Best, N Bourret, R Akdis, M Arshad, SH Bedbrook, A Berr, C Bush, A Cavalli, G Charles, MA Clavel-Chapelon, F Gillman, M Gold, DR Goldberg, M Holloway, JW Iozzo, P Jacquemin, S Jeandel, C Kauffmann, F Keil, T Koppelman, GH Krauss-Etschmann, S Kuh, D Lehmann, S Carlsen, KCL Maier, D Mechali, M Melen, E Moatti, JP Momas, I Nerin, P Postma, DS Ritchie, K Robine, JM Samolinski, B Siroux, V Slagboom, PE Smit, HA Sunyer, J Valenta, R Van de Perre, P Verdier, JM Vrijheid, M Wickman, M Yiallouros, P Zins, M AF Bousquet, J. Anto, J. M. Berkouk, K. Gergen, P. Antunes, J. Pinto Auge, P. Camuzat, T. Bringer, J. Mercier, J. Best, N. Bourret, R. Akdis, M. Arshad, S. H. Bedbrook, A. Berr, C. Bush, A. Cavalli, G. Charles, M. A. Clavel-Chapelon, F. Gillman, M. Gold, D. R. Goldberg, M. Holloway, J. W. Iozzo, P. Jacquemin, S. Jeandel, C. Kauffmann, F. Keil, T. Koppelman, G. H. Krauss-Etschmann, S. Kuh, D. Lehmann, S. Carlsen, K. C. Lodrup Maier, D. Mechali, M. Melen, E. Moatti, J. P. Momas, I. Nerin, P. Postma, D. S. Ritchie, K. Robine, J. M. Samolinski, B. Siroux, V. Slagboom, P. E. Smit, H. A. Sunyer, J. Valenta, R. Van de Perre, P. Verdier, J. M. Vrijheid, M. Wickman, M. Yiallouros, P. Zins, M. TI Developmental determinants in non-communicable chronic diseases and ageing SO THORAX LA English DT Article DE Asthma; COPD u Mechanisms; Paediatric asthma AB Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases. C1 [Bousquet, J.] Univ Hosp, Montpellier, France. [Bousquet, J.] INSERM, U1168, Paris, France. [Bousquet, J.; Auge, P.; Camuzat, T.; Bringer, J.; Mercier, J.; Best, N.; Bourret, R.; Bedbrook, A.; Berr, C.; Cavalli, G.; Jacquemin, S.; Jeandel, C.; Lehmann, S.; Nerin, P.; Ritchie, K.; Robine, J. M.; Verdier, J. M.] Contre Malad Chron Vieillissement Actif Languedoc, Site Reference EIP AHA, Montpellier, France. [Bousquet, J.; Anto, J. M.; Akdis, M.; Kauffmann, F.; Keil, T.; Koppelman, G. H.; Carlsen, K. C. Lodrup; Maier, D.; Melen, E.; Momas, I.; Postma, D. S.; Siroux, V.; Smit, H. A.; Sunyer, J.; Valenta, R.; Wickman, M.] MeDALL, Mech Dev Allergy, Groningen, Netherlands. [Anto, J. M.; Sunyer, J.; Vrijheid, M.] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Anto, J. M.; Sunyer, J.] IMIM Hosp Mar Med Res Inst, Barcelona, Spain. [Anto, J. M.; Sunyer, J.; Vrijheid, M.] UPF, Barcelona, Spain. [Anto, J. M.; Sunyer, J.; Vrijheid, M.] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Berkouk, K.] Commiss European Communities, DG Res & Innovat, Unit Med Res & Challenge Ageing, Brussels, Belgium. [Gergen, P.] NIAID, Bethesda, MD 20892 USA. [Antunes, J. Pinto] Commiss European Communities, Directorate Gen Hlth & Consumers, B-1049 Brussels, Belgium. [Auge, P.; Mercier, J.] Univ Montpellier I, F-34006 Montpellier, France. [Camuzat, T.] Reg Languedoc Roussillon, Montpellier, France. [Bringer, J.] Montpellier Med Sch, Montpellier, France. [Mercier, J.] Montpellier Univ Hosp, Dept Physiol, Montpellier, France. [Best, N.] Univ Nimes Hosp, Nimes, France. 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[Gillman, M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gold, D. R.] Harvard Univ, Brigham & Womens Hosp, Channing Div Network Med, Dept Med,Med Sch, Boston, MA USA. [Gold, D. R.] Harvard Univ, Sch Publ Hlth, Boston, MA USA. [Goldberg, M.] INSERM, UVSQ, UMS 011, Populat Based Epidemiol Cohorts, Villejuif, France. [Holloway, J. W.] Univ Southampton, Fac Med, Human Dev & Hlth, Southampton SO9 5NH, Hants, England. [Iozzo, P.] CNR, Inst Clin Physiol, I-56100 Pisa, Italy. [Jacquemin, S.] Horiba, Montpellier, France. [Jeandel, C.] Univ Hosp, Dept Geriatr, Montpellier, France. [Kauffmann, F.] Univ Paris 11, CESP Team Resp & Environm Epidemiol, INSERM, UMR S1018, Villejuif, France. [Keil, T.] Charite, Inst Social Med Epidemiol & Hlth Econ, D-13353 Berlin, Germany. [Keil, T.] Julius Maximilian Univ Wuerzburg, Inst Clin Epidemiol & Biometry, Wurzburg, Germany. [Koppelman, G. H.] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Dept Pediat Pulmonol & Pediat Allergol,Groningen, Groningen, Netherlands. [Krauss-Etschmann, S.] Univ Munich, Comprehens Pneumol Ctr, Grosshansdorf, Germany. [Krauss-Etschmann, S.] Helmholtz Zentrum Muenchen, Grosshansdorf, Germany. [Kuh, D.] UCL, MRC Unit Lifelong Hlth & Ageing, London, England. [Lehmann, S.] Univ Hosp, INSERM, U1040, IMRB, Montpellier, France. [Carlsen, K. C. Lodrup] Univ Oslo, Dept Paediat, Oslo, Norway. [Carlsen, K. C. Lodrup] Oslo Univ Hosp, Oslo, Norway. [Maier, D.] Biomax Informat AG, Planegg, Germany. [Melen, E.; Wickman, M.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Melen, E.; Wickman, M.] Karolinska Inst, Sachs Childrens Hosp, Stockholm, Sweden. [Moatti, J. P.] AMU, Res Unit 912, INSERM, IRD Social & Econ Sci Appl Hlth SESSTIM, Marseille, France. [Momas, I.] Descartes Univ, Dept Publ Hlth & Biostat, Paris, France. [Momas, I.] Municipal Dept Social Act Childhood & Hlth, Paris, France. [Nerin, P.] SATT AxLR, Montpellier, France. [Postma, D. S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, GRIAC Res Inst, Groningen, Netherlands. [Ritchie, K.] Univ London Imperial Coll Sci Technol & Med, INSERM, U1061, Neuropsychiat, London, England. [Ritchie, K.] Univ London Imperial Coll Sci Technol & Med, Fac Med, London, England. [Robine, J. M.] INSERM, Res Unit 988, Paris, France. [Robine, J. M.] INSERM, Res Unit 710, Montpellier, France. [Robine, J. M.] EPHE, F-75006 Paris, France. [Samolinski, B.] Med Univ Warsaw, Dept Prevent Environm Hazards & Allergol, Warsaw, Poland. [Siroux, V.] Univ Grenoble Alpes, IAB, Team Environm Epidemiol Appl Reprod & Resp Hlth, Grenoble, France. [Siroux, V.] INSERM, IAB, Team Environm Epidemiol Appl Reprod & Resp Hlth, Grenoble, France. [Siroux, V.] CHU Grenoble, IAB, Team Environm Epidemiol Appl Reprod & Resp Hlth, F-38043 Grenoble, France. [Slagboom, P. E.] Leiden Univ, Med Ctr, Sect Mol Epidemiol, Leiden, Netherlands. [Slagboom, P. E.] Leiden Univ, Med Ctr, Consortium Hlth Aging, Leiden, Netherlands. [Smit, H. A.] Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Valenta, R.] Med Univ Vienna, Ctr Pathophysiol Infectiol & Immunol, Dept Pathophysiol & Allergy Res, Div Immunopathol, Vienna, Austria. [Van de Perre, P.] Univ Hosp, Montpellier, France. [Van de Perre, P.] INSERM, U1058, Montpellier, France. [Verdier, J. M.] EPHE, Sect Sci Vie & Terre, F-75006 Paris, France. [Verdier, J. M.] Univ Montpellier 2, UMR S 710, Paris, France. [Verdier, J. M.] Inst Transdisciplinaire Etud Vieillissement, Montpellier, France. [Yiallouros, P.] Cyprus Univ Technol, Harvard Sch Publ Hlth, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus. [Zins, M.] UVSQ, INSERM, UMS 011, Populat Based Epidemiol Cohorts, Villejuif, France. RP Bousquet, J (reprint author), 273 Av Occitanie, F-34090 Montpellier, France. EM fabienne.portejoie@gmail.com RI Holloway, John/B-5424-2009; Iozzo, Patricia/O-2893-2015; Ritchie, Karen/G-3571-2013; Slagboom, P. Eline/R-4790-2016; Vrijheid, M/H-2702-2014; Sunyer, J/G-6909-2014; Anto, J/H-2676-2014; Robine, Jean-Marie/F-5439-2011; OI Krauss-Etschmann, Susanne/0000-0001-5945-5702; Holloway, John/0000-0001-9998-0464; Iozzo, Patricia/0000-0001-6443-7074; Slagboom, P. Eline/0000-0002-2875-4723; Vrijheid, M/0000-0002-7090-1758; Sunyer, J/0000-0002-2602-4110; Anto, J/0000-0002-4736-8529; Robine, Jean-Marie/0000-0002-4111-6195; VERDIER, Jean-Michel/0000-0002-7252-1556; Wickman, Magnus/0000-0003-2710-8620 FU Region Languedoc Roussillon FX The meeting was supported by an unrestricted educational grant from the Region Languedoc Roussillon awarded by Mr. C Bourquin (President). NR 5 TC 13 Z9 13 U1 0 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD JUN PY 2015 VL 70 IS 6 BP 595 EP 597 DI 10.1136/thoraxjnl-2014-206304 PG 3 WC Respiratory System SC Respiratory System GA CJ0YL UT WOS:000355206900018 PM 25616486 ER PT J AU AlGhatrif, M Choi, S Fishbein, K Simonsick, E Oberdier, M Ratchford, E Salameh, M Thakkar, R Studenski, S Spencer, R Reiter, D Ferrucci, L AF AlGhatrif, Majd Choi, Seongjin Fishbein, Kenneth Simonsick, Eleanor Oberdier, Matt Ratchford, Elizabeth Salameh, Maya Thakkar, Rajiv Studenski, Stephanie Spencer, Richard Reiter, David Ferrucci, Luigi TI Lower Ankle-Brachial Index within the Normal Range is Associated with Delayed Post-Exercise Phosphocreatine Recovery of the Thigh Muscles SO VASCULAR MEDICINE LA English DT Meeting Abstract C1 [AlGhatrif, Majd] NIA, Johns Hopkins Sch Med, Baltimore, MD 21224 USA. [Choi, Seongjin; Fishbein, Kenneth; Simonsick, Eleanor; Oberdier, Matt; Studenski, Stephanie; Spencer, Richard; Reiter, David; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Ratchford, Elizabeth; Salameh, Maya; Thakkar, Rajiv] Johns Hopkins Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD JUN PY 2015 VL 20 IS 3 MA Poster 8 BP 282 EP 282 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CJ2SE UT WOS:000355334000027 ER PT J AU AlGhatrif, M Fabbri, E Moore, AZ Oberdier, M Thakkar, R Ratchford, E Salameh, M Simonsick, E Studneski, S Ferrucci, L AF AlGhatrif, Majd Fabbri, Ellisa Moore, Ann Zenobia Oberdier, Matt Thakkar, Rajiv Ratchford, Elizabeth Salameh, Maya Simonsick, Eleanor Studneski, Stephanie Ferrucci, Luigi TI Lower Ankle-Brachial Index within the Normal Range is Associated with Accelerated Decline in Thigh Muscle Strength and Quality: Results from the Baltimore Longitudinal Study of Aging SO VASCULAR MEDICINE LA English DT Meeting Abstract C1 [AlGhatrif, Majd] NIA, Johns Hopkins Sch Med, Baltimore, MD 21224 USA. [Fabbri, Ellisa; Moore, Ann Zenobia; Oberdier, Matt; Simonsick, Eleanor; Studneski, Stephanie; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Thakkar, Rajiv; Ratchford, Elizabeth; Salameh, Maya] Johns Hopkins Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD JUN PY 2015 VL 20 IS 3 MA Poster 11 BP 283 EP 284 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CJ2SE UT WOS:000355334000030 ER PT J AU Lange-Maia, BS Newman, AB Strotmeyer, ES Harris, TB Caserotti, P Glynn, NW AF Lange-Maia, Brittney S. Newman, Anne B. Strotmeyer, Elsa S. Harris, Tamara B. Caserotti, Paolo Glynn, Nancy W. TI Performance on fast- and usual-paced 400-m walk tests in older adults: are they comparable? SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Physical function; Measurement methods; Gait speed; Physical performance ID LOWER-EXTREMITY FUNCTION; DISTANCE CORRIDOR WALK; MOBILITY LIMITATION; DISABILITY; ASSOCIATION; MORTALITY; FITNESS; LIFE AB Background and aims Fast- and usual-paced 400-m walking tests are often used to assess physical fitness or function, respectively, though it is not known how performance converges on these tests. This study aims to determine whether performance on the fast- and usual-paced 400-m walks varies based upon age and physical function. Methods Participants (26 men, 38 women aged 70-92) completed a fast- and usual-paced 400-m walk. The Short Physical Performance Battery was used to assess function (score range 0-12). Body mass index and health history were also assessed. Results Finish times for the fast- and usual-paced 400-m walks were 333.3 and 380.3 s, respectively (P < 0.0001), and highly correlated (r = 0.88, P < 0.001). Higher functioning participants (SPPB > 10) had greater differences between tests compared to lower functioning participants (SPPB a parts per thousand currency sign 10) (52.9 vs. 26.2 s, P = 0.005), as did younger participants (age < 80) compared to those age 80 and older (56.8 vs. 32.8 s, P = 0.003). Discussion Older and lower functioning participants had greater convergence on the fast- and usual-paced 400-m walks. Potentially some of these lower functioning and older adults may have already performed at their maximal capacity during the usual-paced walk, while the younger and higher functioning participants were able to walk substantially faster when asked. Conclusions Choice of walking test should consider the age and functional capacity of the population as well as whether function or fitness is of interest. C1 [Lange-Maia, Brittney S.; Newman, Anne B.; Strotmeyer, Elsa S.; Glynn, Nancy W.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Glynn, Nancy W.] Univ Southern Denmark, Odense, Denmark. RP Glynn, NW (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Ctr Aging & Populat Hlth, 130 DeSoto St,A531 Crabtree Hall, Pittsburgh, PA 15261 USA. EM bsl14@pitt.edu; newmana@edc.pitt.edu; strotmeyere@edc.pitt.edu; harris99@nia.nih.gov; pcaserotti@sdu.dk; epidnwg@pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Strotmeyer, Elsa/0000-0002-4093-6036; Glynn, Nancy/0000-0003-2265-0162 FU Pittsburgh Claude D. Pepper Older Americans Independence Center, Research Registry and Developmental Pilot Grant [NIH P30 AG024826, NIH P30 AG024827]; National Institute on Aging Professional Services [HHSN271201100605P]; Intramural Research Program of the National Institute on Aging; National Institute on Aging Training Grant [T32-AG000181] FX This research was supported by Pittsburgh Claude D. Pepper Older Americans Independence Center, Research Registry and Developmental Pilot Grant-NIH P30 AG024826 and NIH P30 AG024827 and National Institute on Aging Professional Services Contract HHSN271201100605P. This project was also supported, in part, by the Intramural Research Program of the National Institute on Aging. Brittney S. Lange-Maia is funded by a National Institute on Aging Training Grant T32-AG000181. This work was presented as an oral presentation at the 66th Annual Meeting of the Gerontological Society of America on November 23, 2013 in New Orleans, Louisiana. NR 14 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1594-0667 EI 1720-8319 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD JUN PY 2015 VL 27 IS 3 BP 309 EP 314 DI 10.1007/s40520-014-0287-y PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CH9ZG UT WOS:000354394600009 PM 25373610 ER PT J AU Uldrick, TS AF Uldrick, Thomas S. TI HAART and lungs: do HIV protease inhibitors impact cancer risk? SO AIDS LA English DT Editorial Material ID NELFINAVIR C1 [Uldrick, Thomas S.] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Uldrick, TS (reprint author), 10 Ctr Dr,Room 6N106,MSC 1868, Bethesda, MD 20892 USA. EM uldrickts@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 11 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUN PY 2015 VL 29 IS 9 BP 1111 EP 1112 DI 10.1097/QAD.0000000000000644 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CI4OH UT WOS:000354730000015 PM 26125143 ER PT J AU Tang, WH Cushman, M Green, D Rich, SS Lange, LA Yang, Q Tracy, RP Tofler, GH Basu, S Wilson, JG Keating, BJ Weng, LC Taylor, HA Jacobs, DR Delaney, JA Palmer, CD Young, T Pankow, JS O'Donnell, CJ Smith, NL Reiner, AP Folsom, AR AF Tang, Weihong Cushman, Mary Green, David Rich, Stephen S. Lange, Leslie A. Yang, Qiong Tracy, Russell P. Tofler, Geoffrey H. Basu, Saonli Wilson, James G. Keating, Brendan J. Weng, Lu-Chen Taylor, Herman A. Jacobs, David R. Delaney, Joseph A. Palmer, Cameron D. Young, Taylor Pankow, James S. O'Donnell, Christopher J. Smith, Nicholas L. Reiner, Alexander P. Folsom, Aaron R. TI Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID VON-WILLEBRAND-FACTOR; GENOME-WIDE ASSOCIATION; PARTIAL THROMBOPLASTIN TIME; CORONARY-HEART-DISEASE; FACTOR-VIII ACTIVITY; VENOUS THROMBOEMBOLISM; HEMOSTATIC FACTORS; PLASMA-LEVELS; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK AB Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII:C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII:C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, P=5.10 x 10(-7) in EAs and P=3.88 x 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg, P=6.30 x 10(-9) in EAs and P=2.98 x 10(-2) in AAs). Significant associations for FVIII:C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P=8.02 x 10(-10)), with VWF rs1800380 in AAs (P=5.62 x 10(-11)), and with MAT1A rs2236568 in AAs (P=1.69 x 10(-6)). We replicated previously reported associations of FVIII:C and VWF:Ag with the ABO blood group, VWF rs1063856 (Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII:C and VWF:Ag in both EAs and AAs. Am. J. Hematol. 90:534-540, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Tang, Weihong; Weng, Lu-Chen; Jacobs, David R.; Pankow, James S.; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Green, David] Northwestern Univ, Dept Med, Div Hematol Oncol, Feinberg Sch Med, Chicago, IL 60611 USA. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. [Tofler, Geoffrey H.] Univ Sydney, Royal N Shore Hosp, Dept Cardiol, Sydney, NSW 2006, Australia. [Basu, Saonli] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Keating, Brendan J.] Univ Penn, Dept Surg, Div Transplantat, Philadelphia, PA 19104 USA. [Taylor, Herman A.] Univ Mississippi, Med Ctr, Dept Med, Jackson Heart Study, Jackson, MS 39216 USA. [Delaney, Joseph A.; Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Palmer, Cameron D.; Young, Taylor] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [O'Donnell, Christopher J.] NHLBI, Dept Cardiovasc Epidemiol & Human Genom, NIH, Bethesda, MD 20892 USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Smith, Nicholas L.] VA Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. RP Tang, WH (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. EM tang0097@umn.edu OI Pankow, James/0000-0001-7076-483X FU NIH [R01-HL095603, R01-HL59367] FX Contract grant sponsor: NIH; Contract grant number: R01-HL095603, R01-HL59367. NR 56 TC 3 Z9 3 U1 0 U2 4 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 JUN PY 2015 VL 90 IS 6 BP 534 EP 540 DI 10.1002/ajh.24005 PG 7 WC Hematology SC Hematology GA CI5OK UT WOS:000354806500020 PM 25779970 ER PT J AU Koh, DH Locke, SJ Chen, YC Purdue, MP Friesen, MC AF Koh, Dong-Hee Locke, Sarah J. Chen, Yu-Cheng Purdue, Mark P. Friesen, Melissa C. TI Lead exposure in US worksites: A literature review and development of an occupational lead exposure database from the published literature SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE lead; occupational exposure; exposure assessment; review; population-based studies ID BLOOD LEAD; FORMALDEHYDE EXPOSURE; UNITED-STATES; WORKERS; COHORT; SIZE; INDUSTRIES; MORTALITY; PRESSURE; SHANGHAI AB BackgroundRetrospective exposure assessment of occupational lead exposure in population-based studies requires historical exposure information from many occupations and industries. MethodsWe reviewed published US exposure monitoring studies to identify lead measurement data. We developed an occupational lead exposure database from the 175 identified papers containing 1,111 sets of lead concentration summary statistics (21% area air, 47% personal air, 32% blood). We also extracted ancillary exposure-related information, including job, industry, task/location, year collected, sampling strategy, control measures in place, and sampling and analytical methods. ResultsThe measurements were published between 1940 and 2010 and represented 27 2-digit standardized industry classification codes. The majority of the measurements were related to lead-based paint work, joining or cutting metal using heat, primary and secondary metal manufacturing, and lead acid battery manufacturing. ConclusionsThis database can be used in future statistical analyses to characterize differences in lead exposure across time, jobs, and industries. Am. J. Ind. Med. 58:605-616, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Koh, Dong-Hee; Locke, Sarah J.; Chen, Yu-Cheng; Purdue, Mark P.; Friesen, Melissa C.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Koh, Dong-Hee; Locke, Sarah J.] Catholic Kwandong Univ, Int St Marys Hosp, Dept Occupat & Environm Med, Inchon, South Korea. [Chen, Yu-Cheng] Natl Hlth Res Inst, Natl Environm Hlth Res Ctr, Zhunan, Taiwan. RP Locke, SJ (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E550, Rockville, MD 20850 USA. EM lockesj@mail.nih.gov RI Purdue, Mark/C-9228-2016; Friesen, Melissa/A-5362-2009 OI Purdue, Mark/0000-0003-1177-3108; FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [Z01 CP10122] FX This study was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (Z01 CP10122). NR 46 TC 1 Z9 1 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD JUN PY 2015 VL 58 IS 6 BP 605 EP 616 DI 10.1002/ajim.22448 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI0TH UT WOS:000354450400003 PM 25968240 ER PT J AU Margolis, L AF Margolis, Leonid TI Immunoactivation at the Crossroads of Human Disease SO AMERICAN JOURNAL OF MEDICINE LA English DT Review DE Inflammation; Pathogens; Pathogenesis; Viruses ID HIV-INFECTION; RHEUMATOID-ARTHRITIS; MACULAR DEGENERATION; INFLAMMATION; ATHEROSCLEROSIS; ACTIVATION; AGE; PATHOGENESIS; IMMUNITY; MECHANISMS AB It is becoming increasingly clear that immunoactivation, which evolved as a system of host defense against pathogens, can become dysregulated and promote the pathogenesis of diverse diseases with both known and unknown etiologies (eg, acquired immune deficiency syndrome, age-related macular degeneration, cancer, as well as aging). Immunoactivation seems to be a "common denominator" or general mechanism of pathogenesis and may explain the association and similarities in pathology among otherwise unrelated human diseases. Identification of general mechanisms of immunoactivation may lead to the development of new therapeutic strategies applicable to many diseases even before detailed knowledge of specific etiology and pathogenesis may be available. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license C1 [Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Margolis, L (reprint author), NIH, 10 Ctr Dr 10-9D58, Bethesda, MD 20892 USA. EM margolil@mail.nih.gov FU Intramural Program, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Intramural Program, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 35 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JUN PY 2015 VL 128 IS 6 BP 562 EP 566 DI 10.1016/j.amjmed.2014.12.026 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA CI6NR UT WOS:000354877200012 PM 25637756 ER PT J AU Sipe, TA Finnie, RKC Knopf, JA Qu, SL Reynolds, JA Thota, AB Hahn, RA Goetzel, RZ Hennessy, KD McKnight-Eily, LR Chapman, DP Anderson, CW Azrin, S Abraido-Lanza, AF Gelenberg, AJ Vernon-Smiley, ME Nease, DE AF Sipe, Theresa Ann Finnie, Ramona K. C. Knopf, John A. Qu, Shuli Reynolds, Jeffrey A. Thota, Anilkrishna B. Hahn, Robert A. Goetzel, Ron Z. Hennessy, Kevin D. McKnight-Eily, Lela R. Chapman, Daniel P. Anderson, Clinton W. Azrin, Susan Abraido-Lanza, Ana F. Gelenberg, Alan J. Vernon-Smiley, Mary E. Nease, Donald E., Jr. CA Community Prevent Serv Task Force TI Effects of Mental Health Benefits Legislation A Community Guide Systematic Review SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID STATE PARITY LAWS; COMORBIDITY SURVEY REPLICATION; LARGE EMPLOYER GROUP; DSM-IV DISORDERS; FEDERAL-EMPLOYEES; INSURANCE PARITY; PREVENTIVE-SERVICES; MANAGED CARE; DRUG-ABUSE; COVERAGE AB Context: Health insurance benefits for mental health services typically have paid less than benefits for physical health services, resulting in potential underutilization or financial burden for people with mental health conditions. Mental health benefits legislation was introduced to improve financial protection (i.e., decrease financial burden) and to increase access to, and use of, mental health services. This systematic review was conducted to determine the effectiveness of mental health benefits legislation, including executive orders, in improving mental health. Evidence acquisition: Methods developed for the Guide to Community Preventive Services were used to identify, evaluate, and analyze available evidence. The evidence included studies published or reported from 1965 to March 2011 with at least one of the following outcomes: access to care, financial protection, appropriate utilization, quality of care, diagnosis of mental illness, morbidity and mortality, and quality of life. Analyses were conducted in 2012. Evidence synthesis: Thirty eligible studies were identified in 37 papers. Implementation of mental health benefits legislation was associated with financial protection (decreased out-of-pocket costs) and appropriate utilization of services. Among studies examining the impact of legislation strength, most found larger positive effects for comprehensive parity legislation or policies than for less-comprehensive ones. Few studies assessed other mental health outcomes. Conclusions: Evidence indicates that mental health benefits legislation, particularly comprehensive parity legislation, is effective in improving financial protection and increasing appropriate utilization of mental health services for people with mental health conditions. Evidence was limited for other mental health outcomes. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Sipe, Theresa Ann; Finnie, Ramona K. C.; Knopf, John A.; Qu, Shuli; Reynolds, Jeffrey A.; Thota, Anilkrishna B.; Hahn, Robert A.] CDC, Ctr Surveillance Epidemiol & Lab Serv, Community Guide Branch, Div Epidemiol Anal & Lib Serv, Atlanta, GA 30329 USA. [McKnight-Eily, Lela R.; Chapman, Daniel P.] CDC, Div Populat Hlth, Atlanta, GA 30329 USA. [Vernon-Smiley, Mary E.] CDC, Div Adolescent, Atlanta, GA 30329 USA. [Vernon-Smiley, Mary E.] CDC, Sch Hlth, Atlanta, GA 30329 USA. [Goetzel, Ron Z.] Emory Univ, Truven Hlth Analyt & Thomson Reuters, Atlanta, GA 30322 USA. [Anderson, Clinton W.] Amer Psychol Assoc, Washington, DC 20036 USA. [Hennessy, Kevin D.] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Azrin, Susan] NIMH, Bethesda, MD 20892 USA. [Abraido-Lanza, Ana F.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Gelenberg, Alan J.] Penn State Hershey Med Ctr, Dept Psychiat, Hershey, PA USA. [Nease, Donald E., Jr.] Amer Acad Family Phys, Denver, CO USA. RP Sipe, TA (reprint author), CDC, Prevent Res Branch, Div HIV AIDS Prevent, 1600 Clifton Rd,Mailstop E 37, Atlanta, GA 30329 USA. EM tsipe@cdc.gov RI Nease, Donald/B-6206-2013 OI Nease, Donald/0000-0001-8323-3720 FU Oak Ridge Institute for Scientific Education (ORISE) FX The work of Ramona K.C. Finnie, John A. Knopf, Shuli Qu, Jeffrey A. Reynolds, Cristian Dumitru, Sierra Baker, Guthrie Byard, Su Su, and Elena Watzke was supported with funds from the Oak Ridge Institute for Scientific Education (ORISE). NR 79 TC 1 Z9 1 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUN PY 2015 VL 48 IS 6 BP 755 EP 766 DI 10.1016/j.amepre.2015.01.022 PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CI5EK UT WOS:000354776000015 PM 25998926 ER PT J AU Lv, QW Zhang, W Shi, Q Zheng, WJ Li, X Chen, H Wu, QJ Jiang, WL Li, HB Gong, L Wei, W Liu, H Liu, AJ Jin, HT Wang, JX Liu, XM Li, ZB Liu, B Shen, M Wang, Q Wu, XN Liang, D Yin, YF Fei, YY Su, JM Zhao, LD Jiang, Y Li, J Tang, FL Zhang, FC Lipsky, PE Zhang, X AF Lv, Qian-wen Zhang, Wen Shi, Qun Zheng, Wen-jie Li, Xin Chen, Hua Wu, Qing-jun Jiang, Wan-lan Li, Hong-bin Gong, Lu Wei, Wei Liu, Hui Liu, Ai-jing Jin, Hong-tao Wang, Jun-xiang Liu, Xiu-mei Li, Zhen-bin Liu, Bin Shen, Min Wang, Qian Wu, Xiang-ni Liang, Di Yin, Yu-feng Fei, Yun-yun Su, Jing-mei Zhao, Li-dan Jiang, Ying Li, Jing Tang, Fu-lin Zhang, Feng-chun Lipsky, Peter E. Zhang, Xuan TI Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID MALE ANTIFERTILITY COMPOUNDS; THUNDER GOD VINE; DOUBLE-BLIND; ANTICANCER; TRIPTOLIDE; CHEMISTRY; CHANNELS; PROGRESS; EXTRACT; CELLS AB Objectives To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA). Methods Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. Intervention: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5mg once a week, or TwHF 20mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24. Results 174/207 (84.1%) patients completed 24weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216). Conclusions TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA. Trial registration number NCT01613079. C1 [Lv, Qian-wen; Zhang, Wen; Shi, Qun; Zheng, Wen-jie; Li, Xin; Chen, Hua; Wu, Qing-jun; Jiang, Wan-lan; Shen, Min; Wang, Qian; Wu, Xiang-ni; Liang, Di; Yin, Yu-feng; Fei, Yun-yun; Su, Jing-mei; Zhao, Li-dan; Jiang, Ying; Li, Jing; Tang, Fu-lin; Zhang, Feng-chun; Zhang, Xuan] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100730, Peoples R China. [Lv, Qian-wen; Zhang, Wen; Shi, Qun; Zheng, Wen-jie; Li, Xin; Chen, Hua; Wu, Qing-jun; Jiang, Wan-lan; Shen, Min; Wang, Qian; Wu, Xiang-ni; Liang, Di; Yin, Yu-feng; Fei, Yun-yun; Su, Jing-mei; Zhao, Li-dan; Jiang, Ying; Li, Jing; Tang, Fu-lin; Zhang, Feng-chun; Zhang, Xuan] Peking Union Med Coll, Beijing 100730, Peoples R China. [Li, Hong-bin] Inner Mongolia Med Coll, Affiliated Hosp, Dept Rheumatol, Hohhot, Peoples R China. [Gong, Lu; Wei, Wei] Tianjin Med Univ, Gen Hosp, Dept Rheumatol, Tianjin, Peoples R China. [Liu, Hui] Beijing Dongfang Hosp, Dept Rheumatol, Beijing, Peoples R China. [Liu, Ai-jing; Jin, Hong-tao] Hebei Med Univ, Hosp 2, Dept Rheumatol, Shijiazhuang, Hebei, Peoples R China. [Wang, Jun-xiang] Hebei Med Univ, Hosp 3, Dept Rheumatol, Shijiazhuang, Hebei, Peoples R China. [Liu, Xiu-mei] Shanxi Med Univ, Hosp 1, Dept Rheumatol, Taiyuan, Shanxi, Peoples R China. [Li, Zhen-bin] Bethune Int Heping Hosp Hebei, Dept Rheumatol, Shijiazhuang, Hebei, Peoples R China. [Liu, Bin] Qingdao Univ, Coll Med, Affiliated Hosp, Dept Rheumatol, Qingdao, Shandong, Peoples R China. [Lipsky, Peter E.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Zhang, X (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100730, Peoples R China. EM peterlipsky@comcast.net; zxpumch2003@sina.com OI zhang, xuan/0000-0001-8775-1699 FU National Natural Science Foundation of China [81325019, 81172859, 81273312]; Beijing Municipal Natural Science Foundation [7141008]; Research Special Fund for Public Welfare Industry of Health [20120217]; Capital Health Research and Development of Special Fund [2011-4001-02]; National laboratory Special Fund [2060204] FX This work was supported by the grants from the National Natural Science Foundation of China (81325019, 81172859 and 81273312), Beijing Municipal Natural Science Foundation (7141008), the Research Special Fund for Public Welfare Industry of Health (20120217), the Capital Health Research and Development of Special Fund (2011-4001-02) and the National laboratory Special Fund (2060204). NR 28 TC 15 Z9 17 U1 5 U2 20 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2015 VL 74 IS 6 BP 1078 EP 1086 DI 10.1136/annrheumdis-2013-204807 PG 9 WC Rheumatology SC Rheumatology GA CH9QO UT WOS:000354371200020 PM 24733191 ER PT J AU Hair, BY Xu, ZL Kirk, EL Harlid, S Sandhu, R Robinson, WR Wu, MC Olshan, AF Conway, K Taylor, JA Troester, MA AF Hair, Brionna Y. Xu, Zongli Kirk, Erin L. Harlid, Sophia Sandhu, Rupninder Robinson, Whitney R. Wu, Michael C. Olshan, Andrew F. Conway, Kathleen Taylor, Jack A. Troester, Melissa A. TI Body mass index associated with genome-wide methylation in breast tissue SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Obesity; Methylation; Breast cancer; BMI; Epigenetics ID DEMONSTRATE FIELD CANCERIZATION; DNA METHYLATION; AROMATASE-ACTIVITY; CANCER-RISK; OBESITY; INFLAMMATION; EXPRESSION; TUMORS; RECEPTOR; SUBTYPES AB Gene expression studies indicate that body mass index (BMI) is associated with molecular pathways involved in inflammation, insulin-like growth factor activation, and other carcinogenic processes in breast tissue. The goal of this study was to determine whether BMI is associated with gene methylation in breast tissue and to identify pathways that are commonly methylated in association with high BMI. Epigenome-wide methylation profiles were determined using the Illumina HumanMethylation450 BeadChip array in the non-diseased breast tissue of 81 women undergoing breast surgery between 2009 and 2013 at the University of North Carolina Hospitals. Multivariable, robust linear regression was performed to identify methylation sites associated with BMI at a false discovery rate q value < 0.05. Gene expression microarray data was used to identify which of the BMI-associated methylation sites also showed correlation with gene expression. Gene set enrichment analysis was conducted to assess which pathways were enriched among the BMI-associated methylation sites. Of the 431,568 methylation sites analyzed, 2573 were associated with BMI (q value < 0.05), 57 % of which showed an inverse correlation with BMI. Pathways enriched among the 2573 probe sites included those involved in inflammation, insulin receptor signaling, and leptin signaling. We were able to map 1251 of the BMI-associated methylation sites to gene expression data, and, of these, 226 (18 %) showed substantial correlations with gene expression. Our results suggest that BMI is associated with genome-wide methylation in non-diseased breast tissue and may influence epigenetic pathways involved in inflammatory and other carcinogenic processes. C1 [Hair, Brionna Y.; Kirk, Erin L.; Robinson, Whitney R.; Olshan, Andrew F.; Conway, Kathleen; Troester, Melissa A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Xu, Zongli; Harlid, Sophia; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Xu, Zongli; Harlid, Sophia; Taylor, Jack A.] NIEHS, Epigen & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Sandhu, Rupninder; Robinson, Whitney R.; Conway, Kathleen] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Wu, Michael C.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Hair, BY (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435,2101 McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. EM bhair@email.unc.edu OI Harlid, Sophia/0000-0001-8540-6891; xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398; Wu, Michael C./0000-0002-3357-6570 FU National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer [NIH/NCI P50-CA58223]; National Cancer Institute/National Institute of Environmental Health Sciences Breast Cancer and the Environment Research Program [U01 - ES019472]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ZIA-ES049032-18, ZIA-ES049033-18]; National Cancer Institute [K01-CA172717-01] FX This research was funded, in part, by the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer (NIH/NCI P50-CA58223), the National Cancer Institute/National Institute of Environmental Health Sciences Breast Cancer and the Environment Research Program (U01 - ES019472), and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA-ES049032-18, ZIA-ES049033-18). WRR was supported by the National Cancer Institute (K01-CA172717-01). NR 49 TC 4 Z9 4 U1 1 U2 12 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 JUN PY 2015 VL 151 IS 2 BP 453 EP 463 DI 10.1007/s10549-015-3401-8 PG 11 WC Oncology SC Oncology GA CI1JC UT WOS:000354499200023 PM 25953686 ER PT J AU Swamydas, M Break, TJ Lionakis, MS AF Swamydas, Muthulekha Break, Timothy J. Lionakis, Michail S. TI Mononuclear phagocyte-mediated antifungal immunity: the role of chemotactic receptors and ligands SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Fungal infections; Monocytes; Macrophages; Dendritic cells; Chemotactic factors; Candidiasis; Aspergillosis; Cryptococcosis ID CRYPTOCOCCUS-NEOFORMANS INFECTION; TUMOR-NECROSIS-FACTOR; INVASIVE PULMONARY ASPERGILLOSIS; RAT ALVEOLAR MACROPHAGES; SURVEILLANCE NETWORK TRANSNET; CELL TRANSPLANT RECIPIENTS; HUMAN DENDRITIC CELLS; FUNGAL-INFECTIONS; HISTOPLASMA-CAPSULATUM; HOST-DEFENSE AB Over the past two decades, fungal infections have emerged as significant causes of morbidity and mortality in patients with hematological malignancies, hematopoietic stem cell or solid organ transplantation and acquired immunodeficiency syndrome. Besides neutrophils and CD4(+) T lymphocytes, which have long been known to play an indispensable role in promoting protective antifungal immunity, mononuclear phagocytes are now being increasingly recognized as critical mediators of host defense against fungi. Thus, a recent surge of research studies has focused on understanding the mechanisms by which resident and recruited monocytes, macrophages and dendritic cells accumulate and become activated at the sites of fungal infection. Herein, we critically review how a variety of G-protein coupled chemoattractant receptors and their ligands mediate mononuclear phagocyte recruitment and effector function during infection by the most common human fungal pathogens. C1 [Swamydas, Muthulekha; Break, Timothy J.; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 10,Room 11C102, Bethesda, MD 20892 USA. EM lionakism@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 134 TC 2 Z9 2 U1 0 U2 6 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUN PY 2015 VL 72 IS 11 BP 2157 EP 2175 DI 10.1007/s00018-015-1858-6 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CI6PV UT WOS:000354883800008 PM 25715741 ER PT J AU Grodin, EN White, TL AF Grodin, Erica N. White, Tara L. TI The neuroanatomical delineation of agentic and affiliative extraversion SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Positive emotion; Extraversion; Personality traits; Individual differences; Neuroanatomical basis; Neuroanatomical differences; Neuroanatomical dissociation; Voxel-based morphometry; VBM; MPQ; Healthy adult volunteers; Human subjects; Discriminant validity; Personality neuroscience ID VOXEL-BASED MORPHOMETRY; MULTIDIMENSIONAL PERSONALITY QUESTIONNAIRE; BIG 5; PARAHIPPOCAMPAL CORTEX; INCENTIVE MOTIVATION; GENDER-DIFFERENCES; PREFRONTAL CORTEX; CINGULATE CORTEX; BRAIN; REWARD AB Extraversion is a fascinating personality dimension that consists of two major components, agentic extraversion and affiliative extraversion. Agentic extraversion involves incentive motivation and is expressed as a tendency toward assertiveness, persistence, and achievement. Affiliative extraversion involves the positive emotion of social warmth and is expressed as a tendency toward amicability, gregariousness, and affection. Here we investigate the neuroanatomical correlates of the personality traits of agentic and affiliative extraversion using the Multidimensional Personality Questionnaire Brief Form, structural magnetic resonance imaging, and voxel-based morphometry in a sample of 83 healthy adult volunteers. We found that trait agentic extraversion and trait affiliative extraversion were each positively associated with the volume of the medial orbitofrontal cortex bilaterally (t's a parts per thousand yen 2.03, r's a parts per thousand yen .23, p's < .05). Agentic extraversion was specifically and positively related to the volume of the left parahippocampal gyrus (t = 4.08, r = .21, p < .05), left cingulate gyrus (t = 4.75, r = .28, p < .05), left caudate (t = 4.29, r = .24, p < .05), and left precentral gyrus (t = 4.00, r = .18, p < .05) in males and females, and the volume of the right nucleus accumbens in males (t = 2.92, r = .20, p < .05). Trait affiliative extraversion was not found to be associated with additional regions beyond the medial orbitofrontal cortex. The findings provide the first evidence of a neuroanatomical dissociation between the personality traits of agentic and affiliative extraversion in healthy adults. C1 [Grodin, Erica N.; White, Tara L.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. [Grodin, Erica N.] NIAAA, Brown NIH Grad Partnership Program, Bethesda, MD USA. RP White, TL (reprint author), Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Box G-S121-4,121 South Main St, Providence, RI 02912 USA. EM Tara_White@Brown.edu RI Grodin, Erica/G-1054-2015; OI Grodin, Erica/0000-0001-5528-4918 FU National Institute on Drug Abuse [DA R01 020725, DA R21 029189]; Lifespan/Tufts/Brown Center for AIDS Research; Foundation for Alcohol Research; National Institute on Alcohol Abuse and Alcoholism [AA P01 019072] FX The authors report that they had no conflicts of interest. This research was supported by grants from the National Institute on Drug Abuse to T.L.W. (Grant Nos. DA R01 020725, DA R21 029189), the Lifespan/Tufts/Brown Center for AIDS Research to T.L.W., the Foundation for Alcohol Research to T.L.W., and the National Institute on Alcohol Abuse and Alcoholism (Grant No. AA P01 019072). We would like to thank Adam Nitenson for his assistance with the figures. NR 64 TC 3 Z9 3 U1 6 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD JUN PY 2015 VL 15 IS 2 BP 321 EP 334 DI 10.3758/s13415-014-0331-6 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CI3IQ UT WOS:000354641800006 PM 25712871 ER PT J AU Decker, B Masur, H AF Decker, Brooke Masur, Henry TI Bad Bugs, No Drugs: Are We Part of the Problem, or Leaders in Developing Solutions? SO CRITICAL CARE MEDICINE LA English DT Editorial Material ID INTENSIVE-CARE-UNIT; METALLO-BETA-LACTAMASE; ANTIMICROBIAL STEWARDSHIP; CEFTAZIDIME-AVIBACTAM; DE-ESCALATION; HAND HYGIENE; ENTEROBACTERIACEAE; EPIDEMIOLOGY; INFECTION C1 [Decker, Brooke] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Masur, Henry] NIH, Ctr Clin, Bethesda, MD USA. RP Decker, B (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. OI Decker M.D., Brooke K/0000-0002-3404-9115 NR 28 TC 0 Z9 0 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2015 VL 43 IS 6 BP 1153 EP 1155 DI 10.1097/CCM.0000000000001039 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA CI4LL UT WOS:000354720300021 PM 25978153 ER PT J AU Torabi-Parizi, P AF Torabi-Parizi, Parizad TI Critical Care Management of Two Patients With Ebola: A Biocontainment Unit Demystified SO CRITICAL CARE MEDICINE LA English DT Editorial Material C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Torabi-Parizi, P (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 6 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2015 VL 43 IS 6 BP 1326 EP 1327 DI 10.1097/CCM.0000000000001009 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA CI4LL UT WOS:000354720300040 PM 25978155 ER PT J AU Suffredini, AF AF Suffredini, Anthony F. TI Targeting Sirtuin to Modulate Human Inflammation SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE deacetylation; epigenetics; histones; metabolomics; sirtuin ID IMMUNOSUPPRESSION; METABOLISM; SEPSIS; FLAME C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Suffredini, AF (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NR 15 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2015 VL 43 IS 6 BP 1348 EP 1349 DI 10.1097/CCM.0000000000001030 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA CI4LL UT WOS:000354720300053 PM 25978168 ER PT J AU Linetzky, M Pergamin-Hight, L Pine, DS Bar-Haim, Y AF Linetzky, Marian Pergamin-Hight, Lee Pine, Daniel S. Bar-Haim, Yair TI QUANTITATIVE EVALUATION OF THE CLINICAL EFFICACY OF ATTENTION BIAS MODIFICATION TREATMENT FOR ANXIETY DISORDERS SO DEPRESSION AND ANXIETY LA English DT Review DE anxiety; anxiety disorders; clinical trials; treatment; cognition; computer; Internet technology ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; GENERALIZED SOCIAL PHOBIA; MODIFICATION PROGRAM; INDIVIDUALS; THREAT; METAANALYSIS; DEPRESSION; CHILDREN; STIMULI AB BackgroundAttention bias modification treatment (ABMT) is a novel treatment for anxiety disorders. Although a number of other meta-analytic reviews exist, the purpose of the present meta-analysis is to examine issues unaddressed in prior reviews. Specifically, the review estimates the efficacy of ABMT in clinically anxious patients and examines the effect of delivery context (clinic vs. home) on symptom reduction. MethodsA literature search using PsychInfo and Web of Science databases was performed. Only randomized controlled trials (RCTs) examining dot-probe-based ABMT in clinically diagnosed anxious patients were included. From 714 articles located through the search, 36 ABMT studies were identified and 11 studies met inclusion criteria (N = 589 patients). ResultsABMT was associated with greater clinician-rated reductions in anxiety symptoms relative to control training: between-groups effect (d = 0.42, P = .001, confidence interval (CI) = 0.18-0.66), contrast of within-group effects (Q = 7.25, P < .01). More patients in the treatment group no longer met formal diagnostic criteria for their anxiety disorder posttreatment relative to patients in the control condition (P < .05). Analyses of patients' self-reported anxiety were nonsignificant for the between-groups contrast (P = .35), and were at a trend level of significance for the contrast between the within-group effects (P = .06). Moderation analysis of the between-groups effect revealed a significant effect for ABMT delivered in the clinic (d = 0.34, P = 0.01, CI = 0.07-0.62), and a nonsignificant effect for ABMT delivered at home (d = -0.10, P = 0.40, CI = -0.33-0.13). ConclusionsThe current meta-analysis provides support for ABMT as a novel evidenced-based treatment for anxiety disorders. Overall, ABMT effects are mainly evident when it is delivered in the clinic and when clinical outcome is evaluated by a clinician. More RCTs of ABMT in specific anxiety disorders are warranted. C1 [Linetzky, Marian; Pergamin-Hight, Lee; Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Bar-Haim, Yair] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. RP Linetzky, M (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. EM marian.linetzky@post.tau.ac.il FU United States-Israel Binational Science Foundation (BSF) [01014599] FX This research was supported by Grant No 01014599 from the United States-Israel Binational Science Foundation (BSF). NR 37 TC 32 Z9 32 U1 9 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUN PY 2015 VL 32 IS 6 BP 383 EP 391 DI 10.1002/da.22344 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CI2IB UT WOS:000354568500001 PM 25708991 ER PT J AU Maul, RW Saribasak, H Cao, Z Gearhart, PJ AF Maul, Robert W. Saribasak, Huseyin Cao, Zheng Gearhart, Patricia J. TI Topoisomerase I deficiency causes RNA polymerase II accumulation and increases AID abundance in immunoglobulin variable genes SO DNA REPAIR LA English DT Article DE DT40; Topoisomerase I; RNA polymerase II; Activation-induced deaminase; Somatic hypermutation; Gene conversion ID CLASS SWITCH RECOMBINATION; ACTIVATION-INDUCED DEAMINASE; LIGHT-CHAIN GENE; CENTER B-CELLS; SOMATIC HYPERMUTATION; SEQUENCING REVEALS; DNA; TRANSCRIPTION; CONVERSION; REGION AB Activation-induced deaminase (AID) is a DNA cytosine deaminase that diversifies immunoglobulin genes in B cells. Recent work has shown that RNA polymerase II (Pol II) accumulation correlates with AID recruitment. However, a direct link between Vol II and AID abundance has not been tested. We used the DT40 B-cell line to manipulate levels of Pol II by decreasing topoisomerase I (Top1), which relaxes DNA supercoiling in front of the transcription complex. Top1 was decreased by stable transfection of a short hairpin RNA against Top 1,which produced an accumulation of Pol II in transcribed genes, compared to cells transfected with sh-control RNA. The increased Pol II density enhanced AID recruitment to variable genes in the lambda light chain locus, and resulted in higher levels of somatic hypermutation and gene conversion. It has been proposed by another lab that AID itself might directly suppress Top 1 to increase somatic hypermutation. However, we found that in both AID(+/+) and AID(-/-) B cells from DT40 and mice, Top1 protein levels were identical, indicating that the presence or absence of AID did not decrease Top1 expression. Rather, our results suggest that the mechanism for increased diversity when Topl is reduced is that Pol II accumulates and recruits AID to variable genes. Published by Elsevier B.V. C1 [Maul, Robert W.; Saribasak, Huseyin; Cao, Zheng; Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Biol & Immunol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM gearhartp@mail.nih.gov RI Saribasak, Huseyin/C-9331-2012 OI Saribasak, Huseyin/0000-0003-0055-062X FU Intramural Research Program of the NIH; National Institute on Aging FX We thank William Yang for technical assistance, Jean Marie Buerstedde and Hiroshi Arakawa for generously providing DT40 cell lines, and Ranjan Sen and David Wilson III for critical reading of the manuscript. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 36 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUN PY 2015 VL 30 BP 46 EP 52 DI 10.1016/j.dnarep.2015.03.004 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CI8VW UT WOS:000355050800006 PM 25869824 ER PT J AU London, RE AF London, Robert E. TI The structural basis of XRCC1-mediated DNA repair SO DNA REPAIR LA English DT Review DE XRCC1; DNA repair; DNA polymerase beta; DNA ligase 3 alpha; Single-strand break repair ID STRAND-BREAK REPAIR; LIGASE-III-ALPHA; N-TERMINAL DOMAIN; PROTEOME-WIDE IDENTIFICATION; POLYMERASE-BETA INTERACTION; NUCLEOTIDE EXCISION-REPAIR; DISULFIDE BOND FORMATION; CELL NUCLEAR ANTIGEN; ANEMIA CORE COMPLEX; TRIPLE-A-SYNDROME AB Scaffold proteins play a central role in DNA repair by recruiting and organizing sets of enzymes required to perform multi-step repair processes. X-ray cross complementing group 1 protein (XRCC1) forms enzyme complexes optimized for single-strand break repair, but participates in other repair pathways as well. Available structural data for XRCC1 interactions is summarized and evaluated in terms of its proposed roles in DNA repair. Mutational approaches related to the abrogation of specific XRCC1 interactions are also discussed. Although substantial progress has been made in elucidating the structural basis for XRCC1 function, the molecular mechanisms of XRCC1 recruitment related to several proposed roles of the XRCC1 DNA repair complex remain undetermined. Published by Elsevier B.V. C1 [London, Robert E.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Genome Integr & Struct Biol Lab, MR-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [1ZIA ES050111-26] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, project number 1ZIA ES050111-26. NR 166 TC 10 Z9 10 U1 8 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUN PY 2015 VL 30 BP 90 EP 103 DI 10.1016/j.dnarep.2015.02.005 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CI8VW UT WOS:000355050800010 PM 25795425 ER PT J AU Grillon, C Quispe-Escudero, D Mathur, A Ernst, M AF Grillon, Christian Quispe-Escudero, David Mathur, Ambika Ernst, Monique TI Mental Fatigue Impairs Emotion Regulation SO EMOTION LA English DT Article DE emotion regulation; mental fatigue; ego depletion; startle ID SELF-REGULATION; NEGATIVE AFFECT; EGO DEPLETION; COGNITIVE REAPPRAISAL; EXECUTIVE FUNCTIONS; LIMITED RESOURCES; WORKING-MEMORY; STARTLE REFLEX; METAANALYSIS; MODULATION AB Because healthy physical and mental functioning depends on the ability to regulate emotions, it is important to identify moderators of such regulations. Whether mental fatigue, subsequent to the depletion of cognitive resources, impairs explicit emotion regulation to negative stimuli is currently unknown. This study explored this possibility. In a within-subject design over 2 separate sessions, healthy individuals performed easy (control session) or difficult (depletion session) cognitive tasks. Subsequently, they were presented with neutral and negative pictures, with instructions to either maintain or regulate (i.e., reduce) the emotions evoked by the pictures. Emotional reactivity was probed with the startle reflex. The negative pictures evoked a similar aversive state in the control and depletion sessions as measured by startle potentiation. However, subjects were able to down-regulate their aversive state only in the control session, not in the depletion session. These results indicate that mental fatigue following performance of cognitive tasks impairs emotion regulation without affecting emotional reactivity. These findings suggest that mental fatigue needs to be incorporated into models of emotion regulation. C1 [Grillon, Christian; Quispe-Escudero, David; Mathur, Ambika; Ernst, Monique] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, MAP, 15K North Dr,Bldg 15K,Room 203,MSC 2670, Bethesda, MD 20892 USA. EM Christian.grillon@nih.gov FU National Institute of Mental Health [MH002798, 01-M-0185] FX Financial support for this study was provided by the Intramural Research Program of the National Institute of Mental Health (MH002798, Protocol 01-M-0185). We declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and that there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NR 43 TC 0 Z9 0 U1 2 U2 28 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 EI 1931-1516 J9 EMOTION JI Emotion PD JUN PY 2015 VL 15 IS 3 BP 383 EP 389 DI 10.1037/emo0000058 PG 7 WC Psychology, Experimental SC Psychology GA CI1ZS UT WOS:000354544600013 PM 25706833 ER PT J AU Kennedy, DA Dukic, V Dwyer, G AF Kennedy, David A. Dukic, Vanja Dwyer, Greg TI Combining principal component analysis with parameter line-searches to improve the efficacy of Metropolis-Hastings MCMC SO ENVIRONMENTAL AND ECOLOGICAL STATISTICS LA English DT Article DE Birth-death model; MCMC; Parameter line-search; Survival-time data; Within-host model ID APPROXIMATE BAYESIAN COMPUTATION; NUCLEAR POLYHEDROSIS-VIRUS; SURVIVAL-TIME RELATIONSHIP; MONTE-CARLO METHODS; DATA CLONING; STOCHASTIC SIMULATION; HELIOTHIS-VIRESCENS; POPULATION-DYNAMICS; INDEPENDENT ACTION; MODELS AB When Markov chain Monte Carlo (MCMC) algorithms are used with complex mechanistic models, convergence times are often severely compromised by poor mixing rates and a lack of computational power. Methods such as adaptive algorithms have been developed to improve mixing, but these algorithms are typically highly sophisticated, both mathematically and computationally. Here we present a nonadaptive MCMC algorithm, which we term line-search MCMC, that can be used for efficient tuning of proposal distributions in a highly parallel computing environment, but that nevertheless requires minimal skill in parallel computing to implement. We apply this algorithm to make inferences about dynamical models of the growth of a pathogen (baculovirus) population inside a host (gypsy moth, Lymantria dispar). The line-search MCMC appeal rests on its ease of implementation, and its potential for efficiency improvements over classical MCMC in a highly parallel setting, which makes it especially useful for ecological models. C1 [Kennedy, David A.; Dwyer, Greg] Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. [Kennedy, David A.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Kennedy, David A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Dukic, Vanja] Univ Colorado, Dept Appl Math, Boulder, CO 80309 USA. RP Dwyer, G (reprint author), Univ Chicago, Dept Ecol & Evolut, 940 E 57Th St, Chicago, IL 60637 USA. EM dkenned1@gmail.com; Vanja.Dukic@colorado.edu; gdwyer@uchicago.edu RI Dwyer, Greg/L-1134-2015 OI Dwyer, Greg/0000-0002-7387-2075 FU ARCS fellowship; GAANN training grant at the University of Chicago; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, National Institutes of Health (NIH); NIH [R01GM096655]; [NSF-DEB 1316334]; [NSF-GEO 1211668] FX DAK was supported by an ARCS fellowship, a GAANN training grant while at the University of Chicago, and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, National Institutes of Health (NIH). GD and VD were supported by NIH Grant R01GM096655. VD was also supported by Grants NSF-DEB 1316334 and NSF-GEO 1211668. We thank two anonymous reviewers for comments that substantially improved the manuscript. NR 78 TC 0 Z9 0 U1 2 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1352-8505 EI 1573-3009 J9 ENVIRON ECOL STAT JI Environ. Ecol. Stat. PD JUN PY 2015 VL 22 IS 2 BP 247 EP 274 DI 10.1007/s10651-014-0297-0 PG 28 WC Environmental Sciences; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Environmental Sciences & Ecology; Mathematics GA CI2ZW UT WOS:000354618100003 ER PT J AU Tegla, CA Cudrici, CD Nguyen, V Danoff, J Kruszewski, AM Boodhoo, D Mekala, AP Vlaicu, SI Chen, C Rus, V Badea, TC Rus, H AF Tegla, Cosmin A. Cudrici, Cornelia D. Vinh Nguyen Danoff, Jacob Kruszewski, Adam M. Boodhoo, Dallas Mekala, Armugam P. Vlaicu, Sonia I. Chen, Ching Rus, Violeta Badea, Tudor C. Rus, Horea TI RGC-32 is a novel regulator of the T-lymphocyte cell cycle SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE T-cells; Cell cycle; RGC-32; Knockout mouse; Akt; IL-2 ID FORKHEAD TRANSCRIPTION FACTOR; GROWTH-FACTOR-BETA; RESPONSE GENE; COMPLEMENT 32; MULTIPLE-SCLEROSIS; ACTIVATION; AKT; P27(KIP1); SURVIVAL; KINASE AB We have previously shown that RGC-32 is involved in cell cycle regulation in vitro. To define the in vivo role of RGC-32, we generated RGC-32 knockout mice. These mice developed normally and did not spontaneously develop overt tumors. To assess the effect of RGC-32 deficiency on cell cycle activation in T cells, we determined the proliferative rates of CD4(+) and CD8(+) T cells from the spleens of RGC-32(-/-) mice, as compared to wild-type (WT, RGC-32(+/+)) control mice. After stimulation with anti-CD3/anti-CD28, CD4+ T cells from RGC-32(-/-) mice displayed a significant increase in [H-3]-thymidine incorporation when compared to WT mice. In addition, both CD4(+) and CD8(+) T cells from RGC-32(-/-) mice displayed a significant increase in the proportion of proliferating Ki67(+) cells, indicating that in T cells, RGC-32 has an inhibitory effect on cell cycle activation induced by T-cell receptor/CD28 engagement. Furthermore, Akt and FOXO1 phosphorylation induced in stimulated CD4(+) T-cells from RGC-32(-/-) mice were significantly higher, indicating that RGC-32 inhibits cell cycle activation by suppressing FOXO1 activation. We also found that IL-2 mRNA and protein expression were significantly increased in RGC-32(-/-) CD4(+) T cells when compared to RGC-32(+/+) CD4(+) T cells. In addition, the effect of RGC-32 on the cell cycle and IL-2 expression was inhibited by pretreatment of the samples with LY294002, indicating a role for phosphatidylinositol 3-kinase (PI3K). Thus, RGC-32 is involved in controlling the cell cycle of T cells in vivo, and this effect is mediated by IL-2 in a PI3K-dependent fashion. (C) 2015 Elsevier Inc. All rights reserved. C1 [Tegla, Cosmin A.; Cudrici, Cornelia D.; Danoff, Jacob; Kruszewski, Adam M.; Boodhoo, Dallas; Mekala, Armugam P.; Vlaicu, Sonia I.; Rus, Horea] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Tegla, Cosmin A.; Rus, Horea] Vet Adm Maryland Hlth Care Syst, Res Serv, Baltimore, MD USA. [Vinh Nguyen; Rus, Violeta] Univ Maryland, Sch Med, Dept Med, Div Clin Immunol & Rheumatol, Baltimore, MD 21201 USA. [Chen, Ching] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Badea, Tudor C.] NEI, Retinal Circuit Dev & Genet Unit, N NRL, Bethesda, MD 20892 USA. [Vlaicu, Sonia I.] Iuliu Hatieganu Univ Med & Pharm, Dept Internal Med, Cluj Napoca, Romania. [Rus, Horea] Vet Adm Multiple Sclerosis Ctr Excellence, Baltimore, MD USA. RP Rus, H (reprint author), Univ Maryland, Sch Med, Dept Neurol, 655 W Baltimore St,BRB 12-033, Baltimore, MD 21201 USA. EM hrus@umaryland.edu FU Veterans Administration [BX001458, IMMB-002-065]; POSDRU grant [159/1.5/S/138776] FX We thank Dr. Deborah McClellan for editing this manuscript. This work was supported in part by Veterans Administration Merit Awards BX001458 (to H.R.) and IMMB-002-065 (to H.R.). Dr Sonia Vlaicu's work was partially financed by POSDRU grant no. 159/1.5/S/138776 with the title: "Model colaborativ institutional pentru translatarea cercetarii stiintifice biomedicale in practica clinica-TRANSCENT". Cosmin A. Tegla and Cornelia D. Cudrici have contributed equally to this manuscript. NR 33 TC 3 Z9 3 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 0014-4800 EI 1096-0945 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD JUN PY 2015 VL 98 IS 3 BP 328 EP 337 DI 10.1016/j.yexmp.2015.03.011 PG 10 WC Pathology SC Pathology GA CI6YE UT WOS:000354909300002 PM 25770350 ER PT J AU Hayakawa, EH Tokumasu, F Usukura, J Matsuoka, H Tsuboi, T Wellems, TE AF Hayakawa, Eri H. Tokumasu, Fuyuki Usukura, Jiro Matsuoka, Hiroyuki Tsuboi, Takafumi Wellems, Thomas E. TI Imaging of the subsurface structures of "unroofed" Plasmodium falciparum-infected erythrocytes SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE Malaria parasite; Maurer's clefts; Cytoskeleton; Electron microscopy; Freeze etching ID RED-BLOOD-CELLS; VESICLE-MEDIATED TRAFFICKING; PLASMA-MEMBRANE INTERFACE; MAURERS CLEFT ORGANELLES; ETCH ELECTRON TOMOGRAPHY; ATOMIC-FORCE MICROSCOPY; PARASITE PROTEINS; MALARIA PARASITES; SURFACE-MEMBRANE; CYTOSKELETON AB Intraerythrocytic stages of Plasmodium falciparum parasites modify the membranes of their host erythrocytes with numerous expressed proteins. They also install new membranous structures in the erythrocyte cytoplasm, including Maurer's clefts (MC) and a tubulovesicular network. These structures support molecular trafficking processes that are necessary for the growth and multiplication of P. falciparum intraerythrocytic stages. To study the morphology and organization of these modifications, we prepared samples of P. falciparum-infected erythrocytes by 'unroofing' techniques and examined them by transmission electron microscopy. Images of the 'unroofed' parasitized erythrocytes feature cytoskeleton alterations and the presence of new membranous structures generated by P. falciparum, including small vesicles and MC connected by extensions to the inner erythrocyte membrane. Non-parasitized erythrocytes showed no evidence of these structures or extensions. In further experiments, we observed a relative absence of MC and extensions after treatment of parasitized erythrocytes with aluminum tetrafluoride (AlF4-), an inhibitor of vesicle trafficking. The morphology and physical location of MC, extensions and small vesicles in unroofed specimens are consistent with the role of these structures in the trafficking of P. falciparum proteins to the surface of parasitized erythrocytes. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hayakawa, Eri H.; Matsuoka, Hiroyuki] Jichi Med Univ, Dept Infect & Immun, Lab Med Zool & Parasitol, Shimotsuke, Tochigi 3290498, Japan. [Tokumasu, Fuyuki] Univ Tokyo, Grad Sch Med, Dept Lipid, Bunkyo Ku, Tokyo 1130033, Japan. [Usukura, Jiro] Nagoya Univ, EcoTopia Sci Inst, Div Integrated Project, Nagoya, Aichi 4648603, Japan. [Tsuboi, Takafumi] Ehime Univ, Proteo Sci Ctr, Div Malaria Res, Matsuyama, Ehime 7908577, Japan. [Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Hayakawa, EH (reprint author), Jichi Med Univ, Dept Infect & Immun, Lab Med Zool & Parasitol, Shimotsuke, Tochigi 3290498, Japan. EM erihayakawa@jichi.ac.jp; TWELLEMS@niaid.nih.gov OI Tokumasu, Fuyuki/0000-0003-2790-1071; Hayakawa, Eri/0000-0001-5067-2161; Matsuoka, Hiroyuki/0000-0001-8839-0012 FU NIAID, NIH; JSPS KAKENHI [24500992]; Ohyama Health Foundation Inc. FX We thank Dr. Motomi Toni, Division of Molecular Parasitology, Proteo-Science Center, Ehime University, for discussions and advice on electron microscopy of the inner membrane structure of parasitized erythrocytes. We are grateful to Japanese Red Cross Society for supplying human erythrocytes. This research was supported in part by the Intramural Research Program of the NIAID, NIH. E.H.H. was partially supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (C), grant number 24500992) and the Ohyama Health Foundation Inc.. NR 36 TC 2 Z9 2 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 0014-4894 EI 1090-2449 J9 EXP PARASITOL JI Exp. Parasitol. PD JUN PY 2015 VL 153 BP 174 EP 179 DI 10.1016/j.exppara.2015.03.021 PG 6 WC Parasitology SC Parasitology GA CI4XA UT WOS:000354756000024 PM 25825251 ER PT J AU Hsu, L Jeon, J Brenner, H Gruber, SB Schoen, RE Berndt, SI Chan, AT Chang-Claude, J Du, MM Gong, J Harrison, TA Hayes, RB Hoffmeister, M Hutter, CM Lin, Y Nishihara, R Ogino, S Prentice, RL Schumacher, FR Seminara, D Slattery, ML Thomas, DC Thornquist, M Newcomb, PA Potter, JD Zheng, YY White, E Peters, U AF Hsu, Li Jeon, Jihyoun Brenner, Hermann Gruber, Stephen B. Schoen, Robert E. Berndt, Sonja I. Chan, Andrew T. Chang-Claude, Jenny Du, Mengmeng Gong, Jian Harrison, Tabitha A. Hayes, Richard B. Hoffmeister, Michael Hutter, Carolyn M. Lin, Yi Nishihara, Reiko Ogino, Shuji Prentice, Ross L. Schumacher, Fredrick R. Seminara, Daniela Slattery, Martha L. Thomas, Duncan C. Thornquist, Mark Newcomb, Polly A. Potter, John D. Zheng, Yingye White, Emily Peters, Ulrike CA Colorectal Transdisciplinary Genetics Epidemiology Colorectal TI A Model to Determine Colorectal Cancer Risk Using Common Genetic Susceptibility Loci SO GASTROENTEROLOGY LA English DT Article DE Risk Determination; Genome-Wide Association Study; Colorectal Cancer Screening; Risk Stratification ID GENOME-WIDE ASSOCIATION; MUTATION CARRIERS; AMERICAN-COLLEGE; PROSTATE-CANCER; CHROMOSOME 8Q24; COLON-CANCER; TASK-FORCE; PREDICTION; METAANALYSIS; HEALTH AB BACKGROUND & AIMS: Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci. METHODS: By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States. RESULTS: We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age-and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women. CONCLUSIONS: By incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies. C1 [Hsu, Li; Jeon, Jihyoun; Du, Mengmeng; Gong, Jian; Harrison, Tabitha A.; Lin, Yi; Prentice, Ross L.; Thornquist, Mark; Newcomb, Polly A.; Potter, John D.; Zheng, Yingye; White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [Brenner, Hermann; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium, Heidelberg, Germany. [Gruber, Stephen B.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hutter, Carolyn M.; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chan, Andrew T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. [Chan, Andrew T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Nishihara, Reiko] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Nishihara, Reiko] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Thomas, Duncan C.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Slattery, Martha L.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. RP Hsu, L (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,M2-B500, Seattle, WA 98109 USA. EM lih@fhcrc.org; upeters@fhcrc.org RI Hoffmeister, Michael/B-5745-2012; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Brenner, Hermann/0000-0002-6129-1572; Potter, John/0000-0001-5439-1500; Hayes, Richard/0000-0002-0918-661X FU National Institutes of Health [P01 CA53996, R01AG14358, R25CA094880, U01 HG004446, GEI U01 HG 004438]; Genetics and Epidemiology of Colorectal Cancer Consortium: National Cancer Institute; Genetics and Epidemiology of Colorectal Cancer Consortium: National Institutes of Health; Genetics and Epidemiology of Colorectal Cancer Consortium: US Department of Health and Human Services [U01 CA137088, R01 CA059045]; Colorectal Transdisciplinary Study: National Cancer Institute, National Institutes of Health under Requests for Applications [CA-09-002 (U19 CA148107)]; Genes, Environment and Health Initiative [Z01 CP 010200] FX This work was supported by the National Institutes of Health (P01 CA53996, R01AG14358, and R25CA094880). The grant support for individual studies was as follows: Genetics and Epidemiology of Colorectal Cancer Consortium: National Cancer Institute, National Institutes of Health, and US Department of Health and Human Services (U01 CA137088 and R01 CA059045); Colorectal Transdisciplinary Study: National Cancer Institute, National Institutes of Health under Requests for Applications #CA-09-002 (U19 CA148107). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Colorectal Transdisciplinary Study, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Colorectal Transdisciplinary Study; Darmkrebs: Chancen der Verhutung durch Screening: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814); Diet, Activity and Lifestyle Study: National Institutes of Health (R01 CA48998 to M.L.S.); Health Professionals Follow-up Study: National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003); Nurses' Health Study: National Institutes of Health (R01 CA137178, P01 CA 087969, and P50 CA 127003); Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility prostate cancer genome-wide association study, Colon Cancer Genetic Markers of Susceptibility pancreatic cancer scan (PanScan), and the Lung Cancer and Smoking study. The prostate and PanScan study data sets were accessed with appropriate approval through the database of Genotypes and Phenotypes online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by the National Institutes of Health and the Genes, Environment and Health Initiative Z01 CP 010200, National Institutes of Health U01 HG004446 and GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping; Vitamins And Lifestyle Study: National Institutes of Health (K05 CA154337); Women's Health Initiative: the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 60 TC 10 Z9 10 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2015 VL 148 IS 7 BP 1330 EP + DI 10.1053/j.gastro.2015.02.010 PG 24 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI8IC UT WOS:000355014700025 PM 25683114 ER PT J AU Chalasani, N Bonkovsky, HL Fontana, R Lee, W Stolz, A Talwalkar, J Reddy, KR Watkins, PB Navarro, V Barnhart, H Gu, JZ AF Chalasani, Naga Bonkovsky, Herbert L. Fontana, Robert Lee, William Stolz, Andrew Talwalkar, Jayant Reddy, K. Rajendar Watkins, Paul B. Navarro, Victor Barnhart, Huiman Gu, Jiezhun CA US Drug Induced Liver Injury Netwo TI Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study SO GASTROENTEROLOGY LA English DT Article DE Idiosyncratic; DILI; DILIN; Toxicity; Medication ID CAUSALITY ASSESSMENT; ADVERSE REACTIONS; HEPATOTOXICITY; NETWORK; POPULATION; EXPERIENCE; HEPATITIS; CHILDREN; FAILURE; SERIES AB BACKGROUND & AIMS: The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. METHODS: In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. RESULTS: Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency <= 7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. CONCLUSIONS: Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality. C1 [Chalasani, Naga] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Bonkovsky, Herbert L.] Carolinas Hlth Care Syst, Charlotte, NC USA. [Fontana, Robert] Univ Michigan, Ann Arbor, MI 48109 USA. [Lee, William] Univ Texas Southwestern, Dallas, TX USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Talwalkar, Jayant] Mayo Clin, Rochester, MN USA. [Reddy, K. Rajendar] Univ Penn, Philadelphia, PA 19104 USA. [Watkins, Paul B.] Univ N Carolina, Chapel Hill, NC USA. [Navarro, Victor] Albert Einstein Med Ctr, Philadelphia, PA 19141 USA. [Barnhart, Huiman; Gu, Jiezhun] Duke Clin Res Inst, Raleigh, NC USA. [Gu, Jiezhun] NIDDK, Bethesda, MD 20892 USA. RP Chalasani, N (reprint author), Indiana Univ Sch Med, Div Gastroenterol & Hepatol, 703 Rotary Circle,Suite 225, Indianapolis, IN 46202 USA. RI de Boer, Ynto/D-9242-2013; OI de Boer, Ynto/0000-0002-4066-7593; Ghabril, Marwan/0000-0002-4784-3246 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) [U01-DK065176, U01-DK065201, U01-DK065184, U01-DK065211, U01DK065193, U01-DK065238, U01-DK083023, U01-DK083027, U01-DK082992, U01-DK083020]; CTSA [UL1 RR025761, UL1 RR025747, UL1 RR024134, UL1 RR024986, UL1 RR024982, UL1 RR024150]; Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH) FX The DILIN (https://dilin.dcri.duke.edu/) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) as a Cooperative Agreement (U01s) under grants: U01-DK065176 (Duke), U01-DK065201 (UNC), U01-DK065184 (Michigan), U01-DK065211 (Indiana), U01DK065193 (UConn), U01-DK065238 (UCSF/CPMC), U01-DK083023 (UTSW), U01-DK083027 (TJH/UPenn), U01-DK082992 (Mayo), U01-DK083020 (USC). Additional funding is provided by CTSA Grants: UL1 RR025761 (Indiana), UL1 RR025747 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH). A complete list of participants in DILIN is given in the Acknowledgments. NR 34 TC 51 Z9 56 U1 1 U2 17 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2015 VL 148 IS 7 BP 1340 EP + DI 10.1053/j.gastro.2015.03.006 PG 20 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI8IC UT WOS:000355014700026 PM 25754159 ER PT J AU Palmore, TN Barrett, K Michelin, A Ramsburg, A Lee, LM Davey, RT Henderson, DK AF Palmore, Tara N. Barrett, Kevin Michelin, Angela Ramsburg, Amanda Lee, Laura M. Davey, Richard T., Jr. Henderson, David K. TI Challenges in Managing Patients who have Suspected or Confirmed Ebola Virus Infection at the National Institutes of Health SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Editorial Material C1 [Palmore, Tara N.; Michelin, Angela; Ramsburg, Amanda] NIH, Hosp Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Barrett, Kevin] NIAID, Intramural Clin Management & Operat Branch, NIH, Bethesda, MD 20892 USA. [Lee, Laura M.; Henderson, David K.] NIH, Clin Care, Ctr Clin, Bethesda, MD 20892 USA. [Davey, Richard T., Jr.] NIAID, NIH, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Clin Care, Ctr Clin, Bldg 10 Room 6-1480,10 Ctr Dr, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 0 TC 1 Z9 1 U1 2 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUN PY 2015 VL 36 IS 6 BP 623 EP 626 DI 10.1017/ice.2015.60 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CI7XZ UT WOS:000354981400001 PM 25994322 ER PT J AU Lukacz, ES Warren, LK Richter, HE Brubaker, L Barber, MD Norton, P Weidner, AC Nguyen, JN Gantz, MG Meikle, SF AF Lukacz, E. S. Warren, L. K. Richter, H. E. Brubaker, L. Barber, M. D. Norton, P. Weidner, A. C. Nguyen, J. N. Gantz, M. G. Meikle, S. F. TI LONG-TERM QUALITY OF LIFE AND SEXUAL FUNCTION AFTER VAGINAL SURGERY FOR APICAL PROLAPSE SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the International-Urogynecological-Association CY JUN 09-13, 2015 CL Nice, FRANCE SP Int Urogynecol Assoc C1 [Lukacz, E. S.] UC San Diego Hlth Syst, La Jolla, CA USA. [Warren, L. K.; Gantz, M. G.] RTI Intl, Social Stat & Environm Sci, Res Triangle Pk, NC USA. [Richter, H. E.] Univ Alabama Birmingham, Birmingham, AL USA. [Brubaker, L.] Loyola Univ Chicago, Maywood, IL USA. [Barber, M. D.] Cleveland Clin, Cleveland, OH 44106 USA. [Norton, P.] Univ Utah, Salt Lake City, UT USA. [Weidner, A. C.] Duke Univ, Durham, NC USA. [Nguyen, J. N.] Kaiser Permanente So Calif, Obstet & Gynecol, Downey, CA USA. [Meikle, S. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD JUN PY 2015 VL 26 SU 1 MA OP 089 BP S117 EP S118 PG 2 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA CI3AF UT WOS:000354619100090 ER PT J AU Weidner, AC Barber, MD Markland, AD Rahn, DD Hsu, Y Mueller, ER Jakus-Waldman, S Dyer, KY Warren, LK Gantz, M Meikle, S AF Weidner, A. C. Barber, M. D. Markland, A. D. Rahn, D. D. Hsu, Y. Mueller, E. R. Jakus-Waldman, S. Dyer, K. Y. Warren, L. K. Gantz, M. Meikle, S. TI PERIOPERATIVE BEHAVIORAL THERAPY & PELVIC MUSCLE STRENGTHENING DOES NOT IMPROVE QUALITY OF LIFE AFTER APICAL PROLAPSE SURGERY: A RANDOMIZED CONTROLLED TRIAL SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the International-Urogynecological-Association CY JUN 09-13, 2015 CL Nice, FRANCE SP Int Urogynecol Assoc C1 [Weidner, A. C.] Duke Univ, Durham, NC USA. [Barber, M. D.] Cleveland Clin, Cleveland, OH 44106 USA. [Markland, A. D.] Univ Alabama, Birmingham, VA USA. [Markland, A. D.] Univ Alabama Birmingham, Birmingham, AL USA. [Rahn, D. D.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Hsu, Y.] Univ Utah, Salt Lake City, UT USA. [Mueller, E. R.] Loyola Univ, Chicago Stritch Sch Med, Maywood, IL 60153 USA. [Jakus-Waldman, S.] Southern Calif Kaiser Permanente, Downey, CA USA. [Dyer, K. Y.] Kaiser Permanente, San Diego, CA USA. [Warren, L. K.; Gantz, M.] RTI Int, Res Triangle Pk, NC USA. [Meikle, S.] NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD JUN PY 2015 VL 26 SU 1 MA PP 34 BP S59 EP S61 PG 3 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA CI3AF UT WOS:000354619100035 ER PT J AU Do, K Speranza, G Bishop, R Khin, S Rubinstein, L Kinders, RJ Datiles, M Eugeni, M Lam, MH Doyle, LA Doroshow, JH Kummar, S AF Khanh Do Speranza, Giovanna Bishop, Rachel Khin, Sonny Rubinstein, Larry Kinders, Robert J. Datiles, Manuel Eugeni, Michelle Lam, Michael H. Doyle, L. Austin Doroshow, James H. Kummar, Shivaani TI Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE MK-2206; Selumetinib; pAKT; pERK; Colorectal carcinoma ID AKT INHIBITOR; SOLID TUMORS; IN-VIVO; KRAS; TRIALS AB Purpose PI3K/AKT/mTOR and RAS/RAF/MEK pathways are frequently dysregulated in colorectal cancer (CRC). We conducted a biomarker-driven trial of the combination of MK-2206, an allosteric AKT 1/2/3 inhibitor, and selumetinib, a MEK 1/2 inhibitor, in patients with CRC to evaluate inhibition of phosphorylated ERK (pERK) and AKT (pAKT) in paired tumor biopsies. Patients and Methods Adult patients with advanced CRC were enrolled in successive cohorts stratified by KRAS mutation status. Initially, 12 patients received oral MK-2206 90 mg weekly with oral selumetinib 75 mg daily in 28-day cycles. Following an interim analysis, the doses of MK-2206 and selumetinib were increased to 135 mg weekly and 100 mg daily, respectively. Paired tumor biopsies were evaluated for target modulation. Results Common toxicities were gastrointestinal, hepatic, dermatologic, and hematologic. Of 21 patients enrolled, there were no objective responses. Target modulation did not achieve the pre-specified criteria of dual 70 % inhibition of pERK and pAKT levels in paired tumor biopsies. Conclusion Despite strong scientific rationale and preclinical data, clinical activity was not observed. The desired level of target inhibition was not achieved. Overlapping toxicities limited the ability to dose escalate to achieve exposures likely needed for clinical activity, highlighting the challenges in developing optimal combinations of targeted agents. C1 [Khanh Do; Speranza, Giovanna; Rubinstein, Larry; Eugeni, Michelle; Doyle, L. Austin; Doroshow, James H.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Bishop, Rachel; Datiles, Manuel] NEI, Bethesda, MD 20892 USA. [Khin, Sonny; Kinders, Robert J.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Lam, Michael H.] Merck Res Labs Oncol, Boston, MA USA. RP Kummar, S (reprint author), NCI, Div Canc Treatment & Diag, 31 Ctr Dr,Bldg 31,Rm3A44, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov OI Datiles, Manuel III B./0000-0003-4660-1664 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E, N01-CM-2011-00032] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contracts No. HHSN261200800001E and N01-CM-2011-00032. 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. MK-2206 and selumetinib were generously provided by Merck and AstraZeneca, respectively, under a collaborative agreement with the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH. NR 17 TC 20 Z9 20 U1 1 U2 7 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 JUN PY 2015 VL 33 IS 3 BP 720 EP 728 DI 10.1007/s10637-015-0212-z PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CI3AZ UT WOS:000354621100018 PM 25637165 ER PT J AU Blevins, MA Kouznetsova, J Krueger, AB King, R Griner, LM Hu, X Southall, N Marugan, JJ Zhang, QH Ferrer, M Zhao, R AF Blevins, Melanie A. Kouznetsova, Jennifer Krueger, Aaron B. King, Rebecca Griner, Lesley Mathews Hu, Xin Southall, Noel Marugan, Juan J. Zhang, Qinghong Ferrer, Marc Zhao, Rui TI Small Molecule, NSC95397, Inhibits the CtBP1-Protein Partner Interaction and CtBP1-Mediated Transcriptional Repression SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE CtBP1; NSC95397; E1A; AlphaScreen; protein-protein interaction ID TERMINAL-BINDING-PROTEIN; COREPRESSOR CTBP; MITOTIC FIDELITY; BREAST-CANCER; EXPRESSION; SITE; METABOLISM; SUBSTRATE; BRCA1; CELLS AB Carboxyl-terminal binding protein (CtBP) is a transcriptional corepressor that suppresses multiple proapoptotic and epithelial genes. CtBP is overexpressed in many human cancers, and its overexpression increases stem cell-like features, epithelial-mesenchymal transition, and cancer cell survival. Knockdown of CtBP also increases apoptosis independent of p53 in cell culture. Therefore, targeting CtBP with small molecules that disrupt its interaction with transcription factor partners may be an effective cancer therapy. To elicit its corepressing effect, CtBP binds to a conserved peptide motif in each transcription factor partner. We developed an AlphaScreen high-throughput screening assay to monitor the interaction between CtBP and E1A (which mimics the interaction between CtBP and its transcriptional partners). We screened the LOPAC library of 1280 bioactive compounds and identified NSC95397, which inhibits the CtBP-E1A interaction (IC50 = 2.9 mu M). The inhibitory activity of NSC95397 was confirmed using two secondary assays and a counterscreen. NSC95397 also behaved as a weak substrate of CtBP dehydrogenase activity and did not inhibit another dehydrogenase, lactase dehydrogenase. Finally, NSC95397 was able to disrupt CtBP-mediated transcriptional repression of a target gene. These studies present a new possibility for the development of a therapeutic agent targeting tumors through disrupting the CtBP transcriptional complex. C1 [Blevins, Melanie A.; Krueger, Aaron B.; Zhao, Rui] Univ Colorado, Dept Biochem & Mol Genet, Sch Med, Aurora, CO 80045 USA. [Kouznetsova, Jennifer; King, Rebecca; Griner, Lesley Mathews; Hu, Xin; Southall, Noel; Marugan, Juan J.; Ferrer, Marc] NIH, Div Preclin Innovat, NCATS, Rockville, MD 20850 USA. [Zhang, Qinghong] Univ Colorado, Dept Dermatol, Sch Med, Aurora, CO 80045 USA. RP Zhang, QH (reprint author), Univ Colorado, Dept Dermatol, Sch Med, Aurora, CO 80045 USA. EM qinghong.zhang@ucdenver.edu; marc.ferrer@nih.gov; rui.zhao@ucdenver.edu RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU NIH [R03DA033982]; NIH/NCRR Colorado CTSI [UL1 RR025780]; Golfers Against Cancer Foundation; NIH Common Fund Molecular Libraries and Imaging Program [U54 MH084681] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by a grant NIH R03DA033982 a pilot grant from the NIH/NCRR Colorado CTSI grant UL1 RR025780, and a pilot grant from Golfers Against Cancer Foundation to R.Z. and Q.Z., as well as grant U54 MH084681 to the National Center for Advancing Translational Sciences (NCATS) from the NIH Common Fund Molecular Libraries and Imaging Program. NR 29 TC 4 Z9 4 U1 0 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUN PY 2015 VL 20 IS 5 BP 663 EP 672 DI 10.1177/1087057114561400 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA CI5DV UT WOS:000354774100011 PM 25477201 ER PT J AU Remoli, C Michienzi, S Sacchetti, B Di Consiglio, A Cersosimo, S Spica, E Robey, PG Holmbeck, K Cumano, A Boyde, A Davis, G Saggio, I Riminucci, M Bianco, P AF Remoli, Cristina Michienzi, Stefano Sacchetti, Benedetto Di Consiglio, Alberto Cersosimo, Stefania Spica, Emanuela Robey, Pamela G. Holmbeck, Kenn Cumano, Ana Boyde, Alan Davis, Graham Saggio, Isabella Riminucci, Mara Bianco, Paolo TI Osteoblast-specific expression of the fibrous dysplasia (FD)-causing mutation Gs(R201C) produces a high bone mass phenotype but does not reproduce FD in the mouse SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE FIBROUS DYSPLASIA; MOUSE MODELS; GS; GNAS; OSTEOBLASTS; BONE MARROW; HEMATOPOIETIC NICHE ID MCCUNE-ALBRIGHT SYNDROME; SCANNING-ELECTRON-MICROSCOPY; SYMPATHETIC-NERVOUS-SYSTEM; STEM-CELLS; GS-ALPHA; HEMATOPOIETIC MICROENVIRONMENT; ACTIVATING MUTATIONS; SKELETAL PROGENITORS; PARATHYROID-HORMONE; TRABECULAR BONE AB We recently reported the generation and initial characterization of the first direct model of human fibrous dysplasia (FD; OMIM #174800), obtained through the constitutive systemic expression of one of the disease-causing mutations, Gs(R201C), in the mouse. To define the specific pathogenetic role(s) of individual cell types within the stromal/osteogenic system in FD, we generated mice expressing Gs(R201C) selectively in mature osteoblasts using the 2.3kb Col1a1 promoter. We show here that this results in a striking high bone mass phenotype but not in a mimicry of human FD. The high bone mass phenotype involves specifically a deforming excess of cortical bone and prolonged and ectopic cortical bone remodeling. Expression of genes characteristic of late stages of bone cell differentiation/maturation is profoundly altered as a result of expression of Gs(R201C) in osteoblasts, and expression of the Wnt inhibitor Sost is reduced. Although high bone mass is, in fact, a feature of some types/stages of FD lesions in humans, it is marrow fibrosis, localized loss of adipocytes and hematopoietic tissue, osteomalacia, and osteolytic changes that together represent the characteristic pathological profile of FD, as well as the sources of specific morbidity. None of these features are reproduced in mice with osteoblast-specific expression of Gs(R201C). We further show that hematopoietic progenitor/stem cells, as well as more mature cell compartments, and adipocyte development are normal in these mice. These data demonstrate that effects of Gs mutations underpinning FD-defining tissue changes and morbidity do not reflect the effects of the mutations on osteoblasts proper. (c) 2015 American Society for Bone and Mineral Research. (c) 2014 American Society for Bone and Mineral Research C1 [Remoli, Cristina; Michienzi, Stefano; Sacchetti, Benedetto; Di Consiglio, Alberto; Cersosimo, Stefania; Spica, Emanuela; Riminucci, Mara; Bianco, Paolo] Univ Roma La Sapienza, Dept Mol Med, I-00161 Rome, Italy. [Robey, Pamela G.; Holmbeck, Kenn] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Cumano, Ana] Inst Pasteur, INSERM, Lymphopoiesis Unit, F-75724 Paris, France. [Boyde, Alan; Davis, Graham] Queen Mary Univ London, Dent Phys Sci, London, England. [Saggio, Isabella] Univ Roma La Sapienza, Dept Biol & Biotechnol C Darwin, I-00161 Rome, Italy. [Saggio, Isabella] IBPM CNR, Rome, Italy. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dept Mol Med, Viale Regina Elena 324, I-00161 Rome, Italy. EM paolo.bianco@uniroma1.it RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [GGP09227]; Fondazione Institut Pasteur-Cenci Bolognetti; MIUR; Ministry of Health; Sapienza University; EU (PluriMes consortium); Fondazione Roma; DIR, NIDCR of the IRP, NIH, DHHS FX This work was supported by grants from Telethon (grant GGP09227), Fondazione Institut Pasteur-Cenci Bolognetti, MIUR, Ministry of Health, Sapienza University, and EU (PluriMes consortium) to PB; by Fondazione Roma to PB and MR; and by the DIR, NIDCR of the IRP, NIH, DHHS to PGR and KH. NR 71 TC 3 Z9 3 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 2015 VL 30 IS 6 BP 1030 EP 1043 DI 10.1002/jbmr.2425 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CI3CG UT WOS:000354624500012 PM 25487351 ER PT J AU Leach, CR Weaver, KE Aziz, NM Alfano, CM Bellizzi, KM Kent, EE Forsythe, LP Rowland, JH AF Leach, Corinne R. Weaver, Kathryn E. Aziz, Noreen M. Alfano, Catherine M. Bellizzi, Keith M. Kent, Erin E. Forsythe, Laura P. Rowland, Julia H. TI The complex health profile of long-term cancer survivors: prevalence and predictors of comorbid conditions SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Cancer survivor; Chronic disease; Comorbidity; Multimorbidity ID QUALITY-OF-LIFE; BREAST-CANCER; CARDIOVASCULAR COMPLICATIONS; OLDER-ADULTS; POPULATION; THERAPY; SOCIETY; WOMEN; ASSOCIATION; CARCINOMA AB Adult cancer survivors have complex medical profiles that may include chronic conditions beyond cancer. Few studies have examined the prevalence of comorbidities before and after a cancer diagnosis. Cancer cases were sampled from two California cancer registries to examine medical conditions (ever experienced and developed after cancer) among 1,527 long-term breast, prostate, colorectal, and gynecological cancer survivors by socio-demographic, cancer-related, and health behavior variables. On average, survivors reported five medical conditions ever diagnosed (95 % CI, 4.8, 5.1) and 1.9 conditions (95 % CI, 1.8, 2.0) diagnosed after cancer. Breast cancer survivors reported the highest (5.8 ever, 2.9 post-cancer) and prostate survivors the lowest (4.0 ever, 1.0 post-cancer) comorbidity burden. Higher comorbidity burden was associated with older age, being a breast cancer survivor, divorced, widowed or separated, non-Hispanic White, overweight or obese, and not receiving chemotherapy. Breast and endometrial cancer survivors, as well as those more than 10 years post-diagnosis, obese, or physically inactive were more likely to report that these comorbidities occurred after cancer. Cancer treatment type, smoking, age, race/ethnicity, marital status, and education were not significant predictors of comorbidities acquired post-cancer. Cancer survivors report a large number of medical conditions, many identified after a cancer diagnosis. Findings suggest that time since cancer diagnosis, body mass index, and activity level are important contextual variables when managing survivor's post-treatment follow-up care. Survivors may benefit when health professionals recommend specific strategies to achieve a healthy weight and regular physical activity for better long-term health outcomes after cancer. C1 [Leach, Corinne R.] Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30303 USA. [Weaver, Kathryn E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Aziz, Noreen M.] NINR, NIH, Bethesda, MD 20892 USA. [Alfano, Catherine M.; Kent, Erin E.; Rowland, Julia H.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Bellizzi, Keith M.] Univ Connecticut, Dept Human Dev & Family Studies, Storrs, CT USA. [Forsythe, Laura P.] Patient Ctr Outcomes Res Inst, Washington, DC USA. RP Leach, CR (reprint author), Amer Canc Soc, Behav Res Ctr, 250 Williams St, Atlanta, GA 30303 USA. EM corinne.leach@cancer.org FU National Cancer Institute at the National Institutes of Health [N01-PC-35136, HHSN 261201100189P] FX The views expressed in this paper are those of the authors and do not necessarily reflect the views of the American Cancer Society, the Federal Government, or the Patient-Centered Outcomes Research Institute. This study was supported by the National Cancer Institute at the National Institutes of Health contracts No. N01-PC-35136 and HHSN 261201100189P. The authors would like to acknowledge: Dr. Neeraj Arora (NCI) for his survey development work and guidance, Dr. Arti Hurria (City of Hope) for her clinical expertise and assistance in categorizing medical conditions, and Dr. Ann Hamilton and Dr. Ingrid Oakley-Girvan for their oversight of the FOCUS study at their respective centers. The authors would also like to acknowledge Ms. Gretchen Keel and Mr. Todd Gibson (Information Management Services, Inc., Rockville, MD) for their assistance with data analysis on this project. NR 37 TC 15 Z9 15 U1 3 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD JUN PY 2015 VL 9 IS 2 BP 239 EP 251 DI 10.1007/s11764-014-0403-1 PG 13 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA CI8AB UT WOS:000354988400011 PM 25319681 ER PT J AU Chrischilles, EA McDowell, BD Rubenstein, L Charlton, M Pendergast, J Juarez, GY Arora, NK AF Chrischilles, Elizabeth A. McDowell, Bradley D. Rubenstein, Linda Charlton, Mary Pendergast, Jane Juarez, Grelda Yazmin Arora, Neeraj K. TI Survivorship care planning and its influence on long-term patient-reported outcomes among colorectal and lung cancer survivors: the CanCORS disease-free survivor follow-up study SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Cohort studies; Colorectal neoplasms; Lung neoplasms; Survivors; Quality of life ID BREAST-CANCER; PLANS; PHYSICIANS; PERSPECTIVES; ONCOLOGISTS; TRIAL AB This study aims to evaluate the relationship between survivorship care planning (SCP) and survivorship care and health outcomes reported by long-term lung and colorectal cancer survivors. Participants (n = 832) were diagnosed and enrolled during 2003-2005. In 2012, patient-reported outcomes (survivorship care and health outcomes) and two patient-reported SCP measures (receipt of written summary of cancer treatment and receipt of instructions on who to see for routine cancer follow-up) were collected. Analyses controlled for SCP predictors collected from medical records and an interview 1 year after diagnosis. One in four survivors reported receiving both SCP elements. Those receiving both were more certain which doctor was in charge (odds ratio (OR) 7.0; 95 % confidence intervals (95 % CI) 3.9-12.5), more likely to report follow-up checkup (OR 5.1; 95 % CI 3.3-8.0), and had an MRI/PET/CT scan in the past 2 years (OR 2.8; 95 % CI 1.7-4.7) compared to those receiving neither. Physician communication experiences were significantly more positive and having physical exams (OR 2.0; 95 % CI 1.2-3.4) and meeting exercise guidelines (OR 1.6; 95 % CI 1.004-2.4) more likely. Physical health (p = 0.012) and good-to-excellent self-perceived health status (OR 2.2; 95 % CI 1.3-3.9) were better for those receiving both elements. SCP may lead to better cancer follow-up care, long-term physical health, and physician-patient communication experiences. The positive association between outcomes and SCP suggests that efforts to implement SCP should be fruitful. C1 [Chrischilles, Elizabeth A.; Rubenstein, Linda; Charlton, Mary] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [McDowell, Bradley D.] Univ Iowa, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. [Pendergast, Jane] Univ Iowa, Dept Biostat, Iowa City, IA 52242 USA. [Juarez, Grelda Yazmin] Univ Iowa, Ctr Publ Hlth Stat, Iowa City, IA 52242 USA. [Arora, Neeraj K.] NCI, Bethesda, MD 20892 USA. RP Chrischilles, EA (reprint author), Univ Iowa, Dept Epidemiol, S424 CPHB, Iowa City, IA 52242 USA. EM e-chrischilles@uiowa.edu FU National Cancer Institute (NCI) [U01 CA093344]; NCI (Dana-Farber Cancer Institute/Cancer Research Network) [U01 CA093332]; NCI (Harvard Medical School/Northern California Cancer Center) [U01 CA093324]; NCI (RAND/UCLA) [U01 CA093348]; NCI (University of Alabama at Birmingham) [U01 CA093329]; NCI (University of Iowa) [U01 CA093339]; NCI (University of North Carolina) [U01 CA093326]; Department of Veterans Affairs [CRS 02-164]; University of Iowa Holden Comprehensive Cancer Center (HCCC) Population Research Core [P30 CA086862]; American Cancer Society [IRG-77-004-34] FX The work of the CanCORS Consortium was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01 CA093344) and the NCI supported Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network U01 CA093332, Harvard Medical School/Northern California Cancer Center U01 CA093324, RAND/UCLA U01 CA093348, University of Alabama at Birmingham U01 CA093329, University of Iowa U01 CA093339, University of North Carolina U01 CA093326) and by a Department of Veterans Affairs grant to the Durham VA Medical Center CRS 02-164. This project was also supported in part by the University of Iowa Holden Comprehensive Cancer Center (HCCC) Population Research Core, funded in part by P30 CA086862, as well as Institutional Research Grant IRG-77-004-34 from the American Cancer Society to the HCCC. NR 30 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD JUN PY 2015 VL 9 IS 2 BP 269 EP 278 DI 10.1007/s11764-014-0406-y PG 10 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA CI8AB UT WOS:000354988400014 PM 25354481 ER PT J AU Ward, MM Guthrie, LC Alba, M AF Ward, Michael M. Guthrie, Lori C. Alba, Maria TI Domain-specific transition questions demonstrated higher validity than global transition questions as anchors for clinically important improvement SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Clinically important difference; Outcome measures; Anchor-based methods; Transition questions; Rheumatoid arthritis; Pain; Physical function ID QUALITY-OF-LIFE; HEALTH-STATUS; IMPORTANT DIFFERENCE; RESPONSIVENESS; DISABILITY; OUTCOMES; RATINGS; PAIN AB Objectives: Estimates of minimal clinically important differences in health measures may be affected by the anchor used. We examined if domain-specific transition questions had higher construct validity than global health transition questions as anchors for measures in a given domain. Study Design and Setting: In a prospective study of 249 patients with rheumatoid arthritis, we examined changes in pain, physical function, joint swelling, stiffness, fatigue, and depression with treatment. We related these changes to a domain-specific transition question, global arthritis transition question, and the Short Form-36 (SF-36) health transition item. Results: Changes in all six clinical measures were more highly correlated with the domain-specific transition questions than with the global arthritis question and SF-36 transition question. Discrimination between patients who improved or not was also better using domain-specific questions. Estimates of minimal clinically important improvement (MCII) differed with the anchor when these were based on mean changes. MCII estimates from receiver operating characteristic curve analysis were not influenced by the choice of anchor when anchors had high agreement. Conclusion: Domain-specific transition questions had higher construct validity as anchors for determining clinically important differences in health measures focused on a single domain than either global disease or general health transition questions. Published by Elsevier Inc. C1 [Ward, Michael M.; Guthrie, Lori C.; Alba, Maria] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20819 USA. RP Ward, MM (reprint author), NIAMS, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health [ZIA AR041153]; U.S. Public Health Service [AR45177] FX This study was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health grant ZIA AR041153 and U.S. Public Health Service grant AR45177. NR 23 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 EI 1878-5921 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD JUN PY 2015 VL 68 IS 6 BP 655 EP 661 DI 10.1016/j.jclinepi.2015.01.028 PG 7 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CI4XE UT WOS:000354756400008 PM 25769795 ER PT J AU Moutsopoulos, NM Lionakis, MS Hajishengallis, G AF Moutsopoulos, N. M. Lionakis, M. S. Hajishengallis, G. TI Inborn Errors in Immunity: Unique Natural Models to Dissect Oral Immunity SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE monogenic immune defects; periodontitis susceptibility; oral candidiasis susceptibility; human oral immunity; IL-17; Th17 ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; PRIMARY IMMUNODEFICIENCY DISEASES; SEVERE PERIODONTAL-DISEASE; PAPILLON-LEFEVRE SYNDROME; MUTATIONS; DEFICIENCY; LESSONS; HUMANS; INFECTIONS; PHENOTYPE AB In recent years, the study of genetic defects arising from inborn errors in immunity has resulted in the discovery of new genes involved in the function of the immune system and in the elucidation of the roles of known genes whose importance was previously unappreciated. With the recent explosion in the field of genomics and the increasing number of genetic defects identified, the study of naturally occurring mutations has become a powerful tool for gaining mechanistic insight into the functions of the human immune system. In this concise perspective, we discuss emerging evidence that inborn errors in immunity constitute real-life models that are indispensable both for the in-depth understanding of human biology and for obtaining critical insights into common diseases, such as those affecting oral health. In the field of oral mucosal immunity, through the study of patients with select gene disruptions, the interleukin-17 (IL-17) pathway has emerged as a critical element in oral immune surveillance and susceptibility to inflammatory disease, with disruptions in the IL-17 axis now strongly linked to mucosal fungal susceptibility, whereas overactivation of the same pathways is linked to inflammatory periodontitis. C1 [Moutsopoulos, N. M.] NIDCR, Oral Immun & Inflammat Unit, NIH, Bethesda, MD 20892 USA. [Lionakis, M. S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hajishengallis, G.] Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. RP Moutsopoulos, NM (reprint author), NIDCR, Oral Immun & Inflammat Unit, NIH, 30 Convent Dr, Bethesda, MD 20892 USA. EM nmoutsop@mail.nih.gov FU National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Allergy and Infectious Diseases (NIAID); NIDCR [DE024716, DE015254] FX The authors were funded in part by the intramural programs of the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of Allergy and Infectious Diseases (NIAID) and extramural grants from NIDCR DE024716 and DE015254. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 46 TC 4 Z9 4 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2015 VL 94 IS 6 BP 753 EP 758 DI 10.1177/0022034515583533 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CI6JX UT WOS:000354866300001 PM 25900229 ER PT J AU Hatch, EE Troisi, R Palmer, JR Wise, LA Titus, L Strohsnitter, WC Ricker, W Hyer, M Hoover, RN AF Hatch, E. E. Troisi, R. Palmer, J. R. Wise, L. A. Titus, L. Strohsnitter, W. C. Ricker, W. Hyer, M. Hoover, R. N. TI Prenatal diethylstilbestrol exposure and risk of obesity in adult women SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE adult; epidemiology; public health; human; pregnancy ID ENDOCRINE DISRUPTORS; BREAST-CANCER; PERINATAL EXPOSURE; ADIPOSE-TISSUE; WEIGHT-GAIN; IN-UTERO; PREGNANCY; OVERWEIGHT; HORMONES; METAANALYSIS AB Diethylstilbestrol (DES) is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age (median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height. The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22], and RRs were 1.23 (CI: 1.07, 1.42) and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure. DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)]. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity. C1 [Hatch, E. E.; Wise, L. A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Troisi, R.; Hoover, R. N.] NCI, Div Epidemiol & Genet, Bethesda, MD 20892 USA. [Palmer, J. R.; Wise, L. A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Titus, L.] Hood Ctr Children & Families, Geisel Sch Med Dartmouth, Lebanon, NH USA. [Strohsnitter, W. C.] Tufts Univ New England Med Ctr, Dept Obstet & Gynecol, Boston, MA USA. [Ricker, W.; Hyer, M.] Informat Management Serv Inc, Rockville, MD USA. RP Hatch, EE (reprint author), Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St Talbot 318E, Boston, MA 02118 USA. EM eehatch@bu.edu FU NCI [HHSN261201000 128C] FX The study was funded by the NCI contract HHSN261201000 128C. NR 44 TC 5 Z9 5 U1 1 U2 11 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 EI 2040-1752 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD JUN PY 2015 VL 6 IS 3 BP 201 EP 207 DI 10.1017/S2040174415000033 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI6OK UT WOS:000354879500005 PM 25697972 ER PT J AU Wise, LA Troisi, R Hatch, EE Titus, LJ Rothman, KJ Harlow, BL AF Wise, L. A. Troisi, R. Hatch, E. E. Titus, L. J. Rothman, K. J. Harlow, B. L. TI Prenatal diethylstilbestrol exposure and reproductive hormones in premenopausal women SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE diethylstilbestrol; endocrine disrupting chemicals; estrogens; females; hormones ID FOLLICLE-STIMULATING-HORMONE; INHIBIN-B LEVELS; SERUM INHIBIN; DIMERIC INHIBIN; MENSTRUAL-CYCLE; MENOPAUSAL AGE; FOLLOW-UP; IN-UTERO; DEPRESSION; PATTERNS AB Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-1900s, is a potent endocrine disruptor. Prenatal DES exposure has been associated with reproductive disorders in women, but little is known about its effects on endogenous hormones. We assessed the association between prenatal DES exposure and reproductive hormones among participants from the Harvard Study of Moods and Cycles (HSMC), a longitudinal study of premenopausal women aged 36-45 years from Massachusetts (1995-1999). Prenatal DES exposure was reported at baseline (43 DES exposed and 782 unexposed). Early follicular-phase concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured at baseline and every 6 months during 36 months of follow-up. Inhibin B concentrations were measured through 18 months. We used multivariable logistic and repeated-measures linear regression to estimate odds ratios (OR) and percent differences in mean hormone values (), respectively, comparing DES exposed with unexposed women, adjusted for potential confounders. DES-exposed women had lower mean concentrations of estradiol (pg/ml) (=-15.6%, 95% confidence interval (CI): -26.5%, -3.2%) and inhibin B (pg/ml) (=-20.3%, CI: -35.1%, -2.3%), and higher mean concentrations of FSH (IU/I) (=12.2%, CI: -1.5%, 27.9%) and LH (IU/I) (=10.4%, CI: -7.2%, 31.3%), than unexposed women. ORs for the association of DES with maximum FSH>10 IU/I and minimum inhibin B<45 pg/ml - indicators of low ovarian reserve - were 1.90 (CI: 0.86, 4.22) and 4.00 (CI: 0.88-18.1), respectively. Prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age. C1 [Wise, L. A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Wise, L. A.; Hatch, E. E.; Rothman, K. J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Troisi, R.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Titus, L. J.] Geisel Sch Med Dartmouth, Hood Ctr Children & Families, Lebanon, NH USA. [Rothman, K. J.] RTI Hlth Solut, Res Triangle Pk, NC USA. [Harlow, B. L.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Wise, LA (reprint author), Boston Univ, Slone Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. EM lwise@bu.edu FU NIH [R01-MH50013, R01-MH69732] FX This work was supported by NIH grants R01-MH50013 and R01-MH69732 (PI: Harlow). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. The authors have no competing interests to report. NR 41 TC 5 Z9 5 U1 0 U2 9 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 EI 2040-1752 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD JUN PY 2015 VL 6 IS 3 BP 208 EP 216 DI 10.1017/S2040174415000082 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI6OK UT WOS:000354879500006 PM 25698132 ER PT J AU Luck, ME Muljo, SA Collins, CB AF Luck, Marisa E. Muljo, Stefan A. Collins, Colm B. TI Prospects for Therapeutic Targeting of MicroRNAs in Human Immunological Diseases SO JOURNAL OF IMMUNOLOGY LA English DT Review ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CHIMERIC MONOCLONAL-ANTIBODY; INFLAMMATORY-BOWEL-DISEASE; ALLERGIC AIRWAYS DISEASE; NECROSIS-FACTOR-ALPHA; III ENZYME DICER; MESSENGER-RNA; IN-VIVO; T-CELLS; RHEUMATOID-ARTHRITIS AB MicroRNAs (miRNAs) are endogenous oligoribonucleotides with exciting therapeutic potential. Early studies established a clear role for miRNAs in leukocyte biology. The first miRNA-based therapy, miravirsen, is now in phase 2 clinical trials, making the reality of these therapies undeniable. The capacity for miRNAs to fine-tune inflammatory signaling make them attractive treatment targets for immunological diseases. Nonetheless, the degree of redundancy among miRNAs, coupled with the promiscuity of miRNA binding sites in the transcriptome, require consideration when designing miRNA-directed interventions. Altered miRNA expression occurs across a range of inflammatory conditions, including inflammatory bowel disease, arthritis, and diabetes. However, very few studies successfully treated murine models of immunological diseases with miRNA-based approaches. While discussing recent studies targeting miRNAs to treat immunological conditions, we also reflect on the risks of miRNA targeting and showcase some newer delivery systems that may improve the pharmacological profile of this class of therapeutics. C1 [Luck, Marisa E.; Collins, Colm B.] Univ Colorado, Sch Med, Dept Pediat, Mucosal Inflammat Program, Aurora, CO 80045 USA. [Muljo, Stefan A.] NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Muljo, SA (reprint author), NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, Bldg 10,Room 11N308,10 Ctr Dr,M51892, Bethesda, MD 20892 USA. EM Stefan.Muljo@nih.gov; Colm.Collins@ucdenver.edu FU National Institutes of Health Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases Grant [K01 DK099403-01]; Crohn's & Colitis Foundation of America Grant [CDA 253596] FX This work is supported by the National Institutes of Health Intramural Research Program of the National Institute of Allergy and Infectious Diseases (to S.A.M.), National Institute of Diabetes and Digestive and Kidney Diseases Grant K01 DK099403-01 (to C.B.C.), and Crohn's & Colitis Foundation of America Grant CDA 253596 (to C.B.C.). NR 90 TC 11 Z9 11 U1 1 U2 8 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 JUN 1 PY 2015 VL 194 IS 11 BP 5047 EP 5052 DI 10.4049/jimmunol.1403146 PG 6 WC Immunology SC Immunology GA CI6WS UT WOS:000354905300005 PM 25980029 ER PT J AU Liu, BY Dhanda, A Hirani, S Williams, EL Sen, HN Estrada, FM Ling, D Thompson, I Casady, M Li, ZY Si, H Tucker, W Wei, L Jawad, S Sura, A Dailey, J Hannes, S Chen, P Chien, JL Gordon, S Lee, RWJ Nussenblatt, RB AF Liu, Baoying Dhanda, Ashwin Hirani, Sima Williams, Emily L. Sen, H. Nida Estrada, Fernando Martinez Ling, Diamond Thompson, Ian Casady, Megan Li, Zhiyu Si, Han Tucker, William Wei, Lai Jawad, Shayma Sura, Amol Dailey, Jennifer Hannes, Susan Chen, Ping Chien, Jason L. Gordon, Siamon Lee, Richard W. J. Nussenblatt, Robert B. TI CD14(++)CD16(+) Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RHEUMATOID-ARTHRITIS; BLOOD MONOCYTES; CD16(+) MONOCYTES; PERIPHERAL-BLOOD; ACTIVATED MONOCYTES; TISSUE MACROPHAGES; GROWTH-FACTOR; FC-GAMMA; SUBSET; DIFFERENTIATION AB Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles that each subset plays in autoimmunity are not well studied. In this study, we show that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype toward intermediate CD14(++)CD16(+) cells, and that this is associated with glucocorticoid therapy. We further demonstrate that CD14(++) CD16(+) monocytes from patients and healthy control donors share a similar cell-surface marker and gene expression profile. Comparison of the effects of intermediate CD14(++)CD16(+) monocytes with classical CD14(++)CD16(-) and nonclassical CD14(+)CD16(++) monocytes revealed that the intermediate CD14(++)CD16(+) subset had an attenuated capacity to promote both naive CD4(+) T cell proliferation and polarization into a Th1 phenotype, and memory CD4(+) T cell proliferation and IL-17 expression. Furthermore, CD14(++)CD16(+) cells inhibit CD+ T cell proliferation induced by other monocyte subsets and enhance CD4(+) T regulatory cell IL-10 expression. These data demonstrate the impact of glucocorticoids on monocyte phenotype in the context of autoimmune disease and the differential effects of monocyte subsets on effector T cell responses. C1 [Liu, Baoying; Hirani, Sima; Sen, H. Nida; Ling, Diamond; Thompson, Ian; Casady, Megan; Li, Zhiyu; Si, Han; Tucker, William; Wei, Lai; Jawad, Shayma; Sura, Amol; Dailey, Jennifer; Hannes, Susan; Chen, Ping; Chien, Jason L.; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Dhanda, Ashwin; Williams, Emily L.; Lee, Richard W. J.] Univ Bristol, Sch Clin Sci, Bristol B58 1TD, Avon, England. [Dhanda, Ashwin; Williams, Emily L.; Lee, Richard W. J.] Moorfields Eye Hosp, Natl Inst Hlth Res Biomed Res Ctr, London EC1V 2PD, England. [Dhanda, Ashwin; Williams, Emily L.; Lee, Richard W. J.] UCL, Inst Ophthalmol, London EC1V 2PD, England. [Estrada, Fernando Martinez; Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, 9000 Rockville Pike,Bldg 10,Room 10N109, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov RI Lee, Richard/A-3116-2017; OI Lee, Richard/0000-0002-9480-6843; Dhanda, Ashwin/0000-0002-0523-0193 FU Intramural Research Program of the National Eye Institute, National Institutes of Health; National Institute for Health Research Biomedical Research Centre based at Moorfields Eye Hospital National Health Service Foundation Trust; University College London Institute of Ophthalmology, United Kingdom FX This work was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. A.D., E.L.W., and R.W.J.L. also received support from the National Institute for Health Research Biomedical Research Centre based at Moorfields Eye Hospital National Health Service Foundation Trust and University College London Institute of Ophthalmology, United Kingdom. NR 46 TC 9 Z9 9 U1 2 U2 13 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 JUN 1 PY 2015 VL 194 IS 11 BP 5150 EP 5160 DI 10.4049/jimmunol.1402409 PG 11 WC Immunology SC Immunology GA CI6WS UT WOS:000354905300017 PM 25911752 ER PT J AU Sokolowska, M Chen, LY Liu, YQ Martinez-Anton, A Qi, HY Logun, C Alsaaty, S Park, YH Kastner, DL Chae, JJ Shelhamer, JH AF Sokolowska, Milena Chen, Li-Yuan Liu, Yueqin Martinez-Anton, Asuncion Qi, Hai-Yan Logun, Carolea Alsaaty, Sara Park, Yong Hwan Kastner, Daniel L. Chae, Jae Jin Shelhamer, James H. TI Prostaglandin E-2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-KINASE-A; INTERLEUKIN-1 PRODUCTION; NALP3 INFLAMMASOME; CUTTING EDGE; PERITONEAL-MACROPHAGES; PROSTANOID RECEPTORS; IL-1-BETA PRODUCTION; PHOSPHOLIPASE A(2); ADENYLYL-CYCLASE; SILICA CRYSTALS AB PGE(2) is a potent lipid mediator involved in maintaining homeostasis but also promotion of acute inflammation or immune suppression in chronic inflammation and cancer. Nucleotide-binding domain, leucine-rich repeat-containing protein (NLR)P3 inflammasome plays an important role in host defense. Uncontrolled activation of the NLRP3 inflammasome, owing to mutations in the NLRP3 gene, causes cryopyrin-associated periodic syndromes. In this study, we showed that NLRP3 inflammasome activation is inhibited by PGE(2) in human primary monocyte-derived macrophages. This effect was mediated through PGE(2) receptor subtype 4 (EP4) and an increase in intracellular cAMP, independently of protein kinase A or exchange protein directly activated by cAMP. A specific agonist of EP4 mimicked, whereas its antagonist or EP4 knockdown reversed, PGE(2)-mediated NLRP3 inhibition. PGE(2) caused an increase in intracellular cAMP. Blockade of adenylate cyclase by its inhibitor reversed PGE(2)-mediated NLRP3 inhibition. Increase of intracellular cAMP by an activator of adenylate cyclase or an analog of cAMP, or a blockade of cAMP degradation by phosphodiesterase inhibitor decreased NLRP3 activation. Protein kinase A or exchange protein directly activated by cAMP agonists did not mimic, and their antagonists did not reverse, PGE(2)-mediated NLRP3 inhibition. Additionally, constitutive IL-1 beta secretion from LPS-primed PBMCs of cryopyrin-associated periodic fever syndromes patients was substantially reduced by high doses of PGE(2). Moreover, blocking cytosolic phospholipase A(2)alpha by its inhibitor or small interfering RNA or inhibiting cyclooxygenase 2, resulting in inhibition of endogenous PGE(2) production, caused an increase in NLRP3 inflammasome activation. Our results suggest that PGE(2) might play a role in maintaining homeostasis during the resolution phase of inflammation and might serve as an autocrine and paracrine regulator. C1 [Sokolowska, Milena; Chen, Li-Yuan; Liu, Yueqin; Martinez-Anton, Asuncion; Qi, Hai-Yan; Logun, Carolea; Alsaaty, Sara; Shelhamer, James H.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Park, Yong Hwan; Kastner, Daniel L.; Chae, Jae Jin] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Shelhamer, JH (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jshelhamer@cc.nih.gov RI Martinez Anton, Asuncion/A-5806-2017 OI Martinez Anton, Asuncion/0000-0001-9758-5911 FU National Institutes of Health Intramural Program FX This work was supported by the National Institutes of Health Intramural Program. NR 71 TC 25 Z9 25 U1 3 U2 7 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 JUN 1 PY 2015 VL 194 IS 11 BP 5472 EP 5487 DI 10.4049/jimmunol.1401343 PG 16 WC Immunology SC Immunology GA CI6WS UT WOS:000354905300048 PM 25917098 ER PT J AU Sado, DM Maestrini, V Piechnik, SK Banypersad, SM White, SK Flett, AS Robson, MD Neubauer, S Ariti, C Arai, A Kellman, P Yamamura, J Schoennagel, BP Shah, F Davis, B Trompeter, S Walker, M Porter, J Moon, JC AF Sado, Daniel M. Maestrini, Viviana Piechnik, Stefan K. Banypersad, Sanjay M. White, Steven K. Flett, Andrew S. Robson, Matthew D. Neubauer, Stefan Ariti, Cono Arai, Andrew Kellman, Peter Yamamura, Jin Schoennagel, Bjoern P. Shah, Farrukh Davis, Bernard Trompeter, Sara Walker, Malcolm Porter, John Moon, James C. TI Noncontrast myocardial T-1 mapping using cardiovascular magnetic resonance for iron overload SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE MRI; iron; T-1 ID THALASSEMIA MAJOR; CARDIAC IRON; DIAGNOSTIC-ACCURACY; T1; CARDIOMYOPATHY; QUANTIFICATION; FIBROSIS; DISEASE; REPRODUCIBILITY; DEFEROXAMINE AB PurposeTo explore the use and reproducibility of magnetic resonance-derived myocardial T-1 mapping in patients with iron overload. Materials and MethodsThe research received ethics committee approval and all patients provided written informed consent. This was a prospective study of 88 patients and 67 healthy volunteers. Thirty-five patients underwent repeat scanning for reproducibility. T-1 mapping used the shortened modified Look-Locker inversion recovery sequence (ShMOLLI) with a second, confirmatory MOLLI sequence in the reproducibility group. T-2* was performed using a commercially available sequence. The analysis of the T-2* interstudy reproducibility data was performed by two different research groups using two different methods. ResultsMyocardial T-1 was lower in patients than healthy volunteers (836138 msec vs. 968 +/- 32 msec, P<0.0001). Myocardial T-1 correlated with T-2* (R=0.79, P<0.0001). No patient with low T-2* had normal T-1, but 32% (n=28) of cases characterized by a normal T-2* had low myocardial T-1. Interstudy reproducibility of either T-1 sequence was significantly better than T-2*, with the results suggesting that the use of T-1 in clinical trials could decrease potential sample sizes by 7-fold. ConclusionMyocardial T-1 mapping is an alternative method for cardiac iron quantification. T-1 mapping shows the potential for improved detection of mild iron loading. The superior reproducibility of T-1 has potential implications for clinical trial design and therapeutic monitoring. J. Magn. Reson. Imaging 2015;41:1505-1511. (c) 2014 Wiley Periodicals, Inc. C1 [Sado, Daniel M.; Banypersad, Sanjay M.; White, Steven K.; Flett, Andrew S.; Walker, Malcolm; Moon, James C.] Heart Hosp, London W1G 8PH, England. [Sado, Daniel M.; Banypersad, Sanjay M.; White, Steven K.; Walker, Malcolm; Moon, James C.] UCL, Inst Cardiovasc Sci, London, England. [Maestrini, Viviana] Univ Roma La Sapienza, Dept Cardiovasc Resp Nephrol & Geriatr Sci, I-00185 Rome, Italy. [Piechnik, Stefan K.; Robson, Matthew D.; Neubauer, Stefan] Univ Oxford, Dept Cardiovasc Med, Oxford Ctr Clin Magnet Resonance Res, Oxford, England. [Ariti, Cono] London Sch Hyg & Trop Med, Dept Stat, London WC1, England. [Arai, Andrew; Kellman, Peter] NHLBI, NIH, Bethesda, MD 20892 USA. [Yamamura, Jin; Schoennagel, Bjoern P.] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Radiol, Hamburg, Germany. [Shah, Farrukh; Davis, Bernard] Whittington Hosp, London N19 5NF, England. [Trompeter, Sara; Porter, John] Univ Coll London Hosp, London, England. RP Moon, JC (reprint author), Heart Hosp, 16-18 Westmoreland St, London W1G 8PH, England. EM james.moon@uclh.nhs.uk OI moon, james/0000-0001-8071-1491 FU British Heart Foundation [FS/10/040/28260] FX Contract grant sponsor: British Heart Foundation; Contract grant number: FS/10/040/28260. NR 40 TC 23 Z9 24 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUN PY 2015 VL 41 IS 6 BP 1505 EP 1511 DI 10.1002/jmri.24727 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CI4QU UT WOS:000354738100002 PM 25104503 ER PT J AU Li, NZ Wang, WT Pham, DL Butman, JA AF Li, Ningzhi Wang, Wen-Tung Pham, Dzung L. Butman, John A. TI Artifactual microhemorrhage generated by susceptibility weighted image processing SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE susceptibility weighted imaging; homodyne filter; phase unwrapping; microhemorrhage ID PHASE UNWRAPPING ALGORITHM; MRI; VENOGRAPHY AB BackgroundTo report that artifactual microhemorrhages are introduced by the two-dimensional (2D) homodyne filtering method of generating susceptibility weighted images (SWI) when open-ended fringelines (OEF) are present in phase data. MethodsSWI data from 28 traumatic brain injury (TBI) patients was obtained on a 3 tesla clinical Siemens scanner using both the product 3D gradient echo sequence (GRE) with generalized autocalibrating partially parallel acquisition acceleration and an in-house developed segmented echo planar imaging (sEPI) sequence without GRAPPA acceleration. SWI processing included (i) 2D homodyne method implemented on the scanner console and (ii) a 3D Fourier-based phase unwrapping followed by 3D high pass filtering. Original and enhanced magnitude and phase images were carefully reviewed for sites of type III OEFs and microhemorrhages by a neuroradiologist on a PACS workstation. ResultsNineteen of 28 (68%) phase datasets acquired using GRAPPA-accelerated GRE acquisition demonstrated type III OEFs. In SWI images, artifactual microhemorrhages were found on 17 of 19 (89%) cases generated using 2D homodyne processing. Application of a 3D Fourier-based unwrapping method prior HP filtering minimized the appearance of the phase singularities in the enhanced phase, and did not generate microhemorrhage-like artifacts in magnitude images. ConclusionThe 2D homodyne filtering method may introduce artifacts mimicking intracranial microhemorrhages in SWI images when type III OEFs are present in phase images. Such artifacts could lead to overestimation of pathology, e.g., TBI. This work demonstrates that 3D phase unwrapping methods minimize this artifact. However, methods to properly combine phase across coils are needed to eliminate this artifact. J. Magn. Reson. Imaging 2015;41:1695-1700. (c) 2014 Wiley Periodicals, Inc. C1 [Li, Ningzhi; Wang, Wen-Tung; Pham, Dzung L.; Butman, John A.] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Butman, John A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Butman, JA (reprint author), 10 Ctr Dr,BLDG 10,RM 1C373, Bethesda, MD 21046 USA. EM jbutman@nih.gov RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU Intramural Program in the National Institutes of Health; Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) FX Contract grant sponsor: Intramural Program in the National Institutes of Health and the Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM). NR 20 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD JUN PY 2015 VL 41 IS 6 BP 1695 EP 1700 DI 10.1002/jmri.24728 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CI4QU UT WOS:000354738100025 PM 25143262 ER PT J AU Pratt, D Mehta, G Wang, HW Chittiboina, P Quezado, M AF Pratt, Drew Mehta, Gautam Wang, Hao-Wei Chittiboina, Prashant Quezado, Martha TI Sellar atypical teratoid rhabdoid tumor (AT/RT) in an adult female SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 91st Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 11-14, 2015 CL Denver, CO SP Amer Assoc Neuropathologists Inc C1 [Pratt, Drew; Wang, Hao-Wei] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Mehta, Gautam; Chittiboina, Prashant] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Quezado, Martha] NIH, Pathol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2015 VL 74 IS 6 MA 80 BP 609 EP 610 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA CI5UH UT WOS:000354824800090 ER PT J AU Bell, WR Pletnikova, O Crain, B Rudow, G Moghekar, A Thambisetty, M Rabins, P Albert, M Resnick, S Troncoso, J AF Bell, W. Robert Pletnikova, Olga Crain, Barbara Rudow, Gay Moghekar, Abhay Thambisetty, Modhav Rabins, Peter Albert, Marilyn Resnick, Susan Troncoso, Juan TI Primary Age-Related Tauopathy (PART) in Autopsies of the Baltimore Longitudinal Study of Aging (BLSA) SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 91st Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 11-14, 2015 CL Denver, CO SP Amer Assoc Neuropathologists Inc C1 [Bell, W. Robert] Johns Hopkins Sch Med, Baltimore, MD USA. [Pletnikova, Olga; Crain, Barbara; Rudow, Gay; Troncoso, Juan] Johns Hopkins Univ, Sch Med, Neuropathol, Baltimore, MD 21218 USA. [Moghekar, Abhay] Johns Hopkins Univ, Sch Med, Neurol, Baltimore, MD 21218 USA. [Thambisetty, Modhav; Resnick, Susan] NIA, Behav Neurosci, NIH, Bethesda, MD 20892 USA. [Rabins, Peter] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21218 USA. [Albert, Marilyn] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2015 VL 74 IS 6 MA 113 BP 619 EP 619 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA CI5UH UT WOS:000354824800123 ER PT J AU Oblak, A Epperson, F Huey, E Wassermann, E Grafman, J Ghetti, B AF Oblak, Adrian Epperson, Francine Huey, Edward Wassermann, Eric Grafman, Jordan Ghetti, Bernardino TI Difficulties in Identifying Individuals with Alzheimer Disease in a Cohort of Patients Presenting as Corticobasal Syndrome SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 91st Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 11-14, 2015 CL Denver, CO SP Amer Assoc Neuropathologists Inc C1 [Oblak, Adrian; Epperson, Francine; Ghetti, Bernardino] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Huey, Edward] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Wassermann, Eric] NINDS, Bethesda, MD 20892 USA. [Grafman, Jordan] Rehabil Inst Chicago, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2015 VL 74 IS 6 MA 132 BP 624 EP 625 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA CI5UH UT WOS:000354824800142 ER PT J AU Pratt, D Edwards, N Tinaz, S Hallett, M Ray-Chaudhury, A AF Pratt, Drew Edwards, Nancy Tinaz, Sule Hallett, Mark Ray-Chaudhury, Abhik TI Neuropathology of DYT1 dystonia: Supplementary findings SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 91st Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 11-14, 2015 CL Denver, CO SP Amer Assoc Neuropathologists Inc C1 [Pratt, Drew] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Edwards, Nancy; Ray-Chaudhury, Abhik] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Tinaz, Sule; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2015 VL 74 IS 6 MA 142 BP 627 EP 627 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA CI5UH UT WOS:000354824800151 ER PT J AU Sloan, JL Manoli, I Venditti, CP AF Sloan, Jennifer L. Manoli, Irini Venditti, Charles P. TI Liver or Combined Liver-Kidney Transplantation for Patients with Isolated Methylmalonic Acidemia: Who and When? SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID OF-THE-LITERATURE; RENAL-TRANSPLANTATION; METABOLIC-DISORDERS; ACIDURIA; MANAGEMENT; DEFICIENCY; CHILDREN; DISEASE; MUT(0); GIRL C1 [Sloan, Jennifer L.; Manoli, Irini; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, NIH, Bldg 49,Room 4A18, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941 FU Intramural NIH HHS NR 39 TC 6 Z9 6 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2015 VL 166 IS 6 BP 1346 EP 1350 DI 10.1016/j.jpeds.2015.03.026 PG 6 WC Pediatrics SC Pediatrics GA CI8JI UT WOS:000355018200006 PM 25882873 ER PT J AU Rothman, RB Ananthan, S Partilla, JS Saini, SK Moukha-Chafiq, O Pathak, V Baumann, MH AF Rothman, Richard B. Ananthan, Subramaniam Partilla, John S. Saini, Surendra K. Moukha-Chafiq, Omar Pathak, Vibha Baumann, Michael H. TI Studies of the Biogenic Amine Transporters 15. Identification of Novel Allosteric Dopamine Transporter Ligands with Nanomolar Potency SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MONOAMINE TRANSPORTERS; SEROTONIN TRANSPORTER; AMPHETAMINE; RELEASE; INHIBITORS; EFFLUX; DRUGS; NOREPINEPHRINE; MODULATORS; MECHANISM AB Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We have shown previously that SRI-9804 [N-(diphenylmethyl)-2-phenyl-4-quinazolinamine], SRI-20040 [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine] partially inhibit [I-125]RTI-55 ([I-125]3 beta-(4'-iodophenyl)tropan-2 beta-carboxylic acid methyl ester) binding and [H-3] dopamine ([H-3] DA) uptake, slow the dissociation rate of [I-125] RTI-55 from the DAT, and allosterically modulate d-amphetamine-induced, DAT-mediated DA release. We synthesized and evaluated the activity of >500 analogs of these ligands and report here on 36 selected compounds. Using synaptosomes prepared from rat caudate, we conducted [3H] DA uptake inhibition assays, DAT binding assays with [H-3]WIN35428 ([H-3] 2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane), and DAT-mediated release assays with either [H-3] MPP+ ([H-3] 1-methyl-4-phenylpyridinium) or [H-3] DA. We observed three groups of [H-3] DA uptake inhibitors: 1) full-efficacy agents with a one-site fit, 2) fullefficacy agents with a two-site fit, and 3) partial-efficacy agents with a one-site fit-the focus of further studies. These agents partially inhibited DA, serotonin, and norepinephrine uptake, yet were much less potent at inhibiting [H-3] WIN35428 binding to the DAT. For example, SRI-29574 [N-(2,2-diphenylethyl)-2-(imidazo[1,2-a] pyridin-6-yl) quinazolin-4-amine] partially inhibited DAT uptake, with an IC50 = 2.3 +/- 0.4 nM, without affecting binding to the DAT. These agents did not alter DAT-mediated release of [H-3] MPP1 in the absence or presence of 100 nM d-amphetamine. SRI-29574 had no significant effect on the d-amphetamine EC50 or E-max value for DAT-mediated release of [H-3] MPP1. These studies demonstrate the existence of potent DAT ligands that partially block [H-3] DA uptake, without affecting DAT binding or d-amphetamine-induced [H-3] MPP1 release. These compounds may prove to be useful probes of biogenic amine transporter function as well as novel therapeutics. C1 [Rothman, Richard B.; Partilla, John S.; Baumann, Michael H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Ananthan, Subramaniam; Saini, Surendra K.; Moukha-Chafiq, Omar; Pathak, Vibha] So Res Inst, Drug Discovery Div, Dept Chem, Birmingham, AL 35255 USA. RP Rothman, RB (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM rrothman@mail.nih.gov FU Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse]; National Institutes of Health National Institute on Drug Abuse [R33-DA029962] FX This work was supported by the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse]; and the National Institutes of Health National Institute on Drug Abuse [Grant R33-DA029962 (to S.A.)]. NR 26 TC 2 Z9 2 U1 1 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2015 VL 353 IS 3 BP 529 EP 538 DI 10.1124/jpet.114.222299 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CH9YA UT WOS:000354391400010 PM 25788711 ER PT J AU Jiang, B Woodell, GA Jobson, DJ AF Jiang, Bo Woodell, Glenn A. Jobson, Daniel J. TI Novel multi-scale retinex with color restoration on graphics processing unit SO JOURNAL OF REAL-TIME IMAGE PROCESSING LA English DT Article DE Multi-scale Retinex; Image enhancement; Autolevels; Real time; GPU ID IMAGE-ENHANCEMENT; VISION; GPU AB The multi-scale retinex with color restoration (MSRCR) was developed as a general-purpose image enhancement algorithm that provides simultaneous dynamic range compression, local lightness/contrast enhancement, and good color rendition, and has been successfully used for a wide variety of imagery from diverse fields. While the MSRCR performs good enhancement in most images, the output image can sometimes be further visually optimized during our experiments. An improved MSRCR+Autolevels (AL) algorithm is presented, which can eliminate the impact of a small number of outliers in the histogram of the image and further improve the contrast of an image. New extension significantly improves the visual performance of the MSRCR algorithm. However, the MSRCR+AL containing a large number of complex calculations is computationally expensive, limiting real-time applications. In this paper, a parallel application of the MSRCR+AL algorithm on a graphics processing unit (GPU) is presented. For the various configurations in our test, the GPU-accelerated MSRCR+AL shows a scalable speedup as the resolution of an image increases. The up to 45x speedup (1,024 x 1,024) over the single-threaded CPU counterpart shows a promising direction of using the GPU-based MSRCR+AL in large-scale, time-critical applications. We also achieved 17 frames per second in video processing (1,280 x 720). C1 [Jiang, Bo] NIA, Hampton, VA 23666 USA. [Woodell, Glenn A.; Jobson, Daniel J.] NASA, Langley Res Ctr, Electromagnet & Sensors Branch, Hampton, VA 23665 USA. RP Jiang, B (reprint author), NIA, 100 Explorat Way, Hampton, VA 23666 USA. EM bjiang07@gmail.com FU NASA [NNL09AA00A] FX The authors wish to thank the NASA Aviation Safety Program, External Hazards Sensing and Mitigation for the funding which made this work possible. In particular, Dr. Jiang was funded by NASA Grant#NNL09AA00A to the National Institute of Aerospace. NR 37 TC 2 Z9 3 U1 2 U2 20 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-8200 EI 1861-8219 J9 J REAL-TIME IMAGE PR JI J. Real-Time Image Process. PD JUN PY 2015 VL 10 IS 2 SI SI BP 239 EP 253 DI 10.1007/s11554-014-0399-9 PG 15 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA CI4JU UT WOS:000354715300005 ER PT J AU Nelson, MI Stratton, J Killian, ML Janas-Martindale, A Vincent, AL AF Nelson, Martha I. Stratton, Jered Killian, Mary Lea Janas-Martindale, Alicia Vincent, Amy L. TI Continual Reintroduction of Human Pandemic H1N1 Influenza A Viruses into Swine in the United States, 2009 to 2014 SO JOURNAL OF VIROLOGY LA English DT Article ID PIGS; TRANSMISSION; EVOLUTION; FARM; REASSORTMENT; MODELS AB The diversity of influenza A viruses in swine (swIAVs) presents an important pandemic threat. Knowledge of the human-swine interface is particularly important for understanding how viruses with pandemic potential evolve in swine hosts. Through phylogenetic analysis of contemporary swIAVs in the United States, we demonstrate that human-to-swine transmission of pandemic H1N1 (pH1N1) viruses has occurred continuously in the years following the 2009 H1N1 pandemic and has been an important contributor to the genetic diversity of U.S. swIAVs. Although pandemic H1 and N1 segments had been largely removed from the U.S. swine population by 2013 via reassortment with other swIAVs, these antigens reemerged following multiple human-to-swine transmission events during the 2013-2014 seasonal epidemic. These findings indicate that the six internal gene segments from pH1N1 viruses are likely to be sustained long term in the U.S. swine population, with periodic reemergence of pandemic hemagglutinin (HA) and neuraminidase (NA) segments in association with seasonal pH1N1 epidemics in humans. Vaccinating U.S. swine workers may reduce infection of both humans and swine and in turn limit the role of humans as sources of influenza virus diversity in pigs. IMPORTANCE Swine are important hosts in the evolution of influenza A viruses with pandemic potential. Here, we analyze influenza virus sequence data generated by the U.S. Department of Agriculture's national surveillance system to identify the central role of humans in the reemergence of pandemic H1N1 (pH1N1) influenza viruses in U.S. swine herds in 2014. These findings emphasize the important role of humans as continuous sources of influenza virus diversity in swine and indicate that influenza viruses with pandemic HA and NA segments are likely to continue to reemerge in U.S. swine in association with seasonal pH1N1 epidemics in humans. C1 [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Stratton, Jered; Vincent, Amy L.] ARS, Virus & Prion Res Unit, Natl Anim Dis Ctr, USDA, Ames, IA USA. [Killian, Mary Lea; Janas-Martindale, Alicia] APHIS, Diagnost Virol Lab, Natl Vet Serv Labs, Sci Technol & Anal Serv,Vet Serv,USDA, Ames, IA USA. RP Nelson, MI (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov FU Multinational Influenza Seasonal Mortality Study (MISMS); Office of Global Affairs at the Department of Health and Human Services; USDA-ARS; USDA-APHIS FX This work was supported in part by the Multinational Influenza Seasonal Mortality Study (MISMS), an ongoing international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, National Institutes of Health, with funding from the Office of Global Affairs at the Department of Health and Human Services (M.I.N.). Funding was provided by USDA-ARS (J.S. and A.L.V.) and by USDA-APHIS (A.J.-M. and M.L.K.). NR 36 TC 21 Z9 22 U1 0 U2 7 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 JUN PY 2015 VL 89 IS 12 BP 6218 EP 6226 DI 10.1128/JVI.00459-15 PG 9 WC Virology SC Virology GA CI3OU UT WOS:000354657900007 PM 25833052 ER PT J AU Gromowski, GD Firestone, CY Whitehead, SS AF Gromowski, Gregory D. Firestone, Cai-Yen Whitehead, Stephen S. TI Genetic Determinants of Japanese Encephalitis Virus Vaccine Strain SA14-14-2 That Govern Attenuation of Virulence in Mice SO JOURNAL OF VIROLOGY LA English DT Article ID SA 14-14-2 VACCINE; NEPALESE CHILDREN; MOLECULAR-BASIS; NUCLEOTIDE; GENOME; REGION; JE; NEUROVIRULENCE; FLAVIVIRUSES; IMMUNIZATION AB The safety and efficacy of the live-attenuated Japanese encephalitis virus (JEV) SA14-14-2 vaccine are attributed to mutations that accumulated in the viral genome during its derivation. However, little is known about the contribution that is made by most of these mutations to virulence attenuation and vaccine immunogenicity. Here, we generated recombinant JEV (rJEV) strains containing JEV SA14-14-2 vaccine-specific mutations that are located in the untranslated regions (UTRs) and seven protein genes or are introduced from PCR-amplified regions of the JEV SA14-14-2 genome. The resulting mutant viruses were evaluated in tissue culture and in mice. The authentic JEV SA14-14-2 (E) protein, with amino acid substitutions L107F, E138K, I176V, T177A, E244G, Q264H, K279M, A315V, S366A, and K439R relative to the wild-type rJEV clone, was essential and sufficient for complete attenuation of neurovirulence. Individually, the nucleotide substitution T39A in the 5' UTR (5'-UTR-T39A), the capsid (C) protein amino acid substitution L66S (C-L66S), and the complete NS1/2A genome region containing 10 mutations each significantly reduced virus neuroinvasion but not neurovirulence. The levels of peripheral virulence attenuation imposed by the 5'-UTR-T39A and C-L66S mutations, individually, were somewhat mitigated in combination with other vaccine strain-specific mutations, which might be compensatory, and together did not affect immunogenicity. However, a marked reduction in immunogenicity was observed with the addition of the NS1/2A and NS5 vaccine virus genome regions. These results suggest that a second-generation recombinant vaccine can be rationally engineered to maximize levels of immunogenicity without compromising safety. C1 [Gromowski, Gregory D.; Firestone, Cai-Yen; Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Gromowski, GD (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM gregory.d.gromowski.civ@mail.mil FU Intramural NIH HHS NR 39 TC 3 Z9 3 U1 1 U2 3 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 JUN PY 2015 VL 89 IS 12 BP 6328 EP 6337 DI 10.1128/JVI.00219-15 PG 10 WC Virology SC Virology GA CI3OU UT WOS:000354657900016 PM 25855730 ER PT J AU Hulot, SL Korber, B Giorgi, EE Vandergrift, N Saunders, KO Balachandran, H Mach, LV Lifton, MA Pantaleo, G Tartaglia, J Phogat, S Jacobs, B Kibler, K Perdiguero, B Gomez, CE Esteban, M Rosati, M Felber, BK Pavlakis, GN Parks, R Lloyd, K Sutherland, L Scearce, R Letvin, NL Seaman, MS Alam, SM Montefiori, D Liao, HX Haynes, BF Santra, S AF Hulot, Sandrine L. Korber, Bette Giorgi, Elena E. Vandergrift, Nathan Saunders, Kevin O. Balachandran, Harikrishnan Mach, Linh V. Lifton, Michelle A. Pantaleo, Giuseppe Tartaglia, Jim Phogat, Sanjay Jacobs, Bertram Kibler, Karen Perdiguero, Beatriz Gomez, Carmen E. Esteban, Mariano Rosati, Margherita Felber, Barbara K. Pavlakis, George N. Parks, Robert Lloyd, Krissey Sutherland, Laura Scearce, Richard Letvin, Norman L. Seaman, Michael S. Alam, S. Munir Montefiori, David Liao, Hua-Xin Haynes, Barton F. Santra, Sampa TI Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; IMMUNE-RESPONSES; LYMPHOCYTE RESPONSES; AIDS VACCINE; MONKEYS; DIVERSITY; ANTIBODIES; INFECTION; EFFICACY AB An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4(+) and CD8(+) T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot assay (ELISpot) responses than B. 1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B. 1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. C1 [Hulot, Sandrine L.; Balachandran, Harikrishnan; Mach, Linh V.; Lifton, Michelle A.; Letvin, Norman L.; Seaman, Michael S.; Santra, Sampa] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Korber, Bette; Giorgi, Elena E.] Los Alamos Natl Lab, Los Alamos, NM USA. [Vandergrift, Nathan; Saunders, Kevin O.; Parks, Robert; Lloyd, Krissey; Sutherland, Laura; Scearce, Richard; Alam, S. Munir; Montefiori, David; Liao, Hua-Xin; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Pantaleo, Giuseppe] Univ Lausanne, CHUV, Lausanne, Switzerland. [Tartaglia, Jim; Phogat, Sanjay] Sanofi Pasteur, Toronto, ON, Canada. [Jacobs, Bertram; Kibler, Karen] Arizona State Univ, Ctr Infect Dis & Vaccinol, Biodesign Inst, Tempe, AZ USA. [Perdiguero, Beatriz; Gomez, Carmen E.; Esteban, Mariano] Ctr Nacl Biotecnol, Madrid, Spain. [Rosati, Margherita; Felber, Barbara K.; Pavlakis, George N.] NCI, Frederick, MD 21701 USA. RP Santra, S (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. EM ssantra@bidmc.harvard.edu OI Korber, Bette/0000-0002-2026-5757 FU NIAID NIH HHS [P30-AI060354, U19 AI067854, U19-AI067854-07, UM1 AI100645, P30 AI060354, UM1-AI-100645]; NIH HHS [OD011103, P51 OD011103] NR 50 TC 11 Z9 11 U1 2 U2 6 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 JUN PY 2015 VL 89 IS 12 BP 6462 EP 6480 DI 10.1128/JVI.00383-15 PG 19 WC Virology SC Virology GA CI3OU UT WOS:000354657900028 PM 25855741 ER PT J AU Kuroda, M Fujikura, D Nanbo, A Marzi, A Noyori, O Kajihara, M Maruyama, J Matsuno, K Miyamoto, H Yoshida, R Feldmann, H Takada, A AF Kuroda, Makoto Fujikura, Daisuke Nanbo, Asuka Marzi, Andrea Noyori, Osamu Kajihara, Masahiro Maruyama, Junki Matsuno, Keita Miyamoto, Hiroko Yoshida, Reiko Feldmann, Heinz Takada, Ayato TI Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus SO JOURNAL OF VIROLOGY LA English DT Article ID NIEMANN-PICK C1; MARBURG VIRUS; DC-SIGN; PHOSPHATIDYLSERINE RECEPTORS; ENVELOPE GLYCOPROTEIN; APOPTOTIC CELLS; PROTEIN; INFECTION; ANTIBODIES; FILOVIRUS AB Multiple host molecules are known to be involved in the cellular entry of filoviruses, including Ebola virus (EBOV); T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) have been identified as attachment and fusion receptors, respectively. However, the molecular mechanisms underlying the entry process have not been fully understood. We found that TIM-1 and NPC1 colocalized and interacted in the intracellular vesicles where EBOV glycoprotein (GP)-mediated membrane fusion occurred. Interestingly, a TIM-1-specific monoclonal antibody (MAb), M224/1, prevented GP-mediated membrane fusion and also interfered with the binding of TIM-1 to NPC1, suggesting that the interaction between TIM-1 and NPC1 is important for filovirus membrane fusion. Moreover, MAb M224/1 efficiently inhibited the cellular entry of viruses from all known filovirus species. These data suggest a novel mechanism underlying filovirus membrane fusion and provide a potential cellular target for antiviral compounds that can be universally used against filovirus infections. C1 [Kuroda, Makoto; Noyori, Osamu; Kajihara, Masahiro; Maruyama, Junki; Matsuno, Keita; Miyamoto, Hiroko; Yoshida, Reiko; Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido, Japan. [Fujikura, Daisuke] Hokkaido Univ, Div Infect & Immun, Res Ctr Zoonosis Control, Sapporo, Hokkaido, Japan. [Nanbo, Asuka] Hokkaido Univ, Grad Sch Med, Dept Cell Physiol, Sapporo, Hokkaido, Japan. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Takada, Ayato] Hokkaido Univ, Global Inst Collaborat Res & Educ, Sapporo, Hokkaido, Japan. RP Takada, A (reprint author), Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido, Japan. EM atakada@czc.hokudai.ac.jp RI Nanbo, Asuka/C-6630-2012; YOSHIDA, Reiko/F-6883-2012; Maruyama, Junki/H-7993-2013 OI Nanbo, Asuka/0000-0001-8764-1350; FU Intramural NIH HHS NR 52 TC 10 Z9 12 U1 1 U2 29 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 JUN PY 2015 VL 89 IS 12 BP 6481 EP 6493 DI 10.1128/JVI.03156-14 PG 13 WC Virology SC Virology GA CI3OU UT WOS:000354657900029 PM 25855742 ER PT J AU Ingale, J Tran, K Kong, L Dey, B McKee, K Schief, W Kwong, PD Mascola, JR Wyatt, RT AF Ingale, Jidnyasa Tran, Karen Kong, Leopold Dey, Barna McKee, Krisha Schief, William Kwong, Peter D. Mascola, John R. Wyatt, Richard T. TI Hyperglycosylated Stable Core Immunogens Designed To Present the CD4 Binding Site Are Preferentially Recognized by Broadly Neutralizing Antibodies (vol 88, pg 14002, 2014) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Ingale, Jidnyasa; Schief, William; Wyatt, Richard T.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Tran, Karen; Schief, William; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Kong, Leopold] Scripps Res Inst, Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Dey, Barna] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [McKee, Krisha; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Ingale, J (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2015 VL 89 IS 12 BP 6526 EP 6526 DI 10.1128/JVI.00596-15 PG 1 WC Virology SC Virology GA CI3OU UT WOS:000354657900036 PM 25979984 ER PT J AU Chowell, G Viboud, C AF Chowell, Gerardo Viboud, Cecile TI Ebola vaccine trials: a race against the clock SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID VIRUS DISEASE; TRANSMISSION; OUTBREAK C1 [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. EM gchowell@gsu.edu NR 12 TC 1 Z9 1 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2015 VL 15 IS 6 BP 624 EP 626 DI 10.1016/S1473-3099(15)70159-3 PG 4 WC Infectious Diseases SC Infectious Diseases GA CI3HI UT WOS:000354638000008 PM 25886800 ER PT J AU Anstey, NM Price, RN Davis, TME Karunajeewa, HA Mueller, I Karunajeewa, HA D'Alessandro, U Massougbodji, A Nikiema, F Ouedraogo, JB Tinto, H Zongo, I Ouedraogo, JB Tinto, H Same-Ekobo, A Kone, M Menan, H Toure, AO Yavo, W Yavo, W Kofoed, PE Alemayehu, BH Jima, D Baudin, E Espie, E Nabasumba, C Pinoges, L Schramm, B Cot, M Deloron, P Faucher, JF Cot, M Deloron, P Faucher, JF Faucher, JF Guthmann, JP Lell, B Borrmann, S Lell, B Adjei, GO Kofoed, PE Ursing, J Tjitra, E Borrmann, S Marsh, K Peshu, J Juma, E Ogutu, BR Omar, SA Sawa, P Talisuna, AO Talisuna, AO Khanthavong, M Mayxay, M Newton, PN Mayxay, M Piola, P Djimde, AA Doumbo, OK Fofana, B Sagara, I Bassat, Q Gonzalez, R Menendez, C Smithuis, F Smithuis, F Bousema, T Kager, PA Mens, PF Mens, PF Schallig, HDFH Van den Broek, I Van Vugt, M Ibrahim, ML Falade, CO Meremikwu, M Meremikwu, M Gil, JP Karema, C Ba, MS Faye, B Faye, O Gaye, O Ndiaye, JL Pene, M Sow, D Sylla, K Tine, RCK Penali, LK Barnes, KI Workman, LJ Barnes, KI Workman, LJ Bassat, Q Gonzalez, R Menendez, C Mueller, I Lima, A Adam, I Gadalla, NB Malik, EFM Bjorkman, A Gil, JP Martensson, A Ngasala, BE Ursing, J Rombo, L Rombo, L Rombo, L Aliu, P Duparc, S Filler, S Genton, B Genton, B Hodel, EM Olliaro, P Abdulla, S Kamugisha, E Ngasala, BE Premji, Z Shekalaghe, SA Shekalaghe, SA Ashley, EA Carrara, VI McGready, R Nosten, F Ashley, EA Faiz, AM Lee, SJ White, NJ Carrara, VI Dondorp, AM Smith, JJ D'Alessandro, U Tarning, J Achan, J Bukirwa, H Yeka, A Arinaitwe, E Staedke, SG Kamya, MR Kironde, F Nabasumba, C Bousema, T Drakeley, CJ Gadalla, NB Oguike, M Sutherland, CJ Checchi, F Dahal, P Flegg, JA Guerin, PJ Moreira, C Newton, PN Nsanzabana, C Price, RN Sibley, CH Stepniewska, K Tarning, J Dahal, P Dondorp, AM Flegg, JA Guerin, PJ Lee, SJ Marsh, K McGready, R Moreira, C Newton, PN Nosten, F Nsanzabana, C Olliaro, P Price, RN Tarning, J White, NJ Gething, PW Hay, SI Greenwood, B Hodel, EM Ward, SA Staedke, SG Van den Broek, I Winstanley, PA Dorsey, G Greenhouse, B Rosenthal, PJ Gadalla, NB Gil, JP Grivoyannis, A Hamed, K Hwang, J Kachur, PS Hwang, J Sibley, CH Nambozi, M AF Anstey, N. M. Price, R. N. Davis, T. M. E. Karunajeewa, H. A. Mueller, I. Karunajeewa, H. A. D'Alessandro, U. Massougbodji, A. Nikiema, F. Ouedraogo, J-B Tinto, H. Zongo, I. Ouedraogo, J-B Tinto, H. Same-Ekobo, A. Kone, M. Menan, H. Toure, A. O. Yavo, W. Yavo, W. Kofoed, P-E Alemayehu, B. H. Jima, D. Baudin, E. Espie, E. Nabasumba, C. Pinoges, L. Schramm, B. Cot, M. Deloron, P. Faucher, J-F Cot, M. Deloron, P. Faucher, J-F Faucher, J-F Guthmann, J-P Lell, B. Borrmann, S. Lell, B. Adjei, G. O. Kofoed, P-E Ursing, J. Tjitra, E. Borrmann, S. Marsh, K. Peshu, J. Juma, E. Ogutu, B. R. Omar, S. A. Sawa, P. Talisuna, A. O. Talisuna, A. O. Khanthavong, M. Mayxay, M. Newton, P. N. Mayxay, M. Piola, P. Djimde, A. A. Doumbo, O. K. Fofana, B. Sagara, I. Bassat, Q. Gonzalez, R. Menendez, C. Smithuis, F. Smithuis, F. Bousema, T. Kager, P. A. Mens, P. F. Mens, P. F. Schallig, H. D. F. H. Van den Broek, I. Van Vugt, M. Ibrahim, M. L. Falade, C. O. Meremikwu, M. Meremikwu, M. Gil, J. P. Karema, C. Ba, M. S. Faye, B. Faye, O. Gaye, O. Ndiaye, J-L Pene, M. Sow, D. Sylla, K. Tine, R. C. K. Penali, L. K. Barnes, K. I. Workman, L. J. Barnes, K. I. Workman, L. J. Bassat, Q. Gonzalez, R. Menendez, C. Mueller, I. Lima, A. Adam, I. Gadalla, N. B. Malik, E. F. M. Bjorkman, A. Gil, J. P. Martensson, A. Ngasala, B. E. Ursing, J. Rombo, L. Rombo, L. Rombo, L. Aliu, P. Duparc, S. Filler, S. Genton, B. Genton, B. Hodel, E. M. Olliaro, P. Abdulla, S. Kamugisha, E. Ngasala, B. E. Premji, Z. Shekalaghe, S. A. Shekalaghe, S. A. Ashley, E. A. Carrara, V. I. McGready, R. Nosten, F. Ashley, E. A. Faiz, A. M. Lee, S. J. White, N. J. Carrara, V. I. Dondorp, A. M. Smith, J. J. D'Alessandro, U. Tarning, J. Achan, J. Bukirwa, H. Yeka, A. Arinaitwe, E. Staedke, S. G. Kamya, M. R. Kironde, F. Nabasumba, C. Bousema, T. Drakeley, C. J. Gadalla, N. B. Oguike, M. Sutherland, C. J. Checchi, F. Dahal, P. Flegg, J. A. Guerin, P. J. Moreira, C. Newton, P. N. Nsanzabana, C. Price, R. N. Sibley, C. H. Stepniewska, K. Tarning, J. Dahal, P. Dondorp, A. M. Flegg, J. A. Guerin, P. J. Lee, S. J. Marsh, K. McGready, R. Moreira, C. Newton, P. N. Nosten, F. Nsanzabana, C. Olliaro, P. Price, R. N. Tarning, J. White, N. J. Gething, P. W. Hay, S. I. Greenwood, B. Hodel, E. M. Ward, S. A. Staedke, S. G. Van den Broek, I. Winstanley, P. A. Dorsey, G. Greenhouse, B. Rosenthal, P. J. Gadalla, N. B. Gil, J. P. Grivoyannis, A. Hamed, K. Hwang, J. Kachur, P. S. Hwang, J. Sibley, C. H. Nambozi, M. CA Worldwide Antimalarial Resistance TI The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data SO LANCET INFECTIOUS DISEASES LA English DT Review ID PLASMODIUM-FALCIPARUM MALARIA; POPULATION PHARMACOKINETICS; UNCOMPLICATED MALARIA; AFRICAN INFANTS; CHILDREN; SAFETY; PHARMACODYNAMICS; CHLOROQUINE; ARTESUNATE; RESISTANCE AB Background Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. Methods We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. Findings We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97.6% (95% CI 97.4-97.9) at day 28 and 96.0% (95.6-96.5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0.92, 95% CI 0.86-0.99 for every 1 mg/kg increase in daily artemether dose; p=0.024), but not on day 2 (p=0.69) or day 3 (0.087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91.7%, 95% CI 86.5-96.9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94.3%, 95% CI 92.3-96.3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0.92, 95% CI 0.85-0.99; p=0.037 for every 1 mg/kg increase in total artemether dose). Interpretation The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. C1 [Anstey, N. M.; Price, R. N.] Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia. [Anstey, N. M.] Charles Darwin Univ, Darwin, NT 0909, Australia. [Davis, T. M. E.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Karunajeewa, H. A.; Mueller, I.] Walter & Eliza Hall Inst Med Res, Infect & Immun Div, Melbourne, Vic, Australia. Western Hlth, Div Med, Melbourne, Vic, Australia. [D'Alessandro, U.] Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium. [Massougbodji, A.] Univ dAbomey Calavi, Fac Sci Sante, Ctr Etud & Rech Paludisme Associe Grossesse & Enf, Cotonou, Benin. [Nikiema, F.; Ouedraogo, J-B; Tinto, H.] Inst Rech Sci Sante, Direct Reg Ouest, Bobo Dioulasso, Burkina Faso. Ctr Muraz, Bobo Dioulasso, Burkina Faso. [Same-Ekobo, A.] Univ Yaounde, Ctr Hosp, Fac Med & Sci Biomed, Yaounde, Cameroon. [Kone, M.; Menan, H.; Yavo, W.] Univ Cocody, Fac Pharm, Dept Parasitol & Mycol, Abidjan, Cote Ivoire. [Toure, A. O.] Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire. [Yavo, W.] Natl Inst Publ Hlth, Malaria Res & Control Ctr, Abidjan, Cote Ivoire. [Kofoed, P-E] Kolding Cty Hosp, Dept Paediat, Kolding, Denmark. [Alemayehu, B. H.] Int Ctr AIDS Care & Treatment Programs, Addis Ababa, Ethiopia. [Jima, D.] Fed Minist Hlth, Addis Ababa, Ethiopia. [Baudin, E.; Espie, E.; Nabasumba, C.; Pinoges, L.; Schramm, B.] Epictr, Paris, France. [Cot, M.; Deloron, P.; Faucher, J-F] Inst Rech Dev, Mother & Child Hlth Trop Res Unit, Paris, France. [Cot, M.; Deloron, P.; Faucher, J-F] Univ Paris 05, Sorbonne Paris Cite, PRES, Paris, France. [Faucher, J-F] Univ Besancon, Med Ctr, Dept Infect Dis, F-25030 Besancon, France. [Guthmann, J-P] Inst Veille Sanit, Dept Malad Infect, St Maurice, France. [Lell, B.] Ctr Rech Med Lambarene, Lambarene, Gabon. [Lell, B.; Borrmann, S.] Univ Tubingen, Inst Trop Med, Tubingen, Germany. [Adjei, G. O.] Univ Ghana, Sch Med, Ctr Trop Clin Pharmacol & Therapeut, Accra, Ghana. [Kofoed, P-E] Projecto Saude Bandim, Bissau, Guinea Bissau. [Tjitra, E.] Minist Hlth, Natl Inst Hlth Res & Dev, Jakarta, Indonesia. [Borrmann, S.; Marsh, K.; Peshu, J.] Kenya Govt Med Res Ctr, Kilifi, Kenya. [Borrmann, S.; Marsh, K.; Peshu, J.] Wellcome Trust Res Programme, Kilifi, Kenya. [Juma, E.] Kenya Govt Med Res Ctr, Nairobi, Kenya. [Ogutu, B. R.] Kenya Govt Med Res Ctr, Kisumu, Kenya. [Ogutu, B. R.] US Army Med Res Unit, Kisumu, Kenya. [Omar, S. A.; Sawa, P.] Int Ctr Insect Physiol & Ecol, Human Hlth Div, Mbita Point, Kenya. [Talisuna, A. O.] WWARN East Africa Reg Ctr, Nairobi, Kenya. [Talisuna, A. O.] Univ Oxford, KEMRI, Oxford OX3 7LJ, England. [Talisuna, A. O.] Wellcome Trust Res Programme, Nairobi, Kenya. [Khanthavong, M.] Ctr Malariol Parasitol & Entomol, Viangchan, Laos. [Mayxay, M.; Newton, P. N.] Oxford Univ Trop Med Res Collaborat, Mahosot Hosp, Wellcome Trust Mahosot Hosp, Viangchan, Laos. [Mayxay, M.] Natl Univ Laos, Fac Med Sci, Viangchan, Laos. [Piola, P.] Inst Pasteur Madagascar, Antananarivo, Madagascar. [Djimde, A. A.; Doumbo, O. K.; Fofana, B.; Sagara, I.] Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. [Bassat, Q.; Gonzalez, R.; Menendez, C.] Ctr Invest Saude Manhica, Manhica, Mozambique. [Smithuis, F.] Myanmar Oxford Clin Res Unit, Yangon, Myanmar. [Smithuis, F.] Myanmar & Med Act Myanmar, Yangon, Myanmar. [Bousema, T.] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Njimegen, Netherlands. [Kager, P. A.; Mens, P. F.] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINEMA, Div Infect Dis Trop Med & AIDS, NL-1105 AZ Amsterdam, Netherlands. [Mens, P. F.; Schallig, H. D. F. H.] Royal Trop Inst, KIT Biomed Res, NL-1105 AZ Amsterdam, Netherlands. [Van den Broek, I.] Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, NL-3720 BA Bilthoven, Netherlands. [Van Vugt, M.] Univ Amsterdam, Acad Med Ctr, Ctr Trop Med & Travel Med, Div Infect Dis, NL-1012 WX Amsterdam, Netherlands. [Ibrahim, M. L.] Ctr Rech Med & Sanit, Niamey, Niger. [Falade, C. O.] Univ Ibadan, Coll Med, Ibadan, Nigeria. [Meremikwu, M.] Univ Calabar, Dept Paediat, Calabar, Nigeria. Inst Trop Dis Res & Prevent, Calabar, Nigeria. [Gil, J. P.] Univ Lisbon, Fac Ciencias, Ctr Biodivers Funct & Integrat Genom, Drug Resistance & Pharmacogenet, P-1699 Lisbon, Portugal. [Karema, C.] Minist Hlth, Malaria & Other Parasit Dis Div RBC, Kigali, Rwanda. [Ba, M. S.; Faye, B.; Faye, O.; Gaye, O.; Ndiaye, J-L; Pene, M.; Sow, D.; Sylla, K.; Tine, R. C. K.] Univ Cheikh Anta Diop, Fac Med, Dept Parasitol & Mycol, Dakar, Senegal. [Penali, L. K.] WWARN West Africa Reg Ctr, Dakar, Senegal. [Barnes, K. I.; Workman, L. J.] WWARN, Pharmacol Module, Cape Town, South Africa. [Barnes, K. I.; Workman, L. J.] Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7925 Cape Town, South Africa. [Bassat, Q.; Gonzalez, R.; Menendez, C.] Ctr Recerca Salut Int Barcelona, Barcelona, Spain. [Lima, A.] Medecins Sans Frontieres Operat Ctr Barcelona Ath, Barcelona, Spain. [Adam, I.] Univ Khartoum, Fac Med, Khartoum, Sudan. [Gadalla, N. B.] Natl Res Ctr, Res Inst Trop Med, Dept Epidemiol, Khartoum, Sudan. [Malik, E. F. M.] Fed Minist Hlth, Khartoum, Sudan. [Bjorkman, A.] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Infect Dis Unit, Stockholm, Sweden. [Gil, J. P.] Karolinska Inst, Dept Physiol & Pharmacol, Drug Resistance Unit, Pharmacogenet Sect, Stockholm, Sweden. [Ursing, J.; Martensson, A.; Ngasala, B. E.] Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden. [Martensson, A.] Karolinska Inst, Dept Publ Hlth Sci, Div Global Hlth, Stockholm, Sweden. [Rombo, L.] Karolinska Univ Hosp, Dept Med, Malaria Res Lab, Infect Dis Unit, Stockholm, Sweden. [Rombo, L.] Dept Infect Dis, Eskilstuna, Sweden. [Rombo, L.] Sormland Cty Council, Clin Res Ctr, Sormland, Sweden. [Aliu, P.] Novartis Pharma AG, Basel, Switzerland. [Duparc, S.] Med Malaria Venture, Geneva, Switzerland. [Filler, S.] Global Fund Fight AIDS TB & Malaria, Geneva, Switzerland. [Genton, B.] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Genton, B.] Univ Lausanne Hosp, Div Infect Dis, Lausanne, Switzerland. [Genton, B.] Univ Lausanne Hosp, Dept Ambulatory Care & Community Med, Lausanne, Switzerland. [Hodel, E. M.] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Olliaro, P.] UNDP, UNICEF, World Bank, Geneva, Switzerland. [Olliaro, P.] WHO, Special Programme Res & Training Trop Dis, CH-1211 Geneva, Switzerland. [Abdulla, S.] Ifakara Hlth Inst, Dar Es Salaam, Tanzania. [Kamugisha, E.] Catholic Univ Hlth & Allied Sci, Mwanza, Tanzania. [Ngasala, B. E.; Premji, Z.] Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania. [Shekalaghe, S. A.] Kilimanjaro Christian Med Ctr, Kilimanjaro Clin Med Res Inst, Moshi, Tanzania. [Shekalaghe, S. A.] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Ashley, E. A.; Carrara, V. I.; McGready, R.; Nosten, F.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand. [Ashley, E. A.; Faiz, A. M.; Lee, S. J.; White, N. J.] Mahidol Univ, Fac Trop Med, Bangkok, Thailand. [Carrara, V. I.; Dondorp, A. M.] Mahidol Univ, Mahidol Oxford Univ Res Unit, Bangkok, Thailand. [Smith, J. J.] WWARN Asia Reg Ctr, Bangkok, Thailand. MRC Unit, Fajara, Gambia. [Tarning, J.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Achan, J.; Bukirwa, H.; Yeka, A.] Uganda Malaria Surveillance Project, Kampala, Uganda. [Arinaitwe, E.; Staedke, S. G.] Infect Dis Res Collaborat, Kampala, Uganda. [Kamya, M. R.] Makerere Univ, Coll Hlth Sci, Kampala, Uganda. [Kironde, F.] Makerere Univ, Dept Biochem, Kampala, Uganda. [Nabasumba, C.] Mbarara Univ Sci & Technol, Fac Med, Mbarara, Uganda. [Bousema, T.; Gadalla, N. B.; Drakeley, C. J.; Oguike, M.; Sutherland, C. J.] London Sch Hyg & Trop Med, Immunol & Infect Dept, London WC1, England. [Checchi, F.] Save Children, Humanitarian Dept, London, England. [Newton, P. N.; Tarning, J.; Dahal, P.; Flegg, J. A.; Guerin, P. J.; Moreira, C.; Nsanzabana, C.; Sibley, C. H.; Stepniewska, K.] Worldwide Antimalarial Resistance Network, Oxford, England. [Marsh, K.; Newton, P. N.; Olliaro, P.; McGready, R.; Nosten, F.; Lee, S. J.; White, N. J.; Dondorp, A. M.; Tarning, J.; Dahal, P.; Flegg, J. A.; Guerin, P. J.; Moreira, C.; Nsanzabana, C.] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England. [Gething, P. W.; Hay, S. I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Greenwood, B.] London Sch Hyg & Trop Med, Dept Dis Control, London WC1, England. [Hodel, E. M.; Ward, S. A.] Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England. [Staedke, S. G.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Clin Res, London WC1, England. [Van den Broek, I.] Medecins Sans Frontieres, London, England. [Winstanley, P. A.] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Dorsey, G.; Greenhouse, B.; Rosenthal, P. J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Gadalla, N. B.] NIAID, Rockville, MD USA. [Gil, J. P.] SUNY Binghamton, Harpur Coll Arts & Sci, Binghamton, NY USA. [Grivoyannis, A.] Univ Washington, Div Emergency Med, Seattle, WA 98195 USA. [Hamed, K.] Novartis, E Hanover, NJ USA. [Hwang, J.; Kachur, P. S.] US Ctr Dis Control & Prevent, Atlanta, GA USA. [Hwang, J.] Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA. [Sibley, C. H.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Nambozi, M.] Trop Dis Res Ctr, Ndola, Zambia. RP Price, RN (reprint author), Univ Oxford, Ctr Trop Med & Global Hlth, Worldwide Antimalarial Resistance Network, S Parks Rd, Oxford OX3 7LJ, England. EM ric.price@wwarn.org; christian.nsanzabana@wwarn.org RI Hodel, Eva Maria/E-1258-2014; Bousema, Teun/N-3574-2014; Ward, Steve/G-6003-2015; Hay, Simon/F-8967-2015; OI Guerin, Philippe/0000-0002-6008-2963; Hamed, Kamal/0000-0003-1896-9736; Price, Richard/0000-0003-2000-2874; Hodel, Eva Maria/0000-0001-5821-1685; Ward, Steve/0000-0003-2331-3192; Hay, Simon/0000-0002-0611-7272; Gething, Peter/0000-0001-6759-5449; GADALLA, NAHLA/0000-0002-6177-6705; Dahal, Prabin/0000-0002-2158-846X; Flegg, Jennifer/0000-0002-8809-726X; Nosten, Francois/0000-0002-7951-0745; McGready, Rose/0000-0003-1621-3257 FU Bill & Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 32 TC 16 Z9 16 U1 4 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2015 VL 15 IS 6 BP 692 EP 702 DI 10.1016/S1473-3099(15)70024-1 PG 11 WC Infectious Diseases SC Infectious Diseases GA CI3HI UT WOS:000354638000034 ER PT J AU Nachman, S Ahmed, A Amanullah, F Becerra, MC Botgros, R Brigden, G Browning, R Gardiner, E Hafner, R Hesseling, A How, C Jean-Philippe, P Lessem, E Makhene, M Mbelle, N Marais, B McIlleron, H McNeeley, DF Mendel, C Murray, S Navarro, E Anyalechi, EG Porcalla, AR Powell, C Powell, M Rigaud, M Rouzier, V Samson, P Schaaf, HS Shah, S Starke, J Swaminathan, S Wobudeya, E Worrell, C AF Nachman, Sharon Ahmed, Amina Amanullah, Farhana Becerra, Mercedes C. Botgros, Radu Brigden, Grania Browning, Renee Gardiner, Elizabeth Hafner, Richard Hesseling, Anneke How, Cleotilde Jean-Philippe, Patrick Lessem, Erica Makhene, Mamodikoe Mbelle, Nontombi Marais, Ben McIlleron, Helen McNeeley, David F. Mendel, Carl Murray, Stephen Navarro, Eileen Anyalechi, E. Gloria Porcalla, Ariel R. Powell, Clydette Powell, Mair Rigaud, Mona Rouzier, Vanessa Samson, Pearl Schaaf, H. Simon Shah, Seema Starke, Jeff Swaminathan, Soumya Wobudeya, Eric Worrell, Carol TI Towards early inclusion of children in tuberculosis drugs trials: a consensus statement SO LANCET INFECTIOUS DISEASES LA English DT Review ID MULTIDRUG-RESISTANT TUBERCULOSIS; SOUTH-AFRICAN CHILDREN; CHILDHOOD TUBERCULOSIS; ANTITUBERCULOSIS AGENTS; MANAGEMENT CHALLENGES; WESTERN CAPE; RISK-FACTORS; HIV; RECOMMENDATIONS; MORTALITY AB Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained. C1 [Nachman, Sharon] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Ahmed, Amina] Carolinas Med Ctr, Levine Childrens Hosp, Charlotte, NC 28203 USA. [Amanullah, Farhana] Indus Hosp, Karachi, Pakistan. [Becerra, Mercedes C.] Harvard Univ, Sch Med, Boston, MA USA. [Botgros, Radu; Powell, Mair] European Med Agcy, London, England. [Brigden, Grania] Access Campaign, Medecins Sans Frontieres, Geneva, Switzerland. [Browning, Renee; Hafner, Richard; Makhene, Mamodikoe] NIAID, NIH, Div Aids, Bethesda, MD 20892 USA. [Gardiner, Elizabeth; Mendel, Carl; Murray, Stephen] TB Alliance, New York, NY USA. [Hesseling, Anneke; Schaaf, H. Simon] Univ Stellenbosch, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa. [How, Cleotilde] Univ Philippines, Dept Pharmacol & Toxicol, Manila, Philippines. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn, Div Aids, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lessem, Erica] Treatment Act Grp, New York, NY USA. [Mbelle, Nontombi] Univ Pretoria, Dept Med Microbiol, ZA-0002 Pretoria, South Africa. [Marais, Ben] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Marais, Ben] Univ Sydney, Sydney Emerging Infect Dis & Biosecur Inst, Sydney, NSW 2006, Australia. [Marais, Ben] Univ Sydney, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [McIlleron, Helen] Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7700 Rondebosch, South Africa. [McNeeley, David F.] Novartis Pharmaceut, E Hanover, NJ USA. [Navarro, Eileen; Porcalla, Ariel R.] US FDA, Div Antiinfect Prod, Off Antimicrobial Prod, Off New Drugs, Silver Spring, MD USA. [Anyalechi, E. Gloria] US Ctr Dis Control & Prevent, Div TB Eliminat, Int Res & Programs Branch, Atlanta, GA USA. [Powell, Clydette] Agcy Int Dev, Washington, DC USA. [Rigaud, Mona] NYU, Sch Med, New York, NY 10003 USA. [Rouzier, Vanessa] GHESKIO, Port Au Prince, Haiti. [Samson, Pearl] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res & Frontier Sci, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Shah, Seema] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Starke, Jeff] Baylor Coll Med, Houston, TX 77030 USA. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Wobudeya, Eric] Makerere Univ Johns Hopkins Res Collaborat, Kampala, Uganda. [Wobudeya, Eric] Mulago Natl Referral Hosp, Kampala, Uganda. [Worrell, Carol] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, NIH, Rockville, MD USA. RP Nachman, S (reprint author), Hlth Sci SUNY Stony Brook, Stony Brook Childrens Hosp, Dept Pediat, Stony Brook, NY 11794 USA. EM sharon.nachman@stonybrook.edu OI wobudeya, eric/0000-0001-9574-5539; McIlleron, Helen/0000-0002-0982-6226 FU National Institute of Allergy and Infectious Diseases; National Institute of Health; Department of Health and Human Services; HHS FX We thank the following individuals for assistance in the planning and conduct of the workshop or drafting of the manuscript, or both: Sheryl Zwerski, Sarah Read, Larry Fox, Devasena Gnanashanmugam, Judi Miller, Ellen O'Gara, Paul Sato, Peter Kim, Tyseaia Squirewell McFarlane, Rahel Abebe, and Andrea Williams. This work was funded by National Institute of Allergy and Infectious Diseases and National Institute of Health. This project has also been funded in part with federal funds from the Department of Health and Human Services. The views expressed in written conference materials or publications and by speakers and moderators at HHS-sponsored conferences, do not necessarily show the official policies of the Department of Health and Human Services (DHHS) or individual DHHS or other US government agencies including the National Institute of Health, the Center for Disease Control and Prevention, the Food and Drug Administration or the US Agency for International Development; nor does mention of trade names, commercial practices, or organisations imply endorsement by the US Government. The views expressed in this consensus statement are the personal views of the authors and cannot be understood or quoted as made on behalf of the position of the European Medicines Agency, or one of its committees or working parties. NR 75 TC 21 Z9 21 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2015 VL 15 IS 6 BP 711 EP 720 DI 10.1016/S1473-3099(15)00007-9 PG 10 WC Infectious Diseases SC Infectious Diseases GA CI3HI UT WOS:000354638000036 PM 25957923 ER PT J AU Colberg-Poley, AM Patterson, GH Salka, K Bhuvanendran, S Yang, D Jaiswal, JK AF Colberg-Poley, Anamaris M. Patterson, George H. Salka, Kyle Bhuvanendran, Shivaprasad Yang, David Jaiswal, Jyoti K. TI Superresolution imaging of viral protein trafficking SO MEDICAL MICROBIOLOGY AND IMMUNOLOGY LA English DT Review DE Cytomegalovirus; Superresolution imaging; vMIA; MAM; Mitochondria; MSIM; PALM; STED ID HUMAN CYTOMEGALOVIRUS-INFECTION; MITOCHONDRION-ASSOCIATED MEMBRANES; ENDOPLASMIC-RETICULUM; RIG-I; UL37 PROTEINS; FLUORESCENCE NANOSCOPY; LOCALIZED INHIBITOR; STRUCTURAL BASIS; INNATE IMMUNITY; INNER MEMBRANE AB The endoplasmic reticulum (ER) membrane is closely apposed to the outer mitochondrial membrane (OMM), which facilitates communication between these organelles. These contacts, known as mitochondria-associated membranes (MAM), facilitate calcium signaling, lipid transfer, as well as antiviral and stress responses. How cellular proteins traffic to the MAM, are distributed therein, and interact with ER and mitochondrial proteins are subject of great interest. The human cytomegalovirus UL37 exon 1 protein or viral mitochondria-localized inhibitor of apoptosis (vMIA) is crucial for viral growth. Upon synthesis at the ER, vMIA traffics to the MAM and OMM, where it reprograms the organization and function of these compartments. vMIA significantly changes the abundance of cellular proteins at the MAM and OMM, including proteins that regulate calcium homeostasis and cell death. Through the use of superresolution imaging, we have shown that vMIA is distributed at the OMM in nanometer scale clusters. This is similar to the clusters reported for the mitochondrial calcium channel, VDAC, as well as electron transport chain, translocase of the OMM complex, and mitochondrial inner membrane organizing system components. Thus, aside from addressing how vMIA targets the MAM and regulates survival of infected cells, biochemical studies and superresolution imaging of vMIA offer insights into the formation, organization, and functioning of MAM. Here, we discuss these insights into trafficking, function, and organization of vMIA at the MAM and OMM and discuss how the use of superresolution imaging is contributing to the study of the formation and trafficking of viruses. C1 [Colberg-Poley, Anamaris M.; Salka, Kyle; Bhuvanendran, Shivaprasad; Jaiswal, Jyoti K.] Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC 20010 USA. [Colberg-Poley, Anamaris M.; Jaiswal, Jyoti K.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20037 USA. [Colberg-Poley, Anamaris M.; Jaiswal, Jyoti K.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20037 USA. [Colberg-Poley, Anamaris M.] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem, Washington, DC 20037 USA. [Colberg-Poley, Anamaris M.] George Washington Univ, Sch Med & Hlth Sci, Dept Mol Med, Washington, DC 20037 USA. [Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD 20892 USA. [Yang, David] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. RP Colberg-Poley, AM (reprint author), Childrens Natl Hlth Syst, Med Genet Res Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM acolberg-poley@childrensnational.org; pattersg@mail.nih.gov; jkjaiswal@childrensnational.org RI Jaiswal, Jyoti/M-5891-2013 OI Jaiswal, Jyoti/0000-0002-5992-5185 FU NSF [MCB 1244509]; National Institutes of Health; National Institute of Biomedical Imaging and Bioengineering; [1P30HD40677] FX This work was partially funded by the NSF Grant (MCB 1244509) to ACP and JKJ. The confocal microscopy imaging was supported by a core Grant (1P30HD40677) to the Children's Intellectual and Developmental Disabilities Research Center. This work was also supported by the Intramural Research Program of the National Institutes of Health including the National Institute of Biomedical Imaging and Bioengineering. We thank Kristen Rainey for assisting with imaging and analysis. We thank Andrew York and Hari Shroff for sharing MSIM analysis and deconvolution software. We thank Harald Hess for the use of the PALM analysis software, PeakSelector. NR 100 TC 3 Z9 3 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0300-8584 EI 1432-1831 J9 MED MICROBIOL IMMUN JI Med. Microbiol. Immunol. PD JUN PY 2015 VL 204 IS 3 BP 449 EP 460 DI 10.1007/s00430-015-0395-0 PG 12 WC Immunology; Microbiology SC Immunology; Microbiology GA CI6UI UT WOS:000354897600022 PM 25724304 ER PT J AU Boyington, J Joseph, L Fielding, R Pate, R AF Boyington, Josephine Joseph, Lyndon Fielding, Roger Pate, Russell TI Sedentary Behavior Research Priorities-NHLBI/NIA Sedentary Behavior Workshop Summary SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article ID TYPE-2 DIABETES-MELLITUS; PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; TIME SPENT; US ADULTS; RISK; MORTALITY; MEN; OBESITY; WOMEN C1 [Boyington, Josephine] NHLBI, NIH, Bethesda, MD 20892 USA. [Joseph, Lyndon] NIA, NIH, Bethesda, MD 20892 USA. [Fielding, Roger] Tufts Univ, Nutr Exercise Physiol & Sarcopenia Lab, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Pate, Russell] Univ S Carolina, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. RP Pate, R (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Suite 212,921 Assembly St, Columbia, SC 29208 USA. EM rpate@mailbox.sc.edu FU National Heart, Lung, and Blood Institute; National Institute on Aging; Office of Disease Prevention of the National Institutes of Health; U.S. Department of Agriculture [58-19500-014]; Boston Claude D. Pepper Older Americans Independence Center [1P30AG031679]; U.S. Department of Agriculture; National Institutes of Health; Nestec Ltd.; Regeneron Pharmaceutical; Centers for Disease Control and Prevention; Duke Endowment; FTZ Coca-Cola Service Company FX The workshop was sponsored by the National Heart, Lung, and Blood Institute, the National Institute on Aging, and the Office of Disease Prevention of the National Institutes of Health. The views expressed in this document reflect the collective ideas and opinions of the authors and do not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Health and Human Services, or the other workshop participants.; Dr. Fielding's participation in this project was partially supported by the U.S. Department of Agriculture, under agreement no. 58-19500-014, and the Boston Claude D. Pepper Older Americans Independence Center (1P30AG031679). Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the U.S. Department of Agriculture.; Dr. Fielding receives grant support from the U.S. Department of Agriculture, National Institutes of Health, Nestec Ltd., and Regeneron Pharmaceutical; is a consultant to Regeneron Pharmaceuticals and Nestec, Ltd; serves on the Scientific Advisory Boards of Cytokinetics, Inc., Pronutria, Inc., Amonnett, Inc., and Inside Tracker, Inc,; and owns stock or options in Pronutria, Amonnett, Inc., Inside Tracker, and Myosyntax.; Dr. Pate receives grant support from the National Institutes of Health, Centers for Disease Control and Prevention, Duke Endowment, and FTZ Coca-Cola Service Company. He serves on the Scientific Advisory Board of Curves, Inc. NR 17 TC 4 Z9 4 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUN PY 2015 VL 47 IS 6 BP 1291 EP 1294 DI 10.1249/MSS.0000000000000516 PG 4 WC Sport Sciences SC Sport Sciences GA CI4TC UT WOS:000354745500024 PM 25222819 ER PT J AU Peyrot, WJ Lee, SH Milaneschi, Y Abdellaoui, A Byrne, EM Esko, T de Geus, EJC Hemani, G Hottenga, JJ Kloiber, S Levinson, DF Lucae, S Martin, NG Medland, SE Metspalu, A Milani, L Noethen, MM Potash, JB Rietschel, M Rietveld, CA Ripke, S Shi, J Willemsen, G Zhu, Z Boomsma, DI Wray, NR Penninx, BWJH AF Peyrot, W. J. Lee, S. H. Milaneschi, Y. Abdellaoui, A. Byrne, E. M. Esko, T. de Geus, E. J. C. Hemani, G. Hottenga, J. J. Kloiber, S. Levinson, D. F. Lucae, S. Martin, N. G. Medland, S. E. Metspalu, A. Milani, L. Noethen, M. M. Potash, J. B. Rietschel, M. Rietveld, C. A. Ripke, S. Shi, J. Willemsen, G. Zhu, Z. Boomsma, D. I. Wray, N. R. Penninx, B. W. J. H. CA Major Depressive Disorder Working Social Sci Genetic Assoc Consortiu TI The association between lower educational attainment and depression owing to shared genetic effects? Results in similar to 25 000 subjects SO MOLECULAR PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; SOCIOECONOMIC DISPARITIES; DISORDER; HEALTH; EPIDEMIOLOGY; POPULATION; STRESS; COMMON; LOCI; TWIN AB An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on similar to 120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. C1 [Peyrot, W. J.; Milaneschi, Y.; Penninx, B. W. J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Peyrot, W. J.; Milaneschi, Y.; Penninx, B. W. J. H.] GGZ inGeest, Amsterdam, Netherlands. [Lee, S. H.; Byrne, E. M.; Hemani, G.; Zhu, Z.; Wray, N. R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Abdellaoui, A.; Hottenga, J. J.; Willemsen, G.; Boomsma, D. I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Esko, T.; Metspalu, A.; Milani, L.] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Esko, T.; Metspalu, A.] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA. [Esko, T.; Metspalu, A.] Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA USA. [Esko, T.; Metspalu, A.] Harvard Univ, Sch Med, Boston, MA USA. [Esko, T.; Metspalu, A.] Broad Inst, Cambridge, MA USA. [Hemani, G.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England. [Kloiber, S.] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Levinson, D. F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Martin, N. G.; Medland, S. E.] QIMR Berhgofer Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld, Australia. [Noethen, M. M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Potash, J. B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Rietschel, M.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Heidelberg, Germany. [Rietveld, C. A.] Erasmus Univ, Erasmus Sch Econ, Rotterdam, Netherlands. [Rietveld, C. A.] Erasmus Univ, Inst Behav & Biol, Rotterdam, Netherlands. [Ripke, S.] MIT & Harvard, Stanley Ctr Psychiat Res, Broad Inst, Cambridge, MA USA. [Shi, J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD USA. RP Peyrot, WJ (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, AJ Ernststr 1187, Amsterdam, Netherlands. EM w.peyrot@ggzingeest.nl RI Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Lee, Sang Hong/A-2569-2011; Polasek, Ozren/B-6002-2011; Mattheisen, Manuel/B-4949-2012; Breen, Gerome/A-5540-2010; Smith, Albert/K-5150-2015; Holle, Rolf/D-9333-2013; Lewis, Glyn/E-9944-2012; Deloukas, Panos/B-2922-2013; Fehrmann, Rudolf/E-2551-2011; Colaus, PsyColaus/K-6607-2013; Allik, Juri/D-5609-2009; Realo, Anu/M-9524-2016; Lewis, Cathryn/A-5225-2010; Karjalainen, Juha/P-8624-2016; Palmer, Lyle/K-3196-2014; Kolcic, Ivana/E-2713-2017; OI Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Lee, Sang Hong/0000-0001-9701-2718; Polasek, Ozren/0000-0002-5765-1862; Mattheisen, Manuel/0000-0002-8442-493X; Breen, Gerome/0000-0003-2053-1792; Smith, Albert/0000-0003-1942-5845; Holle, Rolf/0000-0001-5395-2695; Lewis, Glyn/0000-0001-5205-8245; Deloukas, Panos/0000-0001-9251-070X; Fehrmann, Rudolf/0000-0002-7516-315X; Allik, Juri/0000-0002-8358-4747; Kloiber, Stefan/0000-0002-6838-4114; Evans, David/0000-0003-0663-4621; Lawlor, Debbie A/0000-0002-6793-2262; Middeldorp, Christel/0000-0002-6218-0428; Thorgeirsson, Thorgeir/0000-0002-5149-7040; de Geus, Eco/0000-0001-6022-2666; Li, Jingmei/0000-0001-8587-7511; Lewis, Cathryn/0000-0002-8249-8476; Palmer, Lyle/0000-0002-1628-3055; Kolcic, Ivana/0000-0001-7918-6052; Cesarini, David/0000-0002-0043-009X; Joshi, Peter/0000-0002-6361-5059; Tozzi, Federica/0000-0002-3536-2920; Kristiansson, Kati/0000-0003-4688-107X; Viktorin, Alexander/0000-0003-2141-2816 FU Australian Research Council [FT0991360, DE130100614]; National Health and Medical Research Council [613608, 1011506, 1047956]; National Institute of Mental Health (NIMH) [U01 MH085520]; Netherlands Scientific Organization; German Federal Ministry of Education and Research, within the context of the National Genome Research Network 2 (NGFN2); National Genome Research Network plus (NGFNplus); Integrated Genome Research Network (IG) MooDS [01GS08144, 01GS08147]; European Union [LSHM-CT-2006-037761, PIAP-GA-2008-218251, HEALTH-F2-2009-223423]; Medical Research Council (UK); Mental Health Research Network; Innovative Medicines Initiative Joint Undertaking [115008]; NIMH [MH061686, MH059542, MH075131, MH059552, MH059541, MH060912]; Broad Institute Center for Genotyping and Analysis [U54 RR020278]; GenRED; NIMH; National Alliance for Research on Schizophrenia and Depression; Depression Genes and Networks ARRA grant [RC2MH089916]; Harvard i2b2; i2b2 Center; NIH-funded National Center for Biomedical Computing based at Partners HealthCare System [U54LM008748]; BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression [01ES0811]; Bavarian Ministry of Commerce; Federal Ministry of Education and Research (BMBF) [FKZ 01GS0481, 01GS08145]; Netherlands Organization for Scientific Research (MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04- 004, 400-05-717, 912-100-20]; Netherlands Organization for Scientific Research (Spinozapremie) [56-464-14192]; Netherlands Organization for Scientific Research (Geestkracht program) [10-000-1002]; Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/RK [2008.024]; European Science Foundation [EU/QLRT-2001-01254]; European Community's Seventh Framework Program; ENGAGE [HEALTH-F4-2007-201413]; European Science Council (ERC) [230374]; Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health; GAIN; Swiss National Science Foundation [3200B0-105993, 3200B0-118'308, 33CSC0-122661]; GlaxoSmithKline; Australian National Health and Medical Research Council [613608, 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613674, 619667]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health [AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951]; Center for Inherited Disease Research (Baltimore, MD, USA); UK Medical Research Council and GlaxoSmithKline [G0701420]; National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London; UK Medical Research Council [G0000647]; European Commission [LSHB-CT-2003-503428]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; German Research Foundation (DFG) [GR 1912/5-1]; NIMH Grant [MH072802]; National Institute of Mental Health [N01MH90003]; Swedish Ministry for Higher Education; Swedish Research Council [M-2005-1112]; GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254]; Swedish Foundation for Strategic Research; Wellcome Trust [076113, 085475]; European Regional Development Fund [3.2.0304.11-0312]; 'Center of Excellence in Genomics' (EXCEGEN); Estonian Government [IUT24-6, IUT20-60]; CTG grant from Development Fund of the University of Tartu [SP1GVAR-ENG]; National Health and Medical Research Early Career Fellowship Scheme; [MH086026]; [MH081802]; [FT0991022]; [03ZIK012]; [U01 DK066134]; [313010] FX NRW and SHL supported by the Australian Research Council (FT0991360 and DE130100614) and the National Health and Medical Research Council (613608, 1011506 and 1047956). The PGC is supported by National Institute of Mental Health (NIMH) Grant U01 MH085520. Statistical analyses were carried out on the Genetic Cluster Computer (see Web Resources), which is financially supported by the Netherlands Scientific Organization. The Bonn/Mannheim (BoMa) GWAS was supported by the German Federal Ministry of Education and Research, within the context of the National Genome Research Network 2 (NGFN2), the National Genome Research Network plus (NGFNplus) and the Integrated Genome Research Network (IG) MooDS (Grant 01GS08144 to S Cichon and MMN, and Grant 01GS08147 to MR). The work at deCODE was funded by European Union Grants LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs). GenPod was funded by the Medical Research Council (UK) and supported by the Mental Health Research Network. Genotyping of the GenPod sample was funded by the Innovative Medicines Initiative Joint Undertaking under Grant Agreement number 115008 (NEWMEDS). The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (to DFL), MH059542 (to WHC), MH075131 (to WBL), MH059552 (to JBP), MH059541 (to WAS) and MH060912 (to MMW). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The Depression Genes and Networks ARRA grant was funded by RC2MH089916. Funding for the Harvard i2b2 sample was provided by a subcontract to RH Perlis and JW Smoller as part of the i2b2 Center (Informatics for Integrating Biology and the Bedside), an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System (U54LM008748, PI: IS Kohane), and by an NIMH Grant (to RH Perlis; MH086026). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000.; This study was funded by: the Netherlands Organization for Scientific Research (MagW/ZonMW Grants 904-61-090, 985-10-002, 904-61-193, 480-04- 004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded, in part, by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). The PsyCoLaus study was supported by grants from the Swiss National Science Foundation (nos. 3200B0-105993, 3200B0-118'308, 33CSC0-122661) and from GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery-Verona, R&D). We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We also thank V Mooser, G Weaber and P Vollenweider who initiated the CoLaus project. Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (FT0991360, FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. RADIANT was funded by: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. 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 (Grant nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. 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. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG. SHIP-LEGEND is funded by the German Research Foundation (DFG: GR 1912/5-1). Genotyping of STAR*D was supported by an NIMH Grant to SP Hamilton (MH072802). STAR*D was funded by the National Institute of Mental Health (Contract No. N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator).; The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (U01 DK066134). This study makes use of 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 from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. EGCUT received financing from FP7 Grant 313010 and from European Regional Development Fund, road map Grant No. 3.2.0304.11-0312 and grant 'Center of Excellence in Genomics' (EXCEGEN). EGCUT studies were covered also by targeted financing from Estonian Government (IUT24-6, IUT20-60) and CTG grant (SP1GVAR-ENG) from Development Fund of the University of Tartu. We acknowledge EGCUT technical personnel, especially Mr V Soo and S Smit and Mari-Liis Tammesoo. EMB is supported by the National Health and Medical Research Early Career Fellowship Scheme. NR 42 TC 6 Z9 6 U1 2 U2 29 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 JUN PY 2015 VL 20 IS 6 BP 735 EP 743 DI 10.1038/mp.2015.50 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CI6SB UT WOS:000354890200012 PM 25917368 ER PT J AU Cheng, Y Rodriguiz, RM Murthy, SRK Senatorov, V Thouennon, E Cawley, NX Aryal, DK Ahn, S Lecka-Czernik, B Wetsel, WC Loh, YP AF Cheng, Y. Rodriguiz, R. M. Murthy, S. R. K. Senatorov, V. Thouennon, E. Cawley, N. X. Aryal, D. K. Ahn, S. Lecka-Czernik, B. Wetsel, W. C. Loh, Y. P. TI Neurotrophic factor-alpha 1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone SO MOLECULAR PSYCHIATRY LA English DT Article ID FIBROBLAST GROWTH FACTOR-2; HIPPOCAMPAL NEUROGENESIS; CARBOXYPEPTIDASE-E; ANTIDEPRESSANT TREATMENT; CELL-PROLIFERATION; FGF-2 ISOFORMS; MICE; BEHAVIOR; ANXIETY; EXPRESSION AB Major depressive disorder is often linked to stress. Although short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1 h per day for 7 days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-alpha 1 (NF-alpha 1; also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6 h per day for 21 days) CRS, mice show decreased hippocampal NF-alpha 1 and FGF2 levels and depressive-like responses. In NF-alpha 1-knockout mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior that is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF-alpha 1 treatment directly upregulates FGF2 expression through extracellular signal-regulated kinase-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-alpha 1 expression is upregulated and has a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone (Rosi), a PPAR. agonist, which has been shown to have antidepressant activity in rodents and humans. Rosi upregulates FGF2 expression in a NF-alpha 1-dependent manner in hippocampal neurons. Mice fed Rosi show increased hippocampal NF-alpha 1 levels and neurogenesis compared with controls, thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF-alpha 1/FGF2/neurogenesis pathway can offer a new approach to depression therapy. C1 [Cheng, Y.; Murthy, S. R. K.; Senatorov, V.; Thouennon, E.; Cawley, N. X.; Loh, Y. P.] Program Dev Neurosci, Sect Cellular Neurobiol, Bethesda, MD 20892 USA. [Rodriguiz, R. M.; Aryal, D. K.; Wetsel, W. C.] Dept Psychiat & Behav Sci, Durham, NC USA. [Ahn, S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. [Lecka-Czernik, B.] Univ Toledo, Ctr Diabet & Endocrine Res, Dept Orthoped Surg, Toledo, OH 43606 USA. [Lecka-Czernik, B.] Univ Toledo, Ctr Diabet & Endocrine Res, Dept Physiol & Pharmacol, Toledo, OH 43606 USA. [Wetsel, W. C.] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC USA. [Wetsel, W. C.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC USA. RP Loh, YP (reprint author), NICHD, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, 49 Convent Dr,Bldg 49,Room 6C80, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health, USA; National Institutes of Health [HD36015]; American Diabetes Association Award [7-13-BS-089] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA and in part by National Institutes of Health grant HD36015 (WCW) and the American Diabetes Association Award 7-13-BS-089 (BL-C). We thank Lynne Holtzclaw, Dr Vincent Schram in the MIC at NICHD for their help in the immunocytochemistry and confocal microscopy, Dr Cheol Lee (Program on Genomics of Differentiation, NICHD) for his helpful discussions on markers for detecting neurogenesis in the hippocampus, Drs Zhihong Jiang and Lee Eiden (NIMH) for help with the sucrose preference test. We also thank the following people from the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center: Theodore Rhodes and Christopher Means for helping with the daily restraint and forced swim tests. Thanks also to Dr Chris McBain (NICHD), Dr Owen Rennert (NICHD), Dr Harold Gainer (NINDS) and Dr Hao Yang Tan (Lieber Institute for Brain Development, Johns Hopkins University) for critical reading of the manuscript. NR 58 TC 10 Z9 11 U1 2 U2 7 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 JUN PY 2015 VL 20 IS 6 BP 744 EP 754 DI 10.1038/mp.2014.136 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CI6SB UT WOS:000354890200013 PM 25330741 ER PT J AU Tiihonen, J Rautiainen, MR Ollila, HM Repo-Tiihonen, E Virkkunen, M Palotie, A Pietilainen, O Kristiansson, K Joukamaa, M Lauerma, H Saarela, J Tyni, S Vartiainen, H Paananen, J Goldman, D Paunio, T AF Tiihonen, J. Rautiainen, M-R Ollila, H. M. Repo-Tiihonen, E. Virkkunen, M. Palotie, A. Pietilainen, O. Kristiansson, K. Joukamaa, M. Lauerma, H. Saarela, J. Tyni, S. Vartiainen, H. Paananen, J. Goldman, D. Paunio, T. TI Genetic background of extreme violent behavior SO MOLECULAR PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; ANTISOCIAL PERSONALITY; CHILDHOOD MALTREATMENT; SEROTONIN REUPTAKE; ALCOHOL DEPENDENCE; MONOAMINE-OXIDASE; AGGRESSION; CRIMINALITY; GENOTYPE AB In developed countries, the majority of all violent crime is committed by a small group of antisocial recidivistic offenders, but no genes have been shown to contribute to recidivistic violent offending or severe violent behavior, such as homicide. Our results, from two independent cohorts of Finnish prisoners, revealed that a monoamine oxidase A (MAOA) low-activity genotype (contributing to low dopamine turnover rate) as well as the CDH13 gene (coding for neuronal membrane adhesion protein) are associated with extremely violent behavior (at least 10 committed homicides, attempted homicides or batteries). No substantial signal was observed for either MAOA or CDH13 among non-violent offenders, indicating that findings were specific for violent offending, and not largely attributable to substance abuse or antisocial personality disorder. These results indicate both low monoamine metabolism and neuronal membrane dysfunction as plausible factors in the etiology of extreme criminal violent behavior, and imply that at least about 5-10% of all severe violent crime in Finland is attributable to the aforementioned MAOA and CDH13 genotypes. C1 [Tiihonen, J.] Karolinska Inst, Dept Clin Neurosci, S-17176 Stockholm, Sweden. [Tiihonen, J.; Repo-Tiihonen, E.] Univ Eastern Finland, Niuvanniemi Hosp, Dept Forens Psychiat, Kuopio, Finland. [Tiihonen, J.; Rautiainen, M-R; Ollila, H. M.; Pietilainen, O.; Kristiansson, K.; Lauerma, H.; Paunio, T.] Natl Inst Hlth & Welf, Helsinki, Finland. [Ollila, H. M.] Stanford Univ, Ctr Sleep Sci, Palo Alto, CA 94304 USA. [Virkkunen, M.; Paunio, T.] Univ Helsinki, Dept Psychiat, Inst Clin Med, SF-00180 Helsinki, Finland. [Virkkunen, M.; Paunio, T.] Univ Helsinki, Cent Hosp, Dept Psychiat, Helsinki, Finland. [Palotie, A.] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Palotie, A.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Palotie, A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Palotie, A.] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Palotie, A.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Joukamaa, M.] Univ Tampere, Sch Hlth Sci, Social Psychiat Unit, FIN-33101 Tampere, Finland. [Lauerma, H.] Psychiat Hosp Prisoners, Turku, Finland. [Lauerma, H.] Univ Turku, Turku, Finland. [Saarela, J.] Finnish Genome Ctr, Helsinki, Finland. [Tyni, S.; Vartiainen, H.] Criminal Sanct Agcy, Helsinki, Finland. [Paananen, J.] Univ Eastern Finland, Bioinformat Ctr, Kuopio, Finland. [Goldman, D.] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Tiihonen, J (reprint author), Karolinska Inst, Dept Clin Neurosci, Byggnad R5, S-17176 Stockholm, Sweden. EM jari.tiihonen@ki.se; tiina.paunio@thl.fi RI Goldman, David/F-9772-2010 OI Paananen, Jussi/0000-0001-5100-4907; Saarela, Janna/0000-0002-0853-6219; Kristiansson, Kati/0000-0003-4688-107X; Goldman, David/0000-0002-1724-5405 FU Finnish Ministry of Health and Social Affairs through the development fund for Niuvanniemi Hospital, Finland; Instrumentarium Science Foundation; Orion-Farmos Research Foundation; Academy of Finland [250207] FX We thank Auli Toivola for her contribution in the Sequenom Mass Array and MAOA VNTR genotyping and Aija Rasanen for secretarial assistance. The study was funded by the Finnish Ministry of Health and Social Affairs through the development fund for Niuvanniemi Hospital, Finland. Hanna M Ollila has received funds from Instrumentarium Science Foundation and Orion-Farmos Research Foundation. Kati Kristiansson has received grant from Orion-Farmos Research Foundation and Academy of Finland (grant number 250207). NR 40 TC 17 Z9 17 U1 10 U2 61 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 JUN PY 2015 VL 20 IS 6 BP 786 EP 792 DI 10.1038/mp.2014.130 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CI6SB UT WOS:000354890200018 PM 25349169 ER PT J AU Migueles, SA Connors, M AF Migueles, Stephen A. Connors, Mark TI Success and failure of the cellular immune response against HIV-1 SO NATURE IMMUNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD8(+) T-CELLS; LONG-TERM NONPROGRESSORS; TYPE-1 ELITE CONTROLLERS; HIGHLY PATHOGENIC SIV; CTL ESCAPE MUTATIONS; ANTIRETROVIRAL TREATMENT; LYMPHOCYTE RESPONSES; VIRAL REPLICATION; INFECTED INDIVIDUALS AB The cellular immune response to HIV-1 has now been studied in extraordinary detail. A very large body of data provides the most likely reasons that the HIV-specific cellular immune response succeeds in a small number of people but fails in most. Understanding the success and failure of the HIV-specific cellular immune response has implications that extend not only to immunotherapies and vaccines for HIV-1 but also to the cellular immune response in other disease states. This Review focuses on the mechanisms that are most likely responsible for durable and potent immunologic control of HIV-1. Although we now have a detailed picture of the cellular immune responses to HIV-1, important questions remain regarding the nature of these responses and how they arise. C1 [Migueles, Stephen A.; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Connors, M (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mconnors@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX S.A.M. and M.C. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 116 TC 20 Z9 20 U1 4 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2015 VL 16 IS 6 BP 563 EP 570 DI 10.1038/ni.3161 PG 8 WC Immunology SC Immunology GA CI4VM UT WOS:000354751900004 PM 25988888 ER PT J AU Burton, DR Mascola, JR AF Burton, Dennis R. Mascola, John R. TI Antibody responses to envelope glycoproteins in HIV-1 infection SO NATURE IMMUNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; BROADLY NEUTRALIZING ANTIBODIES; DEPENDENT CELLULAR CYTOTOXICITY; MUCOSAL SHIV CHALLENGE; NONNEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; IN-VITRO; ENV TRIMERS; MEDIATED CYTOTOXICITY; ANTIVIRAL ANTIBODIES AB Antibody responses to the HIV-1 envelope glycoproteins can be classified into three groups. Binding but non-neutralizing responses are directed to epitopes that are expressed on isolated envelope glycoproteins but not on the native envelope trimer found on the surface of virions and responsible for mediating the entry of virus into target cells. Strain-specific responses and broadly neutralizing responses, in contrast, target epitopes that are expressed on the native trimer, as revealed by recently resolved structures. The past few years have seen the isolation of many broadly neutralizing antibodies of remarkable potency that have shown prophylactic and therapeutic activities in animal models. These antibodies are helping to guide rational vaccine design and therapeutic strategies for HIV-1. C1 [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Burton, Dennis R.] Harvard Univ, Boston, MA 02115 USA. [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM burton@scripps.edu; jmascola@nih.gov FU National Institute of Allergy and Infectious Diseases; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation; Ragon Institute of MGH, MIT and Harvard; Vaccine Research Center, National Institute of Allergy and Infectious Diseases FX Supported by the National Institute of Allergy and Infectious Diseases (D.R.B.), the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (D.R.B.), the International AIDS Vaccine Initiative (D.R.B.), the Bill and Melinda Gates Foundation (D.R.B.), the Ragon Institute of MGH, MIT and Harvard (D.R.B.) and the intramural research program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (J.R.M.). NR 108 TC 112 Z9 115 U1 9 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2015 VL 16 IS 6 BP 571 EP 576 DI 10.1038/ni.3158 PG 6 WC Immunology SC Immunology GA CI4VM UT WOS:000354751900005 PM 25988889 ER PT J AU McLaren, PJ Carrington, M AF McLaren, Paul J. Carrington, Mary TI The impact of host genetic variation on infection with HIV-1 SO NATURE IMMUNOLOGY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HLA-C EXPRESSION; GENOME-WIDE ASSOCIATION; CELL-SURFACE EXPRESSION; CLASS-I; VIRAL LOAD; UNINFECTED INDIVIDUALS; ANTIRETROVIRAL THERAPY; RHEUMATOID-ARTHRITIS; DISEASE PROGRESSION AB The outcome after infection with the human immunodeficiency virus type 1 (HIV-1) is a complex phenotype determined by interactions among the pathogen, the human host and the surrounding environment. An impact of host genetic variation on HIV-1 susceptibility was identified early in the pandemic, with a major role attributed to the genes encoding class I human leukocyte antigens (HLA) and the chemokine receptor CCR5. Studies using genome-wide data sets have underscored the strength of these associations relative to variants located throughout the rest of the genome. However, the extent to which additional polymorphisms influence HIV-1 disease progression, and how much of the variability in outcome can be attributed to host genetics, remain largely unclear. Here we discuss findings concerning the functional impact of associated variants, outline methods for quantifying the host genetic component and examine how available genome-wide data sets may be leveraged to discover gene variants that affect the outcome of HIV-1 infection. C1 [McLaren, Paul J.] Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland. [Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD USA. [Carrington, Mary] Ragon Inst MGH & Harvard, Cambridge, MA USA. RP McLaren, PJ (reprint author), Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland. EM paul.mclaren@epfl.ch; carringm@mail.nih.gov FU Frederick National Laboratory for Cancer Research [HHSN261200800001E]; National Institutes of Health, Frederick National Laboratory, Center for Cancer Research FX We thank A. Bashirova and I. Bartha for helpful suggestions. This project was funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, 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. This research was supported in part by the Intramural Research Program of the National Institutes of Health, Frederick National Laboratory, Center for Cancer Research. NR 73 TC 18 Z9 18 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2015 VL 16 IS 6 BP 577 EP 583 DI 10.1038/ni.3147 PG 7 WC Immunology SC Immunology GA CI4VM UT WOS:000354751900006 PM 25988890 ER PT J AU Chun, TW Moir, S Fauci, AS AF Chun, Tae-Wook Moir, Susan Fauci, Anthony S. TI HIV reservoirs as obstacles and opportunities for an HIV cure SO NATURE IMMUNOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; BROADLY NEUTRALIZING ANTIBODIES; HISTONE DEACETYLASE INHIBITORS; VIRAL RESERVOIR; LATENT RESERVOIR; HIV-1-INFECTED PATIENTS; ANTIVIRAL THERAPY; EXTENDED PERIODS; RHESUS-MONKEYS AB The persistence of HIV reservoirs remains a formidable obstacle to achieving sustained virologic remission in HIV-infected individuals after antiretroviral therapy (ART) is discontinued, even if plasma viremia has been successfully suppressed for prolonged periods of time. Numerous approaches aimed at eradicating the virus, as well as maintaining its prolonged suppression in the absence of ART, have had little success. A better understanding of the pathophysiologic nature of HIV reservoirs and the impact of various interventions on their persistence is essential for the development of successful therapeutic strategies against HIV or the long-term control of infection. Here, we discuss the persistent HIV reservoir as a barrier to cure as well as the current therapeutic strategies aimed at eliminating or controlling the virus in the absence of ART. C1 [Chun, Tae-Wook; Moir, Susan; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Chun, TW (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov FU National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 63 TC 32 Z9 34 U1 7 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2015 VL 16 IS 6 BP 584 EP 589 DI 10.1038/ni.3152 PG 6 WC Immunology SC Immunology GA CI4VM UT WOS:000354751900007 PM 25990814 ER PT J AU Holliday, GL Bairoch, A Bagos, PG Chatonnet, A Craik, DJ Finn, RD Henrissat, B Landsman, D Manning, G Nagano, N O'Donovan, C Pruitt, KD Rawlings, ND Saier, M Sowdhamini, R Spedding, M Srinivasan, N Vriend, G Babbitt, PC Bateman, A AF Holliday, Gemma L. Bairoch, Amos Bagos, Pantelis G. Chatonnet, Arnaud Craik, David J. Finn, Robert D. Henrissat, Bernard Landsman, David Manning, Gerard Nagano, Nozomi O'Donovan, Claire Pruitt, Kim D. Rawlings, Neil D. Saier, Milton Sowdhamini, Ramanathan Spedding, Michael Srinivasan, Narayanaswamy Vriend, Gert Babbitt, Patricia C. Bateman, Alex TI Key challenges for the creation and maintenance of specialist protein resources SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Editorial Material DE specialist protein resource; key challenges; biocuration; longevity; big data; misannotation ID FAMILIES DATABASE; INFORMATION; KNOWLEDGE; UPDATE; COLLECTION; DIVERSITY; DISCOVERY; SEQUENCES; ENZYMES; BIOLOGY AB As the volume of data relating to proteins increases, researchers rely more and more on the analysis of published data, thus increasing the importance of good access to these data that vary from the supplemental material of individual articles, all the way to major reference databases with professional staff and long-term funding. Specialist protein resources fill an important middle ground, providing interactive web interfaces to their databases for a focused topic or family of proteins, using specialized approaches that are not feasible in the major reference databases. Many are labors of love, run by a single lab with little or no dedicated funding and there are many challenges to building and maintaining them. This perspective arose from a meeting of several specialist protein resources and major reference databases held at the Wellcome Trust Genome Campus (Cambridge, UK) on August 11 and 12, 2014. During this meeting some common key challenges involved in creating and maintaining such resources were discussed, along with various approaches to address them. In laying out these challenges, we aim to inform users about how these issues impact our resources and illustrate ways in which our working together could enhance their accuracy, currency, and overall value. Proteins 2015; 83:1005-1013. (c) 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc. C1 [Holliday, Gemma L.; Babbitt, Patricia C.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA. [Bairoch, Amos] Univ Geneva, SIB, Geneva, Switzerland. [Bagos, Pantelis G.] Univ Thessaly, Dept Comp Sci & Biomed Informat, Lamia 35100, Greece. [Chatonnet, Arnaud] INRA, Dynam Musculaire & Metab Umr866, F-34000 Montpellier, France. [Chatonnet, Arnaud] Univ Montpellier, F-34000 Montpellier, France. [Craik, David J.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Finn, Robert D.; O'Donovan, Claire; Rawlings, Neil D.; Bateman, Alex] EBI, EMBL, Cambridge CB10 1SD, England. [Henrissat, Bernard] Aix Marseille Univ, CNRS, Architecture & Fonct Macromol Biol, F-13288 Marseille, France. [Henrissat, Bernard] King Abdulaziz Univ, Dept Biol Sci, Jeddah 21413, Saudi Arabia. [Landsman, David; Pruitt, Kim D.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. [Manning, Gerard] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA USA. [Nagano, Nozomi] Natl Inst Adv Ind Sci & Technol, Computat Biol Res Ctr, Tokyo 1350064, Japan. [Rawlings, Neil D.] Wellcome Trust Sanger Inst, Cambridge CB10 1SD, England. [Saier, Milton] Univ Calif San Diego, Dept Mol Biol, La Jolla, CA 92093 USA. [Sowdhamini, Ramanathan] TIFR, Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India. [Spedding, Michael] Spedding Res Solut SARL, Chair NC IUPHAR, F-78110 Le Vesinet, France. [Srinivasan, Narayanaswamy] Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. [Vriend, Gert] Radboud Univ Nijmegen, Med Ctr, CMBI, NL-6525 GA Nijmegen, Netherlands. RP Holliday, GL (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA. EM gemma.holliday@ucsf.edu RI Vriend, G./H-8112-2014; Craik, David/B-1695-2010; Nagano, Nozomi/A-5717-2017; Chatonnet, Arnaud/E-2190-2017; Fac Sci, KAU, Biol Sci Dept/L-4228-2013; Rawlings, Neil/M-5566-2013; OI Holliday, Gemma/0000-0002-6731-6398; O'Donovan, Claire/0000-0001-8051-7429; Landsman, David/0000-0002-9819-6675; Craik, David/0000-0003-0007-6796; Nagano, Nozomi/0000-0002-2779-685X; Chatonnet, Arnaud/0000-0002-4057-3896; Spedding, Michael/0000-0002-1248-8221; Bateman, Alex/0000-0002-6982-4660; Rawlings, Neil/0000-0001-5557-7665; Finn, Robert/0000-0001-8626-2148; Bairoch, Amos/0000-0003-2826-6444; Manning, Gerard/0000-0002-5087-9151 FU British Heart Foundation [RG/13/5/30112]; Intramural NIH HHS [Z01 LM000071-13]; NHGRI NIH HHS [U41 HG002273, U41 HG007822, U41HG007822, U41HG02273]; NIGMS NIH HHS [P20GM103446, R01 GM060595, R01 GM60595, R01GM080646]; NLM NIH HHS [G08LM010720]; Parkinson's UK [G-1307]; Wellcome Trust [077044, 099156] NR 50 TC 6 Z9 6 U1 0 U2 6 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 JUN PY 2015 VL 83 IS 6 BP 1005 EP 1013 DI 10.1002/prot.24803 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CJ0CA UT WOS:000355138800001 PM 25820941 ER PT J AU Tully, LA Grady, PA AF Tully, Lois A. Grady, Patricia A. TI A Path Forward for Genomic Nursing Research SO RESEARCH IN NURSING & HEALTH LA English DT Editorial Material DE genomics; nursing research; research policy ID SCIENCE C1 [Tully, Lois A.; Grady, Patricia A.] NINR, NIH, Bethesda, MD 20892 USA. RP Tully, LA (reprint author), NINR, NIH, 6701 Democracy Blvd Suite 710, Bethesda, MD 20892 USA. EM lois.tully@nih.gov FU NIH Office of Rare Diseases Research, National Center for Advancing Translational Sciences FX The National Institute of Nursing Research gratefully acknowledges the NIH Office of Rare Diseases Research, National Center for Advancing Translational Sciences (http://rarediseases.info.nih.gov/) as a cosponsor of the Genomic Nursing Science Workshop. NR 2 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-6891 EI 1098-240X J9 RES NURS HEALTH JI Res. Nurs. Health PD JUN PY 2015 VL 38 IS 3 BP 177 EP 179 DI 10.1002/nur.21659 PG 3 WC Nursing SC Nursing GA CI4SN UT WOS:000354743800001 PM 25872111 ER PT J AU Emoto, C Fukuda, T Mizuno, T Cox, S Schniedewind, B Christians, U Widemann, BC Fisher, MJ Weiss, B Perentesis, J Vinks, AA AF Emoto, Chie Fukuda, Tsuyoshi Mizuno, Tomoyuki Cox, Shareen Schniedewind, Bjoern Christians, Uwe Widemann, Brigitte C. Fisher, Michael J. Weiss, Brian Perentesis, John Vinks, Alexander A. TI Age-Dependent Changes in Sirolimus Metabolite Formation in Patients With Neurofibromatosis Type 1 SO THERAPEUTIC DRUG MONITORING LA English DT Article DE sirolimus; neurofibromatosis; pharmacokinetics; pediatric; metabolite; body size ID NERVE SHEATH TUMORS; PLEXIFORM NEUROFIBROMAS; LIVER VOLUME; CHILDREN; PHARMACOKINETICS; RAPAMYCIN; RECIPIENTS AB Background: Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism. Methods: Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC-UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation. Results: Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults. Conclusions: This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of ageappropriate dosing algorithms for sirolimus in infants and children. C1 [Emoto, Chie; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Cox, Shareen; Vinks, Alexander A.] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA. [Emoto, Chie; Fukuda, Tsuyoshi; Weiss, Brian; Perentesis, John; Vinks, Alexander A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45221 USA. [Schniedewind, Bjoern; Christians, Uwe] Univ Colorado, Integrated Solut Clin Res & Dev iC42, Aurora, CO USA. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Fisher, Michael J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Fisher, Michael J.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weiss, Brian; Perentesis, John] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Div Oncol, Cincinnati, OH 45229 USA. [Vinks, Alexander A.] Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45221 USA. RP Vinks, AA (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, 3333 Burnet Ave,MLC 6018, Cincinnati, OH 45229 USA. EM sander.vinks@cchmc.org OI Mizuno, Tomoyuki/0000-0002-8471-9826 FU Department of Defense [W81XWH-05-615]; Neurofibromatosis Clinical Trials Consortium; National Institutes of Health [5K24HD050387]; Japan Research Foundation for Clinical Pharmacology; internship program at Otsuka Pharmaceutical Co, Ltd, Tokushima, Japan FX Supported in part by Department of Defense grant W81XWH-05-615, Neurofibromatosis Clinical Trials Consortium (B.C.W., M.J.F., B.W., J.P., and A.A.V.), and National Institutes of Health grant 5K24HD050387 (A.A.V.). T. Mizuno is supported by the Japan Research Foundation for Clinical Pharmacology. C. Emoto was supported by an internship program at Otsuka Pharmaceutical Co, Ltd, Tokushima, Japan to study in Cincinnati. NR 20 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD JUN PY 2015 VL 37 IS 3 BP 395 EP 399 PG 5 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA CI4NU UT WOS:000354728400019 PM 25162215 ER PT J AU Dunnick, JK Sanders, JM Kissling, GE Johnson, CL Boyle, MH Elmore, SA AF Dunnick, J. K. Sanders, J. M. Kissling, G. E. Johnson, C. L. Boyle, M. H. Elmore, S. A. TI Environmental Chemical Exposure May Contribute to Uterine Cancer Development: Studies with Tetrabromobisphenol A SO TOXICOLOGIC PATHOLOGY LA English DT Article DE tetrabromobisphenol A; uterine tumors; malignant mixed Mullerian tumors (MMMT); flame retardants ID MIXED MULLERIAN TUMORS; BROMINATED FLAME RETARDANTS; ENDOMETRIAL HYPERPLASIA; OXIDATIVE STRESS; BISPHENOL-A; IN-VITRO; RATS; METABOLISM; CARCINOGENICITY; UTERUS AB Tetrabromobisphenol A (TBBPA), a widely used flame retardant, caused uterine tumors in rats. In this study, TBBPA was administered to male and female Wistar Han rats and B6C3F1/N mice by oral gavage in corn oil for 2 years at doses up to 1,000 mg/kg. TBBPA induced uterine epithelial tumors including adenomas, adenocarcinomas, and malignant mixed Mullerian tumors (MMMTs). In addition, endometrial epithelial atypical hyperplasia occurred in TBBPA-treated rats. Also found to be related to TBBPA treatment, but at lower incidence and at a lower statistical significance, were testicular tumors in rats, and hepatic tumors, hemangiosarcomas (all organs), and intestinal tumors in male mice. It is hypothesized that the TBBPA uterine tumor carcinogenic mechanisms involve altered estrogen levels and/or oxidative damage. TBBPA treatment may affect hydroxysteroid-dehydrogenase-17 (HSD17) and/or sulfotransferases, enzymes involved in estrogen homeostasis. Metabolism of TBBPA may also result in the formation of free radicals. The finding of TBBPA-mediated uterine cancer in rats is of concern because TBBPA exposure is widespread and endometrial tumors are a common malignancy in women. Further work is needed to understand TBBPA cancer mechanisms. C1 [Dunnick, J. K.; Kissling, G. E.; Elmore, S. A.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Sanders, J. M.] NCI, NIH, Res Triangle Pk, NC USA. [Johnson, C. L.] Pathol Associates Inc, Charles River Labs, Res Triangle Pk, NC USA. [Boyle, M. H.] Integrated Syst Lab, Res Triangle Pk, NC USA. RP Dunnick, JK (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC; National Cancer Institute; NIEHS [N01-ES-55541, HHSN291200555547C] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC. Authorial contributions by J. M. Sanders were supported by the Intramural Research Program of the National Cancer Institute. The in-life portion of this study was conducted under the supervision of Dr. M. Hejtmanicik, Battelle Columbus, Columbus, Ohio, under NIEHS contract N01-ES-55541. Statistical support was provided under NIEHS contract HHSN291200555547C. NR 53 TC 7 Z9 7 U1 1 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2015 VL 43 IS 4 BP 464 EP 473 DI 10.1177/0192623314557335 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA CI5YJ UT WOS:000354835400002 PM 25476797 ER PT J AU Davis, M Bunin, DI Samuelsson, SJ Altera, KP Kinders, RJ Lawrence, SM Ji, JP Ames, MM Buhrow, SA Walden, C Reid, JM Rausch, LL Parman, T AF Davis, Myrtle Bunin, Deborah I. Samuelsson, Steven J. Altera, Kenneth P. Kinders, Robert J. Lawrence, Scott M. Ji, Jiuping Ames, Matthew M. Buhrow, Sarah A. Walden, Chad Reid, Joel M. Rausch, Linda L. Parman, Toufan TI Characterization of Batracylin-induced Renal and Bladder Toxicity in Rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE batracylin; renal toxicity; bladder toxicity; H2AX; DNA damage ID ANTITUMOR AGENT BATRACYLIN; SOLID TUMORS; PHASE-I; GAMMA-H2AX; NSC-320846; APOPTOSIS; INHIBITOR; LYMPHOMAS; HISTONE; ANALOGS AB Batracylin (NSC-320846) is a dual inhibitor of DNA topoisomerases I and II. Batracylin advanced as an anticancer agent to Phase I clinical trials where dose limiting hemorrhagic cystitis (bladder inflammation and bleeding) was observed. To further investigate batracylin's mechanism of toxicity, studies were conducted in Fischer 344 rats. Once daily oral administration of 16 or 32 mg/kg batracylin to rats for 4 days caused overt toxicity. Abnormal clinical observations and adverse effects on clinical pathology, urinalysis, and histology indicated acute renal damage and urothelial damage and bone marrow dysfunction. Scanning electron microscopy revealed sloughing of the superficial and intermediate urothelial layers. DNA damage was evident in kidney and bone marrow as indicated by histone -H2AX immunofluorescence. After a single oral administration of 16 or 32 mg/kg, the majority of batracylin was converted to N-acetylbatracylin (NAB) with a half-life of 4 hr to 11 hr. Mesna (Mesnex), a drug known to reduce the incidence of hemorrhagic cystitis induced by ifosfamide or cyclophosphamide, was administered to rats prior to batracylin, but did not alleviate batracylin-induced bladder and renal toxicity. These findings suggest that batracylin results in DNA damage-based mechanisms of toxicity and not an acrolein-based mechanism of toxicity as occurs after ifosfamide or cyclophosphamide administration. C1 [Davis, Myrtle] NCI, Toxicol & Pharmacol Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Bunin, Deborah I.; Samuelsson, Steven J.; Altera, Kenneth P.; Rausch, Linda L.; Parman, Toufan] SRI Int, Menlo Pk, CA 94025 USA. [Kinders, Robert J.; Lawrence, Scott M.; Ji, Jiuping] Frederick Natl Lab Canc Res, Pharmacodynam Assay Dev & Implementat Sect, Lab Human Toxicol & Pharmacol, Appl Dev Res Directorate, Frederick, MD USA. [Ames, Matthew M.; Buhrow, Sarah A.; Walden, Chad; Reid, Joel M.] Mayo Clin, Div Oncol Res, Dept Oncol, Rochester, MN USA. RP Davis, M (reprint author), NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM davismillinm@mail.nih.gov FU Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute under NCI [N01-CM-42203, N01-CM-2011-00028] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported (in part) by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute under NCI Contracts N01-CM-42203, and N01-CM-2011-00028. NR 20 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2015 VL 43 IS 4 BP 519 EP 529 DI 10.1177/0192623314548766 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA CI5YJ UT WOS:000354835400007 PM 25274659 ER PT J AU Quist, EM Filgo, AJ Cummings, CA Kissling, GE Hoenerhoff, MJ Fenton, SE AF Quist, Erin M. Filgo, Adam J. Cummings, Connie A. Kissling, Grace E. Hoenerhoff, Mark J. Fenton, Suzanne E. TI Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA) SO TOXICOLOGIC PATHOLOGY LA English DT Article DE PFOA; PPAR; hepatocellular hypertrophy; mitochondrial damage; peroxisome proliferation; mouse; liver ID PEROXISOME PROLIFERATOR; MOUSE; LIVER; EXPRESSION; PPAR AB Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3, and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA. C1 [Quist, Erin M.; Filgo, Adam J.; Fenton, Suzanne E.] NIEHS, NTP Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Quist, Erin M.; Hoenerhoff, Mark J.] NIEHS, Cellular & Mol Pathol Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Quist, Erin M.] N Carolina State Univ, Coll Vet Med, Comparat Biomed Sci, Raleigh, NC USA. [Filgo, Adam J.] Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC USA. [Cummings, Connie A.] UltraPath Imaging, Durham, NC USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Fenton, SE (reprint author), NIEHS, NTP Lab, 111 TW Alexander Dr Bldg 101,MD E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov FU National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Environmental Health Sciences (NIEHS). NR 20 TC 3 Z9 3 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2015 VL 43 IS 4 BP 546 EP 557 DI 10.1177/0192623314551841 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA CI5YJ UT WOS:000354835400010 PM 25326589 ER PT J AU Filgo, AJ Quist, EM Hoenerhoff, MJ Brix, AE Kissling, GE Fenton, SE AF Filgo, Adam J. Quist, Erin M. Hoenerhoff, Mark J. Brix, Amy E. Kissling, Grace E. Fenton, Suzanne E. TI Perfluorooctanoic Acid (PFOA)-induced Liver Lesions in Two Strains of Mice Following Developmental Exposures: PPAR Is Not Required SO TOXICOLOGIC PATHOLOGY LA English DT Article DE PFOA; PPAR; liver; tumor; pathology; developmental exposure ID ACTIVATED RECEPTOR-ALPHA; MAMMARY-GLAND DEVELOPMENT; AMMONIUM PERFLUOROOCTANOATE; POLYFLUOROALKYL COMPOUNDS; PERFLUORINATED COMPOUNDS; MOUSE; TOXICITY; PROLIFERATION; EXPRESSION; CHEMICALS AB Perfluorooctanoic acid (PFOA) is a ubiquitous pollutant that causes liver toxicity in rodents, a process believed to be dependent on peroxisome proliferator-activated receptor-alpha (PPAR) activation. Differences between humans and rodents have made the human relevance of some health effects caused by PFOA controversial. We analyzed liver toxicity at 18 months following gestational PFOA exposure in CD-1 and 129/Sv strains of mice and compared PFOA-induced effects between strains and in wild type (WT) and PPAR-knockout (KO) 129/Sv mice. Pregnant mice were exposed daily to doses (0.01-5 mg/kg/BW) of PFOA from gestation days 1 to 17. The female offspring were necropsied at 18 months, and liver sections underwent a full pathology review. Hepatocellular adenomas formed in PFOA-exposed PPAR-KO 129/Sv and CD-1 mice and were absent in untreated controls from those groups and WT 129/Sv. Hepatocellular hypertrophy was significantly increased by PFOA exposure in CD-1, and an increased severity was found in WT 129/Sv mice. PFOA significantly increased nonneoplastic liver lesions in PPAR-KO mice (hepatocyte hypertrophy, bile duct hyperplasia, and hematopoietic cell proliferation). Low-dose gestational exposures to PFOA induced latent PPAR-independent liver toxicity that was observed in aged mice. Evidence of liver toxicity in PPAR-KO mice warrants further investigation into PPAR-independent pathways. C1 [Filgo, Adam J.] Univ N Carolina, Sch Med, Curriculum Toxicol, Chapel Hill, NC USA. [Filgo, Adam J.; Quist, Erin M.; Fenton, Suzanne E.] NIEHS, NTP Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Quist, Erin M.] N Carolina State Univ, Coll Vet Med, Comparat Biomed Sci, Raleigh, NC USA. [Quist, Erin M.; Hoenerhoff, Mark J.] NIEHS, Cellular & Mol Pathol Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Brix, Amy E.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Fenton, SE (reprint author), NIEHS, NTP Lab, Div Natl Toxicol Program, 111 TW Alexander Dr,Bldg 101,MD E1-08, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102785-05]; NIEHS NIH HHS [T32 ES007126] NR 34 TC 1 Z9 1 U1 6 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUN PY 2015 VL 43 IS 4 BP 558 EP 568 DI 10.1177/0192623314558463 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA CI5YJ UT WOS:000354835400011 PM 25398757 ER PT J AU Arama, C Maiga, B Dolo, A Kouriba, B Traore, B Crompton, PD Pierce, SK Troye-Blomberg, M Miller, LH Doumbo, OK AF Arama, Charles Maiga, Bakary Dolo, Amagana Kouriba, Bourema Traore, Boubacar Crompton, Peter D. Pierce, Susan K. Troye-Blomberg, Marita Miller, Louis H. Doumbo, Ogobara K. TI Ethnic differences in susceptibility to malaria: What have we learned from immuno-epidemiological studies in West Africa? SO ACTA TROPICA LA English DT Review DE Malaria; Immunity; Ethnic; Fulani; Susceptibility; Sympatric ID PLASMODIUM-FALCIPARUM INFECTION; INTERETHNIC DIFFERENCES; BURKINA-FASO; HUMORAL RESPONSE; MALI; FULANI; POLYMORPHISM; SYMPATRY; COINFECTION; POPULATIONS AB There are many fundamental aspects of the immunobiology of Plasmodium falciparum infections that are not fully understood, therefore limiting our comprehension of how people become immune to malaria and why some ethnic groups living in malaria endemic areas are less susceptible than others. The complexity of parasite-host interactions and the genetic diversity of the parasites as well as the human host complicate our strategy to address this issue. In this mini-review we discuss and summarize what we have learned about African ethnic differences in susceptibility to malaria from immuno-epidemiological studies. Additionally, we suggest research topics that might be of great value for dissecting the mechanisms of protection by providing new insights into molecular interactions between the parasite and the host. (C) 2015 Elsevier B.V. All rights reserved. C1 [Arama, Charles; Maiga, Bakary; Dolo, Amagana; Kouriba, Bourema; Traore, Boubacar; Doumbo, Ogobara K.] Univ Sci Tech & Technol Bamako, ICER Mali NIAID, FMOS FAPH, Malaria Res & Training Ctr,Dept Epidemiol Parasit, Bamako, Mali. [Crompton, Peter D.; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Troye-Blomberg, Marita] Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden. [Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Arama, C (reprint author), Univ Sci Tech & Technol Bamako, ICER Mali NIAID, FMOS FAPH, Malaria Res & Training Ctr,Dept Epidemiol Parasit, Bamako, Mali. EM charama@icermali.org; okd@icermali.org RI Troye-Blomberg, Marita/B-9210-2016; Crompton, Peter/N-1130-2016 OI Troye-Blomberg, Marita/0000-0002-2804-0325; NR 54 TC 5 Z9 5 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X EI 1873-6254 J9 ACTA TROP JI Acta Trop. PD JUN PY 2015 VL 146 BP 152 EP 156 DI 10.1016/j.actatropica.2015.03.023 PG 5 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA CI3QI UT WOS:000354662100023 PM 25820030 ER PT J AU Peskin, VA Ordonez, A Mackin, RS Delucchi, K Monge, S McGough, JJ Chavira, DA Berrocal, M Cheung, E Fournier, E Badner, JA Herrera, LD Mathews, CA AF Peskin, Viviana A. Ordonez, Anna Mackin, R. Scott Delucchi, Kevin Monge, Silvia McGough, James J. Chavira, Denise A. Berrocal, Monica Cheung, Erika Fournier, Eduardo Badner, Judith A. Herrera, Luis Diego Mathews, Carol A. TI Neuropsychological and dimensional behavioral trait profiles in Costa Rican ADHD sib pairs: Potential intermediate phenotypes for genetic studies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; heritability; pedigrees; endophenotypes; cognitive ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY-DISORDER; OSTERRIETH COMPLEX FIGURE; SEVERE BIPOLAR DISORDER; LINKAGE DISEQUILIBRIUM; EXECUTIVE FUNCTIONS; LIFE-SPAN; POPULATION ISOLATE; WORKING-MEMORY; CHILDREN AB Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity. (c) 2015 Wiley Periodicals, Inc. C1 [Peskin, Viviana A.; Mackin, R. Scott; Delucchi, Kevin; Cheung, Erika; Mathews, Carol A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Ordonez, Anna] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Monge, Silvia; Berrocal, Monica; Fournier, Eduardo; Herrera, Luis Diego] Hosp CIMA, Dept Psychiat, San Jose, Costa Rica. [McGough, James J.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Chavira, Denise A.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Badner, Judith A.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Badner, Judith A.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Mathews, Carol A.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. RP Mathews, CA (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM cmathews@lppi.ucsf.edu FU [R01 NS048376]; [K08 MH081065] FX This research was supported by grant R01 NS048376 to C.A.M. and grant K08 MH081065 to R.S.M. We would like to thank the individuals and families who participated in this work. NR 74 TC 1 Z9 1 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUN PY 2015 VL 168 IS 4 BP 247 EP 257 DI 10.1002/ajmg.b.32305 PG 11 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA CI3IA UT WOS:000354640100003 PM 25832558 ER PT J AU Miettinen, M McCue, PA Sarlomo-Rikala, M Biernat, W Czapiewski, P Kopczynski, J Thompson, LD Lasota, J Wang, ZF Fetsch, JF AF Miettinen, Markku McCue, Peter A. Sarlomo-Rikala, Maarit Biernat, Wojciech Czapiewski, Piotr Kopczynski, Janusz Thompson, Lester D. Lasota, Jerzy Wang, Zengfeng Fetsch, John F. TI Sox10-A Marker for Not Only Schwannian and Melanocytic Neoplasms But Also Myoepithelial Cell Tumors of Soft Tissue A Systematic Analysis of 5134 Tumors SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE Sox10; Schwann cell; breast cancer; myoepithelioma; immunohistochemistry ID TRANSCRIPTION FACTOR SOX10; HIRSCHSPRUNG-DISEASE; EXPRESSION; CARCINOMAS; DIAGNOSIS; MELANOMA; GENE; MUTATIONS; LESIONS; MOUSE AB Sox10 transcription factor is expressed in schwannian and melanocytic lineages and is important in their development and can be used as a marker for corresponding tumors. In addition, it has been reported in subsets of myoepithelial/basal cell epithelial neoplasms, but its expression remains incompletely characterized. In this study, we examined Sox10 expression in 5134 human neoplasms spanning a wide spectrum of neuroectodermal, mesenchymal, lymphoid, and epithelial tumors. A new rabbit monoclonal antibody (clone EP268) and Leica Bond Max automation were used on multitumor block libraries containing 30 to 70 cases per slide. Sox10 was consistently expressed in benign Schwann cell tumors of soft tissue and the gastrointestinal tract and in metastatic melanoma and was variably present in malignant peripheral nerve sheath tumors. In contrast, Sox10 was absent in many potential mimics of nerve sheath tumors such as cellular neurothekeoma, meningioma, gastrointestinal stromal tumors, perivascular epithelioid cell tumor and a variety of fibroblastic-myofibroblastic tumors. Sox10 was virtually absent in mesenchymal tumors but occasionally seen in alveolar rhabdomyosarcoma. In epithelial tumors of soft tissue, Sox10 was expressed only in myoepitheliomas, although often absent in malignant variants. Carcinomas, other than basal cell-type breast cancers, were only rarely positive but included 6% of squamous carcinomas of head and neck and 7% of pulmonary small cell carcinomas. Furthermore, Sox10 was often focally expressed in embryonal carcinoma reflecting a primitive Sox10-positive phenotype or neuroectodermal differentiation. Expression of Sox10 in entrapped non-neoplastic Schwann cells or melanocytes in various neoplasms has to be considered in diagnosing Sox10-positive tumors. The Sox10 antibody belongs in a modern immunohistochemical panel for the diagnosis of soft tissue and epithelial tumors. C1 [Miettinen, Markku; Lasota, Jerzy; Wang, Zengfeng] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Fetsch, John F.] Capital Reg, Joint Pathol Ctr, Silver Spring, MD USA. [McCue, Peter A.] Thomas Jefferson Univ, Dept Pathol, Kimmel Med Coll, Philadelphia, PA 19107 USA. [Thompson, Lester D.] So Calif Permanente Med Grp, Woodland Hills, CA USA. [Sarlomo-Rikala, Maarit] Univ Helsinki, Helsinki, Finland. [Sarlomo-Rikala, Maarit] HUSLab Pathol, Helsinki, Finland. [Biernat, Wojciech; Czapiewski, Piotr] Med Univ Gdansk, Dept Pathol, Gdansk, Poland. [Kopczynski, Janusz] Holy Cross Canc Ctr, Kielce, Poland. RP Miettinen, M (reprint author), NCI, Pathol Lab, Surg Pathol Sect, 9000 Rockville Pike,Bldg 10,Rm 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU Intramural Research Program of the NIH/NCI FX The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. This work was supported by the Intramural Research Program of the NIH/NCI. NR 24 TC 19 Z9 20 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JUN PY 2015 VL 39 IS 6 BP 826 EP 835 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA CI1EP UT WOS:000354485400013 PM 25724000 ER PT J AU Epstein, DH Preston, KL AF Epstein, David H. Preston, Kenzie L. TI No Evidence for Reduction of Opioid-Withdrawal Symptoms by Cannabis Smoking During a Methadone Dose Taper SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID MAINTENANCE TREATMENT; SELF-DETOXIFICATION; OPIATE-DEPENDENCE; CONTRASTS AB Background and ObjectivesTo support medication development with cannabinoids, smoked cannabis has been said to alleviate symptoms of opioid withdrawal. We evaluated that hypothesis. MethodsWe analyzed data from the methadone-taper phase of a clinical trial we had conducted. Participants were 116 outpatient heroin and cocaine users (of whom 46 were also cannabis users) who stayed for the 10-week taper. Main outcome measures were weekly urine screens for cannabinoids, plus every-two-week assessments of opioid-withdrawal symptoms. ResultsOpioid-withdrawal scores did not differ overall between users and nonusers of cannabis. In a lagged analysis in the 46 users, there was a slight (not statistically significant) indication that weeks of higher opiate-withdrawal symptoms preceded weeks of cannabis use (effect-size r=.20, 95% CI -.10 to .46, p=.52). Even if this finding is taken to suggest self-medication with cannabis, a lagged analysis in the other temporal direction showed no indication that cannabis use predicted lower opiate-withdrawal symptoms the next week (effect-size r=.01, 95% CI -.28 to .30, p=.69). These findings persisted in sensitivity analyses controlling for each of 17 potential confounds. Discussion and ConclusionWith our findings, the clinical evidence for smoked cannabis as a reducer of opioid-withdrawal symptoms moves slightly further from inconclusive or mixed and closer to negative, at least in the context of a methadone dose taper like the one used here. Scientific SignificanceThis finding may remove one rationale for medication development using cannabinoids to treat opioid withdrawal, but leaves other rationales intact. (Am J Addict 2015;XX: XX-XX) C1 [Epstein, David H.; Preston, Kenzie L.] NIDA, Treatment Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Branch, Baltimore, MD 21224 USA. RP Epstein, DH (reprint author), NIDA, Treatment Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM depstein@intra.nida.nih.gov FU NIH National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the NIH National Institute on Drug Abuse. NR 22 TC 0 Z9 0 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD JUN PY 2015 VL 24 IS 4 BP 323 EP 328 DI 10.1111/ajad.12183 PG 6 WC Substance Abuse SC Substance Abuse GA CH6YT UT WOS:000354183200007 PM 25846329 ER PT J AU Enewold, L Harlan, LC Stevens, JL Sharon, E AF Enewold, Lindsey Harlan, Linda C. Stevens, Jennifer L. Sharon, Elad TI Thyroid Cancer Presentation and Treatment in the United States SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID INCREASING INCIDENCE; RADIOACTIVE IODINE; CARCINOMA; SURVIVAL; SURGERY; EXTENT; RISK AB Thyroid cancer incidence is rising in the United States. Although overall thyroid cancer survival is high, prognostic stratification schemes have been developed to better delineate patients with poor prognoses. A random sample that included 1,003 adult papillary thyroid cancer patients diagnosed in 2006 and reported to the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program had their medical records re-abstracted and additional risk factor data collected. The distribution of patient demographics, medical histories, tumor characteristics and treatment modalities were assessed. Logistic regression was used to assess factors associated with total thyroidectomy (total, subtotal or near total) and radioiodine therapy. All analyses were conducted stratified by the Age, Metastases, Extent and Size (AMES) low/high-risk classification. Receipt of total thyroidectomy was associated with family history of thyroid disease/cancer and larger tumor size among low-risk patients and smaller tumor size among high-risk patients. Among low-risk patients, the receipt of radioiodine was associated with family history of thyroid disease/cancer, larger tumor size, total thyroidectomy, and positive lymph nodes. Among high-risk patients, the receipt of radioiodine was associated with intermediate tumor and hospital sizes. This study provides insight into the patterns of papillary thyroid cancer care in the general population. The findings from this study indicate adherence to guideline recommendations in that family history of thyroid disease/cancer, in addition to tumor characteristics, does appear to inform treatment practices, especially among low-risk patients. C1 [Enewold, Lindsey; Harlan, Linda C.; Sharon, Elad] NCI, Bethesda, MD 20892 USA. [Stevens, Jennifer L.] Informat Management Serv Inc, Calverton, MD USA. RP Harlan, LC (reprint author), NCI, Bethesda, MD 20892 USA. EM lh50w@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 22 TC 0 Z9 0 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 JUN PY 2015 VL 22 IS 6 BP 1789 EP 1797 DI 10.1245/s10434-014-4209-1 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA CH7ON UT WOS:000354226600009 PM 25361888 ER PT J AU Enomoto, A Saito, K Subramanian, S Krishna, MC Hirata, H Devasahayam, N AF Enomoto, Ayano Saito, Keita Subramanian, Sankaran Krishna, Murali C. Hirata, Hiroshi Devasahayam, Nallathamby TI Passive Decoupling Due to Low Q-Factors of Four-Channel Coils in 300-MHz Pulsed EPR Imaging SO APPLIED MAGNETIC RESONANCE LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; TOOTH DOSIMETRY; PHASED-ARRAY; ACQUISITION; MRI; RESONATORS; DESIGN; SYSTEM AB This article describes a four-channel coil array for in vivo time-domain electron paramagnetic resonance (EPR) imaging applications. Decoupling of the individual element coils was achieved with the low-quality factors required in pulsed EPR at radiofrequency to accommodate the imaging bandwidth. No active decoupling method was used in the coil array. Remote control of a coaxial switch connected to the four-channel coil array was performed with voltage signals from a personal computer. To verify the operation of this four-channel coil array, a phantom tube filled with a solution of paramagnetic triarylmethyl radicals (OX063) was visualized by pulsed EPR imaging based on the single-point method involving pure phase encoding. In an in vivo experiment, OX063 in a mouse tumor-bearing right hind leg was visualized by pulsed EPR imaging. Even without active decoupling circuits, there was no shift in resonances for individual coils when those were tuned to the same frequency due to low quality factors and low coupling coefficients with neighboring coils. The coil assembly allowed us to study an object that was larger than an individual coil element, enabling the imaging of larger subjects with reduced overall specific absorption rate. Such strategies should be useful for studying larger objects by EPR imaging. C1 [Enomoto, Ayano; Hirata, Hiroshi] Hokkaido Univ, Grad Sch Informat Sci & Technol, Div Bioengn & Bioinformat, Kita Ku, Sapporo, Hokkaido 0600814, Japan. [Saito, Keita; Subramanian, Sankaran; Krishna, Murali C.; Devasahayam, Nallathamby] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hirata, H (reprint author), Hokkaido Univ, Grad Sch Informat Sci & Technol, Div Bioengn & Bioinformat, Kita Ku, North 14,West 9, Sapporo, Hokkaido 0600814, Japan. EM hhirata@ist.hokudai.ac.jp FU JSPS KAKENHI [26249057]; JSPS [24-1486]; Center for Cancer Research, NCI, NIH FX This work was supported in part by JSPS KAKENHI Grant Number 26249057. A.E. was supported by a Research Fellowship for Young Scientists (24-1486) from JSPS. We also thank the Center for Cancer Research, NCI, NIH for intramural research funding. NR 21 TC 0 Z9 0 U1 2 U2 5 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0937-9347 EI 1613-7507 J9 APPL MAGN RESON JI Appl. Magn. Reson. PD JUN PY 2015 VL 46 IS 6 BP 671 EP 683 DI 10.1007/s00723-015-0671-6 PG 13 WC Physics, Atomic, Molecular & Chemical; Spectroscopy SC Physics; Spectroscopy GA CI3AX UT WOS:000354620900006 ER PT J AU Fontes, JD Rahman, F Lacey, S Larson, MG Vasan, RS Benjamin, EJ Harris, WS Robins, SJ AF Fontes, Joao D. Rahman, Faisal Lacey, Sean Larson, Martin G. Vasan, Ramachandran S. Benjamin, Emelia J. Harris, William S. Robins, Sander J. TI Red blood cell fatty acids and biomarkers of inflammation: A cross-sectional study in a community-based cohort SO ATHEROSCLEROSIS LA English DT Article DE Omega-3 fatty acids; Biomarkers; Inflammation; Cross-sectional study ID C-REACTIVE PROTEIN; CORONARY-ARTERY-DISEASE; PHOSPHOLIPASE A(2); FISH CONSUMPTION; CARDIOVASCULAR-DISEASE; OXIDATIVE STRESS; RHEUMATOID-ARTHRITIS; CIRCULATING LEVELS; HEART-DISEASE; PPAR-GAMMA AB Introduction: Inflammation and inflammatory biomarkers have emerged as integral components and predictors of incident cardiovascular (CV) disease. Omega-3 fatty acids, particularly eicosapentaenoic and docosahexaenoic acids (EPA and DHA) have anti-inflammatory properties, and have been variably associated with lower blood pressure, favorable blood lipid changes, and reduced CV events. Methods and results: We examined the cross-sectional association of red blood cell (RBC) fatty acids, representative of body membrane fatty acid composition, with 10 biomarkers active in multiple inflammatory pathways in 2724 participants (mean age 66 +/- 9 years, 54% women, 8% minorities) from the Framingham Offspring and minority Omni Cohorts. After multivariable adjustment, the RBC EPA and DHA content was inversely correlated (all P <= 0.001) with 8 biomarkers: urinary isoprostanes (r = -0.16); and soluble interleukin-6 (r = -0.10); C-reactive protein (r = -0.08); tumor necrosis factor receptor 2 (r = -0.08); intercellular adhesion molecule-1 (r = -0.08); P-selectin (r = -0.06); lipoprotein-associated phospholipase-A2 mass (r = -0.11) and activity (r = -0.08). The correlations for monocyte chemoattractant protein-1 was -0.05, P = 0.006 and osteoprotegerin (r = -0.06, P = 0.002) were only nominally significant. Conclusion: In our large community-based study, we observed modest inverse associations between several types of inflammatory biomarkers with RBC omega-3 fatty acid levels. Our findings are consistent with the hypothesis that omega-3 fatty acids have anti-inflammatory properties. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Fontes, Joao D.; Lacey, Sean; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Robins, Sander J.] Natl Heart Lung & Blood Inst, Framingham, MA USA. [Fontes, Joao D.; Lacey, Sean; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Robins, Sander J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Fontes, Joao D.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Robins, Sander J.] Boston Univ, Sch Med, Dept Cardiol & Prevent Med, Boston, MA 02118 USA. [Fontes, Joao D.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Robins, Sander J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Rahman, Faisal] Boston Univ, Med Ctr, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Harris, William S.] Univ S Dakota, Sanford Sch Med, Dept Med, Sioux Falls, SD 57106 USA. [Harris, William S.] OmegaQuant Analyt LLC, Sioux Falls, SD 57106 USA. RP Harris, WS (reprint author), Univ S Dakota, Sanford Sch Med, Dept Med, 5009 W 12th St,Ste 8, Sioux Falls, SD 57106 USA. EM bill@omegaquant.com OI Rahman, Faisal/0000-0002-7946-0311; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU [2R01HL092577]; [1RO1-HL64753]; [R01-HL076784]; [1R01-1RO1-AG0283211]; [N01-HC 25195]; [N01-HC25195]; [R01 HL089590] FX Dr. Benjamin is supported by 2R01HL092577; 1RO1-HL64753; R01-HL076784; 1R01-1RO1-AG0283211; N01-HC 25195. Dr. Vasan is supported by N01-HC25195, and Dr. Harris by R01 HL089590. NR 65 TC 11 Z9 11 U1 0 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUN PY 2015 VL 240 IS 2 BP 431 EP 436 DI 10.1016/j.atherosclerosis.2015.03.043 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CI1ZQ UT WOS:000354544300022 PM 25897795 ER PT J AU Lee, SJ Wolff, D Kitko, C Koreth, J Inamoto, Y Jagasia, M Pidala, J Olivieri, A Martin, PJ Przepiorka, D Pusic, I Dignan, F Mitchell, SA Lawitschka, A Jacobsohn, D Hall, AM Flowers, MED Schultz, KR Vogelsang, G Pavletic, S AF Lee, Stephanie J. Wolff, Daniel Kitko, Carrie Koreth, John Inamoto, Yoshihiro Jagasia, Madan Pidala, Joseph Olivieri, Attilio Martin, Paul J. Przepiorka, Donna Pusic, Iskra Dignan, Fiona Mitchell, Sandra A. Lawitschka, Anita Jacobsohn, David Hall, Anne M. Flowers, Mary E. D. Schultz, Kirk R. Vogelsang, Georgia Pavletic, Steven TI Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Response criteria; Consensus; Guidelines ID STEM-CELL TRANSPLANTATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BONE-MARROW-TRANSPLANTATION; CHRONIC GVHD CONSORTIUM; 6-MINUTE WALK TEST; OBLITERANS ORGANIZING PNEUMONIA; HUMAN ACTIVITY PROFILE; FAILURE-FREE SURVIVAL; SLEEP QUALITY INDEX; RHEUMATOID-ARTHRITIS AB In 2005, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. Published by Elsevier Inc. C1 [Lee, Stephanie J.; Martin, Paul J.; Hall, Anne M.; Flowers, Mary E. D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Wolff, Daniel] Univ Regensburg, Dept Internal Med 3, D-93053 Regensburg, Germany. [Kitko, Carrie] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Koreth, John] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Jagasia, Madan] Vanderbilt Univ, Div Hematol Oncol, Nashville, TN 37235 USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Olivieri, Attilio] Univ Ancona, Dept Clin & Mol Sci, Ancona, Italy. [Przepiorka, Donna] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pusic, Iskra] Washington Univ, Dept Med, St Louis, MO USA. [Dignan, Fiona] Univ Manchester, Dept Clin Haematol, Manchester, Lancs, England. [Mitchell, Sandra A.; Pavletic, Steven] NCI, Outcomes Res Branch, Bethesda, MD 20852 USA. [Lawitschka, Anita] Med Univ Vienna, St Anna Childrens Hosp, Stem Cell Transplant Unit, Vienna, Austria. [Jacobsohn, David] Childrens Natl Hlth Syst, Div Blood & Marrow Transplantat, Washington, DC USA. [Schultz, Kirk R.] Univ British Columbia, BC Childrens Hosp, Vancouver, BC V5Z 1M9, Canada. [Vogelsang, Georgia] Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA. RP Pavletic, S (reprint author), NCI, GVHD & Autoimmun Unit, Expt Transplantat & Immunol Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Bldg 10,Room CRC 4-3130, Bethesda, MD 20852 USA. EM pavletis@mail.nih.gov FU Millenium; Otsuka Pharmaceuticals; Prometheus Labs Inc.; Therakos; Johnson and Johnson company FX S.L. scientific advisory board meeting: Bristol Myers Squibb, Kadmon Corp. J.K., research funding: Millenium, Otsuka Pharmaceuticals, Prometheus Labs Inc.; scientific advisory board: Kadmon Corp, Amgen, Takeda Pharmaceuticals. P.M., scientific advisory board meeting: Pharmacyclics. F.D., received research funding, honoraria and speaker fees: Therakos, a Johnson and Johnson company. NR 119 TC 22 Z9 23 U1 2 U2 4 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 JUN PY 2015 VL 21 IS 6 BP 984 EP 999 DI 10.1016/j.bbmt.2015.02.025 PG 16 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CI3SO UT WOS:000354667900004 PM 25796139 ER PT J AU Cuellar-Rodriguez, J Freeman, AF Grossman, J Su, H Parta, M Murdock, H Shah, N Bollard, C Kong, HH Moutsopoulos, N Stone, K Gea-Banacloche, J Holland, SM Hickstein, DD AF Cuellar-Rodriguez, Jennifer Freeman, Alexandra F. Grossman, Jennifer Su, Helen Parta, Mark Murdock, Heardley Shah, Nirali Bollard, Catherine Kong, Heidi H. Moutsopoulos, Niki Stone, Kelly Gea-Banacloche, Juan Holland, Steven M. Hickstein, Dennis D. TI Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic; Transplantation; DOCK8 deficiency ID HYPER-IGE SYNDROME; TOXICITY CONDITIONING REGIMEN; DAILY INTRAVENOUS BUSULFAN; CYTOKINESIS 8 DOCK8; DAILY IV BUSULFAN; PHARMACOKINETICS; FLUDARABINE; DEDICATOR; MUTATIONS; RESPONSES AB We performed allogeneic hematopoietic stem cell transplantation in 6 patients with mutations in the dedicator-of-cytokinesis-8 (DOCK8) gene using a myeloablative conditioning regimen consisting of busulfan 3.2 mg/kg/day i.v. for 4 days and fludarabine 40 mg/m(2)/day for 4 days. Three patients received allografts from matched related donors and 3 patients from matched unrelated donors Two patients received peripheral blood stem cells and 4 patients bone marrow hematopoietic stem cells. Tacrolimus and short-course methotrexate on days 1, 3, 6, and 11, were used for graft-versus-host-disease (GVHD) prophylaxis. All 6 patients are alive at a median follow-up of 22.5 months (range, 14 to 35). All patients achieved rapid and high levels of donor engraftment and complete reversal of the clinical and immunologic phenotype. Adverse events consisted of acute skin GVHD in 2 patients and post-transplant pulmonary infiltrates in a patient with extensive bronchiectasis pretransplant. Thus, a uniform myeloablative conditioning regimen followed by allogeneic hematopoietic stem cell transplantation in DOCK8 deficiency results in reconstitution of immunologic function and reversal of the clinical phenotype with a low incidence of regimen-related toxicity. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Cuellar-Rodriguez, Jennifer; Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Grossman, Jennifer] Alberta Hlth Serv, Div Hematol & Hematol Malignancies, Calgary, AB, Canada. [Su, Helen; Murdock, Heardley] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Parta, Mark] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Shah, Nirali] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Bollard, Catherine] Childrens Natl Med Ctr, Childrens Res Inst, Ctr Canc & Immunol Res, Washington, DC 20010 USA. [Kong, Heidi H.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Moutsopoulos, Niki] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Stone, Kelly] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Gea-Banacloche, Juan; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Hickstein, DD (reprint author), 9000 Rockville Pike,Bldg 10 CRC,3-3142, Bethesda, MD 20892 USA. EM hicksted@mail.nih.gov RI Su, Helen/H-9541-2015; OI Su, Helen/0000-0002-5582-9110; Kong, Heidi/0000-0003-4424-064X FU National Cancer Institute [1ZIABCO11374]; National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases; Division of Intramural Research, Center for Cancer Research FX Supported in whole or in part with federal funds from the National Cancer Institute (1ZIABCO11374), National Institutes of Health under contract no. HHSN261200800001E, in part by the Division of Intramural Research, Center for Cancer Research, and the National Institute of Allergy and Infectious Diseases. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services or does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 24 TC 14 Z9 14 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 JUN PY 2015 VL 21 IS 6 BP 1037 EP 1045 DI 10.1016/j.bbmt.2015.01.022 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CI3SO UT WOS:000354667900009 PM 25636378 ER PT J AU Baird, K Comis, LE Joe, GO Steinberg, SM Hakim, FT Rose, JJ Mitchell, SA Pavletic, SZ Figg, WD Yao, L Flanders, KC Takebe, N Sarantopoulos, S Booher, S Cowen, EW AF Baird, Kristin Comis, Leora E. Joe, Galen O. Steinberg, Seth M. Hakim, Fran T. Rose, Jeremy J. Mitchell, Sandra A. Pavletic, Steven Z. Figg, William D. Yao, Lawrence Flanders, Kathleen C. Takebe, Naoko Sarantopoulos, Stefanie Booher, Susan Cowen, Edward W. TI Imatinib Mesylate for the Treatment of Steroid-Refractory Sclerotic-Type Cutaneous Chronic Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Graft-versus-host disease; Imatinib mesylate; Allogeneic hematopoietic stem cell transplantation; Sclerosis; Fasciitis ID STEM-CELL TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; QUALITY-OF-LIFE; SYSTEMIC-SCLEROSIS; CHRONIC GVHD; STIMULATORY AUTOANTIBODIES; GROWTH-FACTOR; RESPONSE CRITERIA; LIMITED EFFICACY AB Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m2 daily up to 130 mg/m2 daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%). including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (inter-quartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Baird, Kristin] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Comis, Leora E.; Joe, Galen O.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Hakim, Fran T.; Rose, Jeremy J.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Rockville, MD USA. [Figg, William D.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Yao, Lawrence] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Flanders, Kathleen C.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Takebe, Naoko] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Sarantopoulos, Stefanie] Duke Univ, Div Hematol Malignancy & Cell Therapy, Durham, NC USA. [Sarantopoulos, Stefanie] Duke Univ, Dept Med, Duke Canc Inst, Durham, NC USA. [Booher, Susan] NIAID, Autoimmun & Mucosal Immunol Branch, Rockville, MD USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), 10 Ctr Dr, Bethesda, MD 20892 USA. EM edcowen@hotmail.com RI Figg Sr, William/M-2411-2016 FU NIH, Center for Cancer Research, National Cancer Institute; Cancer Therapy Evaluation Program FX This study was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute, and the Cancer Therapy Evaluation Program. NR 45 TC 4 Z9 7 U1 0 U2 3 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 JUN PY 2015 VL 21 IS 6 BP 1083 EP 1090 DI 10.1016/j.bbmt.2015.03.006 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CI3SO UT WOS:000354667900015 PM 25771402 ER PT J AU Roukos, V Voss, TC Misteli, T AF Roukos, Vassilis Voss, Ty C. Misteli, Tom TI Spatial dynamics of chromosome translocations in living cells SO CHROMOSOME RESEARCH LA English DT Meeting Abstract CT 20th International Chromosome Conference (ICC) CY SEP 01-04, 2014 CL Univ Kent, Canterbury, ENGLAND HO Univ Kent C1 [Roukos, Vassilis; Voss, Ty C.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0967-3849 EI 1573-6849 J9 CHROMOSOME RES JI Chromosome Res. PD JUN PY 2015 VL 23 IS 2 MA S20 BP 362 EP 362 PG 1 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CI0EZ UT WOS:000354410600036 ER PT J AU Chlebowski, RT Anderson, GL Prentice, RL Rossouw, JE Aragaki, AK Manson, JE AF Chlebowski, R. T. Anderson, G. L. Prentice, R. L. Rossouw, J. E. Aragaki, A. K. Manson, J. E. TI Reliable evidence from placebo-controlled, randomized, clinical trials for menopausal hormone therapy's influence on incidence and deaths from breast cancer SO CLIMACTERIC LA English DT Editorial Material DE PLACEBO-CONTROLS; RANDOMIZED CLINICAL TRIAL; BREAST CANCER; ESTROGEN; ESTROGEN PLUS PROGESTIN; BREAST CANCER ID ESTROGEN PLUS PROGESTIN; HEALTHY POSTMENOPAUSAL WOMEN; EQUINE ESTROGEN; HYSTERECTOMY; MAMMOGRAPHY; MORTALITY AB In an invited editorial, Dr Shapiro proposes that vaginal bleeding leading to unblinding and subsequent detection bias explains the breast cancer increase seen with estrogen plus progestin in the Women's Health Intiative (WHI) clinical trial(1). In the context of a uniform detection program of protocol-mandated annual mammography and breast examinations, such a proposal is medically implausible. Dr Shapiro suggests detection bias would identify a larger number of 'slowly growing tumors that would otherwise remain clinically silent'. The findings of more advanced cancers with increased deaths from breast cancer in the estrogen plus progestin group refute this conjecture. During early post-intervention phases of both WHI hormone therapy trials, when breast cancer detection bias is asserted by Dr Shapiro because participants had been informed of randomization assignment, breast cancer incidence rates were lower (rather than higher) than during intervention. Thus, Dr Shapiro's claims are directly refuted by findings from the WHI randomized clinical trials. Health-care providers should be aware that randomized clinical trial evidence supports estrogen plus progestin increasing breast cancer incidence and deaths from breast cancer. In contrast, among women with prior hysterectomy, randomized clinical trial evidence supports estrogen alone reducing breast cancer incidence and deaths from breast cancer. C1 [Chlebowski, R. T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90501 USA. [Anderson, G. L.; Prentice, R. L.; Aragaki, A. K.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci, Seattle, WA 98104 USA. [Rossouw, J. E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Manson, J. E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Chlebowski, RT (reprint author), Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, 1024 W Carson St,Bldg J-3, Torrance, CA 90501 USA. EM rowanchlebowski@gmail.com NR 16 TC 2 Z9 2 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1369-7137 EI 1473-0804 J9 CLIMACTERIC JI Climacteric PD JUN PY 2015 VL 18 IS 3 BP 336 EP 338 DI 10.3109/13697137.2015.1038770 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CI0CQ UT WOS:000354403800003 PM 25966858 ER PT J AU Brady, TM Neu, AM Miller, ER Appel, LJ Siberry, GK Solomon, BS AF Brady, Tammy M. Neu, Alicia M. Miller, Edgar R. Appel, Lawrence J. Siberry, George K. Solomon, Barry S. TI Real-Time Electronic Medical Record Alerts Increase High Blood Pressure Recognition in Children SO CLINICAL PEDIATRICS LA English DT Article DE computer alert; automated; triage; screening; hypertension; cardiovascular health; primary care; pediatrics; quality improvement; electronic health record ID HEALTH RECORDS; HYPERTENSION; UNDERDIAGNOSIS AB Objective. Pediatric hypertension remains largely unrecognized. We hypothesized that an electronic medical record (EMR) alert would increase elevated blood pressure (BP) recognition in a pediatric primary care setting. Study Design. Pre-post evaluation of a real-time EMR alert and one-time provider educational session. A total of 1305 encounters of children 3 to 21 years with elevated intake BP and no prior hypertension diagnosis were included. Elevated BP recognition and relationship of recognition with cardiovascular disease (CVD) risk factors during the intervention was compared with an historical control. Results. Recognition increased from 12.5% to 42% (P < .001). Recognition increased soon after alert implementation and was sustained without evidence of "alert fatigue." During both periods, presence of CVD risk factors was associated with recognition. However, the magnitude was lesser in the intervention period. Conclusions. Real-time EMR alerts substantially increase elevated BP recognition in children. However, underrecognition of elevated BP persisted, highlighting the need for additional strategies to improve provider recognition. C1 [Brady, Tammy M.; Neu, Alicia M.; Miller, Edgar R.; Appel, Lawrence J.; Siberry, George K.; Solomon, Barry S.] Johns Hopkins Univ, Baltimore, MD USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Brady, TM (reprint author), Johns Hopkins Sch Med, Div Pediat Nephrol, David M Rubenstein Child Hlth Bldg, Baltimore, MD 21287 USA. EM tbrady8@jhmi.edu FU American Kidney Fund Clinical Scientist in Nephrology Program; National Institutes of Health/Johns Hopkins Institute for Clinical and Translational Research [5KL2RR025006] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded in part by the American Kidney Fund Clinical Scientist in Nephrology Program; and the National Institutes of Health/Johns Hopkins Institute for Clinical and Translational Research KL2 Clinical Research Scholar Award Program (5KL2RR025006; TMB). NR 17 TC 1 Z9 1 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 EI 1938-2707 J9 CLIN PEDIATR JI Clin. Pediatr. PD JUN PY 2015 VL 54 IS 7 BP 667 EP 675 DI 10.1177/0009922814559379 PG 9 WC Pediatrics SC Pediatrics GA CI3OH UT WOS:000354656600009 PM 25416626 ER PT J AU Acharya, P Lusvarghi, S Bewley, CA Kwong, PD AF Acharya, Priyamvada Lusvarghi, Sabrina Bewley, Carole A. Kwong, Peter D. TI HIV-1 gp120 as a therapeutic target: navigating a moving labyrinth SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE HIV antibodies; miniprotein mimetics; natural products; receptor mimetics; small molecule inhibitors; structure-based design ID HUMAN-IMMUNODEFICIENCY-VIRUS; BROADLY NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN GP120; OSCILLATORIA-AGARDHII AGGLUTININ; LECTIN-CARBOHYDRATE INTERACTIONS; SMALL-MOLECULE INHIBITORS; CORECEPTOR-BINDING-SITES; STRUCTURE-BASED DESIGN; INFECTION IN-VIVO; CCR5 N-TERMINUS AB Introduction: The HIV-1 gp120 envelope (Env) glycoprotein mediates attachment of virus to human target cells that display requisite receptors, CD4 and co-receptor, generally CCR5. Despite high-affinity interactions with host receptors and proof-of-principle by the drug maraviroc that interference with CCR5 provides therapeutic benefit, no licensed drug currently targets gp120. Areas covered: An overview of the role of gp120 in HIV-1 entry and of sites of potential gp120 vulnerability to therapeutic inhibition is presented. Viral defenses that protect these sites and turn gp120 into a moving labyrinth are discussed together with strategies for circumventing these defenses to allow therapeutic targeting of gp120 sites of vulnerability. Expert opinion: The gp120 envelope glycoprotein interacts with host proteins through multiple interfaces and has conserved structural features at these interaction sites. In spite of this, targeting gp120 for therapeutic purposes is challenging. Env mechanisms that have evolved to evade the humoral immune response also shield it from potential therapeutics. Nevertheless, substantial progress has been made in understanding HIV-1 gp120 structure and its interactions with host receptors, and in developing therapeutic leads that potently neutralize diverse HIV-1 strains. Synergies between advances in understanding, needs for therapeutics against novel viral targets and characteristics of breadth and potency for a number of gp120-targetting lead molecules bodes well for gp120 as a HIV-1 therapeutic target. C1 [Acharya, Priyamvada; Kwong, Peter D.] NIAID, NIH, Vaccine Res Ctr, Struct Biol Sect, Bethesda, MD 20892 USA. [Lusvarghi, Sabrina; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, NIH, Vaccine Res Ctr, Struct Biol Sect, Room 4609B,40 Convent Dr, Bethesda, MD 20892 USA. EM pdkwong@nih.gov FU AIDS Targeted Antiviral Program, Office of the Director, NIH; Intramural Research program, NIDDK; Intramural Research Program, Vaccine Research Center, NIAID, NIH FX The authors were supported by the AIDS Targeted Antiviral Program, Office of the Director, NIH, Intramural Research program, NIDDK, Intramural Research Program, Vaccine Research Center, NIAID, NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 152 TC 6 Z9 6 U1 3 U2 22 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1472-8222 EI 1744-7631 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD JUN PY 2015 VL 19 IS 6 BP 765 EP 783 DI 10.1517/14728222.2015.1010513 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI1YT UT WOS:000354541900005 PM 25724219 ER PT J AU Choi, CH Chung, JY Park, HS Jun, M Lee, YY Kim, BG Hewitt, SM AF Choi, Chel Hun Chung, Joan-Yang Park, Ho-Seop Jun, Minsik Lee, Yoo-Young Kim, Byung-Gie Hewitt, Stephen M. TI Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients SO HUMAN PATHOLOGY LA English DT Article DE PAUF; Adenocarcinoma; Prognosis; Uterine cervical neoplasms; Survival ID BETA-CATENIN; TUMOR PROGRESSION; CELLS; PAUF; LOCALIZATION; METASTASIS; GALECTIN-3; NEOPLASIA; PROTEIN; PROGNOSIS AB Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel soluble protein involved in tumor development and metastases. This study was to investigate the PAUF expression and its prognostic value in cervical cancer patients. The expression of PAUF was immunohistochemically determined in 345 formalin-fixed, paraffin-embedded cervical cancer tissues and 107 normal cervical epitheliums. Subsequently, its associations with clinicopathological characteristics and patient survival were assessed. PAUF protein was expressed both in cytoplasm and nucleus, and cytoplasmic expression was more frequent in cancers than normal tissues (32% versus 17%, P = .002), and the difference was prominent in glandular cells. Notably, the expression was more frequent in adenocarcinoma than in squamous cell carcinoma (57% versus 25%, respectively; P < .001), and the differential expression was also seen at the messenger RNA level (P = .014). Cox regression analysis showed that the cytoplasmic expression of PAUF protein was independently associated with poor disease-free (hazard ratio = 2.3; 95% confidence interval, 1.2-4.3; P = .008) and overall survival (hazard ratio = 2.9; 95% confidence interval, 1.2-7.5; P = .020). Detection of PAUF expression may aid current evaluation of prognosis in cervical adenocarcinoma. Published by Elsevier Inc. C1 [Choi, Chel Hun; Chung, Joan-Yang; Jun, Minsik; Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Yoo-Young; Kim, Byung-Gie] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, Seoul 135710, South Korea. [Park, Ho-Seop] Univ Ulsan, Sch Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. RP Hewitt, SM (reprint author), NCI, Pathol Lab, NIH, MSC 1500, Bethesda, MD 20892 USA. EM bksong.kim@samsung.com; genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Basic Science Research Program through the National Research Foundation of Korea - Ministry of Education, Republic of Korea [2013R1A1A2013629]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study was supported in part by a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Republic of Korea (2013R1A1A2013629) and Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 35 TC 4 Z9 4 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD JUN PY 2015 VL 46 IS 6 BP 884 EP 893 DI 10.1016/j.humpath.2015.02.016 PG 10 WC Pathology SC Pathology GA CI2QY UT WOS:000354593300012 PM 25870121 ER PT J AU Pingili, AK Kara, M Khan, NS Estes, AM Lin, ZT Li, W Gonzalez, FJ Malik, KU AF Pingili, Ajeeth K. Kara, Mehmet Khan, Nayaab S. Estes, Anne M. Lin, Zongtao Li, Wei Gonzalez, Frank J. Malik, Kafait U. TI 6 beta-Hydroxytestosterone, a Cytochrome P450 1B1 Metabolite of Testosterone, Contributes to Angiotensin II-Induced Hypertension and Its Pathogenesis in Male Mice SO HYPERTENSION LA English DT Article DE castration; CYP1B1 protein; hypertension; oxidative stress ID BLOOD-PRESSURE; RENAL DYSFUNCTION; 20-HYDROXYEICOSATETRAENOIC ACID; SENSITIVE HYPERTENSION; CARDIAC-HYPERTROPHY; GENDER-DIFFERENCES; ANDROGEN RECEPTOR; OXIDATIVE STRESS; FOLLOW-UP; RATS AB Previously, we showed that Cyp1b1 gene disruption minimizes angiotensin II-induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6 beta-hydroxytestosterone and 16a-hydroxytestosterone, contribute to angiotensin II-induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6 beta-hydroxytestosterone, but not 16a-hydroxytestosterone, in Cyp1b1(+/+) mice without altering Cyp1b1 gene expression; these effects of angiotensin II were not observed in Cyp1b1(-/-) mice. Angiotensin II-induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of a-smooth muscle actin, collagen, and transforming growth factor-beta, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, and restored by treatment with 6 beta-hydroxytestoterone. In Cyp1b1(+/+) mice, 6 beta-hydroxytestosterone did not alter the angiotensin II-induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1b1(+/+) or in Cyp1b1(-/-) mice. These data suggest that the testosterone metabolite, 6 beta-hydroxytestosterone, contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin-angiotensin and testosterone-dependent hypertension and associated pathogenesis in males. C1 [Pingili, Ajeeth K.; Kara, Mehmet; Khan, Nayaab S.; Estes, Anne M.; Malik, Kafait U.] Univ Tennessee, Ctr Hlth Sci, Dept Pharmacol, Coll Med, Memphis, TN 38163 USA. [Lin, Zongtao; Li, Wei] Univ Tennessee, Ctr Hlth Sci, Dept Pharmaceut Sci, Coll Pharm, Memphis, TN 38163 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Malik, KU (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Pharmacol, Coll Med, 874 Union Ave, Memphis, TN 38163 USA. EM kmalik@uthsc.edu FU National Institutes of Health National Heart, Lung, and Blood Institute [R01-19134-39, R0-R01HL079109-08]; Department of Pharmacology, Faculty of Medicine, Erciyes University, Kayseri, Turkey FX This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute grants R01-19134-39 and R0-R01HL079109-08 (K.U. Malik). M. Kara was supported by a fellowship from Department of Pharmacology, Faculty of Medicine, Erciyes University, Kayseri 38039, Turkey. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute. NR 52 TC 8 Z9 8 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD JUN PY 2015 VL 65 IS 6 BP 1279 EP 1287 DI 10.1161/HYPERTENSIONAHA.115.05396 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CH9OJ UT WOS:000354364900023 PM 25870196 ER PT J AU Yan, PK Cao, YH Yuan, Y Turkbey, B Choyke, PL AF Yan, Pingkun Cao, Yihui Yuan, Yuan Turkbey, Baris Choyke, Peter L. TI Label Image Constrained Multiatlas Selection SO IEEE TRANSACTIONS ON CYBERNETICS LA English DT Article DE Atlas-based; computer vision; image segmentation; manifold learning ID ATLAS-BASED SEGMENTATION; NONLINEAR DIMENSIONALITY REDUCTION; BRAIN IMAGES; MANIFOLD; STRATEGIES; VALIDATION; PROSTATE AB Multiatlas based method is commonly used in medical image segmentation. In multiatlas based image segmentation, atlas selection and combination are considered as two key factors affecting the performance. Recently, manifold learning based atlas selection methods have emerged as very promising methods. However, due to the complexity of prostate structures in raw images, it is difficult to get accurate atlas selection results by only measuring the distance between raw images on the manifolds. Although the distance between the regions to be segmented across images can be readily obtained by the label images, it is infeasible to directly compute the distance between the test image (gray) and the label images (binary). This paper tries to address this problem by proposing a label image constrained atlas selection method, which exploits the label images to constrain the manifold projection of raw images. Analyzing the data point distribution of the selected atlases in the manifold subspace, a novel weight computation method for atlas combination is proposed. Compared with other related existing methods, the experimental results on prostate segmentation from T2w MRI showed that the selected atlases are closer to the target structure and more accurate segmentation were obtained by using our proposed method. C1 [Yan, Pingkun; Cao, Yihui; Yuan, Yuan] Chinese Acad Sci, Xian Inst Opt & Precis Mech, State Key Lab Transient Opt & Photon, Ctr Opt Imagery Anal & Learning, Xian 710119, Peoples R China. [Turkbey, Baris; Choyke, Peter L.] NCI, NIH, Bethesda, MD 20892 USA. RP Yan, PK (reprint author), Chinese Acad Sci, Xian Inst Opt & Precis Mech, State Key Lab Transient Opt & Photon, Ctr Opt Imagery Anal & Learning, Xian 710119, Peoples R China. EM pingkun.yan@opt.ac.cn; yihui.cao@opt.ac.cn; yuany@opt.ac.cn; turkbeyi@mail.nih.gov; pchoyke@mail.nih.gov FU National Natural Science Foundation of China [61172142, 61172143] FX This work was supported by the National Natural Science Foundation of China under Grant 61172142 and Grant 61172143. This paper was recommended by Associate Editor X. You. NR 41 TC 3 Z9 3 U1 1 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2267 EI 2168-2275 J9 IEEE T CYBERNETICS JI IEEE T. Cybern. PD JUN PY 2015 VL 45 IS 6 BP 1158 EP 1168 DI 10.1109/TCYB.2014.2346394 PG 11 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics SC Computer Science GA CI1VC UT WOS:000354532000005 PM 25415994 ER PT J AU Philippot, E Santosh, KC Belaid, A Belaid, Y AF Philippot, Emilie Santosh, K. C. Belaid, Abdel Belaid, Yolande TI Bayesian networks for incomplete data analysis in form processing SO INTERNATIONAL JOURNAL OF MACHINE LEARNING AND CYBERNETICS LA English DT Article DE Bayesian networks; Electronic note-taking; Form processing ID NAIVE BAYES; CLASSIFIERS; RECOGNITION; CLASSIFICATION AB In this paper, we study Bayesian network (BN) for form identification based on partially filled fields. It uses electronic ink-tracing files without having any information about form structure. Given a form format, the ink-tracing files are used to build the BN by providing the possible relationships between corresponding fields using conditional probabilities, that goes from individual fields up to the complete model construction. To simplify the BN, we sub-divide a single form into three different areas: header, body and footer, and integrate them together, where we study three fundamental BN learning algorithms: Naive, Peter & Clark and maximum weighted spanning tree. Under this framework, we validate it with a real-world industrial problem i.e., electronic note-taking in form processing. The approach provides satisfactory results, attesting the interest of BN for exploiting the incomplete form analysis problems, in particular. C1 [Philippot, Emilie; Santosh, K. C.; Belaid, Abdel; Belaid, Yolande] Univ Lorraine LORIA, UMR 7503, F-54506 Vandoeuvre Les Nancy, France. [Santosh, K. C.] NIH, Commun Engn Branch, US Natl Lib Med NLM, Bethesda, MD 20894 USA. RP Philippot, E (reprint author), Univ Lorraine LORIA, UMR 7503, Campus Sci,BP 239, F-54506 Vandoeuvre Les Nancy, France. EM emilie.philippot@gmail.com; santosh.kc@nih.gov; abdel.belaid@loria.fr; yolande.belaid@loria.fr OI Santosh, K.C./0000-0003-4176-0236 NR 42 TC 0 Z9 0 U1 1 U2 13 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1868-8071 EI 1868-808X J9 INT J MACH LEARN CYB JI Int. J. Mach. Learn. Cybern. PD JUN PY 2015 VL 6 IS 3 BP 347 EP 363 DI 10.1007/s13042-014-0234-4 PG 17 WC Computer Science, Artificial Intelligence SC Computer Science GA CH9YB UT WOS:000354391500001 ER PT J AU Zheng, G Zhang, W Li, QZ Xu, JF Yuan, A Gastwirth, JL AF Zheng, Gang Zhang, Wei Li, Qizhai Xu, Jinfeng Yuan, Ao Gastwirth, Joseph L. TI Analysis of Genetic Association Studies Incorporating Prior Information of Genetic Models SO JOURNAL OF AGRICULTURAL BIOLOGICAL AND ENVIRONMENTAL STATISTICS LA English DT Article DE Case-control design; Estimation of genetic model; Genetic model selection; HWE; Robustness; Replication ID GENOME-WIDE ASSOCIATION; HARDY-WEINBERG DISEQUILIBRIUM; EFFICIENCY ROBUST-TESTS; BAYES FACTORS; TEST STATISTICS; SAMPLE-SIZE; SURVIVAL; POWER AB In genetic association studies, for each underlying genetic model, there is an optimal test. Usually, the true model is unknown, but knowledge from previous genome-wide association studies for the disease under investigation is available and provides information about the underlying model. We study how to incorporate this prior information about plausible genetic models to achieve better efficiency robustness in genetic association studies. Two procedures are proposed and studied. The first one reduces the set of genetic models using the prior information. The second one derives posterior probabilities for the plausible genetic models using trend tests. Then the trend test based on the posterior mean of the genetic model or a weighted trend test over various genetic models can be employed, similar in spirit to the efficiency robustness approach. In the proposed procedures, the strong Hardy-Weinberg disequilibrium in cases is studied. Simulations are conducted to compare the proposed methods with existing ones. The usefulness of the results for the analysis of data collected in replication studies is investigated, the proposed methods are shown to have better overall performance than existing one, and the methods are applied to analyze the real data. C1 [Zheng, Gang] NHLBI, Bethesda, MD 20892 USA. [Zhang, Wei; Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst Sci, Beijing 100190, Peoples R China. [Xu, Jinfeng] NYU, New York, NY USA. [Yuan, Ao] Georgetown Univ, Washington, DC USA. [Gastwirth, Joseph L.] George Washington Univ, Washington, DC USA. RP Li, QZ (reprint author), Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst Sci, Zhongguancun East Rd 55, Beijing 100190, Peoples R China. EM liqz@amss.ac.cn OI Xu, Jinfeng/0000-0002-3165-2015 FU National Science Foundation of hina [11371353, 61134013]; Breakthrough Project of Strategic Priority Program of the Chinese Academy of Sciences [XDB13040600] FX Q. Li was supported in part by the National Science Foundation of hina (Grant No. 11371353, 61134013) and the Breakthrough Project of Strategic Priority Program of the Chinese Academy of Sciences, Grant No. XDB13040600. NR 25 TC 0 Z9 0 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1085-7117 EI 1537-2693 J9 J AGR BIOL ENVIR ST JI J. Agric. Biol. Environ. Stat. PD JUN PY 2015 VL 20 IS 2 BP 173 EP 191 DI 10.1007/s13253-015-0200-y PG 19 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA CI3IU UT WOS:000354642200001 ER PT J AU Dolle, L Gao, B AF Dolle, Laurent Gao, Bin TI Pharmacological chaperone therapies: Can aldehyde dehydrogenase activator make us healthier? SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material DE ALDH2; Acetaldehyde; Alda-1; Pharmacological chaperone ID ALCOHOLIC LIVER-DISEASE; HETEROZYGOTES; INJURY; GENES; CELLS C1 [Dolle, Laurent] Free Univ Brussels VUB, Fac Med & Pharm, Dept Biomed Sci, Lab Liver Cell Biol, Brussels, Belgium. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Dolle, L (reprint author), Free Univ Brussels VUB, Fac Med & Pharm, Dept Biomed Sci, Lab Liver Cell Biol, Brussels, Belgium. EM ldolle@vub.ac.be; bgao@mail.nih.gov FU Intramural NIH HHS NR 22 TC 1 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD JUN PY 2015 VL 62 IS 6 BP 1228 EP 1230 DI 10.1016/j.jhep.2014.12.022 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI2KA UT WOS:000354574800002 PM 25681554 ER PT J AU Gonzalez, FJ Jiang, CT Bisson, WH Patterson, AD AF Gonzalez, Frank J. Jiang, Changtao Bisson, William H. Patterson, Andrew D. TI Inhibition of farnesoid X receptor signaling shows beneficial effects in human obesity SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material ID URSODEOXYCHOLIC ACID; CHOLESTEROL 7-ALPHA-HYDROXYLASE; TAUROURSODEOXYCHOLIC ACID; TRANSGENIC EXPRESSION; INSULIN SENSITIVITY; GUT MICROBIOTA; 1 GP-BAR1; LIVER; MICE; FXR C1 [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. [Jiang, Changtao] Peking Univ, Minist Educ, Key Lab Mol Cardiovasc Sci, Dept Physiol & Pathophysiol,Sch Basic Med Sci, Beijing 100191, Peoples R China. [Bisson, William H.] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. [Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. EM gonzalef@mail.nih.gov RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 NR 24 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD JUN PY 2015 VL 62 IS 6 BP 1234 EP 1236 DI 10.1016/j.jhep.2014.12.034 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI2KA UT WOS:000354574800004 PM 25747705 ER PT J AU Gaskari, SA Liu, HQ D'Mello, C Kunos, G Lee, SS AF Gaskari, Seyed Ali Liu, Hongqun D'Mello, Charlotte Kunos, George Lee, Samuel S. TI Blunted cardiac response to hemorrhage in cirrhotic rats is mediated by local macrophage-released endocannabinoids SO JOURNAL OF HEPATOLOGY LA English DT Article DE Cirrhosis; Cardiomyopathy; Endocannabinoids; AM251; Hemorrhage; CB-1; Monocytes; Macrophages ID ENDOGENOUS CANNABINOIDS; LIVER-TRANSPLANTATION; PORTAL-HYPERTENSION; RECEPTORS MEDIATE; NITRIC-OXIDE; CARDIOMYOPATHY; PRESSURE; SYSTEM; BLOOD; CB1 AB Background & Aims: Cirrhosis is associated with blunted cardiovascular response to stimuli such as hemorrhage, but the mechanism remains unclear. We aimed to clarify the role of endocannabinoids in blunted hemorrhage response in cirrhotic rats. Methods: Cirrhosis was induced by bile duct ligation (BDL). Hemodynamics were measured. Cannabinoid receptor-1 (CB1) antagonist, AM251, and macrophage inhibitor gadolinium chloride (GdCl3) were administered. Myocardial levels of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were measured and resident monocytes and macrophages quantified by immunohistochemistry. Isolated cardiomyocyte contractility was measured before and after incubation with monocytes from BDL and sham controls. Results: Hemorrhage significantly decreased arterial pressure and left ventricular dP/dT. After hemorrhage, these changes quickly reversed in controls, but were severely prolonged in BDL rats. Chronic AM251 treatment restored this impaired response. AEA and 2-AG levels were increased in BDL hearts and further increased after hemorrhage. Sham hearts showed virtually no monocytes or macrophages before or after hemorrhage, whereas BDL hearts had significantly more white blood cells which further increased after hemorrhage. GdCl3 treatment significantly reduced cardiac endocannabinoid levels both at baseline and after hemorrhage. This treatment also restored cardiovascular response to hemorrhage in BDL rats but did not affect sham controls. Monocytes isolated from BDL rats more potently inhibited cardiomyocyte contractility than sham control monocytes. Conclusions: The cirrhotic heart showed increased monocyte recruitment and endocannabinoid levels. CB1 blockade or GdCl3 treatment restored blunted cardiovascular response to hemorrhage. Endocannabinoids released by monocytes blunt cardiac response to hemorrhage. Preventing monocyte recruitment or blocking endocannabinoid signaling may improve cardiovascular homeostasis in cirrhosis. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Gaskari, Seyed Ali; Liu, Hongqun; D'Mello, Charlotte; Lee, Samuel S.] Univ Calgary, Liver Unit, Calgary, AB, Canada. [Kunos, George] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Lee, SS (reprint author), Liver Unit, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. EM samlee@ucalgary.ca FU Canadian Association for Study of Liver fellowship award; Canadian Liver Foundation research grant FX SAG was supported by a Canadian Association for Study of Liver fellowship award. The study was funded by a Canadian Liver Foundation research grant. NR 42 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD JUN PY 2015 VL 62 IS 6 BP 1272 EP 1277 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI2KA UT WOS:000354574800009 PM 25640062 ER PT J AU Xu, CF Wan, XY Xu, L Weng, HL Yan, M Miao, M Sun, Y Xu, GY Dooley, S Li, YM Yu, CH AF Xu, Chengfu Wan, Xingyong Xu, Lei Weng, Honglei Yan, Ming Miao, Min Sun, Yan Xu, Genyun Dooley, Steven Li, Youming Yu, Chaohui TI Xanthine oxidase in non-alcoholic fatty liver disease and hyperuricemia: One stone hits two birds SO JOURNAL OF HEPATOLOGY LA English DT Article DE Fatty liver; Hyperuricemia; Uric acid; Xanthine oxidase; NLRP3 inflammasome ID SERUM URIC-ACID; NLRP3 INFLAMMASOME; INSULIN-RESISTANCE; METABOLIC SYNDROME; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; OXIDOREDUCTASE; OBESITY; ACTIVATION; STEATOHEPATITIS AB Background & Aims: Hyperuricemia is a common feature of patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to explore the causal relationship and underlying mechanisms between NAFLD and hyperuricemia. Methods: We evaluated the impact of NAFLD on the development of hyperuricemia in a cohort of 5541 baseline hyperuricemia-free individuals. We further analyzed xanthine oxidase (XO), a rate-limiting enzyme that catalyzes uric acid production, as a candidate to link NAFLD and hyperuricemia. Results: In the first study, a 7-year prospective analysis found that NAFLD was strongly associated with subsequent development of hyperuricemia. Cox proportional hazards regression analyses showed that age, gender, and body mass index adjusted hazard ratio (95% confidence interval) for incident hyperuricemia was 1.609 (1.129-2.294) in individuals with NAFLD, as compared with those without NAFLD at baseline. In the second study, we observed that expression and activity of XO were significantly increased in cellular and mouse models of NAFLD. Knocking down XO expression or inhibiting XO activity significantly decreases uric acid production and attenuates free fatty acids-induced fat accumulation in HepG2 cells. Inhibiting XO activity also significantly prevents the development of and ameliorates established hepatic steatosis induced by a high-fat diet in mice. Further experiments indicated that XO regulates activation of the NLRP3 inflammasome, which may be essential for the regulatory effect of XO on NAFLD. Conclusions: NAFLD significantly increases the risk of incident hyperuricemia. XO is a mediator of the relationship between NAFLD and hyperuricemia, and may serve as a novel therapeutic target for the two linked diseases. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Xu, Chengfu; Wan, Xingyong; Xu, Lei; Li, Youming; Yu, Chaohui] Zhejiang Univ, Affiliated Hosp 1, Dept Gastroenterol, Coll Med, Hangzhou 310003, Zhejiang, Peoples R China. [Xu, Lei] Zhejiang Univ, Dept Gastroenterol, Ningbo Hosp, Ningbo, Zhejiang, Peoples R China. [Weng, Honglei; Dooley, Steven] Heidelberg Univ, Med Fac Mannheim, Sect Mol Hepatol, Dept Med 2, Mannheim, Germany. [Yan, Ming; Sun, Yan] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, NIH, Bethesda, MD USA. [Yan, Ming; Sun, Yan] Natl Inst Diabet & Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD USA. [Miao, Min] Zhenhai Lianhua Hosp, Dept Internal Med, Ningbo, Zhejiang, Peoples R China. [Xu, Genyun] Zhejiang Univ, Affiliated Hosp 1, Dept Lab Med, Coll Med, Hangzhou 310003, Zhejiang, Peoples R China. RP Li, YM (reprint author), Zhejiang Univ, Affiliated Hosp 1, Dept Gastroenterol, Coll Med, 79 Qingchun Rd, Hangzhou 310003, Zhejiang, Peoples R China. EM xiaofu@zju.edu.cn; ych623@sina.com FU National Key Basic Research Development Program [2012CB524905]; National Science and Technology Support Plan Project [2012BAI06B04]; National Natural Science Foundation of China [81100278, 81470838, 81300703, 81170378, 81230012, 81270487]; Zhejiang Provincial Natural Science Foundation of China [R15H030001]; International Science and Technology Cooperation Projects of Zhejiang Province [2013C24010]; Science Foundation of Health Bureau of Zhejiang Province [2012RCA026] FX This work was supported by National Key Basic Research Development Program (No. 2012CB524905 to Y.L.), National Science and Technology Support Plan Project (No. 2012BAI06B04 to Y.L.), National Natural Science Foundation of China (Nos. 81100278 and 81470838 to C.X., 81300703 to L.X., 81170378 and 81230012 to Y.L., and 81270487 to C.Y.), Zhejiang Provincial Natural Science Foundation of China (No. R15H030001 to C.X.), International Science and Technology Cooperation Projects of Zhejiang Province (No. 2013C24010 to C.X.), and Science Foundation of Health Bureau of Zhejiang Province (No. 2012RCA026 to C.X.). The funders did not play any role in the study design, data collection and analysis, decisions regarding data release or manuscript preparation. NR 44 TC 18 Z9 19 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD JUN PY 2015 VL 62 IS 6 BP 1412 EP 1419 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI2KA UT WOS:000354574800026 PM 25623823 ER PT J AU Makarova-Rusher, OV Medina-Echeverz, J Duffy, AG Greten, TF AF Makarova-Rusher, Oxana V. Medina-Echeverz, Jose Duffy, Austin G. Greten, Tim F. TI The yin and yang of evasion and immune activation in HCC SO JOURNAL OF HEPATOLOGY LA English DT Review DE Hepatocellular carcinoma; Immunotherapy; Immune checkpoints ID T-CELL RESPONSES; ADVANCED HEPATOCELLULAR-CARCINOMA; HEPATITIS-C VIRUS; SINUSOIDAL ENDOTHELIAL-CELLS; PREDICTS POOR-PROGNOSIS; PULSED DENDRITIC CELLS; GROWTH-FACTOR-BETA; PHASE-I TRIAL; ALPHA-FETOPROTEIN; INTERFERON-ALPHA AB Current systemic treatment options for patients with hepatocellular carcinoma (HCC) are limited to sorafenib. With the recent FDA approval of the second PD1-PD-L1 pathway inhibitor, immunotherapy has gained even more interest as a potential novel treatment option for patients with HCC. This is due not only because of the failure of other treatment approaches in the past, but also because immunological mechanisms have been shown to play an important role during tumor development, growth, and treatment. Here we present a review of immunological mechanisms in the liver relevant for tumor progression and treatment. We summarize our current knowledge on immune activating and immune suppressing mechanisms during tumor initiation, development, and treatment. We try to explain the paradox of how inflammatory responses in a setting of chronic infection promote tumor development, while the primary aim of immunotherapy is to activate immunity. Finally we summarize recent advances in addition to providing an outlook for the immunotherapy of HCC. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Makarova-Rusher, Oxana V.; Medina-Echeverz, Jose; Duffy, Austin G.; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, NIH, CCR, Bldg 10 Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov FU NCI, NIH FX This work was supported by the Intramural Research Program of the NCI, NIH. NR 116 TC 20 Z9 24 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD JUN PY 2015 VL 62 IS 6 BP 1420 EP 1429 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI2KA UT WOS:000354574800027 PM 25733155 ER PT J AU Crew, KD Ho, KA Brown, P Greenlee, H Bevers, TB Arun, B Sneige, N Hudis, C McArthur, HL Chang, J Rimawi, M Cornelison, TL Cardelli, J Santella, RM Wang, A Lippman, SM Hershman, DL AF Crew, K. D. Ho, K. A. Brown, P. Greenlee, H. Bevers, T. B. Arun, B. Sneige, N. Hudis, C. McArthur, H. L. Chang, J. Rimawi, M. Cornelison, T. L. Cardelli, J. Santella, R. M. Wang, A. Lippman, S. M. Hershman, D. L. TI Effects of a green tea extract, Polyphenon E, on systemic biomarkers of growth factor signalling in women with hormone receptor-negative breast cancer SO JOURNAL OF HUMAN NUTRITION AND DIETETICS LA English DT Article DE breast cancer; chemoprevention; tea polyphenols ID (-)-EPIGALLOCATECHIN-3-GALLATE; RISK; ANGIOGENESIS; MECHANISMS; DAMAGE; CELLS; ASSAY; EGCG AB BackgroundObservational and experimental data support a potential breast cancer chemopreventive effect of green tea. MethodsWe conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I-III breast cancer who completed adjuvant treatment were randomised to Poly E 400mg (n=16), 600mg (n=11) and 800mg (n=3) twice daily or matching placebo (n=10) for 6months. Blood and urine collection occurred at baseline, and at 2, 4 and 6months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers. ResultsFrom July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (-12.7% versus +6.3%, P=0.04). This trend persisted at 4 and 6months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2months (P=0.02) and 13.9% at 4months (P=0.05) but did not differ compared to placebo. At 2months, there was a trend toward a decrease in serum cholesterol with Poly E (P=0.08). No significant differences were observed for other biomarkers. ConclusionsOur findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism. C1 [Crew, K. D.; Ho, K. A.; Greenlee, H.; Santella, R. M.; Wang, A.; Hershman, D. L.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10107 USA. [Brown, P.; Bevers, T. B.; Arun, B.; Sneige, N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hudis, C.; McArthur, H. L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Chang, J.] Methodist Hosp Canc Ctr, Houston, TX USA. [Rimawi, M.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Cornelison, T. L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Cardelli, J.] Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Lippman, S. M.] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. RP Crew, KD (reprint author), Columbia Univ, Herbert Irving Comprehens Canc Ctr, 161 Ft Washington Ave,10-1072, New York, NY 10107 USA. EM kd59@columbia.edu FU National Cancer Institute [N01-CN-35159]; National Institute of Environmental Health Sciences [ES009089]; American Cancer Society [ACS MRSG-08-021-01-CNE] FX The study was supported by the National Cancer Institute (grant N01-CN-35159), the National Institute of Environmental Health Sciences (grant ES009089) and the American Cancer Society (grant ACS MRSG-08-021-01-CNE). NR 31 TC 4 Z9 4 U1 3 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3871 EI 1365-277X J9 J HUM NUTR DIET JI J. Hum. Nutr. Diet. PD JUN PY 2015 VL 28 IS 3 BP 272 EP 282 DI 10.1111/jhn.12229 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CI1HX UT WOS:000354495700007 PM 24646362 ER PT J AU Joseph, J AF Joseph, Jeymohan TI Eradication of HIV-1 from CNS reservoirs: current strategies and future priorities SO JOURNAL OF NEUROVIROLOGY LA English DT Editorial Material C1 NIMH, Div AIDS Res, Bethesda, MD 20892 USA. RP Joseph, J (reprint author), NIMH, Div AIDS Res, Room 9G20,MSC 9831 5601 Fishers Lane, Bethesda, MD 20892 USA. EM jjeymoha@mail.nih.gov 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 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2015 VL 21 IS 3 SI SI BP 219 EP 221 DI 10.1007/s13365-015-0337-z PG 3 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA CI0SK UT WOS:000354448000001 PM 25939608 ER PT J AU Nath, A AF Nath, Avindra TI Eradication of human immunodeficiency virus from brain reservoirs SO JOURNAL OF NEUROVIROLOGY LA English DT Review DE Compartmentalization; Astrocyte; Microglia; Macrophage; Antiretroviral; Latency ID CENTRAL-NERVOUS-SYSTEM; COMBINATION ANTIRETROVIRAL THERAPY; LASER CAPTURE MICRODISSECTION; HIV-1 INFECTION; TYPE-1 INFECTION; TAT PROTEIN; MACROPHAGE-TROPISM; NEURAL PROGENITORS; PLASMA VIREMIA; IN-VIVO AB Isolated cases in which human immunodeficiency virus (HIV) infection was claimed to have been eradicated generated renewed interest in HIV reservoirs in the brain particularly since attempts to reproduce the findings using genetically engineered stem cells and immune- or myeloablation have failed. A clear understanding of the cell types in which the virus resides in the brain, the mechanism of viral persistence, restricted replication and latency, and the turnover rate of the infected cells is critical for us to develop ways to control or get rid of the virus in the brain. The brain has several unique features compared to other reservoirs. There are no resident T cells in the brain; the virus resides in macrophages and astrocytes where the viral infection is non-cytopathic. The virus evolves in the brain and since the turnover rate of these cells is low, the virus has the potential to reside in these cells for several decades and possibly for the life of the individual. This review discusses the HIV reservoirs in the brain, issues related to eradication of the virus from sanctuaries in the brain, and current challenges faced by neuroscientists in finding a cure. C1 NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 10-7C-103,10 Ctr Dr, Bethesda, MD 20892 USA. EM natha@mail.nih.gov FU NINDS, NIH FX Dr. Dorian McGavern provided a photomicrograph of the meningeal macrophages. This study was supported by intramural funds from NINDS, NIH. NR 75 TC 11 Z9 11 U1 1 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2015 VL 21 IS 3 SI SI BP 227 EP 234 DI 10.1007/s13365-014-0291-1 PG 8 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA CI0SK UT WOS:000354448000003 PM 25366659 ER PT J AU Guendel, I Iordanskiy, S Sampey, GC Van Duyne, R Calvert, V Petricoin, E Saifuddin, M Kehn-Hall, K Kashanchi, F AF Guendel, Irene Iordanskiy, Sergey Sampey, Gavin C. Van Duyne, Rachel Calvert, Valerie Petricoin, Emanuel Saifuddin, Mohammed Kehn-Hall, Kylene Kashanchi, Fatah TI Role of Bruton's tyrosine kinase inhibitors in HIV-1-infected cells SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE HIV-1 replication; BTK; Host cell protein; Inhibitor; Cell death ID X-LINKED AGAMMAGLOBULINEMIA; TRANSCRIPTION FACTOR BRIGHT; PLECKSTRIN HOMOLOGY DOMAIN; KAPPA-B ACTIVATION; LYMPHOID MALIGNANCIES; RECEPTOR ENGAGEMENT; HIV-INFECTION; BTK FUNCTION; TEC FAMILY; T-CELLS AB Many cellular cofactors have been documented to be critical for various stages of viral replication. Using high-throughput proteomic assays, we have previously identified Bruton's tyrosine kinase (BTK) as a host protein that was uniquely upregulated in the plasma membrane of human immunodeficiency virus (HIV-1)-infected T cells. Here, we have further characterized the BTK expression in HIV-1 infection and show that this cellular factor is specifically expressed in infected myeloid cells. Significant upregulation of the phosphorylated form of BTK was observed in infected cells. Using size exclusion chromatography, we found BTK to be virtually absent in the uninfected U937 cells; however, new BTK protein complexes were identified and distributed in both high molecular weight (similar to 600 kDa) and a small molecular weight complex (similar to 60-120 kDa) in the infected U1 cells. BTK levels were highest in cells either chronically expressing virus or induced/infected myeloid cells and that BTK translocated to the membrane following induction of the infected cells. BTK knockdown in HIV-1-infected cells using small interfering RNA (siRNA) resulted in selective death of infected, but not uninfected, cells. Using BTK-specific antibody and small-molecule inhibitors including LFM-A13 and a FDA-approved compound, ibrutinib (PCI-32765), we have found that HIV-1-infected cells are sensitive to apoptotic cell death and result in a decrease in virus production. Overall, our data suggests that HIV-1-infected cells are sensitive to treatments targeting BTK expressed in infected cells. C1 [Guendel, Irene; Iordanskiy, Sergey; Sampey, Gavin C.; Kehn-Hall, Kylene; Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodefense & Infect Dis, Dept Syst Biol, Manassas, VA 20110 USA. [Van Duyne, Rachel] NCI, Ctr Canc Res, NIH, Ft Detrick, MD 21702 USA. [Calvert, Valerie; Petricoin, Emanuel] George Mason Univ, Ctr Appl Prote & Mol Med, Manassas, VA 20110 USA. [Saifuddin, Mohammed] WuXi AppTec Inc, Philadelphia, PA 19112 USA. [Kashanchi, Fatah] George Mason Univ, Mol Virol Lab, Manassas, VA 20110 USA. RP Kashanchi, F (reprint author), George Mason Univ, Mol Virol Lab, Discovery Hall,Room 182,10900 Univ Blvd MS 1H8, Manassas, VA 20110 USA. EM fkashanc@gmu.edu FU National Institutes of Health [AI070740, AI043894, AI11340, AI114490]; Virginia's Commonwealth Health Research Board FX We would like to thank the members of the Kashanchi Lab for experiments and assistance with the manuscript, and the NIH AIDS Research and Reference Reagent Program for the contribution of the important reagents. This work was supported by National Institutes of Health grant AI070740, AI043894, AI11340, and AI114490 to FK and a grant from Virginia's Commonwealth Health Research Board to KK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 83 TC 0 Z9 0 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2015 VL 21 IS 3 SI SI BP 257 EP 275 DI 10.1007/s13365-015-0323-5 PG 19 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA CI0SK UT WOS:000354448000007 PM 25672887 ER PT J AU Brew, BJ Robertson, K Wright, EJ Churchill, M Crowe, SM Cysique, LA Deeks, S Garcia, JV Gelman, B Gray, LR Johnson, T Joseph, J Margolis, DM Mankowski, JL Spencer, B AF Brew, B. J. Robertson, K. Wright, E. J. Churchill, M. Crowe, S. M. Cysique, L. A. Deeks, S. Garcia, J. V. Gelman, B. Gray, L. R. Johnson, T. Joseph, J. Margolis, D. M. Mankowski, J. L. Spencer, B. TI HIV eradication symposium: will the brain be left behind? SO JOURNAL OF NEUROVIROLOGY LA English DT Editorial Material DE Human immunodeficiency virus type 1; Acquired immunodeficiency syndrome; HIV-associated neurocognitive disorders; Eradication; Brain ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; CEREBROSPINAL-FLUID; IN-VIVO; RALTEGRAVIR INTENSIFICATION; SUPPRESSIVE THERAPY; LATENT HIV-1; REPLICATION-COMPETENT; REVERSE TRANSCRIPTION; SITU HYBRIDIZATION AB On 18 July 2014, the National Institute of Mental Health in collaboration with ViiV Health Care and Boehringer Ingelheim supported a symposium on HIV eradication and what it meant for the brain. The symposium was an affiliated event to the 20th International AIDS Conference. The meeting was held in Melbourne, Australia, and brought together investigators currently working on HIV eradication together with investigators who are working on the neurological complications of HIV. The purpose of the meeting was to bring the two fields of HIV eradication and HIV neurology together to foster dialogue and cross talk to move the eradication field forward in the context of issues relating to the brain as a potential reservoir of HIV. The outcomes of the symposium were that there was substantive but not definitive evidence for the brain as an HIV reservoir that will provide a challenge to HIV eradication. Secondly, the brain as a clinically significant reservoir for HIV is not necessarily present in all patients. Consequently, there is an urgent need for the development of biomarkers to identify and quantify the HIV reservoir in the brain. Lastly, when designing and developing eradication strategies, it is critical that approaches to target the brain reservoir be included. C1 [Brew, B. J.; Cysique, L. A.] St Vincents Hosp, St Vincents Ctr Appl Med Res, Dept Neurol, Dept Immunol, Sydney, NSW 2010, Australia. [Brew, B. J.; Cysique, L. A.] St Vincents Hosp, St Vincents Ctr Appl Med Res, Dept Infect Dis, Sydney, NSW 2010, Australia. [Brew, B. J.; Cysique, L. A.] St Vincents Hosp, St Vincents Ctr Appl Med Res, Peter Duncan Neurosci Unit, Sydney, NSW 2010, Australia. [Robertson, K.] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. [Wright, E. J.; Crowe, S. M.] Alfred Hosp Melbourne Australia, Dept Infect Dis, Melbourne, Vic, Australia. [Cysique, L. A.] NeuRA, Sydney, NSW, Australia. [Churchill, M.; Gray, L. R.] Burnet Inst, Melbourne, Vic, Australia. [Deeks, S.] Univ Calif San Francisco, Dept Infect Dis, San Francisco, CA 94143 USA. [Garcia, J. V.] Univ N Carolina, Ctr AIDS Res, Div Infect Dis, Chapel Hill, NC USA. [Gelman, B.] Univ Texas Austin, Austin, TX 78712 USA. [Johnson, T.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Joseph, J.] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. [Margolis, D. M.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Mankowski, J. L.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Mankowski, J. L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Spencer, B.] Univ Calif San Diego, San Diego, CA 92103 USA. RP Brew, BJ (reprint author), St Vincents Hosp, St Vincents Ctr Appl Med Res, Dept Neurol, Dept Immunol, Sydney, NSW 2010, Australia. EM B.Brew@UNSW.edu.au OI Margolis, David/0000-0001-5714-0002 NR 73 TC 2 Z9 2 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2015 VL 21 IS 3 SI SI BP 322 EP 334 DI 10.1007/s13365-015-0322-6 PG 13 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA CI0SK UT WOS:000354448000012 PM 25750070 ER PT J AU Padgett, LS Ferrer, RA AF Padgett, Lynne S. Ferrer, Rebecca A. TI Palliative Care in Cancer: Enhancing Our View with the Science of Emotion and Decision Making SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Letter C1 [Padgett, Lynne S.; Ferrer, Rebecca A.] NCI, Basic Biobehav & Psychol Sci Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. RP Padgett, LS (reprint author), NCI, Behav Res Program, Basic Biobehav & Psychol Sci Branch, 9609 Med Ctr Dr,Room 3E616, Rockville, MD 20850 USA. EM lynne.padgett@nih.gov NR 4 TC 1 Z9 1 U1 1 U2 1 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 JUN 1 PY 2015 VL 18 IS 6 BP 479 EP 479 DI 10.1089/jpm.2015.0024 PG 1 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CI2WJ UT WOS:000354608100002 PM 25919185 ER PT J AU Elagib, KE Xiao, M Hussaini, IM Delehanty, LL Palmer, LA Racke, FK Birrer, MJ Ganapathy-Kanniappan, S McDevitt, MA Goldfarb, AN AF Elagib, Kamaleldin E. Xiao, Mang Hussaini, Isa M. Delehanty, Lorrie L. Palmer, Lisa A. Racke, Frederick K. Birrer, Michael J. Ganapathy-Kanniappan, Shanmugasundaram McDevitt, Michael A. Goldfarb, Adam N. TI Jun Blockade of Erythropoiesis: Role for Repression of GATA-1 by HERP2 (vol 24, pg 7779, 2004) SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Correction C1 [Elagib, Kamaleldin E.; Xiao, Mang; Hussaini, Isa M.; Delehanty, Lorrie L.; Goldfarb, Adam N.] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. [Palmer, Lisa A.] Univ Virginia, Sch Med, Dept Pediat, Charlottesville, VA 22908 USA. [Racke, Frederick K.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Ganapathy-Kanniappan, Shanmugasundaram; McDevitt, Michael A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Birrer, Michael J.] NCI, Mol Mech Sect, Rockville, MD USA. RP Elagib, KE (reprint author), Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. NR 1 TC 0 Z9 0 U1 0 U2 2 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 JUN PY 2015 VL 35 IS 12 BP 2215 EP 2215 DI 10.1128/MCB.00374-15 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CI2ZX UT WOS:000354618200014 PM 25987232 ER PT J AU Bailey, DL Antoch, G Bartenstein, P Barthel, H Beer, AJ Bisdas, S Bluemke, DA Boellaard, R Claussen, CD Franzius, C Hacker, M Hricak, H la Fougere, C Guckel, B Nekolla, SG Pichler, BJ Purz, S Quick, HH Sabri, O Sattler, B Schafer, J Schmidt, H van den Hoff, J Voss, S Weber, W Wehrl, HF Beyer, T AF Bailey, D. L. Antoch, G. Bartenstein, P. Barthel, H. Beer, A. J. Bisdas, S. Bluemke, D. A. Boellaard, R. Claussen, C. D. Franzius, C. Hacker, M. Hricak, H. la Fougere, C. Gueckel, B. Nekolla, S. G. Pichler, B. J. Purz, S. Quick, H. H. Sabri, O. Sattler, B. Schaefer, J. Schmidt, H. van den Hoff, J. Voss, S. Weber, W. Wehrl, H. F. Beyer, T. TI Combined PET/MR: The Real Work Has Just Started. Summary Report of the Third International Workshop on PET/MR Imaging; February 17-21, 2014, Tubingen, Germany SO MOLECULAR IMAGING AND BIOLOGY LA English DT Review DE Hybrid imaging; Molecular imaging; PET/CT; PET/MRI; PET; MRI; Quantification; Attenuation correction; Oncology; Paediatric oncology; Neurology; Cardiology ID POSITRON-EMISSION-TOMOGRAPHY; TIME-OF-FLIGHT; PEDIATRIC DOSAGE CARD; CONTRAST-ENHANCED MRI; WHOLE-BODY PET/MRI; ATTENUATION CORRECTION; PROSTATE-CANCER; EXPECTED MANAGEMENT; MAGNETIC-RESONANCE; PULMONARY-LESIONS AB This paper summarises the proceedings and discussions at the third annual workshop held in Tubingen, Germany, dedicated to the advancement of the technical, scientific and clinical applications of combined PET/MRI systems in humans. Two days of basic scientific and technical instructions with "hands-on" tutorials were followed by 3 days of invited presentations from active researchers in this and associated fields augmented by round-table discussions and dialogue boards with specific themes. These included the use of PET/MRI in paediatric oncology and in adult neurology, oncology and cardiology, the development of multi-parametric analyses, and efforts to standardise PET/MRI examinations to allow pooling of data for evaluating the technology. A poll taken on the final day demonstrated that over 50 % of those present felt that while PET/MRI technology underwent an inevitable slump after its much-anticipated initial launch, it was now entering a period of slow, progressive development, with new key applications emerging. In particular, researchers are focusing on exploiting the complementary nature of the physiological (PET) and biochemical (MRI/MRS) data within the morphological framework (MRI) that these devices can provide. Much of the discussion was summed up on the final day when one speaker commented on the state of PET/MRI: "the real work has just started". C1 [Bailey, D. L.] Univ Sydney, Royal N Shore Hosp, Dept Nucl Med, Sydney, NSW 2006, Australia. [Bailey, D. L.] Univ Sydney, Fac Hlth Sci, Sydney, NSW 2006, Australia. [Antoch, G.] Univ Clin Dusseldorf, Inst Diagnost & Intervent Radiol, Dusseldorf, Germany. [Bartenstein, P.] Univ Munich, Dept Nucl Med, Munich, Germany. [Barthel, H.; Purz, S.; Sabri, O.; Sattler, B.] Univ Leipzig, Dept Nucl Med, D-04109 Leipzig, Germany. [Beer, A. J.] Univ Ulm, Dept Nucl Med, D-89069 Ulm, Germany. [Bisdas, S.; Claussen, C. D.; Gueckel, B.; Schaefer, J.; Schmidt, H.] Univ Tubingen, Dept Intervent & Diagnost Neuroradiol, Tubingen, Germany. [Bluemke, D. A.] NIH, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Boellaard, R.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. [Franzius, C.] MR & PET MRI, Ctr Morphol & Mol Diagnost ZeMoDi, Bremen, Germany. [Franzius, C.] Ctr Nucl Med & PET CT, Bremen, Germany. [Hacker, M.] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Nucl Med, Vienna, Austria. [Hricak, H.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [la Fougere, C.] Univ Tubingen, Dept Nucl Med & Mol Imaging, Tubingen, Germany. [Nekolla, S. G.] Tech Univ Munich, Clin Nucl Med, D-80290 Munich, Germany. [Pichler, B. J.; Wehrl, H. F.] Univ Tubingen, Werner Siemens Imaging Ctr, Dept Preclin Imaging & Radiopharm, Tubingen, Germany. [Quick, H. H.] Univ Duisburg Essen, Erwin L Hahn Inst MR Imaging, Essen, Germany. [Quick, H. H.] Univ Hosp Essen, High Field & Hybrid MR Imaging, Essen, Germany. [van den Hoff, J.] FZD Res Ctr Dresden, PET Ctr, Dresden, Germany. [Voss, S.] Harvard Univ, Sch Med, Dept Radiol, Boston Childrens Hosp, Boston, MA 02115 USA. [Weber, W.] Mem Sloan Kettering Canc Ctr, Dept Radiol Mol Imaging & Therapy Serv, New York, NY 10021 USA. [Beyer, T.] Med Univ Vienna, Gen Hosp Vienna, Ctr Med Phys & Biomed Engn, A-1090 Vienna, Austria. RP Beyer, T (reprint author), Med Univ Vienna, Gen Hosp Vienna, Ctr Med Phys & Biomed Engn, 4 L Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM thomas.beyer@meduniwien.ac.at RI Bisdas, Sotirios/P-2549-2016; la Fougere, Christian/G-6514-2012; OI Bisdas, Sotirios/0000-0001-9930-5549; Beyer, Thomas/0000-0002-8308-3918; Boellaard, Ronald/0000-0002-0313-5686; Bluemke, David/0000-0002-8323-8086 FU Bayer HealthCare; GE Healthcare; Hermes Medical Solutions; Mediso Medical Imaging Systems; Mirada Medical; Pi.pmod Biomedical Image Quantification; Siemens Healthcare; WMIS FX We would further like to acknowledge the generous support of the workshop sponsors: Bayer HealthCare, GE Healthcare, Hermes Medical Solutions, Mediso Medical Imaging Systems, Mirada Medical, Pi.pmod Biomedical Image Quantification, Siemens Healthcare and the WMIS. NR 78 TC 21 Z9 21 U1 1 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD JUN PY 2015 VL 17 IS 3 BP 297 EP 312 DI 10.1007/s11307-014-0818-0 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CH5TE UT WOS:000354097400002 PM 25672749 ER PT J AU Emery, AC Liu, XH Xu, WQ Eiden, MV Eiden, LE AF Emery, Andrew C. Liu, Xiu-Huai Xu, Wenqin Eiden, Maribeth V. Eiden, Lee E. TI Cyclic Adenosine 3 ',5 '-Monophosphate Elevation and Biological Signaling through a Secretin Family G(s)-Coupled G Protein-Coupled Receptor Are Restricted to a Single Adenylate Cyclase Isoform SO MOLECULAR PHARMACOLOGY LA English DT Article ID LIPID RAFTS; PC12 CELLS; CAVEOLAE; NEURITOGENESIS; COMPONENTS; INHIBITORS; DOMAINS; PATHWAY AB PC12 cells express five adenylate cyclase (AC) isoforms, most abundantly AC6 and AC7. These two ACs were individually silenced using lentiviral short hairpin RNAs, which lead to a decrease (>= 80%) of the protein product of each transcript. These stable PC12 sublines were then used to examine potential AC isoform preference for signaling through a family B G protein-coupled receptor (GPCR). Cells were challenged with the endogenous agonist of the pituitary adenylate cyclase-activating polypeptide type I receptor (PAC(1)), pituitary adenylate cyclase-activating polypeptide (PACAP)-38, or the diterpene forskolin as an AC-proximal control. Intracellular cAMP levels were elevated by forskolin about equally in wild-type, AC6, and AC7 knockdown cells. The ability of PACAP-38 and forskolin to activate three cAMP sensors downstream of AC [protein kinase A (PKA), exchange protein activated by cAMP (Epac) 2/Rapgef4, and neuritogenic cAMP sensor (NCS)/Rapgef2] was examined by monitoring the phosphorylation status of their respective targets, cAMP response element-binding protein, p38, and extracellular signal-regulated kinase. Forskolin stimulation of each downstream target of cAMP was unaffected by knockdown of either AC6 or AC7. PACAP-38 activation of all downstream targets of cAMP was unaffected by AC7 knockdown, but abolished following AC6 knockdown. Membrane cholesterol depletion with methyl-beta-cyclodextrin mimicked the effects of AC6 silencing on PACAP signaling, without attenuating forskolin signaling. These data suggest that vicinal constraint of the GPCR PAC(1) and AC6 determines the exclusive requirement for this AC in PACAP signaling, but that the coupling of the cAMP sensors PKA, Epac2/Rapgef4, and NCS/Rapgef2, to their respective downstream signaling targets, determines how cAMP signaling is parcellated to physiologic responses, such as neuritogenesis, upon GPCR-G(s) activation in neuroendocrine cells. C1 [Emery, Andrew C.; Liu, Xiu-Huai; Eiden, Lee E.] Natl Inst Mental Hlth, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Xu, Wenqin; Eiden, Maribeth V.] Natl Inst Mental Hlth, Lab Cellular & Mol Regulat, Directed Gene Transfer, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), Natl Inst Mental Hlth, 49 Convent Dr,Bldg 49,Room 5A 38, Bethesda, MD 20892 USA. EM eidenm@mail.nih.gov; eidenl@mail.nih.gov FU National Institutes of Health National Institute of Mental Health Intramural Research Program [1ZIAMH002386, 1ZIAMH002592]; Brain and Behavior Research Foundation [21356] FX This work was supported by the National Institutes of Health National Institute of Mental Health Intramural Research Program [Projects 1ZIAMH002386 and 1ZIAMH002592]. A.C.E.'s project is supported in part by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation [Grant 21356]. NR 23 TC 1 Z9 3 U1 2 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2015 VL 87 IS 6 BP 928 EP 935 DI 10.1124/mol.115.098087 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI2ZN UT WOS:000354617000004 PM 25769305 ER PT J AU Szakadati, G Toth, AD Olah, I Erdeli, LS Balla, T Varnai, P Hunyady, L Balla, A AF Szakadati, Gyoengyi Toth, Andras D. Olah, Ilona Erdeli, Laszlo Sandor Balla, Tamas Varnai, Peter Hunyady, Laszlo Balla, Andras TI Investigation of the Fate of Type I Angiotensin Receptor after Biased Activation SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; PHOSPHATIDYLINOSITOL 4-PHOSPHATE; SELECTIVE REGULATION; AT(1); ENDOCYTOSIS; INTERNALIZATION; DOMAINS; PHOSPHORYLATION; AGONIST; BINDING AB Biased agonism on the type I angiotensin receptor (AT(1)-R) can achieve different outcomes via activation of G protein-dependent and -independent cellular responses. In this study, we investigated whether the biased activation of AT(1)-R can lead to different regulation and intracellular processing of the receptor. We analyzed beta-arrestin binding, endocytosis, and subsequent trafficking steps, such as early and late phases of recycling of AT(1)-R in human embryonic kidney 293 cells expressing wild-type or biased mutant receptors in response to different ligands. We used Renilla luciferase-tagged receptors and yellow fluorescent protein-tagged beta-arrestin2, Rab5, Rab7, and Rab11 proteins in bioluminescence resonance energy transfer measurements to follow the fate of the receptor after stimulation. We found that not only is the signaling of the receptor different upon using selective ligands, but the fate within the cells is also determined by the type of the stimulation. beta-arrestin binding and the internalization kinetics of the angiotensin II-stimulated AT(1)-R differed from those stimulated by the biased agonists. Similarly, angiotensin II-stimulated wild-type AT(1)-R showed differences compared with a biased mutant AT(1)-R (DRY/AAY AT(1)-R) with regards to beta-arrestin binding and endocytosis. We found that the differences in the internalization kinetics of the receptor in response to biased agonist stimulation are due to the differences in plasma membrane phosphatidylinositol 4,5-bisphosphate depletion. Moreover, the stability of the beta-arrestin binding is a major determinant of the later fate of the internalized AT(1)-R receptor. C1 [Szakadati, Gyoengyi; Toth, Andras D.; Olah, Ilona; Erdeli, Laszlo Sandor; Varnai, Peter; Hunyady, Laszlo; Balla, Andras] Semmelweis Univ, Fac Med, Dept Physiol, H-1085 Budapest, Hungary. [Erdeli, Laszlo Sandor; Varnai, Peter; Hunyady, Laszlo; Balla, Andras] Hungarian Acad Sci, Semmelweis Egyet Lab Mol Physiol, Magyar Tudomanyos Akad, Budapest, Hungary. [Erdeli, Laszlo Sandor; Varnai, Peter; Hunyady, Laszlo; Balla, Andras] Semmelweis Univ, H-1085 Budapest, Hungary. [Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD USA. RP Hunyady, L (reprint author), POB 259, H-1444 Budapest, Hungary. EM Hunyady@eok.sote.hu OI Balla, Tamas/0000-0002-9077-3335; Balla, Andras/0000-0002-6450-2793 FU Hungarian Scientific Research Fund OTKA [NK100883, K105006]; National Development Agency NFU TAMOP [4.2.2-08/1/KMR, 4-2.1/B-09/1/KMR-2010-0001]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; Intramural Research Program of the National Institutes of Health (Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development) FX This work was supported by the Hungarian Scientific Research Fund OTKA [NK100883 and K105006] and National Development Agency NFU TAMOP [4.2.2-08/1/KMR and 4-2.1/B-09/1/KMR-2010-0001]. A.B. was also supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. This research was supported in part by the Intramural Research Program of the National Institutes of Health (Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development). NR 51 TC 4 Z9 4 U1 3 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2015 VL 87 IS 6 BP 972 EP 981 DI 10.1124/mol.114.097030 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI2ZN UT WOS:000354617000008 PM 25804845 ER PT J AU Fernandez, EV Reece, KM Ley, AM Troutman, SM Sissung, TM Price, DK Chau, CH Figg, WD AF Fernandez, Elena V. Reece, Kelie M. Ley, Ariel M. Troutman, Sarah M. Sissung, Tristan M. Price, Douglas K. Chau, Cindy H. Figg, William D. TI Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1 alpha Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID BIOLOGY; ENZALUTAMIDE; ANTIANDROGEN; ENVIRONMENT; ACTIVATION; MECHANISMS AB Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 alpha (HIF-1 alpha) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1a signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1 alpha inhibition was achieved by siRNA silencing HIF-1 alpha or via chetomin, a disruptor of HIF-1 alpha-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1 alpha target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1 alpha inhibition attenuated AR-regulated and HIF-1 alpha-mediated gene transcription. The combination of enzalutamide and HIF-1 alpha inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1 alpha siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1 alpha inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth. C1 [Fernandez, Elena V.; Reece, Kelie M.; Ley, Ariel M.; Troutman, Sarah M.; Sissung, Tristan M.; Price, Douglas K.; Chau, Cindy H.; Figg, William D.] NCI, Ctr Canc Res, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), Bldg 10-Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural Research Program of the National Institutes of Health National Cancer Institute, Center for Cancer Research 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. NR 26 TC 8 Z9 9 U1 5 U2 11 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2015 VL 87 IS 6 BP 1006 EP 1012 DI 10.1124/mol.114.097477 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI2ZN UT WOS:000354617000011 PM 25829060 ER PT J AU Nance, JR Mammen, AL AF Nance, Jessica R. Mammen, Andrew L. TI Diagnostic evaluation of rhabdomyolysis SO MUSCLE & NERVE LA English DT Review DE etiology; inherited myopathy; metabolic myopathy; rhabdomyolysis; symptoms ID ACUTE-RENAL-FAILURE; PHOSPHOGLYCERATE MUTASE DEFICIENCY; B KINASE-DEFICIENCY; MUSCLE PHOSPHOFRUCTOKINASE DEFICIENCY; DEHYDROGENASE M-SUBUNIT; CPT-II DEFICIENCY; TRIFUNCTIONAL PROTEIN-DEFICIENCY; SICKLE-CELL TRAIT; ACUTE EXERTIONAL RHABDOMYOLYSIS; PHOSPHOGLUCOMUTASE 1 DEFICIENCY AB Rhabdomyolysis is characterized by severe acute muscle injury resulting in muscle pain, weakness, and/or swelling with release of myofiber contents into the bloodstream. Symptoms develop over hours to days after an inciting factor and may be associated with dark pigmentation of the urine. Serum creatine kinase and urine myoglobin levels are markedly elevated. Clinical examination, history, laboratory studies, muscle biopsy, and genetic testing are useful tools for diagnosis of rhabdomyolysis, and they can help differentiate acquired from inherited causes of rhabdomyolysis. Acquired causes include substance abuse, medication or toxic exposures, electrolyte abnormalities, endocrine disturbances, and autoimmune myopathies. Inherited predisposition to rhabdomyolysis can occur with disorders of glycogen metabolism, fatty acid -oxidation, and mitochondrial oxidative phosphorylation. Less common inherited causes of rhabdomyolysis include structural myopathies, channelopathies, and sickle-cell disease. This review focuses on the differentiation of acquired and inherited causes of rhabdomyolysis and proposes a practical diagnostic algorithm. Muscle Nerve51: 793-810, 2015 C1 [Nance, Jessica R.; Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Mammen, AL (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. EM andrew.mammen@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 212 TC 9 Z9 9 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD JUN PY 2015 VL 51 IS 6 BP 793 EP 810 DI 10.1002/mus.24606 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI1TG UT WOS:000354526900002 PM 25678154 ER PT J AU Blaisdell, CJ Weinmann, GG AF Blaisdell, Carol J. Weinmann, Gail G. TI NHLBI viewpoint: Lung health and disease prevention research starting in childhood SO PEDIATRIC PULMONOLOGY LA English DT Article DE bronchopulmonary dysplasia (BPD); asthma & early wheeze; cystic fibrosis (CF); developmental biology; pulmonary hypertension ID CYSTIC-FIBROSIS; PRETERM INFANTS; BRONCHOPULMONARY DYSPLASIA; PULMONARY-FUNCTION; MATERNAL SMOKING; CONTROLLED-TRIAL; AIR-POLLUTION; AGE; ASTHMA; SUPPLEMENTATION AB Lung health begins in utero when the complex structure of the airway, alveolar, and vascular structures are formed. To really impact the United States and global burden of chronic lung diseases in both adults and children, we must understand normal and abnormal development, the outcomes of disrupted development, and the effects of in utero and postnatal exposures on lung health. With increasing recognition of early life origins of adult diseases,(1) it is important to know what early events and interventions can alter the trajectory of lung development, growth, and decline to help promote lung health and reduce chronic lung disease. Pediatr Pulmonol. 2015; 50:604-606. (c) 2015 Wiley Periodicals, Inc. C1 [Blaisdell, Carol J.; Weinmann, Gail G.] NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. RP Blaisdell, CJ (reprint author), NHLBI, Div Lung Dis, 6701 Rockledge Dr 10-160, Bethesda, MD 20892 USA. EM Blaisdellcj@nhlbi.nih.gov NR 30 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD JUN PY 2015 VL 50 IS 6 BP 604 EP 606 DI 10.1002/ppul.23198 PG 3 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CI0VZ UT WOS:000354458600012 PM 25857257 ER PT J AU Lin, YJ Ho, TJ Lin, TH Hsu, WY Huang, SM Liao, CC Lai, CH Liu, X Tsang, H Lai, CC Tsai, FJ AF Lin, Ying-Ju Ho, Tsung-Jung Lin, Ting-Hsu Hsu, Wei-Yi Huang, Shao-Mei Liao, Chiu-Chu Lai, Chih-Ho Liu, Xiang Tsang, Hsinyi Lai, Chien-Chen Tsai, Fuu-Jen TI P-coumaric acid regulates exon 12 splicing of the ATP7B gene by modulating hnRNP A1 protein expressions SO BIOMEDICINE-TAIWAN LA English DT Article DE Wilson's disease; Schizonepeta; p-coumaric acid; hnRNP A1; Alternative splicing ID SPINAL MUSCULAR-ATROPHY; WILSON DISEASE GENE; MOTOR-NEURON SMN; POTENTIAL THERAPY; MUTATION ANALYSIS; INCLUSION; CELLS; RNA; IDENTIFICATION; HTRA2-BETA-1 AB Background: Wilson's disease (WD) is a genetic disorder involving the metabolism of copper. WD patients exhibit a wide range of disease phenotypes, including Kayser-Fleischer rings in the cornea, predominant progressive hepatic disease, neurological diseases, and/or psychiatric illnesses, among others. Patients with exon12 mutations of the ATP7B gene have progressive hepatic disease. An ATP7B gene that lacks exon12 retains 80% of its copper transport activities, suggesting that alternative splicing of ATP7B gene may provide alternative therapeutic ways for patients with inherited sequence variants and mutations of this gene. Purpose: We aimed to search for possible Chinese herbs and related compounds for modulating ATP7B pre-mRNA splicing. Methods: We used an ATP7B exon11-12-13 mini-gene vector as a model and screened 18 Chinese herbal extracts and four compounds from Schizonepeta to determine their effects on ATP7B pre-mRNA splicing in vitro. Results: We found that Schizonepeta demonstrated the greatest potential for alternative splicing activity. Specifically, we found that p-coumaric acid from this herb enhanced ATP7B exon12 exclusion through the down-regulation of heterogeneous ribonucleoprotein (hnRNP) A1 protein expressions. Conclusion: These results suggest that there are herbs or herb-related compounds that could modify the alternative splicing of the ATP7B gene via a mechanism that regulates pre-mRNA splicing. C1 [Lin, Ying-Ju; Lin, Ting-Hsu; Hsu, Wei-Yi; Huang, Shao-Mei; Liao, Chiu-Chu; Tsai, Fuu-Jen] China Med Univ Hosp, Dept Med Res, Genet Ctr, Taichung 404, Taiwan. [Lin, Ying-Ju; Ho, Tsung-Jung; Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung 404, Taiwan. [Ho, Tsung-Jung] China Med Univ, Beigang Hosp, Div Chinese Med, Peikang 651, Yunlin County, Taiwan. [Ho, Tsung-Jung] China Med Univ, Tainan Manicipal An Nan Hosp, Div Chinese Med, Tainan 709, Taiwan. [Lai, Chih-Ho] China Med Univ, Sch Med, Dept Microbiol, Taichung 404, Taiwan. [Liu, Xiang; Tsang, Hsinyi] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lai, Chien-Chen] Natl Chung Hsing Univ, Inst Mol Biol, Taichung 402, Taiwan. [Tsai, Fuu-Jen] Asia Univ, Dept Biotechnol, Taichung 413, Taiwan. RP Lai, CC (reprint author), China Med Univ Hosp, Dept Med Res, 2 Yuh Rd, Taichung 404, Taiwan. EM lailai@dragon.nchu.edu.tw; d0704@mail.cmuh.org.tw RI Liu, Xiang/F-5731-2014; Tsai, Fuu-Jen/J-4140-2015 NR 30 TC 2 Z9 2 U1 0 U2 5 PU CHINA MEDICAL UNIV-CMU PI TAICHUNG PA NO 91, HSUEH-SHIH RE, TAICHUNG, 40402, TAIWAN SN 2211-8020 EI 2211-8039 J9 BIOMEDICINE-TAIWAN JI BioMedicine-Taiwan PD JUN PY 2015 VL 5 IS 2 BP 22 EP 30 DI 10.7603/s40681-015-0010-0 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DO6HL UT WOS:000377883800004 PM 26048696 ER PT J AU Arai, AE AF Arai, Andrew E. TI New Insights from Major Prospective Cohort Studies with Cardiovascular Magnetic Resonance (CMR) SO CURRENT CARDIOLOGY REPORTS LA English DT Review DE MRI (magnetic resonance imaging); Cardiovascular; Epidemiology; Myocardial infarction; Cardiomyopathy; Left ventricular hypertrophy ID LEFT-VENTRICULAR HYPERTROPHY; PROATRIAL NATRIURETIC PEPTIDE; INCIDENT HEART-FAILURE; SERUM CYSTATIN-C; ATHEROSCLEROSIS MESA; MYOCARDIAL-PERFUSION; ASYMPTOMATIC ADULTS; ATRIAL-FIBRILLATION; BLOOD-PRESSURE; RISK AB Since 1948, epidemiology studies played an important role in understanding cardiovascular disease and afforded an opportunity to learn about newer diagnostic tests. In 2000, the MESA Study incorporated several advanced cardiovascular imaging modalities including cardiac magnetic resonance imaging (MRI) and coronary artery calciumscans. The decade of follow-up enabled prognosis studies, an important step beyond association studies. In brief, left ventricular hypertrophy by cardiac MRI predicted incident heart failure and stroke. In the MESA Study, coronary artery calcium was a better predictor of coronary artery disease end points than the non-contrast-enhanced MRI scan. In the ICELAND MI substudy of the AGES-Reykjavik Study, a contrast-enhanced MRI scan detected many more unrecognized myocardial infarctions (MIs) (UMIs) than detected by electrocardiography and documented these UMI had adverse prognostic significance. Thus, cardiac MRI has been successfully incorporated into large population studies and shown added value over conventional measurements of cardiovascular disease. C1 [Arai, Andrew E.] NHLBI, NIH, US Dept HHS, Bldg 10,Rm B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, NIH, US Dept HHS, Bldg 10,Rm B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov FU Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA [ZIA HL004607-16, ZIA HL004607-17] FX This work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, 20892-1061 USA [ZIA HL004607-16 and ZIA HL004607-17]. NR 50 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD JUN PY 2015 VL 17 IS 6 AR 46 DI 10.1007/s11886-015-0599-3 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DN6DY UT WOS:000377163500002 PM 25939757 ER PT J AU Figg, WD Thompson, IM AF Figg, William D. Thompson, Ian M. TI Effect of 5 alpha-Reductase Inhibitor Use on Mortality From Prostate Cancer SO JAMA ONCOLOGY LA English DT Editorial Material ID PREVENTION TRIAL; FINASTERIDE; SENSITIVITY C1 [Figg, William D.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. RP Figg, WD (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU NCI NIH HHS [UG1 CA189974, U10 CA037429, UM1 CA182883] NR 10 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA EI 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUN PY 2015 VL 1 IS 3 BP 321 EP 322 DI 10.1001/jamaoncol.2015.0408 PG 2 WC Oncology SC Oncology GA DW5FQ UT WOS:000383669100014 PM 26181178 ER PT J AU Ionescu, DF Nugent, AC Luckenbaugh, DA Niciu, MJ Richards, EM Zarate, CA Furey, ML AF Ionescu, Dawn F. Nugent, Allison C. Luckenbaugh, David A. Niciu, Mark J. Richards, Erica M. Zarate, Carlos A., Jr. Furey, Maura L. TI Baseline working memory activation deficits in dimensional anxious depression as detected by magnetoencephalography SO ACTA NEUROPSYCHIATRICA LA English DT Article DE anxious depression; magnetoencephalography (MEG); major depressive disorder; N-back task; neurobiology ID STAR-ASTERISK-D; NONANXIOUS DEPRESSION; UNIPOLAR DEPRESSION; COGNITIVE THERAPY; MAJOR DEPRESSION; DISORDER; BRAIN; OUTPATIENTS; TASK; IMPROVEMENT AB Objective Anxiety often co-occurs with major depressive disorder (MDD). This preliminary study sought to ascertain the extent to which anxious depression drives group neurobiological differences between patients with MDD and healthy volunteers (HVs). Methods Magnetoencephalography beta-band frequency was used to compare differences in brain response during the N-back working memory task between 30 medication-free patients with treatment-resistant MDD (anxious depression=18; nonanxious depression=12) and 28 HVs. Results Compared to HVs, patients with anxious depression had significantly reduced desynchronisation (less activation) in the left precuneus, right cuneus, and left insula extending into the inferior and middle frontal cortex during the 2-back condition compared with the 1-back condition of the N-back working memory task - indicating less activation of these neural networks in patients with anxious depression during the condition with the highest level of task demands. No other significant group differences were found during the working memory conditions. Conclusion This preliminary study suggests that a subset of patients - those with anxious depression - may be driving observed group differences between patients with MDD and HVs. Further neurobiological studies and replication experiments are necessary to determine the extent to which this subgroup has preferentially influenced our understanding of the underlying neurobiology of depression. C1 [Ionescu, Dawn F.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ionescu, Dawn F.] Harvard Univ, Sch Med, Boston, MA USA. [Nugent, Allison C.; Luckenbaugh, David A.; Niciu, Mark J.; Richards, Erica M.; Zarate, Carlos A., Jr.; Furey, Maura L.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ionescu, DF (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 1 Bowdoin Sq,Floor 6, Boston, MA 02114 USA. EM dionescu@mgh.harvard.edu RI Niciu, Mark/J-1766-2014; Ionescu, Dawn/K-5675-2015; OI Niciu, Mark/0000-0002-5612-3021; Nugent, Allison/0000-0003-2569-2480 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); NARSAD; Brain & Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), by a NARSAD Independent Investigator to C.A.Z., and by the Brain & Behavior Mood Disorders Research Award to C.A.Z. Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. Dr. Furey is listed as a co-inventor on a patent application for the use of scopolamine in psychiatric disorders. Dr. Furey has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. The remaining authors have no conflicts of interest to disclose, financial, or otherwise. NR 40 TC 0 Z9 0 U1 1 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1601-5215 J9 ACTA NEUROPSYCHIATR JI Acta Neuropsychiatr. PD JUN PY 2015 VL 27 IS 3 BP 143 EP 152 DI 10.1017/neu.2014.46 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CH9YC UT WOS:000354391600002 PM 25600154 ER PT J AU Kaburu, SSK Newton-Fisher, NE AF Kaburu, Stefano S. K. Newton-Fisher, Nicholas E. TI Trading or coercion? Variation in male mating strategies between two communities of East African chimpanzees SO BEHAVIORAL ECOLOGY AND SOCIOBIOLOGY LA English DT Article DE Pan troglodytes; Mating strategy; Social grooming; Aggression; Dominance rank; Biological market theory ID PAN-TROGLODYTES-SCHWEINFURTHII; KIBALE-NATIONAL-PARK; WILD MALE CHIMPANZEES; FEMALE MATE CHOICE; CAPTIVE CHIMPANZEES; JAPANESE MACAQUES; NUPTIAL GIFTS; REPRODUCTIVE STRATEGIES; GROOMING RECIPROCITY; MAHALE CHIMPANZEES AB Across taxa, males employ a variety of mating strategies, including sexual coercion and the provision, or trading, of resources. Biological market theory (BMT) predicts that trading of commodities for mating opportunities should exist only when males cannot monopolize access to females and/or obtain mating by force, in situations where power differentials between males are low; both coercion and trading have been reported for chimpanzees (Pan troglodytes). Here, we investigate whether the choice of strategy depends on the variation in male power differentials, using data from two wild communities of East African chimpanzees (Pan troglodytes schweinfurthii): the structurally despotic Sonso community (Budongo, Uganda) and the structurally egalitarian M-group (Mahale, Tanzania). We found evidence of sexual coercion by male Sonso chimpanzees, and of trading-of grooming for mating-by M-group males; females traded sex for neither meat nor protection from male aggression. Our results suggest that the despotism-egalitarian axis influences strategy choice: male chimpanzees appear to pursue sexual coercion when power differentials are large and trading when power differentials are small and coercion consequently ineffective. Our findings demonstrate that trading and coercive strategies are not restricted to particular chimpanzee subspecies; instead, their occurrence is consistent with BMT predictions. Our study raises interesting, and as yet unanswered, questions regarding female chimpanzees' willingness to trade sex for grooming, if doing so represents a compromise to their fundamentally promiscuous mating strategy. It highlights the importance of within-species cross-group comparisons and the need for further study of the relationship between mating strategy and dominance steepness. C1 [Kaburu, Stefano S. K.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Kaburu, Stefano S. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, Poolesville, MD 20842 USA. [Newton-Fisher, Nicholas E.] Univ Kent, Sch Anthropol & Conservat, Canterbury CT2 7NR, Kent, England. RP Kaburu, SSK (reprint author), Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. EM stefano.kaburu@nih.gov OI Newton-Fisher, Nicholas/0000-0002-7657-2641 FU Wenner-Gren foundation [8216]; Leverhulme Trust [F/00236/Z]; H.F. Guggenheim Foundation FX This work was funded by the Wenner-Gren foundation (grant no. 8216), the Leverhulme Trust (grant no. F/00236/Z) and the H.F. Guggenheim Foundation. We thank the Uganda National Council for Science and Technology, the President's Office, the Forest Department, and Vernon Reynolds for granting permission to work in the Budongo forest and the Tanzania Commission for Science and Technology, the Tanzania Wildlife Research Institute and the Mahale Mountains Wildlife Research Centre for allowing research in the Mahale Mountains National Park. We are also very grateful to Geresomu Muhumuza and the other Ugandan and Tanzanian field assistants for their fundamental help during data collection both in Budongo and Mahale. Finally, we would like to thank Robin Dunbar and two anonymous reviewers for insightful comments on a previous draft of the article. NR 110 TC 8 Z9 8 U1 8 U2 28 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-5443 EI 1432-0762 J9 BEHAV ECOL SOCIOBIOL JI Behav. Ecol. Sociobiol. PD JUN PY 2015 VL 69 IS 6 BP 1039 EP 1052 DI 10.1007/s00265-015-1917-x PG 14 WC Behavioral Sciences; Ecology; Zoology SC Behavioral Sciences; Environmental Sciences & Ecology; Zoology GA CH7OR UT WOS:000354227000018 PM 26279605 ER PT J AU Wertheimer, A AF Wertheimer, Alan TI The Social Value Requirement Reconsidered SO BIOETHICS LA English DT Article DE social value; exploitation; research ethics ID BENEFIT AB It is widely assumed that it is ethical to conduct research with human subjects only if the research has social value. There are two standard arguments for this view. The allocation argument claims that public funds should not be devoted to research that lacks social value. The exploitation avoidance argument claims that subjects are exploited if research has no social value. The primary purpose of this article is to argue that these arguments do not succeed. The allocation argument has little relevance to commercial research. Social value is not necessary to avoid exploitation if subjects benefit from participation. Although the standard arguments for a social value requirement do not succeed, that view might be justified in a different way. It might be justified by appeal to the importance of social trust or the integrity of physician investigators. It is possible but doubtful that these arguments succeed. C1 [Wertheimer, Alan] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Wertheimer, Alan] Univ Vermont, Polit Sci, Burlington, VT 05405 USA. RP Wertheimer, A (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM wertheimera@cc.nih.gov FU NIH; Warren G. Magnuson Clinical Center FX The Intramural Research Program of the NIH and the Warren G. Magnuson Clinical Center supported this research. The views expressed here are those of the author. They do not represent any position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. The author also thanks several colleagues for their comments on drafts of this article: Seema Shah, Franklin Miller, and David Wendler. NR 16 TC 8 Z9 8 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD JUN PY 2015 VL 29 IS 5 BP 301 EP 308 DI 10.1111/bioe.12128 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA CH8JK UT WOS:000354282400002 PM 25470450 ER PT J AU Dawson, L Zwerski, S AF Dawson, Liza Zwerski, Sheryl TI Clinical Trial Design for HIV Prevention Research: Determining Standards of Prevention SO BIOETHICS LA English DT Article DE standard of care; researchers' obligations; HIV prevention; clinical trials; biomedical research; low and middle income countries ID CHALLENGES; INTERVENTIONS; COMMUNITY; EQUIPOISE; PREP AB This article seeks to advance ethical dialogue on choosing standards of prevention in clinical trials testing improved biomedical prevention methods for HIV. The stakes in this area of research are high, given the continued high rates of infection in many countries and the budget limitations that have constrained efforts to expand treatment for all who are currently HIV-infected. New prevention methods are still needed; at the same time, some existing prevention and treatment interventions have been proven effective but are not yet widely available in the countries where they most urgently needed. The ethical tensions in this field of clinical research are well known and have been the subject of extensive debate. There is no single clinical trial design that can optimize all the ethically important goals and commitments involved in research. Several recent articles have described the current ethical difficulties in designing HIV prevention trials, especially in resource limited settings; however, there is no consensus on how to handle clinical trial design decisions, and existing international ethical guidelines offer conflicting advice. This article acknowledges these deep ethical dilemmas and moves beyond a simple descriptive approach to advance an organized method for considering what clinical trial designs will be ethically acceptable for HIV prevention trials, balancing the relevant criteria and providing justification for specific design decisions. C1 [Dawson, Liza] NIAID, Res Eth, Div Aids, NIH, Bethesda, MD 20892 USA. [Dawson, Liza] NIH, Bioeth & Human Res Protect, Bethesda, MD USA. [Dawson, Liza] Johns Hopkins Univ, Sch Publ Hlth, Bioeth Inst, Baltimore, MD 21218 USA. [Dawson, Liza] Natl Bioeth Advisory Commiss, Rockville, MD USA. [Zwerski, Sheryl] NIAID, Prevent Sci Program, Div Aids, Bethesda, MD 20892 USA. [Zwerski, Sheryl] NIAID, Bethesda, MD 20892 USA. [Zwerski, Sheryl] NCI, Pediat Branch, Bethesda, MD 20892 USA. [Zwerski, Sheryl] Univ Florida, Pediat Immunol Div, Gainesville, FL 32611 USA. RP Dawson, L (reprint author), NIAID, NIH, Div Aids, 5601 Fishers Lane,Room 9G59, Bethesda, MD 20892 USA. EM dawsonl@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 23 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD JUN PY 2015 VL 29 IS 5 BP 316 EP 323 DI 10.1111/bioe.12113 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA CH8JK UT WOS:000354282400004 PM 25230397 ER PT J AU Medina, SH Li, S Howard, OMZ Dunlap, M Trivett, A Schneider, JP Oppenheim, JJ AF Medina, Scott H. Li, Sandra Howard, O. M. Zack Dunlap, Micah Trivett, Anna Schneider, Joel P. Oppenheim, Joost J. TI Enhanced immunostimulatory effects of DNA-encapsulated peptide hydrogels SO BIOMATERIALS LA English DT Article DE DNA; Peptide; Drug delivery; Self assembly; Gene expression ID GENE DELIVERY; RESPONSIVE HYDROGELS; ANTIGEN PRESENTATION; IMMUNE-RESPONSES; IN-VITRO; VACCINES; RELEASE; SYSTEMS; PROTEIN; DESIGN AB DNA that encodes 'tumor-specific antigens represents potential immunostimulatory agents. However, rapid enzymatic degradation and fragmentation of DNA during administration can result in limited vector expression and, consequently, poor efficacy. These challenges have necessitated the use of novel strategies for DNA delivery. Herein, we study the ability of cationic self-assembling peptide hydrogels to encapsulate plasmid DNA, and enhance its immunostimulatory potential in vivo. The effect of network charge on the gel's ability to retain the DNA was assessed employing three gel-forming peptides that vary systematically in formal charge. The peptide HLT2, having a formal charge of +5 at neutral pH, was optimal in encapsulating microgram quantities of DNA with little effect on its rheological properties, allowing its effective syringe delivery in vivo. The plasmid, DNA(TA), encapsulated within these gels encodes for a melanoma-specific gp100 antigen fused to the alarmin protein adjuvant HMGN1. Implantation of DNA(TA)-loaded HLT2 gels into mice resulted in an acute inflammatory response with the presence of polymorphonuclear cells, which was followed by infiltrating macrophages. These cellular infiltrates aid in the processing of encapsulated DNA, promoting increased lymphoproliferation and producing an enhanced immune response mediated by CD4+/IFN gamma+ expressing Th1 cells, and complemented by the formation of gp100-specific antibodies. Published by Elsevier Ltd. C1 [Medina, Scott H.; Schneider, Joel P.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. [Li, Sandra; Howard, O. M. Zack; Dunlap, Micah; Trivett, Anna; Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. EM Joel.Schneider@nih.gov; oppenheJ@mail.nih.gov RI Schneider, Joel/N-2610-2014 FU National Cancer Institute, National Institutes of Health FX S.H.M. and S.L. contributed equally to this work. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. We thank the core staff at the Pathology/Histotechnology Laboratory (NCI) for their assistance in the processing of histology and immunohistochemistry samples. NR 40 TC 7 Z9 7 U1 8 U2 68 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD JUN PY 2015 VL 53 BP 545 EP 553 DI 10.1016/j.biomaterials.2015.02.125 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CH3KO UT WOS:000353929800050 PM 25890750 ER PT J AU Tran, PT Kim, HS Ann, J Kim, SE Kim, C Hong, M Hoang, VH Ngo, VTH Hong, SH Cui, MH Choi, S Blumberg, PM Frank-Foltyn, R Bahrenberg, G Stockhausen, H Christoph, T Lee, J AF Phuong-Thao Tran Kim, Ho Shin Ann, Jihyae Kim, Sung-Eun Kim, Changhoon Hong, Mannkyu Hoang, Van-Hai Ngo, Van T. H. Hong, Sunhye Cui, Minghua Choi, Sun Blumberg, Peter M. Frank-Foltyn, Robert Bahrenberg, Gregor Stockhausen, Hannelore Christoph, Thomas Lee, Jeewoo TI alpha-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE TRPV1 antagonist; Analgesic; Capsaicin; Molecular modeling ID PYRIDINE C-REGION; VANILLOID CAPSAICIN RECEPTORS; ANALGESIC AGENTS; AGONIST ACTIVITY; ANALOGS; 2-(3-FLUORO-4-METHYLSULFONYLAMINOPHENYL)PROPANAMIDES; DERIVATIVES; ACTIVATION AB A series of alpha-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl) propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an alpha-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with K-i(CAP) = 0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Phuong-Thao Tran; Kim, Ho Shin; Ann, Jihyae; Kim, Sung-Eun; Kim, Changhoon; Hong, Mannkyu; Hoang, Van-Hai; Ngo, Van T. H.; Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. [Hong, Sunhye; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 120750, South Korea. [Hong, Sunhye; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Global Top Res Program 5, Seoul 120750, South Korea. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. RP Lee, J (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Grunenthal in Germany; Korea Science and Engineering Foundation (KOSEF) [NRF-2014M3A9B5073755]; National Leading Research Lab (NLRL) program in South Korea [2011-0028885]; Intramural Research Program of NIH, Center for Cancer Research, NCI in USA [Z1A BC 005270] FX This research was supported by Research Grants from Grunenthal in Germany, Grants from the Korea Science and Engineering Foundation (KOSEF) (NRF-2014M3A9B5073755) and National Leading Research Lab (NLRL) program (2011-0028885) in South Korea, and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270) in USA. NR 29 TC 2 Z9 2 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 1 PY 2015 VL 25 IS 11 BP 2326 EP 2330 DI 10.1016/j.bmcl.2015.04.024 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CH5ZR UT WOS:000354115400012 PM 25937016 ER PT J AU Cross, JL Iben, J Simpson, CL Thurm, A Swedo, S Tierney, E Bailey-Wilson, JE Biesecker, LG Porter, FD Wassif, CA AF Cross, J. L. Iben, J. Simpson, C. L. Thurm, A. Swedo, S. Tierney, E. Bailey-Wilson, J. E. Biesecker, L. G. Porter, F. D. Wassif, C. A. TI Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets SO CLINICAL GENETICS LA English DT Article DE allelic frequency; DHCR7; next generation sequencing; SLOS; Smith-Lemli-Opitz ID DHCR7; CHOLESTEROL; MUTATIONS AB Data from massively parallel sequencing or Next Generation Sequencing' of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7-dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening. C1 [Cross, J. L.; Iben, J.; Porter, F. D.; Wassif, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Simpson, C. L.; Bailey-Wilson, J. E.] NHGRI, Stat Genet Sect, Computat & Stat Genom Branch, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Thurm, A.; Swedo, S.] NIMH, Pediat & Dev Neurosci Branch, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Tierney, E.] Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD USA. [Biesecker, L. G.] NHGRI, Med Genom & Metab Genet Branch, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Wassif, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Univ Oxford Res Associate, NIH, 9000 Rockville Pike Bldg CRC Room 1E-3288, Bethesda, MD 20892 USA. EM wassifc@mail.nih.gov OI Simpson, Claire/0000-0003-2244-7690; Cross, Joanna/0000-0003-2323-7142; Bailey-Wilson, Joan/0000-0002-9153-2920; Wassif, Christopher/0000-0002-2524-1420 FU NIH intramural research program, DHHS; Wellcome Trust [BWRXEN00]; Autism Speaks FX J. L. C., J. I., C.L., A. T., S. S., J.E.B-W., L. G. B., F. D. P., and C. A. W. are all funded by the NIH intramural research program, DHHS. J. L. C. receives funding from the Wellcome Trust [BWRXEN00] E. T. is funded by Autism Speaks. NR 19 TC 10 Z9 10 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD JUN PY 2015 VL 87 IS 6 SI SI BP 570 EP 575 DI 10.1111/cge.12425 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA CH7YH UT WOS:000354252200012 PM 24813812 ER PT J AU Dimond, EP St Germain, D Nacpil, LM Zaren, HA Swanson, SM Minnick, C Carrigan, A Denicoff, AM Igo, KE Acoba, JD Gonzalez, MM McCaskill-Stevens, W AF Dimond, Eileen P. St Germain, Diane Nacpil, Lianne M. Zaren, Howard A. Swanson, Sandra M. Minnick, Christopher Carrigan, Angela Denicoff, Andrea M. Igo, Kathleen E. Acoba, Jared D. Gonzalez, Maria M. McCaskill-Stevens, Worta TI Creating a "culture of research'' in a community hospital: Strategies and tools from the National Cancer Institute Community Cancer Centers Program SO CLINICAL TRIALS LA English DT Article DE Clinical trials; community; culture of research; community hospital research; National Cancer Institute Community Cancer Centers Program ID CLINICAL ONCOLOGY PROGRAM; TRIALS; PARTICIPATION; SITES AB Background The value of community-based cancer research has long been recognized. In addition to the National Cancer Institute's Community Clinical and Minority-Based Oncology Programs established in 1983, and 1991 respectively, the National Cancer Institute established the National Cancer Institute Community Cancer Centers Program in 2007 with an aim of enhancing access to high-quality cancer care and clinical research in the community setting where most cancer patients receive their treatment. This article discusses strategies utilized by the National Cancer Institute Community Cancer Centers Program to build research capacity and create a more entrenched culture of research at the community hospitals participating in the program over a 7-year period. Methods To facilitate development of a research culture at the community hospitals, the National Cancer Institute Community Cancer Centers Program required leadership or chief executive officer engagement; utilized a collaborative learning structure where best practices, successes, and challenges could be shared; promoted site-to-site mentoring to foster faster learning within and between sites; required research program assessments that spanned clinical trial portfolio, accrual barriers, and outreach; increased identification and use of metrics; and, finally, encouraged research team engagement across hospital departments (navigation, multidisciplinary care, pathology, and disparities) to replace the traditionally siloed approach to clinical trials. Limitations The health-care environment is rapidly changing while complexity in research increases. Successful research efforts are impacted by numerous factors (e.g. institutional review board reviews, physician interest, and trial availability). The National Cancer Institute Community Cancer Centers Program sites, as program participants, had access to the required resources and support to develop and implement the strategies described. Metrics are an important component yet often challenging to identify and collect. The model requires a strong emphasis on outreach that challenges hospitals to improve and expand their reach, particularly into underrepresented populations and catchment areas. These efforts build on trust and a referral pipeline within the community which take time and significant commitment to establish. Conclusion The National Cancer Institute Community Cancer Centers Program experience provides a relevant model to broadly address creating a culture of research in community hospitals that are increasingly networked via systems and consortiums. The strategies used align well with the National Cancer InstituteAmerican Society of Clinical Oncology Accrual Symposium recommendations for patient-/community-, physician-/provider-, and site-/organizational-level approaches to clinical trials; they helped sites achieve organizational culture shifts that enhanced their cancer research programs. The National Cancer Institute Community Cancer Centers Program hospitals reported that the strategies were challenging to implement yet proved valuable as they provided useful metrics for programmatic assessment, planning, reporting, and growth. While focused on oncology trials, these concepts may be useful within other disease-focused research as well. C1 [Dimond, Eileen P.; St Germain, Diane; McCaskill-Stevens, Worta] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Nacpil, Lianne M.; Gonzalez, Maria M.] St Joseph Hosp, Orange, CA USA. [Zaren, Howard A.] St Josephs Candler, Savannah, GA USA. [Swanson, Sandra M.] Mercy Med Ctr, Des Moines, IA USA. [Minnick, Christopher] Albert Einstein Healthcare Network, Philadelphia, PA USA. [Carrigan, Angela; Igo, Kathleen E.] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Denicoff, Andrea M.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Acoba, Jared D.] Queens Med Ctr, Honolulu, HI USA. [Gonzalez, Maria M.] Providence St Joseph Med Ctr, Roy & Patricia Disney Family Canc Ctr, Burbank, CA USA. RP Dimond, EP (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM dimonde@mail.nih.gov FU Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health (Contract No. HHSN261200800001E). NR 42 TC 5 Z9 5 U1 2 U2 11 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 JUN PY 2015 VL 12 IS 3 BP 246 EP 256 DI 10.1177/1740774515571141 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CH4EC UT WOS:000353984100009 PM 25691600 ER PT J AU Remy, KE Natanson, C Klein, HG AF Remy, Kenneth E. Natanson, Charles Klein, Harvey G. TI The influence of the storage lesion(s) on pediatric red cell transfusion SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE cell-free hemoglobin; critical care; red blood cell; storage lesion; transfusion ID CARDIAC-SURGERY PATIENTS; CRITICALLY-ILL PATIENTS; TRANSFERRIN-BOUND IRON; OLDER STORED-BLOOD; LUNG INJURY TRALI; OVINE MODEL; PROLONGED STORAGE; RANDOMIZED-TRIAL; FREE HEMOGLOBIN; AFFECT OUTCOMES AB Purpose of review This article will analyze and evaluate the current evidence regarding the use of older, longer-stored red blood cells (RBCs) for trans fusion in pediatric patients and will examine some of the postulated mechanisms of injury related to prolonged refrigerated storage of RBCs and studies reporting clinical outcomes. Recent findings Three randomized controlled trials and seven observational studies have been conducted entirely in pediatric patients. The outcomes, mortality and morbidity in critically ill patients and children undergoing cardiac surgery, and necrotizing enterocolitis in premature infants, have been inconsistent. However, many of these studies have been confounded by study design, mixed patient populations, red cell preparation, and other factors. Summary Further exploration into the possible deleterious effects of older, longer-stored RBC transfusions on mortality and morbidity in different pediatric populations is merited. Understanding the potential mechanisms of injury should help explain the clinical findings. C1 [Remy, Kenneth E.] Washington Univ, Sch Med, Div Pediat Crit Care Med, Dept Pediat, St Louis, MO 63110 USA. [Remy, Kenneth E.; Natanson, Charles] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Klein, Harvey G.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Remy, KE (reprint author), Washington Univ, Sch Med, Div Pediat Crit Care, Dept Pediat, 660 S Euclid Ave, St Louis, MO 63110 USA. EM Remy_k@kids.wustl.edu NR 72 TC 2 Z9 2 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD JUN PY 2015 VL 27 IS 3 BP 277 EP 285 DI 10.1097/MOP.0000000000000224 PG 9 WC Pediatrics SC Pediatrics GA CH7KJ UT WOS:000354214800002 PM 25888156 ER PT J AU Donahue, R Metzger, M Bonifacino, A Parker, D Leitman, S Cullis, H Lienesch, M AF Donahue, R. Metzger, M. Bonifacino, A. Parker, D. Leitman, S. Cullis, H. Lienesch, M. TI OPTIMIZATION OF THE SPECTRA OPTIA FOR LEUKAPHERESIS OF VERY SMALL SUBJECTS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Donahue, R.; Metzger, M.; Bonifacino, A.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Parker, D.; Lienesch, M.] Terumo BCT Inc, Lakewood, CO USA. [Leitman, S.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2015 VL 17 IS 6 SU S MA 273 BP S79 EP S80 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 CH6JK UT WOS:000354142700252 ER PT J AU Frank, JA Nguyen, B Bresler, M Milo, B Kim, S Burks, S AF Frank, J. A. Nguyen, B. Bresler, M. Milo, B. Kim, S. Burks, S. TI ENHANCED STEM CELL AND PROGENITOR CELL HOMING FOLLOWING IV INJECTION TO SKELETAL MUSCLE IN A MURINE MODEL OF MUSCULAR DYSTROPHY INDUCED BY PULSED FOCUSED ULTRASOUND (pFUS) SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Frank, J. A.; Nguyen, B.; Bresler, M.; Milo, B.; Kim, S.; Burks, S.] NIH, Frank Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2015 VL 17 IS 6 SU S MA 29 BP S15 EP S15 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CH6JK UT WOS:000354142700031 ER PT J AU Hanley, P Melenhorst, J Cruz, R Martinez, C Heslop, H Barrett, J Shpall, EJ Bollard, C AF Hanley, P. Melenhorst, J. Cruz, R. Martinez, C. Heslop, H. Barrett, J. Shpall, E. J. Bollard, C. TI CMVpp65-SPECIFIC T CELLS GENERATED FROM NAIVE T CELL POPULATIONS RECOGNIZE ATYPICAL BUT NOT CANONICAL EPITOPES AND MAY BE PROTECTIVE IN VIVO SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Hanley, P.; Cruz, R.; Bollard, C.] Childrens Natl Med Ctr, Program Cell Enhancement & Technol Immunotherapy, Washington, DC 20010 USA. [Melenhorst, J.] Univ Penn, Philadelphia, PA 19104 USA. [Martinez, C.; Heslop, H.] BCm, Houston, TX USA. [Barrett, J.] NIH, Bethesda, MD 20892 USA. [Shpall, E. J.] MDACC, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2015 VL 17 IS 6 SU S MA 10 BP S9 EP S10 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 CH6JK UT WOS:000354142700012 ER PT J AU Lin, Y Atwell, T Weisbrod, A Maas, M Armstrong, A Deeds, M Bulur, P Gustafson, M Zhang, Z Cordes, S Porrata, L Markovic, S Johnston, P Micallef, I Inwards, D Colgan, J Ansell, S Gastineau, D Dietz, A Witzig, T AF Lin, Y. Atwell, T. Weisbrod, A. Maas, M. Armstrong, A. Deeds, M. Bulur, P. Gustafson, M. Zhang, Z. Cordes, S. Porrata, L. Markovic, S. Johnston, P. Micallef, I. Inwards, D. Colgan, J. Ansell, S. Gastineau, D. Dietz, A. Witzig, T. TI DENDRITIC CELL VACCINE TREATMENT FOR INDOLENT B-CELL NON-HODGKIN LYMPHOMA: CLINICAL TRIAL IN PROGRESS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Lin, Y.; Atwell, T.; Weisbrod, A.; Maas, M.; Armstrong, A.; Deeds, M.; Bulur, P.; Gustafson, M.; Zhang, Z.; Porrata, L.; Markovic, S.; Johnston, P.; Micallef, I.; Inwards, D.; Colgan, J.; Ansell, S.; Gastineau, D.; Dietz, A.; Witzig, T.] Mayo Clin, Rochester, MN USA. [Cordes, S.] NIH, Bethesda, MD 20892 USA. RI Dietz, Allan/H-7414-2015; Gustafson, Michael/H-4056-2011 OI Dietz, Allan/0000-0003-3410-9621; Gustafson, Michael/0000-0002-5514-7072 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2015 VL 17 IS 6 SU S MA 35 BP S17 EP S17 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CH6JK UT WOS:000354142700037 ER PT J AU Lu, K West, K Buckler, A Tian, X Cantilena, C Anandi, P Dunavin, N Jain, N Barrett, J Battiwalla, M AF Lu, K. West, K. Buckler, A. Tian, X. Cantilena, C. Anandi, P. Dunavin, N. Jain, N. Barrett, J. Battiwalla, M. TI CLINICAL AND LABORATORY PREDICTORS IMPACTING ALLOGENEIC PERIPHERAL BLOOD STEM CELL MOBILIZATION SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Lu, K.; Anandi, P.; Dunavin, N.; Jain, N.; Barrett, J.; Battiwalla, M.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [West, K.; Buckler, A.; Cantilena, C.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Tian, X.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2015 VL 17 IS 6 SU S MA 220 BP S66 EP S66 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CH6JK UT WOS:000354142700203 ER PT J AU Stroncek, D Jin, P Reems, JA Cancelas, J Nayak, R Shaw, G O'Brien, T McKenna, D Armant, M Silberstein, L Gee, A Hei, D Hematti, P Civini, S Sabatino, M Robey, P AF Stroncek, D. Jin, P. Reems, J-A Cancelas, J. Nayak, R. Shaw, G. O'Brien, T. McKenna, D., Jr. Armant, M. Silberstein, L. Gee, A. Hei, D. Hematti, P. Civini, S. Sabatino, M. Robey, P. TI COMPARISON OF BONE MARROW STROMAL CELL (BMSC) PRODUCTION METHODS AND PRODUCTS FROM MULTIPLE CENTERS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Stroncek, D.; Jin, P.; Civini, S.; Sabatino, M.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Reems, J-A] Univ Utah, Cell Therapy & Regenerat Med, Salt Lake City, UT USA. [Cancelas, J.; Nayak, R.] Univ Cincinnati, Hoxworth Blood Ctr, Cincinnati, OH USA. [Cancelas, J.; Nayak, R.] Univ Cincinnati, Dept Pediat, Cincinnati, OH USA. [Shaw, G.; O'Brien, T.] Natl Univ Ireland Galway, Natl Ctr Biomed Engn & Sci, Regenerat Med Inst, Galway, Ireland. [McKenna, D., Jr.] Univ Minnesota, Mol & Cellular Therapeut, Minneapolis, MN USA. [Armant, M.; Silberstein, L.] Boston Childrens Hosp, Ctr Human Cell Therapy, Programs Cellular & Mol Med, Boston, MA USA. [Gee, A.] Methodist Hosp, Texas Childrens Hosp, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Gee, A.] Baylor Coll Med, Houston, TX 77030 USA. [Hei, D.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Hematti, P.] Univ Wisconsin, Dept Internal Med, Madison, WI USA. [Robey, P.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2015 VL 17 IS 6 SU S MA 175 BP S51 EP S51 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CH6JK UT WOS:000354142700160 ER PT J AU Bao, W Yeung, E Tobias, DK Hu, FB Vaag, AA Chavarro, JE Mills, JL Grunnet, LG Bowers, K Ley, SH Kiely, M Olsen, S Zhang, CL AF Bao, Wei Yeung, Edwina Tobias, Deirdre K. Hu, Frank B. Vaag, Allan A. Chavarro, Jorge E. Mills, James L. Grunnet, Louise G. Bowers, Katherine Ley, Sylvia H. Kiely, Michele Olsen, Sjurdur F. Zhang, Cuilin TI Long-term risk of type 2 diabetes mellitus in relation to BMI and weight change among women with a history of gestational diabetes mellitus: a prospective cohort study SO DIABETOLOGIA LA English DT Article DE BMI; Gestational diabetesmellitus; Type 2 diabetes mellitus; Weight change ID BODY-MASS INDEX; FOOD FREQUENCY QUESTIONNAIRE; LIFE-STYLE INTERVENTION; PHYSICAL-ACTIVITY; GLUCOSE-INTOLERANCE; WAIST CIRCUMFERENCE; FOLLOW-UP; PREGNANCY; DETERMINANTS; METAANALYSIS AB Aims/hypothesis Women with a history of gestational diabetes mellitus (GDM) are advised to control their weight after pregnancy. We aimed to examine how adiposity and weight change influence the long-term risk of developing type 2 diabetes after GDM. Methods We included 1,695 women who had incident GDM between 1991 and 2001, as part of the Diabetes & Women's Health study, and followed them until the return of the 2009 questionnaire. Body weight and incident type 2 diabetic cases were reported biennially. We defined baseline as the questionnaire period when women reported an incident GDM pregnancy. We estimated HRs and 95% CIs using Cox proportional hazards models. Results We documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. The adjusted HRs of type 2 diabetes associated with each 1 kg/m(2) increase in BMI were 1.16 (95% CI 1.12, 1.19) for baseline BMI and 1.16 (95% CI 1.13, 1.20) for most recent BMI. Moreover, each 5 kg increment of weight gain after GDM development was associated with a 27% higher risk of type 2 diabetes (adjusted HR 1.27; 95% CI 1.04, 1.54). Jointly, women who had a BMI >= 30.0 kg/m(2) at baseline and gained >= 5 kg after GDM had an adjusted HR of 43.19 (95% CI 13.60, 137.11), compared with women who had a BMI <25.0 kg/m(2) at baseline and gained <5 kg after GDM. Conclusions/interpretation Baseline BMI, most recent BMI and weight gain after GDM were significantly and positively associated with risk of progression from GDM to type 2 diabetes. C1 [Bao, Wei; Yeung, Edwina; Mills, James L.; Kiely, Michele; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Tobias, Deirdre K.; Hu, Frank B.; Chavarro, Jorge E.; Ley, Sylvia H.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tobias, Deirdre K.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Tobias, Deirdre K.] Harvard Univ, Sch Med, Boston, MA USA. [Hu, Frank B.; Chavarro, Jorge E.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hu, Frank B.; Chavarro, Jorge E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Hu, Frank B.; Chavarro, Jorge E.] Harvard Univ, Sch Med, Boston, MA USA. [Vaag, Allan A.; Grunnet, Louise G.] Rigshosp, Dept Endocrinol, DK-2100 Copenhagen, Denmark. [Bowers, Katherine] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Olsen, Sjurdur F.] Statens Serum Inst, Dept Epidemiol Res, Ctr Fetal Programming, DK-2300 Copenhagen, Denmark. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275201000020C]; National Institutes of Health [DK58845, CA50385, P30 DK46200, UM1 CA176726]; ADA [7-12-MN-34] FX 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 no. HHSN275201000020C). NHS II was funded by research grants DK58845, CA50385, P30 DK46200 and UM1 CA176726 from the National Institutes of Health. DKT was supported by a mentored fellowship from the ADA (no. 7-12-MN-34). NR 44 TC 13 Z9 13 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JUN PY 2015 VL 58 IS 6 BP 1212 EP 1219 DI 10.1007/s00125-015-3537-4 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CH2YX UT WOS:000353893000011 PM 25796371 ER PT J AU Lietman, TM Gebre, T Abdou, A Alemayehu, W Emerson, P Blumberg, S Keenan, JD Porco, TC AF Lietman, Thomas M. Gebre, Teshome Abdou, Amza Alemayehu, Wondu Emerson, Paul Blumberg, Seth Keenan, Jeremy D. Porco, Travis C. TI The distribution of the prevalence of ocular chlamydial infection in communities where trachoma is disappearing SO EPIDEMICS LA English DT Article DE Trachoma; Eradication; Mass drug administration; Transmission model; Geometric distribution ID CLUSTER-RANDOMIZED TRIAL; MASS ANTIBIOTIC DISTRIBUTIONS; QUASI-STATIONARY DISTRIBUTION; AZITHROMYCIN; ELIMINATION; REDUCTION; ETHIOPIA; DISEASE; RETURN; NEPAL AB Mathematical models predict that the prevalence of infection in different communities where an infectious disease is disappearing should approach a geometric distribution. Trachoma programs offer an opportunity to test this hypothesis, as the World Health Organization (WHO) has targeted trachoma to be eliminated as a public health concern by the year 2020. We assess the distribution of the community prevalence of childhood ocular chlamydia infection from periodic, cross-sectional surveys in two areas of Ethiopia. These surveys were taken in a controlled setting, where infection was documented to be disappearing over time. For both sets of surveys, the geometric distribution had the most parsimonious fit of the distributions tested, and goodness-of-fit testing was consistent with the prevalence of each community being drawn from a geometric distribution. When infection is disappearing, the single sufficient parameter describing a geometric distribution captures much of the distributional information found from examining every community. The relatively heavy tail of the geometric suggests that the presence of an occasional high-prevalence community is to be expected, and does not necessarily reflect a transmission hot spot or program failure. A single cross-sectional survey can reveal which direction a program is heading. A geometric distribution of the prevalence of infection across communities may be an encouraging sign, consistent with a disease on its way to eradication. (C) 2015 The Authors. Published by Elsevier B.V. C1 [Lietman, Thomas M.; Alemayehu, Wondu; Blumberg, Seth; Keenan, Jeremy D.; Porco, Travis C.] FI Proctor Fdn, San Francisco, CA USA. [Lietman, Thomas M.; Alemayehu, Wondu; Keenan, Jeremy D.; Porco, Travis C.] Dept Ophthalmol, San Francisco, CA USA. [Lietman, Thomas M.; Alemayehu, Wondu; Porco, Travis C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Gebre, Teshome; Emerson, Paul] Ctr Canc, Atlanta, GA USA. [Abdou, Amza; Alemayehu, Wondu] Programme Natl Lutte Contre La Cecite, Niamey, Niger. [Alemayehu, Wondu; Blumberg, Seth] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Alemayehu, Wondu] Berhan Hlth, Addis Ababa, Ethiopia. RP Lietman, TM (reprint author), Univ Calif San Francisco, FI Proctor Fdn, Room S309 Med Sci,513 Parnassus Ave, San Francisco, CA 94143 USA. EM tom.lietman@ucsf.edu FU NIH NIGMS MIDAS [GM087728]; NEI [U10 EY016214]; NIH-Fogarty International Center RAPIDD Program of the Science and Tenchnology Directorate FX NIH NIGMS MIDAS GM087728, NEI U10 EY016214, NIH-Fogarty International Center RAPIDD Program of the Science and Tenchnology Directorate. NR 31 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD JUN PY 2015 VL 11 BP 85 EP 91 DI 10.1016/j.epidem.2015.03.003 PG 7 WC Infectious Diseases SC Infectious Diseases GA CI0CJ UT WOS:000354403100011 PM 25979286 ER PT J AU Brady, OJ Smith, DL Scott, TW Hay, SI AF Brady, Oliver J. Smith, David L. Scott, Thomas W. Hay, Simon I. TI Dengue disease outbreak definitions are implicitly variable SO EPIDEMICS LA English DT Article DE Outbreak; Response; Dengue; Decision-making; Policy ID PLASMODIUM-FALCIPARUM MALARIA; WEATHER-BASED PREDICTION; EPIDEMIC-PRONE REGIONS; EARLY WARNING SYSTEM; PUBLIC-HEALTH; WESTERN KENYA; VIRUS-DISEASE; PUERTO-RICO; CLIMATE; DETERMINANTS AB Infectious diseases rarely exhibit simple dynamics. Outbreaks (defined as excess cases beyond response capabilities) have the potential to cause a disproportionately high burden due to overwhelming health care systems. The recommendations of international policy guidelines and research agendas are based on a perceived standardised definition of an outbreak characterised by a prolonged, high-caseload, extraseasonal surge. In this analysis we apply multiple candidate outbreak definitions to reported dengue case data from Brazil to test this assumption. The methods identify highly heterogeneous outbreak characteristics in terms of frequency, duration and case burden. All definitions identify outbreaks with characteristics that vary over time and space. Further, definitions differ in their timeliness of outbreak onset, and thus may be more or less suitable for early intervention. This raises concerns about the application of current outbreak guidelines for early warning/identification systems. It is clear that quantitatively defining the characteristics of an outbreak is an essential prerequisite for effective reactive response. More work is needed so that definitions of disease outbreaks can take into account the baseline capacities of treatment, surveillance and control. This is essential if outbreak guidelines are to be effective and generalisable across a range of epidemiologically different settings. (C) 2015 The Authors. Published by Elsevier B.V. C1 [Brady, Oliver J.; Smith, David L.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Smith, David L.; Scott, Thomas W.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Smith, David L.] Sanaria Inst Global Hlth & Trop Med, Rockville, MD USA. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Hay, Simon I.] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. RP Brady, OJ (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,South Parks Rd, Oxford, England. EM oliver.brady.zoo@gmail.com; smitdave@gmail.com; twscott@ucdavis.edu; simon.i.hay@gmail.com RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Brady, Oliver/0000-0002-3235-2129 FU BBSRC studentship; Wellcome Trust [095066]; Research and Policy in Infectious Disease Dynamics (RAPIDD) program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation [OPP1110495]; EU [21803] FX OJB is funded by a BBSRC studentship. SIH is funded by a Senior Research Fellowship from the Wellcome Trust (095066). SIH, DLS and TWS acknowledge funding support from the Research and Policy in Infectious Disease Dynamics (RAPIDD) program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. DLS acknowledges funding from the Bill and Melinda Gates Foundation (#OPP1110495). This study was partially funded by EU grant 21803 IDAMS (http:\\www.idams.cu) and is designated with IDAMS publication reference number IDAMS27. NR 59 TC 12 Z9 12 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD JUN PY 2015 VL 11 BP 92 EP 102 DI 10.1016/j.epidem.2015.03.002 PG 11 WC Infectious Diseases SC Infectious Diseases GA CI0CJ UT WOS:000354403100012 PM 25979287 ER PT J AU Kramer, SC Bansal, S AF Kramer, S. C. Bansal, S. TI Assessing the use of antiviral treatment to control influenza SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Antiviral drugs; control; infectious disease epidemiology; influenza; influenza vaccines ID RANDOMIZED CONTROLLED-TRIAL; PANDEMIC H1N1 2009; SEASONAL INFLUENZA; HOUSEHOLD TRANSMISSION; PROTECTIVE EFFICACY; VIRUS INFECTION; UNITED-STATES; HONG-KONG; VACCINE; CHILDREN AB Vaccines are the cornerstone of influenza control policy, but can suffer from several drawbacks. Seasonal influenza vaccines are prone to production problems and low efficacies, while pandemic vaccines are unlikely to be available in time to slow a rapidly spreading global outbreak. Antiviral therapy was found to be beneficial during the influenza A(H1N1)pdm09 pandemic even with limited use; however, antiviral use has decreased further since then. We sought to determine the role antiviral therapy can play in pandemic and seasonal influenza control using conservative estimates of antiviral efficacy, and to assess if conservative but targeted strategies could be employed to optimize the use of antivirals. Using an age-structured contact network model for an urban population, we compared the transmission-blocking ability of a conservative antiviral therapy strategy to the susceptibility-reducing effects of a robust influenza vaccine. Our results show that while antiviral therapy cannot replace a robust influenza vaccine, it can play a role in reducing attack rates and eliminating outbreaks, and could significantly reduce public health burden when vaccine is either unavailable or ineffective. We also found that antiviral therapy, by treating those who are infected, is naturally a highly optimized strategy, and need not be improved upon with expensive targeted campaigns. C1 [Kramer, S. C.; Bansal, S.] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Bansal, S.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bansal, S (reprint author), 406 Reiss Sci Bldg,37th & O St, Washington, DC 20057 USA. EM sb753@georgetown.edu OI Bansal, Shweta/0000-0002-1740-5421 FU Howard Hughes Medical Institute through the Precollege and Undergraduate Science Education Program; RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We gratefully acknowledge Lauren Ancel Meyers for use of the Vancouver urban contact network. This work was funded by a grant to Georgetown University from the Howard Hughes Medical Institute through the Precollege and Undergraduate Science Education Program; and the RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 40 TC 2 Z9 2 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD JUN PY 2015 VL 143 IS 8 BP 1621 EP 1631 DI 10.1017/S0950268814002520 PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CH5FQ UT WOS:000354061100008 PM 25274250 ER PT J AU Mascalzoni, D Dove, ES Rubinstein, Y Dawkins, HJS Kole, A McCormack, P Woods, S Riess, O Schaefer, F Lochmuller, H Knoppers, BM Hansson, M AF Mascalzoni, Deborah Dove, Edward S. Rubinstein, Yaffa Dawkins, Hugh J. S. Kole, Anna McCormack, Pauline Woods, Simon Riess, Olaf Schaefer, Franz Lochmueller, Hanns Knoppers, Bartha M. Hansson, Mats TI International Charter of principles for sharing bio-specimens and data SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BROAD CONSENT; BIOBANKS; PRIVACY; ETHICS AB There is a growing international agreement on the need to provide greater access to research data and bio-specimen collections to optimize their long-term value and exploit their potential for health discovery and validation. This is especially evident for rare disease research. Currently, the rising value of data and bio-specimen collections does not correspond with an equal increase in data/sample-sharing and data/sample access. Contradictory legal and ethical frameworks across national borders are obstacles to effective sharing: more specifically, the absence of an integrated model proves to be a major logistical obstruction. The Charter intends to amend the obstacle by providing both the ethical foundations on which data sharing should be based, as well as a general Material and Data Transfer Agreement (MTA/DTA). This Charter is the result of a careful negotiation of different stakeholders' interest and is built on earlier consensus documents and position statements, which provided the general international legal framework. Further to this, the Charter provides tools that may help accelerate sharing. The Charter has been formulated to serve as an enabling tool for effective and transparent data and bio-specimen sharing and the general MTA/DTA constitutes a mechanism to ensure uniformity of access across projects and countries, and may be regarded as a consistent basic agreement for addressing data and material sharing globally. The Charter is forward looking in terms of emerging issues from the perspective of a multi-stakeholder group, and where possible, provides strategies that may address these issues. C1 [Mascalzoni, Deborah; Hansson, Mats] Uppsala Univ, Ctr Res Eth & Bioeth, SE-75122 Uppsala, Sweden. [Mascalzoni, Deborah] EURAC Res, Ctr Biomed, Bolzano, Italy. [Dove, Edward S.; Knoppers, Bartha M.] McGill Univ, Ctr Genom & Policy, Montreal, PQ, Canada. [Rubinstein, Yaffa] NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Dawkins, Hugh J. S.] Dept Hlth, Off Populat Hlth Genom, Perth, WA, Australia. [Dawkins, Hugh J. S.] Curtin Univ Technol, Curtin Hlth Innovat Res Inst, Ctr Populat Hlth Res, Bentley, WA 6102, Australia. [Dawkins, Hugh J. S.] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia. [Dawkins, Hugh J. S.] Murdoch Univ, Ctr Comparat Genom, Murdoch, WA 6150, Australia. [Kole, Anna] EURORDIS, Rare Dis Europe, Paris, France. [McCormack, Pauline; Woods, Simon; Lochmueller, Hanns] Newcastle Univ, PEALS Policy Eth & Life Sci Res Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Riess, Olaf] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany. [Schaefer, Franz] Univ Heidelberg Hosp, Pediat Nephrol Div, Heidelberg, Germany. [Schaefer, Franz] Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Mascalzoni, D (reprint author), Uppsala Univ, Ctr Res Eth & Bioeth, BMC, Husargatan 3,Entrance A11 Box 564, SE-75122 Uppsala, Sweden. EM deborah.mascalzoni@crb.uu.se FU European Union Seventh Framework Programme (FP7) [305444, 305121, 305608]; RD Connect from the Australian National Health and Medical Research Council under the NHMRC-European Union Collaborative Research Grants scheme' [APP1055319]; Innovative Medicines Initiative project BTCure [115142-1]; BioBanking and Molecular Resource Infrastructure of Sweden project (Swedish Research Council); Euro-TEAM; BiobankCloud; BioSHaRE and Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)LPC [313010] FX We thank the RD Connect Patient Ethics Council and RD Connect Patient Advisory Council (Jean Jacques Cassiman, Tracy Dudding, Muriel Gevrey, Emma Heslop, Joseph Irwin, Julian Isla, Sigurdur Johannesson, Lydia Lemonnier, Chantal Loirat, Dorthe Lykke, Milan Macek, Caron Molster, Kay Parkinson, Odile Perrousseaux, Marita Pohlschmidt, Daniel Renault, Peter Reussner, Francoise Rouault, Balthasar Schaap, Inge Schwersenz, Chris Sotirelis, Volker Straub, Oliver Timmis, Johannes van Delden, Marieke van Meel, Elizabeth Vroom, Urban Wiesing) and all RD-connect partners for their valuable inputs. This work has been supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreements no. 305444 (RD-Connect), 305121 (Neuromics), and no. 305608 (EURenOmics) and RD Connect from the Australian National Health and Medical Research Council APP1055319 under the NHMRC-European Union Collaborative Research Grants scheme'. In addition, DM and MH have received funding from the Innovative Medicines Initiative project BTCure (grant agreement no. 115142-1), the BioBanking and Molecular Resource Infrastructure of Sweden project (financed by the Swedish Research Council), Euro-TEAM, BiobankCloud, BioSHaRE and Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)LPC (313010). BMK and ESD wish to thank the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Quebec Breast Cancer Foundation, and the Ministere de l'enseignement superieur, de la recherche, de la science et de la technologie du Quebec through Genome Quebec. The funders had no influence on the design or the writing of the article. NR 29 TC 22 Z9 23 U1 1 U2 10 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 JUN PY 2015 VL 23 IS 6 BP 721 EP 728 DI 10.1038/ejhg.2014.197 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CI1BG UT WOS:000354474600008 PM 25248399 ER PT J AU Das, S Stuart, PE Ding, J Tejasvi, T Li, YM Tsoi, LC Chandran, V Fischer, J Helms, C Duffin, KC Voorhees, JJ Bowcock, AM Krueger, GG Lathrop, GM Nair, RP Rahman, P Abecasis, GR Gladman, D Elder, JT AF Das, Sayantan Stuart, Philip E. Ding, Jun Tejasvi, Trilokraj Li, Yanming Tsoi, Lam C. Chandran, Vinod Fischer, Judith Helms, Cynthia Duffin, Kristina Callis Voorhees, John J. Bowcock, Anne M. Krueger, Gerald G. Lathrop, G. Mark Nair, Rajan P. Rahman, Proton Abecasis, Goncalo R. Gladman, Dafna Elder, James T. TI Fine mapping of eight psoriasis susceptibility loci SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ANALYSIS IDENTIFIES 3; RHEUMATOID-ARTHRITIS; HLA-C; COMPLEX DISEASES; CROHN DISEASE; RESPONSES; DISEQUILIBRIUM; HERITABILITY; DISCOVERY AB Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49 239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 x 10(-74)), rs6924962 (P = 3.21 x 10(-19)) and rs892666 (P = 1.11 x 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 x 10(-16)) and rs918518 (P = 3.22 x 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 x 10(-13)), IL13 (rs1295685; P = 1.65 x 10(-7)), IL23A (rs61937678; P = 1.82 x 10(-7)) and TNFAIP3 (rs642627; P = 5.90 x 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC. C1 [Das, Sayantan; Ding, Jun; Li, Yanming; Tsoi, Lam C.; Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA. [Stuart, Philip E.; Tejasvi, Trilokraj; Voorhees, John J.; Nair, Rajan P.; Elder, James T.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. [Ding, Jun] NIA, Lab Genet, NIH, Baltimore, MD 21224 USA. [Chandran, Vinod; Gladman, Dafna] Univ Toronto, Dept Med, Div Rheumatol, Toronto, ON, Canada. [Fischer, Judith; Lathrop, G. Mark] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Helms, Cynthia; Bowcock, Anne M.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Duffin, Kristina Callis; Krueger, Gerald G.] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Rahman, Proton] Mem Univ, Dept Med, St John, NF, Canada. [Gladman, Dafna] Toronto Western Res Inst, Ctr Prognosis Studies Rheumat Dis, Psoriat Arthrit Program, Toronto, ON, Canada. [Elder, James T.] Ann Arbor Veteran Affairs Hosp, Ann Arbor, MI USA. RP Abecasis, GR (reprint author), Univ Michigan, Ctr Stat Genet, Dept Biostat, M4614 SPH I Tower,1415 Washington Hts, Ann Arbor, MI 48109 USA. EM goncalo@umich.edu RI Fischer, Judith/E-6327-2016; OI Bowcock, Anne/0000-0001-8691-9090; Tsoi, Lam Cheung/0000-0003-1627-5722 FU NIH [R01AR042742, R01AR054966, R01AR050511, R01AR050266, R01AR062382]; Krembil Foundation; Ann Arbor Veterans Affairs Hospital; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation International (JDRF) [U01 DK062418]; CIHR FX We thank all the psoriasis patients and normal controls who contributed samples to this study. This work was supported by NIH Grants R01AR042742, R01AR054966, R01AR050511, R01AR050266 and R01AR062382. The University of Toronto Psoriatic Arthritis Program is supported by the Krembil Foundation and the CIHR. JTE is supported by the Ann Arbor Veterans Affairs Hospital. This research uses resources provided by the Type 1 Diabetes Genetics Consortium (T1DGC); a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation International (JDRF), supported by U01 DK062418. NR 51 TC 4 Z9 4 U1 2 U2 6 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 JUN PY 2015 VL 23 IS 6 BP 844 EP 853 DI 10.1038/ejhg.2014.172 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CI1BG UT WOS:000354474600026 PM 25182136 ER PT J AU Li, FY Chaigne-Delalande, B Rao, VK Zhang, Y Matthews, H Kuijpers, T Su, H Uzel, G Lenardo, MJ AF Li, Feng-Yen Chaigne-Delalande, Benjamin Rao, V. Koneti Zhang, Yu Matthews, Helen Kuijpers, Taco (TW) Su, Helen Uzel, Gulbu Lenardo, Michael J. TI Clinical utility gene card for: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material ID NKG2D C1 [Li, Feng-Yen; Chaigne-Delalande, Benjamin; Rao, V. Koneti; Matthews, Helen; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Clin Genom Unit, Immunol Lab,NIH, Bethesda, MD 20892 USA. [Zhang, Yu; Su, Helen] NIAID, Human Immunol Dis Unit, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Kuijpers, Taco (TW)] Univ Amsterdam, Acad Med Ctr, Pediat Immunol & Infect Dis, NL-1105 AZ Amsterdam, Netherlands. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Rao, VK (reprint author), NIAID, Mol Dev Immune Syst Sect, Clin Genom Unit, Immunol Lab,NIH, Bldg 10,Room 11N311,10 Ctr Dr MSC 1892, Bethesda, MD 20892 USA. EM koneti@nih.gov; lenardo@nih.gov RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 NR 5 TC 0 Z9 0 U1 1 U2 6 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 JUN PY 2015 VL 23 IS 6 DI 10.1038/ejhg.2014.179 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CI1BG UT WOS:000354474600004 ER PT J AU Pretegiani, E Rosini, F Federighi, P Cerase, A Dotti, MT Rufa, A AF Pretegiani, E. Rosini, F. Federighi, P. Cerase, A. Dotti, M. T. Rufa, A. TI Pendular nystagmus, palatal tremor and progressive ataxia in GM2-gangliosidosis SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Letter DE ataxia; GM2-gangliosidosis; palatal tremor; pendular nystagmus; Sandhoff disease ID OCULOPALATAL TREMOR; DISEASE C1 [Pretegiani, E.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Pretegiani, E.; Rosini, F.; Federighi, P.; Dotti, M. T.; Rufa, A.] Univ Siena, Dept Med Surg & Neurol Sci, I-53100 Siena, Italy. [Cerase, A.] Azienda Osped Univ Senese, Neuroimaging & Neurointervent Unit, Siena, Italy. RP Pretegiani, E (reprint author), NEI, NIH, 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. EM elena.pretegiani@nih.gov NR 7 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD JUN PY 2015 VL 22 IS 6 BP E67 EP E69 DI 10.1111/ene.12661 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CH4HP UT WOS:000353994900001 PM 25916337 ER PT J AU Stevens, WD Tessler, MH Peng, CS Martin, A AF Stevens, W. Dale Tessler, Michael Henry Peng, Cynthia S. Martin, Alex TI Functional Connectivity Constrains the Category-Related Organization of Human Ventral Occipitotemporal Cortex SO HUMAN BRAIN MAPPING LA English DT Article DE functional MRI; resting-state; tools; objects; scenes; parahippocampal place area; hemispheric asymmetry; lateralization; concepts; localization ID FUSIFORM FACE AREA; SELECTIVE CORTICAL REGIONS; AUTISM SPECTRUM DISORDERS; GLOBAL SIGNAL REGRESSION; RESTING HUMAN BRAIN; HUMAN OBJECT AREAS; WORD FORM AREA; MANIPULATABLE OBJECTS; TEMPORAL CORTEX; INDIVIDUAL VARIABILITY AB One of the most robust and oft-replicated findings in cognitive neuroscience is that several spatially distinct, functionally dissociable ventral occipitotemporal cortex (VOTC) regions respond preferentially to different categories of concrete entities. However, the determinants of this category-related organization remain to be fully determined. One recent proposal is that privileged connectivity of these VOTC regions with other regions that store and/or process category-relevant properties may be a major contributing factor. To test this hypothesis, we used a multicategory functional magnetic resonance imaging (MRI) localizer to individually define category-related brain regions of interest (ROIs) in a large group of subjects (n=33). We then used these ROIs in resting-state functional connectivity MRI analyses to explore spontaneous functional connectivity among these regions. We demonstrate that during rest, distinct category-preferential VOTC regions show differentially stronger functional connectivity with other regions that have congruent category-preference, as defined by the functional localizer. Importantly, a tool-preferential region in the left medial fusiform gyrus showed differentially stronger functional connectivity with other left lateralized cortical regions associated with perceiving and knowing about common toolsposterior middle temporal gyrus (involved in perception of nonbiological motion), lateral parietal cortex (critical for reaching, grasping, manipulating), and ventral premotor cortex (involved in storing/executing motor programs)relative to other category-related regions in VOTC of both the right and left hemisphere. Our findings support the claim that privileged connectivity with other cortical regions that store and/or process category-relevant properties constrains the category-related organization of VOTC. Hum Brain Mapp 36:2187-2206, 2015. (c) Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Stevens, W. Dale; Tessler, Michael Henry; Peng, Cynthia S.; Martin, Alex] NIMH, Sect Cognit Neuropsychol, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Stevens, WD (reprint author), York Univ, Dept Psychol, Sherman Hlth Sci Res Ctr, 281 Ian Macdonald Blvd, Toronto, ON M3J 1P3, Canada. EM stevensd@yorku.ca FU National Institute of Mental Health, National Institutes of Health, Division of Intramural Research FX Contract grant sponsor: The National Institute of Mental Health, National Institutes of Health, Division of Intramural Research. NR 83 TC 11 Z9 11 U1 4 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUN PY 2015 VL 36 IS 6 BP 2187 EP 2206 DI 10.1002/hbm.22764 PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CH4AF UT WOS:000353972000013 PM 25704493 ER PT J AU Weise, CM Thiyyagura, P Reiman, EM Chen, KW Krakoff, J AF Weise, Christopher M. Thiyyagura, Pradeep Reiman, Eric M. Chen, Kewei Krakoff, Jonathan TI A Potential Role for the Midbrain in Integrating Fat-Free Mass Determined Energy Needs: An (H2O)-O-15 PET Study SO HUMAN BRAIN MAPPING LA English DT Article DE energy homeostasis; hunger; brain; body composition; regional cerebral blood flow ID MEDIAL PREFRONTAL CORTEX; VISUAL FOOD CUES; PERIAQUEDUCTAL GRAY; NEURONAL RESPONSE; FEEDING-BEHAVIOR; CINGULATE CORTEX; BODY-COMPOSITION; MACAQUE MONKEYS; BRAIN; NETWORKS AB Little is known on how sensing of energy needs is centrally represented, integrated, and translated into the behavioral aspects of energy homeostasis. Fat free mass (FFM) is the major determinant of energy expenditure. We investigated how interindividual variances in FFM relate to neuronal activity in humans. Healthy adults (n=64, 21F/43M; age 31.3 +/- 9.1y; percentage of body fat [PFAT] 25.6 +/- 10.7%; BMI 30.4 +/- 9) underwent a 36h fast and subsequent (H2O)-O-15 positron emission tomographic (PET) measurement of regional cerebral blood flow (rCBF). Multiple variable regression analysis revealed significant associations of FFM with rCBF within the midbrain [including parts of the periaqueductal gray (PAG), ventral tegmental area (VTA), thalamic and hypothalamic regions], the bilateral parahippocampal region, left anterior cingulate, left insular cortex, right cerebellum, and distinct regions within the temporal and occipital cortex. In contrast, no significant associations were found for fat mass (FM). We investigated the potential functional-anatomical link between FFM and central regulation of food intake by performing a conjunction analysis of FFM and the perceived hunger feelings. This showed a significant overlap within the midbrain PAG. Mediation analysis demonstrated a significant indirect effect of FFM on hunger with PAG rCBF as mediator. Most regions we found to be associated with FFM form part in ascending homeostatic pathways and cortical circuitries implicated in the regulation of basic bodily functions indicating a potential role of these central networks in the integration of FFM determined energy needs. Hum Brain Mapp 36:2406-2415, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Weise, Christopher M.; Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, Phoenix, AZ USA. [Weise, Christopher M.] Univ Leipzig, Dept Neurol, Liebigstr 20, D-04103 Leipzig, Germany. [Thiyyagura, Pradeep; Reiman, Eric M.; Chen, Kewei] Banner Alzheimers Inst, Dept Psychiat, Phoenix, AZ USA. [Reiman, Eric M.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. RP Weise, CM (reprint author), Univ Leipzig, Dept Neurol, Liebigstr 20, D-04103 Leipzig, Germany. EM christopher.weise@medizin.uni-leipzig.de FU NIH; National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) FX Contract grant sponsors: Intramural Research Program of the NIH, The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) NR 64 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUN PY 2015 VL 36 IS 6 BP 2406 EP 2415 DI 10.1002/hbm.22780 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CH4AF UT WOS:000353972000029 PM 25766283 ER PT J AU Vargas-Inchaustegui, DA Xiao, P Demberg, T Pal, R Robert-Guroff, M AF Vargas-Inchaustegui, Diego A. Xiao, Peng Demberg, Thorsten Pal, Ranajit Robert-Guroff, Marjorie TI Therapeutic envelope vaccination in combination with antiretroviral therapy temporarily rescues SIV-specific CD4(+) T-cell-dependent natural killer cell effector responses in chronically infected rhesus macaques SO IMMUNOLOGY LA English DT Article DE antiretroviral therapy; envelope immunization; natural killer cells; T cells ID SIMIAN IMMUNODEFICIENCY VIRUS; NK CELLS; HIV-INFECTION; INNATE IMMUNITY; LYMPH-NODES; IFN-GAMMA; IN-VIVO; ANTIBODIES; MEMORY; ACTIVATION AB Natural killer (NK) cells are essential components of the immune system, and due to their rapid response potential, can have a great impact during early anti-viral immune responses. We have previously shown that interleukin-2-dependent NK and CD4(+) T-cell co-operative immune responses exist in long-term simian immunodeficiency virus (SIV) -infected controlling macaques and can be rescued in SIV-infected non-controlling macaques by a short course of antiretroviral therapy (ART). Given that co-operative responses may play an important role in disease prevention and therapeutic treatment, in the present study we sought to determine if these responses can be enhanced in chronically SIV-infected macaques by vaccination with a single-dose of envelope protein given during ART. To this end, we treated 14 chronically SIV-infected macaques with ART for 11weeks and gave 10 of these macaques a single intramuscular dose of SIV gp120 at week 9 of treatment. ART significantly decreased plasma and mucosal viral loads, increased the numbers of circulating CD4(+) T cells in all macaques, and increased T-cell-dependent envelope- and gag-specific interferon- and tumour necrosis factor- production by circulatory CD56(+) NK cells. The therapeutic envelope immunization resulted in higher envelope-specific responses compared with those in macaques that received ART only. Functional T-cell responses restored by ART and therapeutic Env immunization were correlated with transiently reduced plasma viraemia levels following ART release. Collectively our results indicate that SIV-specific T-cell-dependent NK cell responses can be efficiently rescued by ART in chronically SIV-infected macaques and that therapeutic immunization may be beneficial in previously vaccinated individuals. C1 [Vargas-Inchaustegui, Diego A.; Xiao, Peng; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Pal, Ranajit] Adv Biosci Labs Inc, Rockville, MD USA. RP Robert-Guroff, M (reprint author), NCI, NIH, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute FX We gratefully acknowledge the animal caretakers at Advanced BioScience Laboratories and Katherine McKinnon (Vaccine Branch Flow Core, NCI/NIH) for expert advice. The following reagents were obtained through the NIH Nonhuman Primate Reagent Resource: QDot655 anti-CD4. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: SIVmac239 Gag and Env peptides (complete sets). This study was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 43 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD JUN PY 2015 VL 145 IS 2 BP 288 EP 299 DI 10.1111/imm.12447 PG 12 WC Immunology SC Immunology GA CH6ZN UT WOS:000354185400011 PM 25626488 ER PT J AU Kirkland, RS Nanda, RH Alazraki, A Esiashvili, N AF Kirkland, Robert S. Nanda, Ronica H. Alazraki, Adina Esiashvili, Natia TI Influence of Pulmonary Nodules on Chest Computed Tomography and Risk of Recurrence in Stage IV Wilms Tumor SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CT; METASTASES AB Purpose: Chest computed tomography (CT) is currently accepted as the main modality for initial disease staging and response assessment in Wilms tumor (WT). However, there is great variability in the number and size of lung metastases at the time of diagnosis and after induction chemotherapy. There is a lack of clinical evidence as to how this variability in tumor burden affects choice of therapy and disease outcome. This study sought to evaluate a previously proposed lung metastases risk stratification system based on CT findings and clinical outcomes in stage IV WT patients. Methods and Materials: Thirty-five pediatric patients with a diagnosis of stage IV WT with evaluable pre- and postdiagnosis CT scans between 1997 and 2012 were included in the analysis. Patients were divided into low-, intermediate-, and high-risk categories based on the size and number of pulmonary metastases before and after 6 weeks of chemotherapy. Association of the lung risk groups with lung recurrence-free survival and overall survival at each time point was analyzed with relevant covariates. Results: Risk group distribution both at diagnosis and after induction chemotherapy was not influenced by tumor histology. Initial risk grouping suggested an association with disease-free survival at 5 years (P=. 074); however, the most significant correlation was with postinduction chemotherapy disease status (PZ. 027). In patients with an intermediate or high burden of disease after 6 weeks of chemotherapy, despite receiving whole-lung and boost irradiation, survival outcomes were poorer. Conclusions: Pulmonary tumor burden in stage IV WTon chest CT can predict disease outcome. Patients with intermediate-or low-risk disease, especially after induction therapy, have a higher risk for recurrence. After prospective validation, this method may become a valuable tool in adaptation of therapy to improve outcome. (C) 2015 Elsevier Inc. All rights reserved. C1 [Kirkland, Robert S.] NIH, Bethesda, MD 20892 USA. [Nanda, Ronica H.; Esiashvili, Natia] Emory Univ, Winship Canc Inst, Dept Radiat Oncol, Atlanta, GA 30322 USA. [Alazraki, Adina] Childrens Healthcare Atlanta, Aflac Canc Ctr, Dept Radiol, Atlanta, GA USA. RP Nanda, RH (reprint author), 1365 Clifton Rd NE,Ste A1301, Atlanta, GA 30322 USA. EM rhazari@emory.edu NR 12 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUN 1 PY 2015 VL 92 IS 2 BP 332 EP 338 DI 10.1016/j.ijrobp.2015.01.012 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CH4FO UT WOS:000353989000023 PM 25754630 ER PT J AU Muller, N Michen, S Tietze, S Topfer, K Schulte, A Lamszus, K Schmitz, M Schackert, G Pastan, I Temme, A AF Mueller, Nadja Michen, Susanne Tietze, Stefanie Toepfer, Katrin Schulte, Alexander Lamszus, Katrin Schmitz, Marc Schackert, Gabriele Pastan, Ira Temme, Achim TI Engineering NK Cells Modified With an EGFRvIII-specific Chimeric Antigen Receptor to Overexpress CXCR4 Improves Immunotherapy of CXCL12/SDF-1 alpha-secreting Glioblastoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE adoptive immunotherapy; engineered NK cell chemotaxis; chimeric antigen receptor; EGFRvIII; CXCR4; CXCL12/SDF-1 alpha ID NATURAL-KILLER-CELLS; GROWTH-FACTOR; T-CELLS; CHEMOKINE RECEPTORS; TUMOR-CELLS; IN-VIVO; RETROVIRAL VECTORS; GLIOMA XENOGRAFTS; ENDOTHELIAL-CELLS; EXPRESSION AB Natural killer (NK) cells are promising effector cells for adjuvant immunotherapy of cancer. So far, several preclinical studies have shown the feasibility of gene-engineered NK cells, which upon expression of chimeric antigen receptors (CARs) are redirected to otherwise NK cell-resistant tumors. Yet, we reasoned that the efficiency of an immunotherapy using CAR-modified NK cells critically relies on efficient migration to the tumor site and might be improved by the engraftment of a receptor specific for a chemokine released by the tumor. On the basis of the DNAX-activation protein 12 (DAP12), a signaling adapter molecule involved in signal transduction of activating NK cell receptors, we constructed an epidermal growth factor variant III (EGFRvIII)-CAR, designated MR1.1-DAP12 which confers specific cytotoxicity of NK cell towards EGFRvIII(+) glioblastoma cells in vitro and to established subcutaneous U87-MG(EGFRvIII) tumor xenografts. So far, infusion of NK cells with expression of MR1.1DAP12 caused a moderate but significantly delayed tumor growth and increased median survival time when compared with NK cells transduced with an ITAM-defective CAR. Notably, the further genetic engineering of these EGFRvIII-specific NK cells with the chemokine receptor CXCR4 conferred a specific chemotaxis to CXCL12/SDF-1 alpha secreting U87-MG glioblastoma cells. Moreover, the administration of such NK cells resulted in complete tumor remission in a number of mice and a significantly increased survival when compared with the treatment of xenografts with NK cells expressing only the EGFRvIII-specific CAR or mock control. We conclude that chemokine receptor-engineered NK cells with concomitant expression of a tumor-specific CAR are a promising tool to improve adoptive tumor immunotherapy. C1 [Mueller, Nadja; Michen, Susanne; Tietze, Stefanie; Toepfer, Katrin; Schackert, Gabriele; Temme, Achim] Tech Univ Dresden, Dept Neurosurg, Sect Expt Neurosurg Tumor Immunol, Univ Hosp Carl Gustav Carus, D-01307 Dresden, Germany. [Schmitz, Marc] Tech Univ Dresden, Inst Immunol, Med Fac Carl Gustav Carus, D-01307 Dresden, Germany. [Schackert, Gabriele; Temme, Achim] German Canc Consortium DKTK, Dresden, Germany. [Schulte, Alexander; Lamszus, Katrin] Univ Med Ctr Hamburg Eppendorf, Dept Neurosurg, Lab Brain Tumor Biol, Hamburg, Germany. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Temme, A (reprint author), Tech Univ Dresden, Dept Neurosurg, Sect Expt Neurosurg Tumor Immunol, Univ Hosp Carl Gustav Carus, Fetscherstasse 74, D-01307 Dresden, Germany. EM Achim.Temme@uniklinikum-dresden.de FU Deutsche Krebshilfe e.V. [Az.: 109377]; Doktor Robert Pfleger-Stiftung; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Forschungs und Wissenschaftsstiftung Hamburg FX Supported by the Deutsche Krebshilfe e.V. (Az.: 109377) (A.T.) and Doktor Robert Pfleger-Stiftung (A.T.). This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (I.P.), and in part by a grant from the Forschungs und Wissenschaftsstiftung Hamburg (K.L.). NR 66 TC 7 Z9 8 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD JUN PY 2015 VL 38 IS 5 BP 197 EP 210 PG 14 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA CI1EH UT WOS:000354484300003 PM 25962108 ER PT J AU Screen, HRC Berk, DE Kadler, KE Ramirez, F Young, MF AF Screen, Hazel R. C. Berk, David E. Kadler, Karl E. Ramirez, Francesco Young, Marian F. TI Tendon Functional Extracellular Matrix SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE tenocyte; cell; tendinopathy; collagen; proteoglycans; hierarchy; structure; mechanics ID LEUCINE-RICH PROTEOGLYCANS; FIBRILLOGENESIS IN-SITU; ENERGY-STORING TENDONS; HUMAN ROTATOR CUFF; RAT-TAIL-TENDON; MECHANICAL-PROPERTIES; COLLAGEN FIBRILLOGENESIS; PLASMA-MEMBRANE; ACHILLES-TENDON; SKELETAL-MUSCLE AB This article is one of a series, summarizing views expressed at the Orthopaedic Research Society New Frontiers in Tendon Research Conference. This particular article reviews the three workshops held under the Functional Extracellular Matrix stream. The workshops focused on the roles of the tendon extracellular matrix, such as performing the mechanical functions of tendon, creating the local cell environment, and providing cellular cues. Tendon is a complex network of matrix and cells, and its biological functions are influenced by widely varying extrinsic and intrinsic factors such as age, nutrition, exercise levels, and biomechanics. Consequently, tendon adapts dynamically during development, aging, and injury. The workshop discussions identified research directions associated with understanding cell-matrix interactions to be of prime importance for developing novel strategies to target tendon healing or repair. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:793-799, 2015. C1 [Screen, Hazel R. C.] Queen Mary Univ London, Sch Engn & Mat Sci, Inst Bioengn, London E1 4NS, England. [Berk, David E.] Univ S Florida, Morsani Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL USA. [Kadler, Karl E.] Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England. [Ramirez, Francesco] Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Young, Marian F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Screen, HRC (reprint author), Queen Mary Univ London, Sch Engn & Mat Sci, Inst Bioengn, Mile End Rd, London E1 4NS, England. EM h.r.c.screen@qmul.ac.uk RI Birk, David/I-4072-2012 OI Birk, David/0000-0002-4865-9088 FU BBSRC; Arthritis Research UK; Orthopaedic Research UK; Wellcome Trust; DIR; NIDCR part of the IRP; NIH; DHHS; National Institutes of Health, NIAMS [AR044745, AR065995] FX Grant sponsor: BBSRC, Arthritis Research UK; Grant sponsor: Orthopaedic Research UK; Grant sponsor: The Wellcome Trust; Grant sponsor: DIR, NIDCR, part of the IRP, NIH, and DHHS; Grant sponsor: National Institutes of Health, NIAMS; Grant numbers: AR044745, AR065995. NR 80 TC 8 Z9 8 U1 6 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD JUN PY 2015 VL 33 IS 6 BP 793 EP 799 DI 10.1002/jor.22818 PG 7 WC Orthopedics SC Orthopedics GA CH4SX UT WOS:000354024300005 PM 25640030 ER PT J AU Leyva, B Nguyen, AB Allen, JD Taplin, SH Moser, RP AF Leyva, Bryan Nguyen, Anh B. Allen, Jennifer D. Taplin, Stephen H. Moser, Richard P. TI Is Religiosity Associated with Cancer Screening? Results from a National Survey SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Religiosity; Health care use; Cancer screening; Social support; Ethnicity ID AFRICAN-AMERICAN WOMEN; SOCIAL SUPPORT; MENTAL-HEALTH; PARTICIPATORY APPROACH; CHURCH ATTENDANCE; MODERATING ROLE; BLACK CHURCHES; UNITED-STATES; OLDER-ADULTS; BREAST AB This study examined the following: (1) relationships between religiosity-as measured by religious service attendance-and screening for breast, cervical, and colorectal cancers; (2) the potential mediating role of social support; and (3) the potential moderating effect of race/ethnicity. Statistical analyses showed that religiosity was associated with greater utilization of breast, cervical, and colorectal cancer screening. Social support fully mediated the relationship between religiosity and Pap screening, and partially mediated the relationship between religiosity and colorectal screening, but had no effect on the relationship between religiosity and mammography screening. Race/ethnicity moderated the relationship between religiosity and social support in the cervical cancer screening model, such that the positive association between religiosity and social support was stronger for non-Hispanic Blacks than it was for non-Hispanic Whites. These findings have implications for the role of social networks in health promotion and can inform cancer screening interventions in faith-based settings. C1 [Leyva, Bryan; Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Proc Care Res Branch, Rockville, MD 20850 USA. [Nguyen, Anh B.; Moser, Richard P.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Sci Res & Technol Branch, Rockville, MD 20850 USA. [Allen, Jennifer D.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. [Allen, Jennifer D.] Harvard Univ, Sch Med, Boston, MA USA. RP Leyva, B (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, Proc Care Res Branch, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM leyvavengoechb@mail.nih.gov; Anh.nguyen3@nih.gov; jennifer_allen@dfci.harvard.edu; taplins@mail.nih.gov; moserr@mail.nih.gov RI Allen, Jennifer/M-2113-2015 FU Centers for Disease Control and Prevention [U48DP001946] FX This study was supported in part by Cooperative Agreement Number U48DP001946 from the Centers for Disease Control and Prevention. The findings and conclusions in this journal article are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 72 TC 3 Z9 3 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4197 EI 1573-6571 J9 J RELIG HEALTH JI J. Relig. Health PD JUN PY 2015 VL 54 IS 3 BP 998 EP 1013 DI 10.1007/s10943-014-9843-1 PG 16 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA CH2UA UT WOS:000353879000015 PM 24833158 ER PT J AU Siddiqui, MM Truong, H Rais-Bahrami, S Stamatakis, L Logan, J Walton-Diaz, A Turkbey, B Choyke, PL Wood, BJ Simon, RM Pinto, PA AF Siddiqui, M. Minhaj Hong Truong Rais-Bahrami, Soroush Stamatakis, Lambros Logan, Jennifer Walton-Diaz, Annerleim Turkbey, Baris Choyke, Peter L. Wood, Bradford J. Simon, Richard M. Pinto, Peter A. TI Clinical Implications of a Multiparametric Magnetic Resonance Imaging Based Nomogram Applied to Prostate Cancer Active Surveillance SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; magnetic resonance imaging; biopsy; nomograms; risk ID TRANSRECTAL ULTRASOUND BIOPSY; RADICAL PROSTATECTOMY; FUSION BIOPSY; GLEASON SCORE; PREDICTION; UPDATE; RISK; MEN; CANDIDATES; MANAGEMENT AB Purpose: Multiparametric magnetic resonance imaging may be beneficial in the search for rational ways to decrease prostate cancer intervention in patients on active surveillance. We applied a previously generated nomogram based on multiparametric magnetic resonance imaging to predict active surveillance eligibility based on repeat biopsy outcomes. Materials and Methods: We reviewed the records of 85 patients who met active surveillance criteria at study entry based on initial biopsy and who then underwent 3.0 Tesla multiparametric magnetic resonance imaging with subsequent magnetic resonance imaging/ultrasound fusion guided prostate biopsy between 2007 and 2012. We assessed the accuracy of a previously published nomogram in patients on active surveillance before confirmatory biopsy. For each cutoff we determined the number of biopsies avoided (ie reliance on magnetic resonance imaging alone without rebiopsy) over the full range of nomogram cutoffs. Results: We assessed the performance of the multiparametric magnetic resonance imaging active surveillance nomogram based on a decision to perform biopsy at various nomogram generated probabilities. Based on cutoff probabilities of 19% to 32% on the nomogram the number of patients who could be spared repeat biopsy was 27% to 68% of the active surveillance cohort. The sensitivity of the test in this interval was 97% to 71% and negative predictive value was 91% to 81%. Conclusions: Multiparametric magnetic resonance imaging based nomograms may reasonably decrease the number of repeat biopsies in patients on active surveillance by as much as 68%. Analysis over the full range of nomogram generated probabilities allows patient and caregiver preference based decision making on the risk assumed for the benefit of fewer repeat biopsies. C1 NCI, Urol Oncol Branch, Canc Prevent Div, Mol Imaging Program,NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Dept Radiol & Imaging Sci, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Rockville, MD USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10 CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 FU NIH NCI Center for Cancer Research Intramural Research Program; Philips Healthcare; NIH Health Medical Research Scholars Program; Pfizer; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute FX Supported by the NIH NCI Center for Cancer Research Intramural Research Program, Philips Healthcare, NIH Health Medical Research Scholars Program, Pfizer, The Leona M. and Harry B. Helmsley Charitable Trust, Howard Hughes Medical Institute and others (http://www.fnih.org/work/programs-development/medical-research-scholars -program). NR 26 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUN PY 2015 VL 193 IS 6 BP 1943 EP 1949 DI 10.1016/j.juro.2015.01.088 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CH7DV UT WOS:000354196700022 PM 25633923 ER PT J AU Richter, HE Whitehead, N Arya, L Ridgeway, B Allen-Brady, K Norton, P Sung, V Shepherd, JP Komesu, Y Gaddis, N Fraser, MO Tan-Kim, J Meikle, S Page, GP AF Richter, Holly E. Whitehead, Nedra Arya, Lily Ridgeway, Beri Allen-Brady, Kristina Norton, Peggy Sung, Vivian Shepherd, Jonathan P. Komesu, Yuko Gaddis, Nathan Fraser, Matthew O. Tan-Kim, Jasmine Meikle, Susan Page, Grier P. CA Pelvic Floor Disorders Network TI Genetic Contributions to Urgency Urinary Incontinence in Women SO JOURNAL OF UROLOGY LA English DT Article DE genome-wide association study; urinary incontinence, urge; urinary bladder, overactive ID GENOME-WIDE ASSOCIATION; EFFICIENT; DISEASE AB Purpose: We identify genetic variants associated with urgency urinary incontinence in postmenopausal women. Materials and Methods: A 2-stage genome-wide association analysis was conducted to identify variants associated with urgency urinary incontinence. The WHI GARNET substudy with 4,894 genotyped post-reproductive white women was randomly split into independent discovery and replication cohorts. Genome-wide imputation was performed using IMPUTE2 with the 1000 Genomes ALL Phase I integrated variant set as a reference. Controls reported no urgency urinary incontinence at enrollment or followup. Cases reported monthly or greater urgency urinary incontinence and leaked sufficiently to wet/soak underpants/clothes. Logistic regression models were used to predict urgency urinary incontinence case vs control status based on genotype, assuming additive inheritance. Age, obesity, diabetes and depression were included in the models as covariates. Results: Following quality control, 975,508 single nucleotide polymorphisms in 2,241 cases (discovery 1,102; replication 1,133) and 776 controls (discovery 405, replication 371) remained. Genotype imputation resulted in 9,077,347 single nucleotide polymorphisms and insertions/deletions with minor allele frequency greater than 0.01 available for analysis. Meta-analysis of the discovery and replication samples identified 6 loci on chromosomes 5, 10, 11, 12 and 18 associated with urgency urinary incontinence at p < 10(-6). Of the loci 3 were within genes, the zinc finger protein 521 (ZFP521) gene on chromosome 18q11, the ADAMTS16 gene on chromosome 5p15 and the CIT gene on chromosome 12q24. The other 3 loci were intergenic. Conclusions: Although environmental factors also likely contribute, this first exploratory genome-wide association study for urgency urinary incontinence suggests that genetic variants in the ZFP521, CIT and ADAMTS16 genes might account for some of the observed heritability of the condition. C1 [Richter, Holly E.] Univ Alabama Birmingham, Birmingham, AL 35249 USA. [Whitehead, Nedra; Gaddis, Nathan; Page, Grier P.] Res Triangle Int, Res Triangle Pk, NC USA. [Fraser, Matthew O.] Duke Univ, Durham, NC USA. [Arya, Lily] Univ Penn, Philadelphia, PA 19104 USA. [Shepherd, Jonathan P.] Univ Pittsburgh, Pittsburgh, PA USA. [Ridgeway, Beri] Cleveland Clin, Cleveland, OH 44106 USA. [Allen-Brady, Kristina; Norton, Peggy] Univ Utah, Salt Lake City, UT USA. [Sung, Vivian] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Komesu, Yuko] Univ New Mexico, Albuquerque, NM 87131 USA. [Tan-Kim, Jasmine] Kaiser Permanente, San Diego, CA USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Richter, HE (reprint author), Univ Alabama Birmingham, Div Urogynecol & Pelv Reconstruct Surg, 619 19th St South,176F,Suite 10382, Birmingham, AL 35249 USA. EM hrichter@uabmc.edu OI Gaddis, Nathan/0000-0001-5205-7138 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [2-U10-HD04267, 2-U10-HD041261, 2-U10-HD054215, 2-U10-HD054214, 1-U10-HD069006, 1-U10-HD069025, RO1 HD061821, 1-U10-HD069013, 1-U10-HD069010, 1-U01-HD069010-01]; NIH Office of Research on Women's Health; Pfizer Inc. FX Supported by grants from The Eunice Kennedy Shriver National Institute of Child Health and Human Development (Duke University: 2-U10-HD04267, University of Alabama at Birmingham: 2-U10-HD041261, Cleveland Clinic: 2-U10-HD054215, UCSD: 2-U10-HD054214, University of Pittsburgh: 1-U10-HD069006, University of New Mexico: 1-U10-HD069025, University of Utah: RO1 HD061821, Brown University: 1-U10-HD069013, University of Pennsylvania: 1-U10-HD069010, RTI: 1-U01-HD069010-01), the NIH Office of Research on Women's Health and investigator initiated research support from Pfizer Inc. NR 27 TC 2 Z9 2 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUN PY 2015 VL 193 IS 6 BP 2020 EP 2027 DI 10.1016/j.juro.2014.12.023 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CH7DV UT WOS:000354196700054 PM 25524241 ER PT J AU Blasi, G Selvaggi, P Fazio, L Antonucci, LA Taurisano, P Masellis, R Romano, R Mancini, M Zhang, FY Caforio, G Popolizio, T Apud, J Weinberger, DR Bertolino, A AF Blasi, Giuseppe Selvaggi, Pierluigi Fazio, Leonardo Antonucci, Linda Antonella Taurisano, Paolo Masellis, Rita Romano, Raffaella Mancini, Marina Zhang, Fengyu Caforio, Grazia Popolizio, Teresa Apud, Jose Weinberger, Daniel R. Bertolino, Alessandro TI Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID DORSOLATERAL PREFRONTAL CORTEX; PRIMATE CEREBRAL-CORTEX; ATTENTIONAL CONTROL; CLINICAL-RESPONSE; HIS452TYR POLYMORPHISM; COGNITIVE IMPAIRMENTS; OLANZAPINE TREATMENT; CANDIDATE GENES; SCHIZOPHRENIA; RISK AB Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n = 63 and n = 54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships. C1 [Blasi, Giuseppe; Selvaggi, Pierluigi; Antonucci, Linda Antonella; Taurisano, Paolo; Masellis, Rita; Romano, Raffaella; Mancini, Marina; Caforio, Grazia; Bertolino, Alessandro] Univ Bari Aldo Moro, Dept Basic Med Sci Neurosci & Sense Organs, Grp Psychiat Neurosci, I-70124 Bari, Italy. [Blasi, Giuseppe; Fazio, Leonardo; Taurisano, Paolo; Popolizio, Teresa] IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy. [Antonucci, Linda Antonella] Aldo Moro Univ, Commun Sci, Dept Educ Sci, Psychol, Bari, Italy. [Zhang, Fengyu; Weinberger, Daniel R.] Johns Hopkins Med Campus, Lieber Inst Brain Dev, Baltimore, MD USA. [Apud, Jose] NIMH, NIH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Bertolino, Alessandro] F Hoffman La Roche Ltd, pRED, NORD DTA, Basel, Switzerland. RP Bertolino, A (reprint author), Univ Bari Aldo Moro, Dept Basic Med Sci Neurosci & Sense Organs, Piazza Giulio Cesare 11, I-70124 Bari, Italy. EM alessandro.bertolino@uniba.it OI Selvaggi, Pierluigi/0000-0001-9069-0700 NR 59 TC 8 Z9 8 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2015 VL 40 IS 7 BP 1600 EP 1608 DI 10.1038/npp.2015.5 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CH8YC UT WOS:000354321600005 PM 25563748 ER PT J AU Barlow, RL Alsio, J Jupp, B Rabinovich, R Shrestha, S Roberts, AC Robbins, TW Dalley, JW AF Barlow, Rebecca L. Alsio, Johan Jupp, Bianca Rabinovich, Rebecca Shrestha, Saurav Roberts, Angela C. Robbins, Trevor W. Dalley, Jeffrey W. TI Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphe Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; PREFRONTAL CORTEX; TRYPTOPHAN DEPLETION; COGNITIVE INFLEXIBILITY; ATTENTIONAL CONTROL; DOPAMINE DEPLETION; IMPULSIVE BEHAVIOR; SELECTIVE LESIONS; CORTICAL-LESIONS; CAUDATE-NUCLEUS AB Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid-and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphe nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low-vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior. C1 [Barlow, Rebecca L.; Alsio, Johan; Jupp, Bianca; Rabinovich, Rebecca; Roberts, Angela C.; Robbins, Trevor W.; Dalley, Jeffrey W.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Barlow, Rebecca L.; Alsio, Johan; Jupp, Bianca; Rabinovich, Rebecca; Roberts, Angela C.; Robbins, Trevor W.; Dalley, Jeffrey W.] Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England. [Alsio, Johan] Uppsala Univ, Dept Neurosci, Uppsala, Sweden. [Jupp, Bianca] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia. [Shrestha, Saurav] NIMH, IRP, Bethesda, MD 20892 USA. [Roberts, Angela C.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EB, England. [Dalley, Jeffrey W.] Univ Cambridge, Dept Psychiat, Cambridge CB2 3EB, England. RP Dalley, JW (reprint author), Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England. EM jwd20@cam.ac.uk FU Lilly; Lundbeck FX TWR consults for Cambridge Cognition, Lilly, Merck Sharpe and Dohme, Lundbeck, Teva, Shire Pharmaceuticals, Otsuka, and Chempartners, and has held recent research grants with Lilly and Lundbeck. TWR has also received royalties from Cambridge Cognition (CANTAB), Springer, and Elsevier. All the other authors declare no conflict of interest. NR 63 TC 8 Z9 8 U1 6 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2015 VL 40 IS 7 BP 1619 EP 1630 DI 10.1038/npp.2014.335 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CH8YC UT WOS:000354321600007 PM 25567428 ER PT J AU John, CS Sypek, EI Carlezon, WA Cohen, BM Ongur, D Bechtholt, AJ AF John, Catherine S. Sypek, Elizabeth I. Carlezon, William A. Cohen, Bruce M. Oenguer, Dost Bechtholt, Anita J. TI Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID FEAR-POTENTIATED STARTLE; ASTROCYTIC GLUTAMATE UPTAKE; BRAIN-STIMULATION REWARD; MEDIAL PREFRONTAL CORTEX; MAJOR DEPRESSION; BIPOLAR DISORDER; RAT-BRAIN; MOOD DISORDERS; PERIAQUEDUCTAL GRAY; SELF-STIMULATION AB Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the CEA and examined effects on intracranial self-stimulation (ICSS) as an index of hedonic state, and on behavior in two anxiety paradigms, elevated plus maze (EPM) and fear conditioning. At lower doses, intra-CEA DHK produced modest increases in ICSS responding (T0). Higher doses resulted in complete cessation of responding for 15 min, suggesting an anhedonic or depressive-like effect. Intra-CEA DHK also increased anxiety-like behavior such that percent time in the open arms and total entries were decreased in the EPM and acquisition of freezing behavior to the tone was increased in a fear-conditioning paradigm. These effects did not appear to be explained by non-specific changes in activity, because effects on fear conditioning were assessed in a drug-free state, and a separate activity test showed no significant effects of intra-CEA DHK on locomotion. Taken together, these studies suggest that blockade of GLT-1 in the CEA is sufficient to induce both anhedonia and anxiety and therefore that a lack of glutamate uptake resulting from glial deficits may contribute to the comorbidity of depression and anxiety. C1 [John, Catherine S.; Sypek, Elizabeth I.; Carlezon, William A.; Cohen, Bruce M.; Oenguer, Dost] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA USA. [Bechtholt, Anita J.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Bechtholt, AJ (reprint author), NIAAA, Div Treatment & Recovery Res, NIH, 5635 Fishers Lane,Room 2046, Bethesda, MD 20892 USA. EM Anita.bechtholt@gmail.com OI sypek, elizabeth/0000-0001-6904-2426 FU American College of Neuropsychopharmacology; Myneurolab.com FX The authors have no conflicts of interest relating to this report and Dr Bechtholt, Catherine John, and Elizabeth Sypek have no other potential conflicts to report. Dr Carlezon has a US patent covering the use of kappa antagonists in the treatment of depression (Assignee: McLean Hospital) and is a member of a collaborative group, including Dr Cohen, that has submitted a patent application covering the synthesis and use of salvinorin derivatives (Assignees: McLean Hospital and Temple University). In the last three years, Dr Carlezon has received compensation for professional services from The American College of Neuropsychopharmacology and Myneurolab.com. Dr Ongur is a Principal Investigator on a research contract with Rules Based Medicine Inc., has served on an advisory board for Lilly, and has received income from Archives of General Psychiatry for services in 2012. Dr Cohen has three additional pending patents on Pyrimidines to treat bipolar disorders, Kappa agonists in bipolar mania, and Mitochondrial replacement therapy and a book on bipolar disorder that has been published by Jossey-Bass/Wiley. NR 60 TC 6 Z9 7 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2015 VL 40 IS 7 BP 1700 EP 1708 DI 10.1038/npp.2015.16 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CH8YC UT WOS:000354321600015 PM 25586634 ER PT J AU Cha, J Fekete, T Siciliano, F Biezonski, D Greenhill, L Pliszka, SR Blader, JC Roy, AK Leibenluft, E Posner, J AF Cha, Jiook Fekete, Tomer Siciliano, Francesco Biezonski, Dominik Greenhill, Laurence Pliszka, Steven R. Blader, Joseph C. Roy, Amy Krain Leibenluft, Ellen Posner, Jonathan TI Neural Correlates of Aggression in Medication-Naive Children with ADHD: Multivariate Analysis of Morphometry and Tractography SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; HUMAN CEREBRAL-CORTEX; DEFICIT HYPERACTIVITY DISORDER; SUPPORT VECTOR MACHINES; SURFACE-BASED ANALYSIS; PREFRONTAL CORTEX; WHITE-MATTER; HUMAN BRAIN; CONNECTIVITY; PERFORMANCE AB Aggression is widely observed in children with attention deficit/hyperactivity disorder (ADHD) and has been frequently linked to frustration or the unsatisfied anticipation of reward. Although animal studies and human functional neuroimaging implicate altered reward processing in aggressive behaviors, no previous studies have documented the relationship between fronto-accumbal circuitry-a critical cortical pathway to subcortical limbic regions-and aggression in medication-naive children with ADHD. To address this, we collected behavioral measures and parental reports of aggression and impulsivity, as well as structural and diffusion MRI, from 30 children with ADHD and 31 healthy controls (HC) (mean age, 10 +/- 2.1 SD). Using grey matter morphometry and probabilistic tractography combined with multivariate statistical modeling (partial least squares regression and support vector regression), we identified anomalies within the fronto-accumbal circuit in childhood ADHD, which were associated with increased aggression. More specifically, children with ADHD showed reduced right accumbal volumes and frontal-accumbal white matter connectivity compared with HC. The magnitude of the accumbal volume reductions within the ADHD group was significantly correlated with increased aggression, an effect mediated by the relationship between the accumbal volume and impulsivity. Furthermore, aggression, but not impulsivity, was significantly explained by multivariate measures of fronto-accumbal white matter connectivity and cortical thickness within the orbitofrontal cortex. Our multi-modal imaging, combined with multivariate statistical modeling, indicates that the fronto-accumbal circuit is an important substrate of aggression in children with ADHD. These findings suggest that strategies aimed at probing the fronto-accumbal circuit may be beneficial for the treatment of aggressive behaviors in childhood ADHD. C1 [Cha, Jiook; Siciliano, Francesco; Biezonski, Dominik; Greenhill, Laurence; Posner, Jonathan] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Cha, Jiook; Siciliano, Francesco; Biezonski, Dominik; Greenhill, Laurence; Posner, Jonathan] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Fekete, Tomer] Katholieke Univ Leuven, Fac Psychol & Educ Sci, Lab Perceptual Dynam, Leuven, Belgium. [Pliszka, Steven R.; Blader, Joseph C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, Sch Med, San Antonio, TX 78229 USA. [Roy, Amy Krain] Fordham Univ, Dept Psychol, New York, NY 10023 USA. [Leibenluft, Ellen] NIMH, Bethesda, MD 20892 USA. RP Cha, J (reprint author), Columbia Univ Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr Unit 74,Room 2420, New York, NY 10032 USA. EM chajioo@nyspi.columbia.edu OI Cha, Jiook/0000-0002-5314-7992 FU NIMH [R01-MH101172, K23-MH091249]; Edwin S. Webster Foundation; Shire Pharmaceuticals; Shire US, Inc.; Purdue Pharma FX This study was supported in part by NIMH Grants R01-MH101172 (JP) and K23-MH091249 (JP), and by funding from the Edwin S. Webster Foundation. Dr Posner is a principal investigator on an investigator-initiated grant from Shire Pharmaceuticals. The authors declare that over the last three years, Steven R. Pliszka MD has had research support from Shire US, Inc. and Purdue Pharma. He has received Honoria for participation in advisory boards for Shire and Ironside Pharmaceutical. NR 59 TC 12 Z9 12 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2015 VL 40 IS 7 BP 1717 EP 1725 DI 10.1038/npp.2015.18 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CH8YC UT WOS:000354321600017 PM 25645374 ER PT J AU Wang, XF Bi, GH He, Y Yang, HJ Gao, JT Okunola-Bakare, OM Slack, RD Gardner, EL Xi, ZX Newman, AH AF Wang, Xiao-Fei Bi, Guo-Hua He, Yi Yang, Hong-Ju Gao, Jun-Tao Okunola-Bakare, Oluyomi M. Slack, Rachel D. Gardner, Eliot L. Xi, Zheng-Xiong Newman, Amy Hauck TI R-Modafinil Attenuates Nicotine-Taking and Nicotine-Seeking Behavior in Alcohol-Preferring Rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; COCAINE DEPENDENCE; METHAMPHETAMINE DEPENDENCE; DISCRIMINATIVE STIMULUS; LOCOMOTOR SENSITIZATION; REINSTATEMENT; ARMODAFINIL; DOPAMINE; ABUSE AB (+/-)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (+/-)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long-Evans rats. As Long-Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long-Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans. C1 [Wang, Xiao-Fei; Bi, Guo-Hua; He, Yi; Yang, Hong-Ju; Gao, Jun-Tao; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Neuropsychopharmacol Sect, Mol Target & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Okunola-Bakare, Oluyomi M.; Slack, Rachel D.; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Target & Medicat Discovery Branch, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), NIDA, Neuropsychopharmacol Sect, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zxi@mail.nih.gov; anewman@mail.nih.gov FU Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). We acknowledge Ms J Cao for synthesizing S-MOD, Dr Tom Prisinzano for supplying intermediates and methods for the syntheses of R- and S-modafinil, and Drs Yavin Shaham and Gianluigi Tanda for their helpful suggestions on experimental design and comments on an earlier draft of this manuscript. NR 45 TC 1 Z9 1 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2015 VL 40 IS 7 BP 1762 EP 1771 DI 10.1038/npp.2015.24 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CH8YC UT WOS:000354321600022 PM 25613829 ER PT J AU Nutman, TB AF Nutman, T. B. TI Looking beyond the induction of Th2 responses to explain immunomodulation by helminths SO PARASITE IMMUNOLOGY LA English DT Review DE alternatively activated macrophages; dendritic cells; helminths; IgE; IgG4; IL-10; immune modulation; innate lymphoid cells; regulatory B cells; regulatory T cells; Th2 responses ID HUMAN LYMPHATIC FILARIASIS; REGULATORY T-CELLS; MIGRATION INHIBITORY FACTOR; HOST IMMUNE-RESPONSES; HUMAN DENDRITIC CELLS; GROWTH-FACTOR-BETA; NEMATODE ONCHOCERCA-VOLVULUS; MALAYI MICROFILARIAE INDUCE; HOOKWORM NECATOR-AMERICANUS; SCHISTOSOMA-MANSONI EGGS AB Although helminth infections are characteristically associated with Th2-mediated responses that include the production of the prototypical cytokines IL-4, IL-5 and IL-13 by CD4(+) cells, the production of IgE, peripheral blood eosinophilia and mucus production in localized sites, these responses are largely attenuated when helminth infections become less acute. This modulation of the immune response that occurs with chronic helminth infection is often induced by molecules secreted by helminth parasites, by non-Th2 regulatory CD4(+) cells, and by nonclassical B cells, macrophages and dendritic cells. This review will focus on those parasite- and host-mediated mechanisms underlying the modulated T-cell response that occurs as the default in chronic helminth infections. C1 NIH, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIH, Helminth Immunol Sect, Parasit Dis Lab, 4 Ctr Dr Bldg 4 Rm B1-03, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov FU Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases, NIH FX This work was funded in part by the Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases, NIH. NR 131 TC 5 Z9 5 U1 4 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0141-9838 EI 1365-3024 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUN PY 2015 VL 37 IS 6 SI SI BP 304 EP 313 DI 10.1111/pim.12194 PG 10 WC Immunology; Parasitology SC Immunology; Parasitology GA CH6DX UT WOS:000354127600004 PM 25869527 ER PT J AU Massilamany, C Gangaplara, A Reddy, J AF Massilamany, C. Gangaplara, A. Reddy, J. TI Environmental Microbes and Uveitis: Is Microbial Exposure Always Bad? SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Review ID EXPERIMENTAL AUTOIMMUNE UVEITIS; ACUTE ANTERIOR UVEITIS; CANINE MONOCYTIC EHRLICHIOSIS; MYELIN BASIC-PROTEIN; T-REGULATORY CELLS; RETINAL S-ANTIGEN; MOLECULAR MIMICRY; CROSS-REACTIVITY; UVEITOPATHOGENIC SITE; THYMIC EXPRESSION AB The eye generally is considered to be an immune-privileged organ, but this notion is being increasingly challenged as ocular antigens can be expressed in the generative lymphoid organs, resulting in attainment of self-tolerance. What triggers a break in this tolerant state is a fundamental question in autoimmunity research. The general belief is that exposure to environmental microbes can break self-tolerance in genetically susceptible individuals, leading to the induction of autoimmune responses. The molecular mimicry hypothesis has been proposed as one major mechanistic, pathway through which microbes, by generating cross-reactive immune responses, can induce ocular damage of the kind that might occur in uveitis. However, our recent data suggest that exposure to microbial products containing mimicry epitopes for retinal antigens can potentially be beneficial to the host. In this review, we discuss the immune mechanisms with particular reference to the molecular mimicry hypothesis as it relates to immune-mediated uveitis. C1 [Massilamany, C.; Gangaplara, A.; Reddy, J.] Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. [Gangaplara, A.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Reddy, J (reprint author), Univ Nebraska, Sch Vet Med & Biomed Sci, Room 202,Bldg VBS, Lincoln, NE 68583 USA. EM nreddy2@unl.edu RI Massilamany, Chandirasegaran/D-9305-2016; OI Massilamany, Chandirasegaran/0000-0002-0205-282X; Gangaplara, Arunakumar/0000-0001-6307-9391 NR 76 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-9475 EI 1365-3083 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD JUN PY 2015 VL 81 IS 6 BP 469 EP 475 DI 10.1111/sji.12297 PG 7 WC Immunology SC Immunology GA CI0TU UT WOS:000354451900002 PM 25833717 ER PT J AU Massey, PR Okman, JS Wilkerson, J Cowen, EW AF Massey, Paul R. Okman, Jonathan S. Wilkerson, Julia Cowen, Edward W. TI Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Palmoplantar erythrodysesthesia; Hand-foot syndrome; Hand-foot skin reaction; Toxic erythema of chemotherapy; Tyrosine kinase inhibitor; Vascular endothelial growth factor ID FOOT SKIN REACTION; RENAL-CELL CARCINOMA; HEPATOCELLULAR-CARCINOMA; CONTROLLED-TRIALS; CLINICAL-TRIALS; ADVERSE EVENTS; SORAFENIB; SUNITINIB; CANCER; THERAPY AB Inhibition of the vascular endothelial growth factor receptor (VEGFR) with tyrosine kinase inhibitors (TKIs) is associated with cutaneous adverse effects that increase patient morbidity. Our objective was to examine the skin toxicity profile of anti-VEGFR TKIs and determine the changing incidence in clinical trials. PubMed was queried for phase II or III trials of anti-VEGFR TKIs between 2000 and 2013 involving a parts per thousand yen50 patients. Adverse events were abstracted, with results presented in both fixed and random effects models. Odds ratios (OR) and 95 % confidence intervals (CIs) were estimated for studies with at least two arms. Across 82 included studies, all grades rash (OR, 2.68; 95 % CI, 2.45-2.94), hand-foot skin reaction (HFSR) (OR, 2.70; 95 % CI, 2.43-3.00), and pruritus (OR, 1.25; 95 % CI, 1.12-1.39) were associated with anti-VEGFR TKIs. Vandetanib had the highest incidence of rash (41 %), while sorafenib was most commonly associated with HFSR (37 %) and pruritus (14 %). The incidence of HFSR from 2000 to 2013 showed an upward trend (r (2) = 0.042, p = 0.10) and in sunitinib therapy increased significantly (r (2) = 0.237, p = 0.04). The incidence of HFSR, rash, and pruritus varies considerably by drug. Our data suggest a continued need to address skin toxicities and improve reporting strategies. C1 [Massey, Paul R.] Univ Texas Austin, Dell Med Sch, Austin, TX 78701 USA. [Okman, Jonathan S.] Lankenau Med Ctr, Dept Internal Med, Philadelphia, PA USA. [Wilkerson, Julia] NCI, Med Oncol, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Massey, PR (reprint author), Univ Texas Austin, Dell Med Sch, 601 E 15th St,CEC 2-470, Austin, TX 78701 USA. EM Prmassey@seton.org OI Wilkerson, Julia/0000-0002-6965-0867 FU Intramural Research Program of the NIH, National Cancer Institute FX This research was made possible in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 40 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUN PY 2015 VL 23 IS 6 BP 1827 EP 1835 DI 10.1007/s00520-014-2520-9 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA CH1ON UT WOS:000353791200041 PM 25471178 ER PT J AU Rice, OV Schonhar, CA Gaal, J Gardner, EL Ashby, CR AF Rice, Onarae V. Schonhar, Charles A. Gaal, J. Gardner, Eliot L. Ashby, Charles R., Jr. TI The Selective Dopamine D-3 Receptor Antagonist SB-277011-A Significantly Decreases Binge-Like Consumption of Ethanol in C57BL/J6 Mice SO SYNAPSE LA English DT Article DE dopamine; D3 receptor; binge drinking; ethanol ID ALCOHOL-SEEKING; HIGH-AFFINITY; BRAIN REWARD; ADDICTION; RATS AB The authors show that the dopamine D3 antagonist SB-277011-A consistently and persistently decrease binge-like EtOH consumption at 30 mg/kg and it decreases binge-like consumption on days 3, 7, 9, and 11-13 at 15 mg/kg. These findings suggest that the brain's D3 receptor may also be involved in not only ethanol reward but binge drinking as well. Synapse 69:295-298, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Rice, Onarae V.; Schonhar, Charles A.] Furman Univ, Dept Psychol, Greenville, SC 29613 USA. [Gaal, J.] MegaPharma Pharmaceut Kft, Budapest, Hungary. [Gardner, Eliot L.] NIDA, Neuropsychopharmacol Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Ashby, Charles R., Jr.] St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Allied Hlth Profess, Jamaica, NY 11439 USA. RP Rice, OV (reprint author), Furman Univ, Dept Psychol, 3300 Poinsett Highway, Greenville, SC 29613 USA. EM onarae.rice@furman.edu FU National Institute of General Medical Sciences [P20-GM103499]; U.S. National Institutes of Health FX Contract grant sponsor: National Institute of General Medical Sciences; Contract grant number: P20-GM103499; Contract grant sponsor: U.S. National Institutes of Health. NR 17 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD JUN PY 2015 VL 69 IS 6 BP 295 EP 298 DI 10.1002/syn.21816 PG 4 WC Neurosciences SC Neurosciences & Neurology GA CH4WM UT WOS:000354034000001 PM 25764479 ER PT J AU Ashby, CR Rice, OV Heidbreder, CA Gardner, EL AF Ashby, Charles R., Jr. Rice, Onarae V. Heidbreder, Christian A. Gardner, Eliot L. TI The Selective Dopamine D-3 Receptor Antagonist SB-277011A Attenuates Drug-or Food-Deprivation Reactivation of Expression of Conditioned Place Preference for Cocaine in Male Sprague-Dawley Rats SO SYNAPSE LA English DT Article DE conditioned place preference; dopamine D-3 receptors; SB-277011A ID SEEKING BEHAVIOR; INDUCED REINSTATEMENT; MESSENGER-RNA; HUMAN BRAIN; MEASURING REWARD; INDUCED RELAPSE; STRESS; ADDICTION; NEUROBIOLOGY; CORTICOSTERONE AB We determined the effect of the selective dopamine D-3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mgkg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 mlkg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D-3 receptor antagonist SB-277011A (3-24 mgkg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mgkg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mgkg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D-3 receptors. Synapse 69:336-344, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Ashby, Charles R., Jr.] St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. [Rice, Onarae V.] Furman Univ, Dept Psychol, Greenville, SC 29613 USA. [Heidbreder, Christian A.] Indivior PLC, Richmond, VA USA. [Gardner, Eliot L.] NIDA, Neuropsychopharmacol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Ashby, CR (reprint author), St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, 8000 Utopia Pkwy, Jamaica, NY 11439 USA. EM ashbyc@stjohns.edu FU National Institute of General Medical Sciences; U.S. National Institutes of Health [P20-GM103499] FX Contract grant sponsor: National Institute of General Medical Sciences; Contract grant sponsor: U.S. National Institutes of Health; Contract grant number: P20-GM103499. NR 71 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD JUN PY 2015 VL 69 IS 6 BP 336 EP 344 DI 10.1002/syn.21820 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CH4WM UT WOS:000354034000005 PM 25851636 ER PT J AU Shive, HR West, RR Embree, LJ Sexton, JM Hickstein, DD AF Shive, Heather R. West, Robert R. Embree, Lisa J. Sexton, Jamie M. Hickstein, Dennis D. TI Expression of KRAS(G12V) in Zebrafish Gills Induces Hyperplasia and CXCL8-Associated Inflammation SO ZEBRAFISH LA English DT Article ID INCREASING COMPLEXITY; RAS; SOX9; INTERLEUKIN-8; GROWTH; GONAD; CELLS AB The zebrafish (Danio rerio) represents an important animal model for analyzing genetic contributors to carcinogenesis. To assess the role for mutationally activated Ras in ovarian cancer, we developed a transgenic zebrafish model using the putative promoter for zebrafish insulin-like growth factor 3 (igf3) to drive expression of the human oncogene KRAS(G12V) fused to EGFP. A member of the IGF family, igf3 is unique to teleosts and reportedly exhibits gonad-specific expression in fish species. In contrast to previous studies, we observed igf3 expression in wild-type zebrafish gills in addition to gonads, indicating that igf3 expression is not necessarily gonad specific. In transgenic zebrafish, expression of EGFP-KRAS(G12V) driven by the igf3 promoter occurred only in the gills and resulted in proliferation of a putative progenitor cell population, chondroid hyperplasia, and localized inflammation. KRAS(G12V)-transformed cells in transgenic zebrafish showed activation of the ERK-MAP kinase pathway and expressed the zebrafish homologue for human CXCL8, a cytokine produced by mammalian Ras-transformed cells in tumor-associated inflammatory lesions. These findings indicate that KRAS(G12V)-transformed cells in zebrafish recruit inflammatory cells, but may require additional mutational events for neoplastic transformation. The conserved role for mutationally activated KRAS in leukocyte recruitment indicates that zebrafish can provide a valuable comparative model for Ras-associated inflammation. C1 [Shive, Heather R.; West, Robert R.; Embree, Lisa J.; Sexton, Jamie M.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shive, HR (reprint author), N Carolina State Univ, Dept Populat Hlth & Pathobiol, Coll Vet Med, CVM Res Bldg,Room 248 1060 William Moore Dr, Raleigh, NC 27607 USA. EM hrshive@ncsu.edu FU U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The authors thank Ms. Veena Kapoor for isolation and collection of zebrafish cells by FACS. This work was supported by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 24 TC 0 Z9 0 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 EI 1557-8542 J9 ZEBRAFISH JI Zebrafish PD JUN 1 PY 2015 VL 12 IS 3 BP 221 EP 229 DI 10.1089/zeb.2014.1038 PG 9 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA CI1SU UT WOS:000354525600003 PM 25798815 ER PT J AU Garcia-Matas, S Paul, RK Molina-Martinez, P Palacios, H Gutierrez, VM Corpas, R Pallas, M Cristofol, R de Cabo, R Sanfeliu, C AF Garcia-Matas, Silvia Paul, Rajib K. Molina-Martinez, Patricia Palacios, Hector Gutierrez, Vincent M. Corpas, Ruben Pallas, Merce Cristofol, Rosa de Cabo, Rafael Sanfeliu, Coral TI In vitro caloric restriction induces protective genes and functional rejuvenation in senescent SAMP8 astrocytes SO AGING CELL LA English DT Article DE astrocytes; caloric restriction; mitochondria; oxidative stress; RNA microarrays; SAMP8 ID ALZHEIMERS-DISEASE; OXIDATIVE STRESS; MOUSE MODEL; NEUROPROTECTIVE CAPACITY; ACCELERATED MICE; RHESUS-MONKEYS; WISTAR RATS; HUMANS; HEALTHSPAN; LONGEVITY AB Astrocytes are key cells in brain aging, helping neurons to undertake healthy aging or otherwise letting them enter into a spiral of neurodegeneration. We aimed to characterize astrocytes cultured from senescence-accelerated prone 8 (SAMP8) mice, a mouse model of brain pathological aging, along with the effects of caloric restriction, the most effective rejuvenating treatment known so far. Analysis of the transcriptomic profiles of SAMP8 astrocytes cultured in control conditions and treated with caloric restriction serum was performed using mRNA microarrays. A decrease in mitochondrial and ribosome mRNA, which was restored by caloric restriction, confirmed the age-related profile of SAMP8 astrocytes and the benefits of caloric restriction. An amelioration of antioxidant and neurodegeneration-related pathways confirmed the brain benefits of caloric restriction. Studies of oxidative stress and mitochondrial function demonstrated a reduction of oxidative damage and partial improvement of mitochondria after caloric restriction. In summary, caloric restriction showed a significant tendency to normalize pathologically aged astrocytes through the activation of pathways that are protective against the age-related deterioration of brain physiology. C1 [Garcia-Matas, Silvia; Molina-Martinez, Patricia; Corpas, Ruben; Cristofol, Rosa; Sanfeliu, Coral] CSIC, Biomed Res Inst Barcelona IIBB, Aging & Neurodegenerat Unit, Barcelona 08036, Spain. [Garcia-Matas, Silvia; Molina-Martinez, Patricia; Corpas, Ruben; Cristofol, Rosa; Sanfeliu, Coral] IDIBAPS, Barcelona 08036, Spain. [Paul, Rajib K.; Palacios, Hector; Gutierrez, Vincent M.; de Cabo, Rafael] NIA, Expt Gerontol Sect, TGB, NIH, Baltimore, MD 21224 USA. [Pallas, Merce] Univ Barcelona, Fac Pharm, Dept Pharmacol & Therapeut Chem, IBUB, E-08028 Barcelona, Spain. [Pallas, Merce] CIBERNED, Barcelona 08028, Spain. RP de Cabo, R (reprint author), NIA, Expt Gerontol Sect, TGB, NIH, Suite 100 Room 9C218,251 Bayview Blvd, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693; Pallas, Merce/0000-0003-3095-4254 FU Spanish MINECO [SAF2009-13093, SAF2012-39852, CSD2010-00045]; Generalitat of Catalonia [2009/SGR/214]; European Regional evelopment Fund (ERDF) FX This study was supported by grants SAF2009-13093, SAF2012-39852, and CSD2010-00045 from the Spanish MINECO, 2009/SGR/214 from the Generalitat of Catalonia, and the European Regional evelopment Fund (ERDF). NR 45 TC 2 Z9 2 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD JUN PY 2015 VL 14 IS 3 BP 334 EP 344 DI 10.1111/acel.12259 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CH0DN UT WOS:000353689400004 PM 25711920 ER PT J AU Brockie, TN Dana-Sacco, G Wallen, GR Wilcox, HC Campbell, JC AF Brockie, Teresa N. Dana-Sacco, Gail Wallen, Gwenyth R. Wilcox, Holly C. Campbell, Jacquelyn C. TI The Relationship of Adverse Childhood Experiences to PTSD, Depression, Poly-Drug Use and Suicide Attempt in Reservation-Based Native American Adolescents and Young Adults SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE Native American; Youth; Adverse childhood experiences; Risk behavior; Mental health; Reservation-based; Perceived discrimination; Historical loss associated symptoms ID SHORT SCREENING SCALE; POSTTRAUMATIC-STRESS-DISORDER; PERCEIVED DISCRIMINATION; HOUSEHOLD DYSFUNCTION; INDIGENOUS ADOLESCENTS; PARTNER VIOLENCE; HISTORICAL LOSS; ALCOHOL-ABUSE; SUBSTANCE USE; RISK AB Adverse childhood experiences (ACEs) are associated with numerous risk behaviors and mental health outcomes among youth. This study examines the relationship between the number of types of exposures to ACEs and risk behaviors and mental health outcomes among reservation-based Native Americans. In 2011, data were collected from Native American (N = 288; 15-24 years of age) tribal members from a remote plains reservation using an anonymous web-based questionnaire. We analyzed the relationship between six ACEs, emotional, physical, and sexual abuse, physical and emotional neglect, witness to intimate partner violence, for those < 18 years, and included historical loss associated symptoms, and perceived discrimination for those < 19 years; and four risk behavior/mental health outcomes: post-traumatic stress disorder (PTSD) symptoms, depression symptoms, poly-drug use, and suicide attempt. Seventy-eight percent of the sample reported at least one ACE and 40 % reported at least two. The cumulative impact of the ACEs were significant (p < .001) for the four outcomes with each additional ACE increasing the odds of suicide attempt (37 %), poly-drug use (51 %), PTSD symptoms (55 %), and depression symptoms (57 %). To address these findings culturally appropriate childhood and adolescent interventions for reservation-based populations must be developed, tested and evaluated longitudinally. C1 [Brockie, Teresa N.; Wallen, Gwenyth R.] NIH, Nursing Res & Translat Sci, Ctr Clin, Bethesda, MD 20892 USA. [Dana-Sacco, Gail] Univ Maine, Orono, ME USA. [Wilcox, Holly C.] Johns Hopkins Sch Med, Baltimore, MD USA. [Campbell, Jacquelyn C.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. RP Brockie, TN (reprint author), NIH, Nursing Res & Translat Sci, Ctr Clin, 10 Ctr Dr,Room 3C440, Bethesda, MD 20892 USA. EM brockiet@cc.nih.gov; gail.danasacco@gmail.com; GWallen@cc.nih.gov; hwilcox1@jhmi.edu FU National Institutes of Health Clinical Center; Johns Hopkins Bloomberg School of Public Health Center for American Indian Health FX We gratefully acknowledge Dr. John Umhau, Indian Health Service, for his expertise. This work was supported in part by the intramural research program at the National Institutes of Health Clinical Center and the Johns Hopkins Bloomberg School of Public Health Center for American Indian Health. NR 57 TC 9 Z9 9 U1 2 U2 36 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0562 EI 1573-2770 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD JUN PY 2015 VL 55 IS 3-4 BP 411 EP 421 DI 10.1007/s10464-015-9721-3 PG 11 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA CH1JT UT WOS:000353778300015 PM 25893815 ER PT J AU Piao, YS Hall, FS Moriya, Y Ito, M Ohara, A Kikura-Hanajiri, R Goda, Y Lesch, KP Murphy, DL Uhl, GR Sora, I AF Piao, Ying-Shan Hall, Frank Scott Moriya, Yuki Ito, Miki Ohara, Arihisa Kikura-Hanajiri, Ruri Goda, Yukihiro Lesch, Klaus-Peter Murphy, Dennis L. Uhl, George R. Sora, Ichiro TI Methylone-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE dopamine; hyperthermia; knockout mice; lethality; methylone; serotonin; toxicity; transporter ID CONDITIONED PLACE PREFERENCE; BODY-TEMPERATURE; 3,4-METHYLENEDIOXYMETHAMPHETAMINE ECSTASY; MONOAMINE TRANSPORTERS; AMBIENT-TEMPERATURE; PHARMACOLOGICAL CHARACTERIZATION; METHAMPHETAMINE NEUROTOXICITY; BRAIN HYPERTHERMIA; COCAINE REWARD; MICE LACKING AB Methylone (2-methylamino-1-[3,4-methylenedioxy-phenyl] propan-1-one), an amphetamine analog, has emerged as a popular drug of abuse worldwide. Methylone induces hyperthermia, which is thought to contribute toward the lethal consequences of methylone overdose. Methylone has been assumed to induce hyperthermic effects through inhibition of serotonin and/or dopamine transporters (SERT and DAT, respectively). To examine the roles of each of these proteins in methylone-induced toxic effects, we used SERT and DAT knockout (KO) mice and assessed the hyperthermic and lethal effects caused by a single administration of methylone. Methylone produced higher rates of lethal toxicity compared with other amphetamine analogs in wild-type mice. Compared with wild-type mice, lethality was significantly lower in DAT KO mice, but not in SERT KO mice. By contrast, only a slight diminution in the hyperthermic effects of methylone was observed in DAT KO mice, whereas a slight enhancement of these effects was observed in SERT KO mice. Administration of the selective D1 receptor antagonist SCH 23390 and the D2 receptor antagonist raclopride reduced methylone-induced hyperthermia, but these drugs also had hypothermic effects in saline-treated mice, albeit to a smaller extent than the effects observed in methylone-treated mice. In contradistinction to 3,4-methylenedioxymethamphetamine, which induces its toxicity through SERT and DAT, these data indicate that DAT, but not SERT, is strongly associated with the lethal toxicity produced by methylone, which did not seem to be dependent on the hyperthermic effects of methylone. DAT is therefore a strong candidate molecule for interventions aimed at preventing acute neurotoxic and lethal effects of methylone. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved. C1 [Piao, Ying-Shan; Moriya, Yuki; Ito, Miki; Ohara, Arihisa; Sora, Ichiro] Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 980, Japan. [Kikura-Hanajiri, Ruri; Goda, Yukihiro] Natl Inst Hlth Sci, Div Pharmacognosy Phytochem & Narcot, Tokyo, Japan. [Sora, Ichiro] Kobe Univ, Dept Psychiat, Grad Sch Med, Kobe, Hyogo 6500017, Japan. [Hall, Frank Scott] Univ Toledo, Coll Pharm & Pharmaceut Sci, Dept Pharmacol, Toledo, OH 43606 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. [Uhl, George R.] NIA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Lesch, Klaus-Peter] Univ Wurzburg, Dept Psychiat, Wurzburg, Germany. [Piao, Ying-Shan] Capital Med Univ, Dept Geriatr, Beijing Tiantan, Beijing, Peoples R China. RP Sora, I (reprint author), Kobe Univ, Dept Psychiat, Grad Sch Med, Chuo Ku, 7-5-1 Kusunoki Cho, Kobe, Hyogo 6500017, Japan. EM sora@med.kobe-u.ac.jp RI Hall, Frank/C-3036-2013; Lesch, Klaus-Peter/J-4906-2013 OI Hall, Frank/0000-0002-0822-4063; Lesch, Klaus-Peter/0000-0001-8348-153X FU Ministry of Health, Labor, and Welfare of Japan; Ministry of Education, Culture, Sports, Science, and Technology of Japan; National Institute on Drug abuse, Intramural Research Program, NIH (USA) FX This study was supported in part by a Grant-in-Aid for Health and Labor Science Research (Research on Pharmaceutical and Medical Safety) from the Ministry of Health, Labor, and Welfare of Japan (I.S.), by Grants-in-Aid for Scientific Research (B), Scientific Research on Priority Areas-System study on higher-order brain functions and Research on Pathomechanisms of Brain Disorders, Core Research for Evolutional Science and Technology (CREST), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (I.S.), and by the National Institute on Drug abuse, Intramural Research Program, NIH (USA) (G.R.U.). NR 52 TC 2 Z9 2 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD JUN PY 2015 VL 26 IS 4 BP 345 EP 352 DI 10.1097/FBP.0000000000000135 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA CH2GT UT WOS:000353844400003 PM 25794333 ER PT J AU Maio, N Rouault, TA AF Maio, Nunziata Rouault, Tracey A. TI Iron-sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Review DE LYR motif protein; HSC20; HSPA9; ISCU; SDHB; Mammalian Fe-S cluster assembly ID COMPLEX I DEFICIENCY; LINKED SIDEROBLASTIC ANEMIA; SCAFFOLD PROTEIN ISCU; MITOCHONDRIAL CYSTEINE DESULFURASE; MOLYBDENUM COFACTOR BIOSYNTHESIS; MONOTHIOL GLUTAREDOXINS FUNCTION; RESPIRATORY-CHAIN COMPLEXES; FRIEDREICH ATAXIA PATIENTS; TRIPLET-REPEAT EXPANSION; ABC TRANSPORTER ATM1P AB Iron-sulfur (Fe-S) clusters are ancient, ubiquitous cofactors composed of iron and inorganic sulfur. The combination of the chemical reactivity of iron and sulfur, together with many variations of cluster composition, oxidation states and protein environments, enables Fe-S clusters to participate in numerous biological processes. Fe-S clusters are essential to redox catalysis in nitrogen fixation, mitochondrial respiration and photosynthesis, to regulatory sensing in key metabolic pathways (i.e. cellular iron homeostasis and oxidative stress response), and to the replication and maintenance of the nuclear genome. Fe-S cluster biogenesis is a multistep process that involves a complex sequence of catalyzed protein-protein interactions and coupled conformational changes between the components of several dedicated multimeric complexes. Intensive studies of the assembly process have clarified key points in the biogenesis of Fe-S proteins. However several critical questions still remain, such as: what is the role of frataxin? Why do some defects of Fe-S cluster biogenesis cause mitochondrial iron overload? How are specific Fe-S recipient proteins recognized in the process of Fe-S transfer? This review focuses on the basic steps of Fe-S cluster biogenesis, drawing attention to recent advances achieved on the identification of molecular features that guide selection of specific subsets of nascent Fe-S recipients by the cochaperone HSC20. Additionally, it outlines the distinctive phenotypes of human diseases due to mutations in the components of the basic pathway. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. Published by Elsevier B.V. C1 [Maio, Nunziata; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov FU Intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors are grateful to Dr. Wing-Hang Tong for critical reading of the manuscript and for insightful discussion. This work was supported by the Intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 330 TC 33 Z9 34 U1 6 U2 29 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 JUN PY 2015 VL 1853 IS 6 SI SI BP 1493 EP 1512 DI 10.1016/j.bbamcr.2014.09.009 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CH0RG UT WOS:000353729500020 PM 25245479 ER PT J AU Rossini, PM Burke, D Chen, R Cohen, LG Daskalakis, Z Di Iorio, R Di Lazzaro, V Ferreri, F Fitzgerald, PB George, MS Hallett, M Lefaucheur, JP Langguth, B Matsumoto, H Miniussi, C Nitsche, MA Pascual-Leone, A Paulus, W Rossi, S Rothwell, JC Siebner, HR Ugawa, Y Walsh, V Ziemann, U AF Rossini, P. M. Burke, D. Chen, R. Cohen, L. G. Daskalakis, Z. Di Iorio, R. Di Lazzaro, V. Ferreri, F. Fitzgerald, P. B. George, M. S. Hallett, M. Lefaucheur, J. P. Langguth, B. Matsumoto, H. Miniussi, C. Nitsche, M. A. Pascual-Leone, A. Paulus, W. Rossi, S. Rothwell, J. C. Siebner, H. R. Ugawa, Y. Walsh, V. Ziemann, U. TI Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an IFCN Committee SO CLINICAL NEUROPHYSIOLOGY LA English DT Review DE Non-invasive stimulation; Transcranial magnetic stimulation; Human cortex; Clinical neurophysiology; TMS measures; Excitability threshold ID HUMAN MOTOR CORTEX; THETA-BURST-STIMULATION; PAIRED ASSOCIATIVE STIMULATION; INTRACTABLE DEAFFERENTATION PAIN; DORSOLATERAL PREFRONTAL CORTEX; AMYOTROPHIC-LATERAL-SCLEROSIS; LATENCY AFFERENT INHIBITION; FORAMEN MAGNUM LEVEL; INTERVAL INTRACORTICAL INHIBITION; PROGRESSIVE MYOCLONUS EPILEPSY AB These guidelines provide an up-date of previous IFCN report on ``Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application'' (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 ''Report'', was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments. (C) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. C1 [Rossini, P. M.; Di Iorio, R.] Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, Policlin A Gemelli, Inst Neurol, I-00168 Rome, Italy. [Burke, D.] Univ Sydney, Royal Prince Alfred Hosp, Dept Neurol, Sydney, NSW 2006, Australia. [Chen, R.] Univ Toronto, Toronto Western Res Inst, Div Neurol, Toronto, ON, Canada. [Cohen, L. G.] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Daskalakis, Z.] Univ Toronto, Temerty Ctr Therapeut Brain Intervent, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Di Lazzaro, V.; Ferreri, F.] Univ Campus Biomed, Dept Neurol, Rome, Italy. [Ferreri, F.] Univ Eastern Finland, Dept Clin Neurophysiol, Kuopio, Finland. [Fitzgerald, P. B.] Monash Univ, Cent Clin Sch, Monash Alfred Psychiat Res Ctr, Melbourne, Vic 3004, Australia. [Fitzgerald, P. B.] The Alfred, Melbourne, Vic, Australia. [George, M. S.] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. [Hallett, M.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lefaucheur, J. P.] Henri Mondor Hosp, AP HP, Dept Physiol, F-94010 Creteil, France. [Lefaucheur, J. P.] Paris Est Creteil Univ, Fac Med, Nerve Excitabil & Therapeut Team, EA 4391, F-94010 Creteil, France. [Langguth, B.] Univ Regensburg, Dept Psychiat & Psychotherapy, D-93053 Regensburg, Germany. [Matsumoto, H.] Japanese Red Cross Med Ctr, Dept Neurol, Tokyo, Japan. [Miniussi, C.] Univ Brescia, Dept Clin & Expt Sci, Brescia, Italy. [Miniussi, C.] IRCCS, Ctr San Giovanni Dio Fatebenefratelli, Brescia, Italy. [Nitsche, M. A.] Univ Gottingen, Univ Med Ctr Groningen, Dept Clin Neurophysiol, D-37073 Gottingen, Germany. [Pascual-Leone, A.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA USA. [Paulus, W.] Univ Gottingen, Dept Clin Neurophysiol, D-37073 Gottingen, Germany. [Rossi, S.] Univ Siena, Brain Invest & Neuromodulat Lab, Unit Neurol & Clin Neurophysiol, Dept Neurosci, I-53100 Siena, Italy. [Rothwell, J. C.] UCL, Inst Neurol, London, England. [Siebner, H. R.] Univ Copenhagen, Bispebjerg Hosp, Dept Neurol, Copenhagen, Denmark. [Siebner, H. R.] Univ Copenhagen, Hvidovre Hosp, Danish Res Ctr Magnet Resonance, Ctr Funct & Diagnost Imaging & Res, DK-2650 Hvidovre, Denmark. [Ugawa, Y.] Fukushima Med Univ, Dept Neurol, Sch Med, Fukushima, Japan. [Walsh, V.] UCL, Inst Cognit Neurosci, London, England. [Ziemann, U.] Univ Tubingen, Dept Neurol & Stroke, Tubingen, Germany. [Ziemann, U.] Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany. RP Di Iorio, R (reprint author), Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, Policlin A Gemelli, Inst Neurol, Lgo A Gemelli 8, I-00168 Rome, Italy. EM r.diiorio@live.it RI Siebner, Hartwig/G-4052-2016; Miniussi, Carlo/E-7602-2010; Chen, Robert/B-3899-2009; Paulus, Walter/A-3544-2009; OI Miniussi, Carlo/0000-0002-5436-4745; Chen, Robert/0000-0002-8371-8629; Paulus, Walter/0000-0001-5549-8377; Ferreri, Florinda/0000-0002-7938-905X; Rothwell, John/0000-0003-1367-6467; Di Lazzaro, Vincenzo/0000-0002-9113-5925; rossi, simone/0000-0001-6697-9459 NR 493 TC 140 Z9 141 U1 25 U2 101 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUN PY 2015 VL 126 IS 6 BP 1071 EP 1107 DI 10.1016/j.clinph.2015.02.001 PG 37 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CH1ME UT WOS:000353785000006 PM 25797650 ER PT J AU Penesova, A Koska, J Ortega, E Bunt, JC Bogardus, C de Courten, B AF Penesova, A. Koska, J. Ortega, E. Bunt, J. C. Bogardus, C. de Courten, B. TI Salsalate has no effect on insulin secretion but decreases insulin clearance: a randomized, placebo-controlled trial in subjects without diabetes SO DIABETES OBESITY & METABOLISM LA English DT Article DE C-peptide; insulin secretion; salicylates; salsalate; stepped hyperglycaemia ID GLUCOSE-TOLERANCE; HEALTHY AB To elucidate whether increased insulin concentration after salsalate treatment (3 g/day for 7 days) is attributable to an increased insulin secretion rate (ISR) or to reduced metabolic clearance of endogenous insulin (MCI) during stepped glucose infusion (SGI). The analysis was performed in obese subjects who participated in a randomized double-blind, parallel, placebo-controlled clinical trial. A total of 27 participants (16 on salsalate, 11 on placebo) completed baseline and follow-up SGI. During SGI in the salsalate group, C-peptide concentrations were reduced by 11%, while plasma insulin concentrations were increased by 30%, corresponding to a 30% reduction in MCI (p< 0.0001). At molar increments of glucose, insulin concentrations were increased by 27% (p= 0.02), but ISR was unchanged. Salsalate did not alter insulin secretion, but lowered MCI, indicating that a reduction in insulin clearance is the principal mechanism for increased insulin levels after salsalate administration. C1 [Penesova, A.; Koska, J.; Ortega, E.; Bunt, J. C.; Bogardus, C.; de Courten, B.] NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH,DHHS, Phoenix, AZ USA. [Penesova, A.] Slovak Acad Sci, Inst Expt Endocrinol, Ctr Mol Med, Bratislava, Slovakia. [Koska, J.] Phoenix VA Hlth Care Syst, Phoenix, AZ USA. [Ortega, E.] CIBEROBN, IDIBAPS, Hosp Clin, Dept Endocrinol & Nutr,ICMDM, Barcelona, Spain. [de Courten, B.] Monash Univ, Sch Publ Hlth & Prevent Med, MCHRI, Melbourne, Vic 3004, Australia. RP de Courten, B (reprint author), Monash Univ, Sch Publ Hlth & Prevent Med, Monash Ctr Hlth Res & Implementat, 43-51 Kanooka Grove, Clayton, Vic 3186, Australia. EM barbora.decourten@monash.edu FU National Institute of Diabetes and Digestive and Kidney Diseases FX We would like to thank John Graves, Carol Massengill, Jeanette Impson, metabolic kitchen, nursing and technical staff, and the individuals who volunteered for this study. The contents of this article do not represent the views of the Department of Health and Human Services, Department of Veterans Affairs or the US Government. All the research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases intramural programme. NR 12 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-8902 EI 1463-1326 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD JUN PY 2015 VL 17 IS 6 BP 608 EP 612 DI 10.1111/dom.12450 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CH1EX UT WOS:000353765000013 PM 25683256 ER PT J AU Bornstein, MH Putnick, DL Lansford, JE Pastorelli, C Skinner, AT Sorbring, E Tapanya, S Tirado, LMU Zelli, A Alampay, LP Al-Hassan, SM Bacchini, D Bombi, AS Chang, L Deater-Deckard, K Di Giunta, L Dodge, KA Malone, PS Oburu, P AF Bornstein, Marc H. Putnick, Diane L. Lansford, Jennifer E. Pastorelli, Concetta Skinner, Ann T. Sorbring, Emma Tapanya, Sombat Uribe Tirado, Liliana Maria Zelli, Arnaldo Pena Alampay, Liane Al-Hassan, Suha M. Bacchini, Dario Bombi, Anna Silvia Chang, Lei Deater-Deckard, Kirby Di Giunta, Laura Dodge, Kenneth A. Malone, Patrick S. Oburu, Paul TI Mother and father socially desirable responding in nine countries: Two kinds of agreement and relations to parenting self-reports SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Article DE Mothers; Socially desirable responding; Fathers; Culture ID CROSS-NATIONAL SAMPLES; SHORT FORMS; MULTIATTRIBUTIONAL CAUSALITY; ORGANIZATIONAL-BEHAVIOR; MARLOWE; BIAS; SCALE; CULTURE; GENDER; STYLES AB We assessed 2 forms of agreement between mothers' and fathers' socially desirable responding in China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand and the United States (N = 1110 families). Mothers and fathers in all 9 countries reported socially desirable responding in the upper half of the distribution, and countries varied minimally (but China was higher than the cross-country grand mean and Sweden lower). Mothers and fathers did not differ in reported levels of socially desirable responding, and mothers' and fathers' socially desirable responding were largely uncorrelated. With one exception, mothers' and fathers' socially desirable responding were similarly correlated with self-perceptions of parenting, and correlations varied somewhat across countries. These findings are set in a discussion of socially desirable responding, cultural psychology and family systems. C1 [Bornstein, Marc H.; Putnick, Diane L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD 20892 USA. [Lansford, Jennifer E.; Skinner, Ann T.; Dodge, Kenneth A.] Duke Univ, Ctr Child & Family Policy, Durham, NC USA. [Pastorelli, Concetta; Uribe Tirado, Liliana Maria; Bombi, Anna Silvia; Di Giunta, Laura] Univ Roma La Sapienza, Fac Psychol, I-00185 Rome, Italy. [Sorbring, Emma] Univ West, Dept Psychol, Trollhottan, Sweden. [Tapanya, Sombat] Chiang Mai Univ, Dept Psychiat, Chiang Mai, Thailand. [Uribe Tirado, Liliana Maria] Univ San Buenaventura, Consultorio Psicol Popular, Bolivar, Colombia. [Zelli, Arnaldo] Univ Rome Foro Italico, Dept Educ Sci, Rome, Italy. [Pena Alampay, Liane] Ateneo Manila Univ, Dept Psychol, Quezon City, Philippines. [Al-Hassan, Suha M.] Hashemite Univ, Queen Rania Fac Childhood, Az Zarqa, Jordan. [Bacchini, Dario] Univ Naples 2, Dept Psychol, Naples, Italy. [Chang, Lei] Chinese Univ Hong Kong, Dept Educ Psychol, Hong Kong, Hong Kong, Peoples R China. [Deater-Deckard, Kirby] Virginia Polytech Inst & State Univ, Dept Psychol, Blacksburg, VA 24061 USA. [Malone, Patrick S.] Univ S Carolina, Dept Psychol, Columbia, SC 29208 USA. [Oburu, Paul] Maseno Univ, Dept Psychol, Maseno, Kenya. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov RI ZELLI, ARNALDO/N-2333-2015; OI ZELLI, ARNALDO/0000-0003-4020-8159; Bacchini, Dario/0000-0001-6140-9377; Putnick, Diane/0000-0002-6323-749X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [RO1-HD054805]; Fogarty International Center [RO3-TW008141]; NIH, NICHD FX MHB, DLP and JEL designed the study. MHB and DLP drafted the initial manuscript. DLP conducted the analyses. All other authors collected and coded the data and contributed to revising the manuscript. We thank A. Dovidio and the families who participated in this research. This research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant RO1-HD054805) and the Fogarty International Center (grant RO3-TW008141) and was supported by the Intramural Research Program of the NIH, NICHD. This article has been contributed to by US Government employees and their work is in the public domain in the USA. NR 87 TC 11 Z9 11 U1 5 U2 19 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0020-7594 EI 1464-066X J9 INT J PSYCHOL JI Int. J. Psychol. PD JUN PY 2015 VL 50 IS 3 BP 174 EP 185 DI 10.1002/ijop.12084 PG 12 WC Psychology, Multidisciplinary SC Psychology GA CH4AB UT WOS:000353971500002 PM 25043708 ER PT J AU Gonzalez, CE Pacheco, J Beason-Held, LL Resnick, SM AF Gonzalez, Christopher E. Pacheco, Jennifer Beason-Held, Lori L. Resnick, Susan M. TI Longitudinal changes in cortical thinning associated with hypertension SO JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure variability; brain aging; cortical thickness; longitudinal change; midlife blood pressure ID MIDLIFE BLOOD-PRESSURE; MAGNETIC-RESONANCE IMAGES; HUMAN CEREBRAL-CORTEX; WHITE-MATTER LESIONS; ALZHEIMERS-DISEASE; OLDER-ADULTS; GEOMETRICALLY ACCURATE; COGNITIVE FUNCTION; BRAIN MORPHOLOGY; SEGMENTATION AB Background: Cross-sectional studies of the association between hypertension (HTN) and brain atrophy have shown reductions in prefrontal, temporal, and hippocampal volumes, and have identified thinner cortices across the cortical mantle. Method: In the current study, we followed 96 participants enrolled in the Baltimore Longitudinal Study of Aging over a mean interval of 8 years (mean age at baseline = 68.7) and compared those who are hypertensive (n = 49) throughout the study with those who are normotensive (n = 47). Results: Hypertensive individuals show an increased rate of thinning compared with normotensive individuals in several regions, including the frontomarginal gyrus in the left hemisphere, and the superior temporal, fusiform, and lateral orbitofrontal cortex in the right hemisphere. We also investigated the effects of midlife blood pressure (BP), intervisit variability in BP prior to imaging, and duration of HTN on areas that show subsequent differences in the rates of cortical thinning between groups. We found that higher midlife BP and longer durations of HTN predicted a higher rate of thinning in the right superior temporal gyrus. We also found that greater variability in SBP but not DBP predicted a higher rate of thinning in the right superior temporal gyrus, frontomarginal gyrus, and occipital pole. Conclusion: These findings demonstrate that hypertensive individuals show increased rates of thinning compared with normotensive individuals and suggest intervisit BP variability and midlife BP contribute to these longitudinal differences. C1 [Gonzalez, Christopher E.; Pacheco, Jennifer; Beason-Held, Lori L.; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Pacheco, Jennifer] Walter Reed Natl Mil Med Ctr, Natl Intrepid Ctr Excellence, Bethesda, MD USA. RP Beason-Held, LL (reprint author), NIA, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM heldlo@mail.nih.gov FU NIH, National Institute on Aging; [N01-AG-3-2124] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by Research and Development Contract N01-AG-3-2124. NR 44 TC 4 Z9 4 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2015 VL 33 IS 6 BP 1242 EP 1248 DI 10.1097/HJH.0000000000000531 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CH1YN UT WOS:000353819700019 PM 25693060 ER PT J AU Ortiz, AM DiNapoli, SR Brenchley, JM AF Ortiz, Alexandra M. DiNapoli, Sarah R. Brenchley, Jason M. TI Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID DENDRITIC CELLS; MICROBIAL TRANSLOCATION; IMMUNE ACTIVATION; ALVEOLAR MACROPHAGES; EXPERIMENTAL COLITIS; LY6C(HI) MONOCYTES; INNATE IMMUNITY; SIV INFECTION; HIV-INFECTION; PHAGOCYTOSIS AB Macrophages regulate tissue immunity, orchestrating the initiation and resolution of antimicrobial immune responses and repair of damaged tissue architecture. Their dysfunction can, thus, manifest in either pro-and anti-inflammatory responses. Indeed, despite the importance of macrophage function in health and disease, the role of tissue-resident macrophages in human immunodeficiency virus (HIV) disease progression remains incompletely defined. Here, we use flow cytometry to assess the phenotypes and functions of macrophages isolated from the spleens, axillary lymph nodes, colons, jejuna, and livers of healthy and chronically simian immunodeficiency virus (SIV)-infected Asian macaques, the prominent nonhuman primate model for HIV infection. Our data demonstrate that macrophages from healthy animals exhibit considerable phenotypic and functional heterogeneity across tissues and across a variety of stimuli. Further, our analysis reveals changes in the lipopolysaccharide (LPS) responsiveness of macrophages isolated from SIV-infected animals. We anticipate that our findings will inform future research into macrophage-directed immunity across a variety of primate diseases. IMPORTANCE These findings highlight the functional and phenotypic heterogeneity of tissue macrophages in different anatomic sites and as a result of SIV infection. We believe that our data will lead to novel therapeutic interventions aimed at altering the proinflammatory capacity of tissue macrophages in progressively HIV-infected individuals. C1 [Brenchley, Jason M.] NIAID, Program Tissue Immun & Repair, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunopathogenesis Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Brenchley, JM (reprint author), NIAID, Program Tissue Immun & Repair, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@niaid.nih.gov OI DiNapoli, Sarah/0000-0002-3675-9030 FU Division of Intramural Research/NIAID/NIH FX Funding for this study was provided by the Division of Intramural Research/NIAID/NIH. NR 48 TC 6 Z9 6 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 JUN PY 2015 VL 89 IS 11 BP 5883 EP 5894 DI 10.1128/JVI.00005-15 PG 12 WC Virology SC Virology GA CH3DU UT WOS:000353907900013 PM 25787286 ER PT J AU Saunders, KO Pegu, A Georgiev, IS Zeng, M Joyce, MG Yang, ZY Ko, SY Chen, XJ Schmidt, SD Haase, AT Todd, JP Bao, S Kwong, PD Rao, SS Mascola, JR Nabel, GJ AF Saunders, Kevin O. Pegu, Amarendra Georgiev, Ivelin S. Zeng, Ming Joyce, M. Gordon Yang, Zhi-Yong Ko, Sung-Youl Chen, Xuejun Schmidt, Stephen D. Haase, Ashley T. Todd, John-Paul Bao, Saran Kwong, Peter D. Rao, Srinivas S. Mascola, John R. Nabel, Gary J. TI Sustained Delivery of a Broadly Neutralizing Antibody in Nonhuman Primates Confers Long-Term Protection against Simian/Human Immunodeficiency Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; HIV-1/SIV CHIMERIC VIRUS; MUCOSAL SHIV CHALLENGE; NEONATAL FC-RECEPTOR; IN-VITRO; IMPROVES PROTECTION; RATIONAL DESIGN; MACAQUES; HIV; ENVELOPE AB Pathogen-specific neutralizing antibodies protect against many viral infections and can potentially prevent human immunodeficiency virus (HIV) transmission in humans. However, neutralizing antibodies have so far only been shown to protect nonhuman primates (NHP) against lentiviral infection when given shortly before challenge. Thus, the clinical utility and feasibility of passive antibody transfer to confer long-term protection against HIV-1 are still debated. Here, we investigate the potential of a broadly neutralizing HIV-1 antibody to provide long-term protection in a NHP model of HIV-1 infection. A human antibody was simianized to avoid immune rejection and used to sustain therapeutic levels for similar to 5 months. Two months after the final antibody administration, animals were completely protected against viral challenge. These findings demonstrate the feasibility and potential of long-term passive antibody for protection against HIV-1 in humans and provide a model to test antibody therapies for other diseases in NHP. IMPORTANCE Antibodies against HIV are potential drugs that may be able to prevent HIV infection in humans. However, the long-term protective capacity of antibodies against HIV has not been assessed. Here, we repetitively administered a macaque version of a human anti-HIV antibody to monkeys, after which the antibody persisted in the blood for >5 months. Moreover, the antibody could be sustained at protective levels for 108 days, conferring protection 52 days after the last dose in a monkey model of HIV infection. Thus, passive antibody transfer can provide durable protection against infection by viruses that cause AIDS in primates. C1 [Saunders, Kevin O.; Pegu, Amarendra; Georgiev, Ivelin S.; Joyce, M. Gordon; Yang, Zhi-Yong; Ko, Sung-Youl; Chen, Xuejun; Schmidt, Stephen D.; Todd, John-Paul; Bao, Saran; Kwong, Peter D.; Rao, Srinivas S.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Zeng, Ming; Haase, Ashley T.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM John.Mascola@nih.gov; Gary.Nabel@sanofi.com RI Schmidt, Stephen/B-5398-2012; OI Pegu, Amarendra/0000-0003-3564-6453 FU Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health; NIH Nonhuman Primate Reagent Resource (NIAID) [HHSN 2722000900037C] FX We are thankful for veterinary assistance from the members of the Vaccine Research Center Laboratory of Animal Medicine. We thank Tatsiana Kirys for her help with sequence alignments and VRC01 images. We express our gratitude to the Duke Human Vaccine Institute IVQAC for performing the viral load analyses. We also thank Brenda Hartman for manuscript preparation. The macaque IgG used in these studies was provided by the NIH Nonhuman Primate Reagent Resource (R24 RR016001 and NIAID contract HHSN 2722000900037C).; This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health. NR 42 TC 20 Z9 21 U1 0 U2 3 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 JUN PY 2015 VL 89 IS 11 BP 5895 EP 5903 DI 10.1128/JVI.00210-15 PG 9 WC Virology SC Virology GA CH3DU UT WOS:000353907900014 PM 25787288 ER PT J AU Race, B Phillips, K Meade-White, K Striebel, J Chesebro, B AF Race, Brent Phillips, Katie Meade-White, Kimberly Striebel, James Chesebro, Bruce TI Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice Overexpressing Human Prion Protein SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; CELL-FREE FORMATION; AMINO-ACID; MOLECULAR-CLONING; SPECIES BARRIERS; GENE-EXPRESSION; CULTURED-CELLS; HAMSTER PRP; WILD-TYPE AB Prion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previous in vivo studies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8- to 16-fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2- to 4-fold above normal. IMPORTANCE Prion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by mice expressing only anchorless PrP were more infectious than prions produced in mice expressing anchored PrP. Thus, the lack of the GPI anchor on prions reduced the effect of the mouse-human species barrier. Our results suggest that prion diseases that produce higher levels of anchorless PrP may pose an increased risk for cross-species infection. C1 [Race, Brent; Phillips, Katie; Striebel, James; Chesebro, Bruce] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. [Meade-White, Kimberly] NIAID, Rocky Mt Labs, Rocky Mt Vet Branch, NIH, Hamilton, MT 59840 USA. RP Race, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. EM raceb@niaid.nih.gov FU Intramural Research Program of the NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 75 TC 5 Z9 5 U1 0 U2 8 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 JUN PY 2015 VL 89 IS 11 BP 6022 EP 6032 DI 10.1128/JVI.00362-15 PG 11 WC Virology SC Virology GA CH3DU UT WOS:000353907900024 PM 25810548 ER PT J AU Liu, YN Yin, JJ Barrett, B Sheppard-Tillman, H Li, DM Casey, OM Fang, L Hynes, PG Ameri, AH Kelly, K AF Liu, Yen-Nien Yin, JuanJuan Barrett, Ben Sheppard-Tillman, Heather Li, Dongmei Casey, Orla M. Fang, Lei Hynes, Paul G. Ameri, Amir H. Kelly, Kathleen TI Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RECEPTOR TYROSINE KINASES; TUMOR-SUPPRESSOR; FAMILY KINASES; MOUSE MODEL; DASATINIB; THERAPIES; SELECTION; PROGRAM; PTEN; PHOSPHORYLATION AB Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes. C1 [Liu, Yen-Nien] Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan. [Yin, JuanJuan; Barrett, Ben; Sheppard-Tillman, Heather; Casey, Orla M.; Fang, Lei; Hynes, Paul G.; Ameri, Amir H.; Kelly, Kathleen] NCI, Lab Genitourinary Canc Pathogenesis, NIH, Bethesda, MD 20892 USA. [Li, Dongmei] Nanjing Univ, Sch Med, Immunol & Reprod Biol Lab, Nanjing 210008, Jiangsu, Peoples R China. RP Liu, YN (reprint author), Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan. EM liuy@tmu.edu; kellyka@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Health Research Institutes [NHRI-EX103-10308BC]; Ministry of Science and Technology of Taiwan [MOST 103-2314-B-038-051] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by the National Health Research Institutes (NHRI-EX103-10308BC), and by the Ministry of Science and Technology (MOST 103-2314-B-038-051) of Taiwan. NR 45 TC 9 Z9 10 U1 0 U2 8 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 JUN PY 2015 VL 35 IS 11 BP 1940 EP 1951 DI 10.1128/MCB.00008-15 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CH3FI UT WOS:000353913000005 PM 25802280 ER PT J AU Tsukiyama, T Fukui, A Terai, S Fujioka, Y Shinada, K Takahashi, H Yamaguchi, TP Ohba, Y Hatakeyama, S AF Tsukiyama, Tadasuke Fukui, Akimasa Terai, Sayuri Fujioka, Yoichiro Shinada, Keisuke Takahashi, Hidehisa Yamaguchi, Terry P. Ohba, Yusuke Hatakeyama, Shigetsugu TI Molecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BETA-CATENIN DEGRADATION; ADENOMATOUS POLYPOSIS-COLI; WNT/BETA-CATENIN; STEM-CELLS; E3 LIGASE; PATHWAY; PROTEIN; UBIQUITIN; SPECIFICITY; COMPONENTS AB Wnt signaling pathways are tightly regulated by ubiquitination, and dysregulation of these pathways promotes tumorigenesis. It has been reported that the ubiquitin ligase RNF43 plays an important role in frizzled-dependent regulation of the Wnt/beta-catenin pathway. Here, we show that RNF43 suppresses both Wnt/beta-catenin signaling and noncanonical Wnt signaling by distinct mechanisms. The suppression of Wnt/beta-catenin signaling requires interaction between the extracellular protease-associated (PA) domain and the cysteine-rich domain (CRD) of frizzled and the intracellular RING finger domain of RNF43. In contrast, these N-terminal domains of RNF43 are not required for inhibition of noncanonical Wnt signaling, but interaction between the C-terminal cytoplasmic region of RNF43 and the PDZ domain of dishevelled is essential for this suppression. We further show the mechanism by which missense mutations in the extracellular portion of RNF43 identified in patients with tumors activate Wnt/beta-catenin signaling. Missense mutations of RNF43 change their localization from the endosome to the endoplasmic reticulum (ER), resulting in the failure of frizzled-dependent suppression of Wnt/beta-catenin signaling. However, these mutants retain the ability to suppress noncanonical Wnt signaling, probably due to interaction with dishevelled. RNF43 is also one of the potential target genes of Wnt/beta-catenin signaling. Our results reveal the molecular role of RNF43 and provide an insight into tumorigenesis. C1 [Tsukiyama, Tadasuke; Terai, Sayuri; Shinada, Keisuke; Takahashi, Hidehisa; Hatakeyama, Shigetsugu] Hokkaido Univ, Grad Sch Med, Dept Biochem, Sapporo, Hokkaido, Japan. [Fukui, Akimasa] Hokkaido Univ, Fac Adv Life Sci, Lab Tissue & Polymer Sci, Div Adv Interdisciplinary Sci, Sapporo, Hokkaido, Japan. [Fujioka, Yoichiro; Ohba, Yusuke] Hokkaido Univ, Grad Sch Med, Dept Cell Physiol, Sapporo, Hokkaido, Japan. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Hatakeyama, S (reprint author), Hokkaido Univ, Grad Sch Med, Dept Biochem, Sapporo, Hokkaido, Japan. EM hatas@med.hokudai.ac.jp RI Tsukiyama, Tadasuke/D-7589-2012; Hatakeyama, Shigetsugu/C-8333-2012 OI Hatakeyama, Shigetsugu/0000-0002-2150-9979 FU KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology in Japan [24112006, 24390065, 25430102] FX This work was supported by KAKENHI (funds to S.H. [grants 24112006 and 24390065] and to T.T. [grant 25430102]) from the Ministry of Education, Culture, Sports, Science and Technology in Japan. NR 47 TC 3 Z9 4 U1 1 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 JUN PY 2015 VL 35 IS 11 BP 2007 EP 2023 DI 10.1128/MCB.00159-15 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CH3FI UT WOS:000353913000010 PM 25825523 ER PT J AU Moretti, F Rolando, C Winker, M Ivanek, R Rodriguez, J Von Kriegsheim, A Taylor, V Bustin, M Pertz, O AF Moretti, Francesca Rolando, Chiara Winker, Moritz Ivanek, Robert Rodriguez, Javier Von Kriegsheim, Alex Taylor, Verdon Bustin, Michael Pertz, Olivier TI Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEOSOMAL BINDING-PROTEIN; NEUROBLASTOMA-CELLS; TRANSLATIONAL REGULATION; INTRAAXONAL TRANSLATION; ACTIN CYTOSKELETON; HIGH-MOBILITY; TRANSCRIPTION; EXPRESSION; FAMILY; SIGNAL AB Neurons exploit local mRN Atranslation and retrograde transport of transcription factors to regulate gene expression in response to signaling events at distal neuronal ends. Whether epigenetic factors could also be involved in such regulation is not known. We report that them RNA encoding the high-mobility group N5 (HMGN5) chromatin binding protein localizes to growth cones of both neuronlike cells and of hippocampal neurons, where it has the potential to be translated, and that HMGN5 can be retrogradely transported into the nucleus along neurites. Loss of HMGN5 function induces transcriptional changes and impairs neurite outgrowth, while HMGN5 overexpression induces neurite outgrowth and chromatin decompaction; these effects are dependent on growth cone localization of Hmgn5 mRNA. We suggest that the localization and local translation of transcripts coding for epigenetic factors couple the dynamic neuronal outgrowth process with chromatin regulation in the nucleus. C1 [Moretti, Francesca; Winker, Moritz; Pertz, Olivier] Univ Basel, Dept Biomed, Cell Migrat & Neuritogenesis, Basel, Switzerland. [Rolando, Chiara; Taylor, Verdon] Univ Basel, Embryol & Stem Cell Biol, Dept Biomed, Basel, Switzerland. [Ivanek, Robert] Univ Basel, Bioinformat, Dept Biomed, Basel, Switzerland. [Ivanek, Robert] Swiss Inst Bioinformat, Basel, Switzerland. [Rodriguez, Javier; Von Kriegsheim, Alex] Univ Dublin Trinity Coll, Syst Biol Ireland Conway Inst, Dublin 2, Ireland. [Bustin, Michael] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Pertz, O (reprint author), Univ Basel, Dept Biomed, Cell Migrat & Neuritogenesis, Basel, Switzerland. EM olivier.pertz@unibas.ch RI von Kriegsheim, Alex/C-2371-2016; Bustin, Michael/G-6155-2015; OI von Kriegsheim, Alex/0000-0002-4952-8573; Rolando, Chiara/0000-0003-2418-8346 FU EMBO Long-Term Postdoctoral Fellowship; Swiss National Science Foundation FX This work was supported by an EMBO Long-Term Postdoctoral Fellowship to F.M. and by a grant of the Swiss National Science Foundation to O.P. NR 53 TC 2 Z9 2 U1 1 U2 3 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 JUN PY 2015 VL 35 IS 11 BP 2035 EP 2050 DI 10.1128/MCB.00133-15 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CH3FI UT WOS:000353913000012 PM 25825524 ER PT J AU Hathaway, HA Pshenichkin, S Grajkowska, E Gelb, T Emery, AC Wolfe, BB Wroblewski, JT AF Hathaway, Hannah A. Pshenichkin, Sergey Grajkowska, Ewa Gelb, Tara Emery, Andrew C. Wolfe, Barry B. Wroblewski, Jarda T. TI Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism SO NEUROPHARMACOLOGY LA English DT Article DE Metabotropic glutamate receptor 1; Biased agonism; Glutamate; Quisqualate; DHPG; Cerebellar granule cells ID METABOTROPIC GLUTAMATE-RECEPTOR; 7-TRANSMEMBRANE RECEPTORS; HUMAN-MELANOMA; LIGAND BIAS; RAT-BRAIN; SURVIVAL; ACTIVATION; CULTURE; GLUTAMATE-RECEPTOR-1; DEPOLARIZATION AB The majority of existing research on the function of metabotropic glutamate (mGlu) receptor 1 focuses on G protein-mediated outcomes. However, similar to other G protein-coupled receptors (GPCR), it is becoming apparent that mGlu(1) receptor signaling is multi-dimensional and does not always involve G protein activation. Previously, in transfected CHO cells, we showed that mGlu(1) receptors activate a G protein-independent, beta-arrestin-dependent signal transduction mechanism and that some mGlu(1) receptor ligands were incapable of stimulating this response. Here we set out to investigate the physiological relevance of these findings in a native system using primary cultures of cerebellar granule cells. We tested the ability of a panel of compounds to stimulate two mGlu(1) receptor-mediated outcomes: (1) protection from decreased cell viability after withdrawal of trophic support and (2) G protein-mediated phosphoinositide (PI) hydrolysis. We report that the commonly used mGlu(1) receptor ligands quisqualate, DHPG, and ACPD are completely biased towards PI hydrolysis and do not induce mGlu(1) receptor-stimulated neuroprotection. On the other hand, endogenous compounds including glutamate, aspartate, cysteic acid, cysteine sulfinic acid, and homocysteic acid stimulate both responses. These results show that some commonly used mGlu(1) receptor ligands are biased agonists, stimulating only a fraction of mGlu(1) receptor-mediated responses in neurons. This emphasizes the importance of utilizing multiple agonists and assays when studying GPCR function. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Hathaway, Hannah A.; Pshenichkin, Sergey; Grajkowska, Ewa; Gelb, Tara; Wolfe, Barry B.; Wroblewski, Jarda T.] Georgetown Univ, Dept Physiol & Pharmacol, Washington, DC 20057 USA. [Emery, Andrew C.] NIMH, Sect Mol Neuroscience, IRP, Bethesda, MD 20892 USA. RP Hathaway, HA (reprint author), Georgetown Univ, Dept Pharmacol, 3900 Reservoir Rd,NW,Med Dent Bldg SW406, Washington, DC 20057 USA. EM hah32@georgetown.edu OI Emery, Andrew/0000-0002-6760-2570; Hathaway, Hannah/0000-0003-0906-1726 FU National Institutes of Health [NS37436] FX This work was supported by The National Institutes of Health Grant NS37436 to JTW. NR 44 TC 5 Z9 5 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUN PY 2015 VL 93 BP 199 EP 208 DI 10.1016/j.neuropharm.2015.02.007 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CH0RK UT WOS:000353729900020 PM 25700650 ER PT J AU Hammond, GRV Balla, T AF Hammond, Gerald R. V. Balla, Tamas TI Polyphosphoinositide binding domains: Key to inositol lipid biology SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE Phosphoinositide; PH-domain; PX-domain; Phospholipase C; Fluorescence imaging; Membrane ID PLECKSTRIN-HOMOLOGY-DOMAIN; HIGH-AFFINITY BINDING; BRUTONS TYROSINE KINASE; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE LEVELS; BABY HAMSTER-KIDNEY; PLASMA-MEMBRANE; IN-VIVO; LIVING CELLS; PROTEIN-KINASE; PH-DOMAIN AB Polyphosphoinositides (PPIn) are an important family of phospholipids located on the cytoplasmic leaflet of eukaryotic cell membranes. Collectively, they are critical for the regulation of many aspects of membrane homeostasis and signaling, with notable relevance to human physiology and disease. This regulation is achieved through the selective interaction of these lipids with hundreds of cellular proteins, and thus the capability to study these localized interactions is crucial to understanding their functions. In this review, we discuss current knowledge of the principle types of PPIn-protein interactions, focusing on specific lipid-binding domains. We then discuss how these domains have been re-tasked by biologists as molecular probes for these lipids in living cells. Finally, we describe how the knowledge gained with these probes, when combined with other techniques, has led to the current view of the lipids' localization and function in eulcaryotes, focusing mainly on animal cells. This article is part of a Special Issue entitled Phosphoinositides. Published by Elsevier B.V. C1 [Hammond, Gerald R. V.] Univ Pittsburgh, Sch Med, Dept Cell Biol, Pittsburgh, PA 15260 USA. [Balla, Tamas] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, NIH, Bethesda, MD USA. RP Hammond, GRV (reprint author), Univ Pittsburgh, Sch Med, Dept Cell Biol, Pittsburgh, PA 15260 USA. EM ghammond@pitt.edu2; ballat@mail.nih.gov RI Hammond, Gerald/A-5759-2016; OI Hammond, Gerald/0000-0002-6660-3272; Balla, Tamas/0000-0002-9077-3335 FU Intramural NIH HHS [ZIA HD000196-14] NR 169 TC 31 Z9 33 U1 2 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD JUN PY 2015 VL 1851 IS 6 SI SI BP 746 EP 758 DI 10.1016/j.bbalip.2015.02.013 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CG2HP UT WOS:000353095800006 PM 25732852 ER PT J AU Rauner, M Thiele, S Fert, I Araujo, LM Layh-Schmitt, G Colbert, RA Hofbauer, C Bernhardt, R Burki, A Schwiedrzik, J Zysset, PK Pietschmann, P Taurog, JD Breban, M Hofbauer, LC AF Rauner, Martina Thiele, Sylvia Fert, Ingrid Araujo, Luiza M. Layh-Schmitt, Gerlinde Colbert, Robert A. Hofbauer, Christine Bernhardt, Ricardo Buerki, Alexander Schwiedrzik, Jakob Zysset, Philippe K. Pietschmann, Peter Taurog, Joel D. Breban, Maxime Hofbauer, Lorenz C. TI Loss of bone strength in HLA-B27 transgenic rats is characterized by a high bone turnover and is mainly osteoclast-driven SO BONE LA English DT Article DE Spondyloarthritis; HLA-B27 transgenic rat; Bone loss; Bone remodeling; Inflammatory bowel disease ID TUMOR-NECROSIS-FACTOR; UNFOLDED PROTEIN RESPONSE; ANKYLOSING-SPONDYLITIS; MINERAL DENSITY; HLA-B27-TRANSGENIC RATS; INFLAMMATORY DISEASE; COMPUTED-TOMOGRAPHY; DENDRITIC CELLS; FACTOR-ALPHA; MARKERS AB Objective: Although osteopenia is frequent in spondyloarthritis (SpA), the underlying cellular mechanisms and association with other symptoms are poorly understood. This study aimed to characterize bone loss during disease progression, determine cellular alterations, and assess the contribution of inflammatory bowel disease (IBD) to bone loss in HLA-B27 transgenic rats. Methods: Bones of 2-, 6-, and 12-month-old non-transgenic, disease-free HLA-B7 and disease-associated HLA-B27 transgenic rats were examined using peripheral quantitative computed tomography, mu CT, and nanoindentation. Cellular characteristics were determined by histomorphometry and ex vivo cultures. The impact of IBD was determined using [21-3 x 283-2]F-1 rats, which develop arthritis and spondylitis, but not IBD. Results: HLA-B27 transgenic rats continuously lost bone mass with increasing age and had impaired bone material properties, leading to a 3-fold decrease in bone strength at 12 months of age. Bone turnover was increased in HLA-B27 transgenic rats, as evidenced by a 3-fold increase in bone formation and a 6-fold increase in bone resorption parameters. Enhanced osteoclastic markers were associated with a larger number of precursors in the bone marrow and a stronger osteoclastogenic response to RANKL or TNF alpha. Further, IBD-free [21-3 x 283-2]F-1 rats also displayed decreased total and trabecular bone density. Conclusions: HLA-B27 transgenic rats lose an increasing amount of bone density and strength with progressing age, which is primarily mediated via increased bone remodeling in favor of bone resorption. Moreover, IBD and bone loss seem to be independent features of SpA in HLA-B27 transgenic rats. (C) 2015 Elsevier Inc. All rights reserved. C1 [Rauner, Martina; Thiele, Sylvia; Hofbauer, Lorenz C.] Tech Univ Dresden, Med Ctr, Dept Med 3, D-01307 Dresden, Germany. [Fert, Ingrid; Araujo, Luiza M.; Breban, Maxime] Hop Cochin, Inst Cochin, F-75674 Paris, France. [Layh-Schmitt, Gerlinde; Colbert, Robert A.] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Pediat Translat Res Branch, Bethesda, MD USA. [Hofbauer, Christine] Tech Univ Dresden, Med Ctr, Dept Orthoped, D-01307 Dresden, Germany. [Bernhardt, Ricardo] Tech Univ Dresden, Max Bergmann Ctr Biomat, D-01307 Dresden, Germany. [Buerki, Alexander; Schwiedrzik, Jakob; Zysset, Philippe K.] Univ Bern, Inst Surg Technol & Biomech, CH-3012 Bern, Switzerland. [Pietschmann, Peter] Med Univ Vienna, Dept Pathophysiol & Allergy Res, Vienna, Austria. [Taurog, Joel D.] Univ TX SW Med Ctr, Dallas, TX USA. [Hofbauer, Lorenz C.] Ctr Regenerat Therapies, Dresden, Germany. RP Rauner, M (reprint author), Tech Univ Dresden, Med Ctr, Div Endocrinol Diabet & Metab Bone Dis, Dept Med 3, Fetscherstr 74, D-01307 Dresden, Germany. EM martina.rauner@uniklinikum-dresden.de RI Schwiedrzik, Johann Jakob/I-3346-2016; Hofbauer, Lorenz/G-2490-2010 OI Schwiedrzik, Johann Jakob/0000-0002-6689-2828; Hofbauer, Lorenz/0000-0002-8691-8423 FU Deutsche Forschungsgemeinschaft [RA1923/1-1]; Deutsche Forschungsgemeinschaft ("IMMUNOBONE" priority program 1468) [HO1875/8-2, RA1923/4-2]; Habilitationsforderung fur Frauen der TU Dresden; NIAMS [Z01-AR-041184] FX This work was supported by grants from Deutsche Forschungsgemeinschaft (RA1923/1-1 and the "IMMUNOBONE" priority program 1468 (HO1875/8-2 and RA1923/4-2)) to MR and LCH, the Habilitationsforderung fur Frauen der TU Dresden to MR, and the NIAMS Intramural Research Program, Z01-AR-041184, to RAC. We would like to thank Patrick Bohme, Ina Gloe, and Tina Listner for excellent technical assistance and Riku Kiviranta for stimulating discussions. NR 50 TC 2 Z9 3 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD JUN PY 2015 VL 75 BP 183 EP 191 DI 10.1016/j.bone.2015.02.024 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG1ZQ UT WOS:000353075100024 PM 25746795 ER PT J AU Zilbermint, M Stratakis, CA AF Zilbermint, Mihail Stratakis, Constantine A. TI Protein kinase A defects and cortisol-producing adrenal tumors SO Current Opinion in Endocrinology Diabetes and Obesity LA English DT Review DE adrenal tumor; cortisol-producing adrenal adenoma; Cushing syndrome; protein kinase A; protein kinase catalytic subunit alpha; protein kinase catalytic subunit beta; protein kinase type 1 alpha regulatory subunit ID NODULAR ADRENOCORTICAL DISEASE; PKA CATALYTIC SUBUNIT; CARNEY COMPLEX; CUSHINGS-SYNDROME; SOMATIC MUTATIONS; ARMC5 MUTATIONS; HEPATOCELLULAR-CARCINOMA; REGULATORY SUBUNIT; PRKAR1A GENE; HYPERPLASIA AB Purpose of reviewCushing syndrome caused by cortisol-producing adrenal adenomas is a rare condition, associated with high morbidity due to weight gain, diabetes mellitus, osteoporosis, hypertension, muscle weakness, mood disturbance and others. The first gene to be identified as causative of Cushing syndrome was PRKAR1A. We present an update on protein kinase A (PKA) defects and Cushing syndrome.Recent findingsThe cyclic AMP-dependent PKA catalytic subunit alpha (PRKACA) hotspot point mutation (c.617A>C [p.Leu206Arg]), leading to an increase of basal PKA activity, and formation of cortisol-producing adenoma has been frequently shown to cause the most common form of adrenocorticotropic hormone-independent Cushing syndrome.SummarySomatic PRKACA mutations have been found in up to 50% of patients with adrenal adenomas. Germline PRKACA amplification was also seen in bilateral adrenal hyperplasias. PRKACA activation was associated with higher cortisol levels, smaller tumor size and overt Cushing syndrome. This breakthrough is expected to improve our understanding of how PKA defects lead to Cushing syndrome and may spearhead the development of new, molecularly designed therapies. C1 [Zilbermint, Mihail; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,NIH Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC 1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH). NR 48 TC 4 Z9 4 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD JUN PY 2015 VL 22 IS 3 BP 157 EP 162 DI 10.1097/MED.0000000000000149 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG7CB UT WOS:000353458700003 PM 25871963 ER PT J AU Nieman, LK AF Nieman, Lynnette K. TI Update on subclinical Cushing's syndrome SO Current Opinion in Endocrinology Diabetes and Obesity LA English DT Review DE adrenalectomy; hypercortisolism; subclinical Cushing's syndrome ID ADRENAL INCIDENTALOMAS; CORTISOL HYPERSECRETION; HYPERCORTISOLISM; DIAGNOSIS; MORTALITY; PATTERNS AB Purpose of reviewThe present review summarizes recent findings in the diagnosis and treatment of subclinical Cushing's syndrome, a condition of subtle cortisol dysregulation with a spectrum of clinical and biochemical abnormalities.Recent findingsThe diagnosis of subclinical Cushing's syndrome is suggested by abnormal suppression to dexamethasone in a patient with an adrenal mass. The natural history of this disorder includes progression in a minority of cases, and increased cardiovascular disease in patients with more severe and progressive disease, much as is found in overt Cushing's syndrome. In patients with an abnormal response to dexamethasone, additional biochemical and metabolic features increase confidence in the ability of adrenalectomy to reverse clinical abnormalities. In addition, bilateral masses and larger masses are more likely to be associated with hypercortisolism.SummaryWe review the recent literature on subclinical cortisol secretion and suggest that additional studies are needed to define optimal diagnostic and therapeutic approaches. C1 [Nieman, Lynnette K.] Eunice Kennedy Shriver Inst Child Hlth & Human De, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Eunice Kennedy Shriver Inst Child Hlth & Human De, CRC, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM NiemanL@nih.gov FU intramural division of the National Institutes of Health FX This work was funded by the intramural division of the National Institutes of Health. NR 22 TC 5 Z9 5 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD JUN PY 2015 VL 22 IS 3 BP 180 EP 184 DI 10.1097/MED.0000000000000159 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG7CB UT WOS:000353458700006 PM 25887388 ER PT J AU Jiang, LL Chen, SH Chu, CH Wang, SJ Oyarzabal, E Wilson, B Sanders, V Xie, KQ Wang, QS Hong, JS AF Jiang, Lulu Chen, Shih-Heng Chu, Chun-Hsien Wang, Shi-Jun Oyarzabal, Esteban Wilson, Belinda Sanders, Virginia Xie, Keqin Wang, Qingshan Hong, Jau-Shyong TI A Novel Role of Microglial NADPH Oxidase in Mediating Extra-Synaptic Function of Norepinephrine in Regulating Brain Immune Homeostasis SO GLIA LA English DT Article DE extra-synaptic; neurotransmitter; volume transmission; DSP-4; neurodegeneration ID BETA-ADRENERGIC-RECEPTOR; LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; B-LYMPHOCYTE FUNCTION; TUMOR-NECROSIS-FACTOR; DOPAMINERGIC-NEURONS; NORADRENERGIC NEURONS; LOCUS-COERULEUS; IN-VIVO; SUPEROXIDE-PRODUCTION; PARKINSONS-DISEASE AB Although the peripheral anti-inflammatory effect of norepinephrine (NE) is well documented, the mechanism by which this neurotransmitter functions as an anti-inflammatory/neuroprotective agent in the central nervous system (CNS) is unclear. This article aimed to determine the anti-inflammatory/neuroprotective effects and underlying mechanisms of NE in inflammation-based dopaminergic neurotoxicity models. In mice, NE-depleting toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected at 6 months of lipopolysaccharide (LPS)-induced neuroinflammation. It was found that NE depletion enhanced LPS-induced dopaminergic neuron loss in the substantia nigra. This piece of in vivo data prompted us to conduct a series of studies in an effort to elucidate the mechanism as to how NE affects dopamine neuron survival by using primary midbrain neuron/glia cultures. Results showed that submicromolar concentrations of NE dose-dependently protected dopaminergic neurons from LPS-induced neurotoxicity by inhibiting microglia activation and subsequent release of pro-inflammatory factors. However, NE-elicited neuroprotection was not totally abolished in cultures from 2-adrenergic receptor (2-AR)-deficient mice, suggesting that novel pathways other than 2-AR are involved. To this end, It was found that submicromolar NE dose-dependently inhibited NADPH oxidase (NOX2)-generated superoxide, which contributes to the anti-inflammatory and neuroprotective effects of NE. This novel mechanism was indeed adrenergic receptors independent since both (+) and (-) optic isomers of NE displayed the same potency. We further demonstrated that NE inhibited LPS-induced NOX2 activation by blocking the translocation of its cytosolic subunit to plasma membranes. In summary, we revealed a potential physiological role of NE in maintaining brain immune homeostasis and protecting neurons via a novel mechanism. GLIA 2015;63:1057-1072 C1 [Jiang, Lulu; Xie, Keqin] Shandong Univ, Inst Toxicol, Sch Publ Hlth, Jinan 250012, Shandong, Peoples R China. [Jiang, Lulu; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Shi-Jun; Oyarzabal, Esteban; Wilson, Belinda; Wang, Qingshan; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Sanders, Virginia] Ohio State Univ, Inst Behav Med Res, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Hong, JS (reprint author), NIEHS, F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM keqinx@sdu.edu.cn; wangq4@niehs.nih.gov; hong3@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. We thank Anthony Lockhart for assistance with animal colony management and maintenance. We also thank Dr. Honglei Chen (Epidemiology Branch, NIEHS/NIH), Dr. Ronald E. Cannon (Laboratory of Toxicology and Pharmacology, NIEHS/NIH), and Dr. Sabrina D Robertson (Laboratory of Neurobiology, NIEHS/NIH) for reviewing this manuscript, and Dr. Kissling, Grace (Biostatistics Branch) for the assistance of statistical analysis. NR 76 TC 5 Z9 5 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD JUN PY 2015 VL 63 IS 6 BP 1057 EP 1072 DI 10.1002/glia.22801 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CG4GU UT WOS:000353244400009 PM 25740080 ER PT J AU Resnik, DB AF Resnik, David B. TI Food and Beverage Policies and Public Health Ethics SO HEALTH CARE ANALYSIS LA English DT Article DE Food; Ethics; Policy; Public health; Paternalism; Justice ID OBESITY; FRAMEWORK; INTERVENTIONS AB Government food and beverage policies can play an important role in promoting public health. Few people would question this assumption. Difficult questions can arise, however, when policymakers, public health officials, citizens, and businesses deliberate about food and beverage policies, because competing values may be at stake, such as public health, individual autonomy, personal responsibility, economic prosperity, and fairness. An ethically justified policy strikes a reasonable among competing values by meeting the following criteria: (1) the policy serves important social goal(s); (2) the policy is likely to be effective at achieving those goal(s); (3) less burdensome options are not likely to be effective at achieving the goals; (4) the policy is fair. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Mail Drop CU 03,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 41 TC 2 Z9 2 U1 2 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1065-3058 EI 1573-3394 J9 HEALTH CARE ANAL JI Health Care Anal. PD JUN PY 2015 VL 23 IS 2 BP 122 EP 133 DI 10.1007/s10728-013-0266-z PG 12 WC Ethics; Health Policy & Services; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Biomedical Social Sciences GA CG4WI UT WOS:000353287800002 PM 24132618 ER PT J AU Bao, W Baecker, A Song, YQ Kiely, M Liu, SM Zhang, CL AF Bao, Wei Baecker, Aileen Song, Yiqing Kiely, Michele Liu, Simin Zhang, Cuilin TI Adipokine levels during the first or early second trimester of pregnancy and subsequent risk of gestational diabetes mellitus: A systematic review SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Gestational diabetes mellitus; Adipokines; Adiponectin; Leptin ID SOLUBLE LEPTIN RECEPTOR; BINDING-PROTEIN 4; BODY-MASS INDEX; INSULIN-RESISTANCE; PATHOLOGICAL PREGNANCIES; ADIPONECTIN LEVELS; LIPID-METABOLISM; PLASMA LEPTIN; TNF-ALPHA; WOMEN AB Objective. We aimed to systematically review available literature linking adipokines to gestational diabetes mellitus (GDM) for a comprehensive understanding of the roles of adipokines in the development of GDM. Methods. We searched PubMed/MEDLINE and EMBASE databases for published studies on adipokines and GDM through October 21, 2014. We included articles if they had a prospective study design (i.e., blood samples for adipokines measurement were collected before GDM diagnosis). Random-effects models were used to pool the weighted mean differences comparing levels of adipokines between GDM cases and non-GDM controls. Results. Of 1523 potentially relevant articles, we included 25 prospective studies relating adipokines to incident GDM. Our meta-analysis of nine prospective studies on adiponectin and eight prospective studies on leptin indicated that adiponectin levels in the first or early second trimester of pregnancy were 2.25 mu g/ml lower (95% CI: 1.75-2.75), whereas leptin levels were 7.25 ng/ml higher (95% CI 3.27-11.22), among women who later developed GDM than women who did not. Prospective data were sparse and findings were inconsistent for visfatin, retinol binding protein (RBP-4), resistin, tumor necrosis factor-alpha (TNF-alpha), interleuldn-6 (IL-6), and vaspin. We did not identify prospective studies for several novel adipokines, including chemerin, apelin, omentin, or adipocyte fatty acid-binding protein. Moreover, no published prospective studies with longitudinal assessment of adipokines and incident GDM were identified. Conclusion. Adiponectin levels in the first or second trimester of pregnancy are lower among pregnant women who later develop GDM than non-GDM women, whereas leptin levels are higher. Well-designed prospective studies with longitudinal assessment of adipokines during pregnancy are needed to understand the trajectories and dynamic associations of adipoldnes with GDM risk. Published by Elsevier Inc. C1 [Bao, Wei; Kiely, Michele; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Baecker, Aileen] Univ Calif Los Angeles, Dept Epidemiol, Los Angeles, CA USA. [Song, Yiqing] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Providence, RI 02912 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov OI Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [R01-DK-062290, R01-DK-58845, R01-DK-088078] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (to C.Z., W.B., and M.K.) and research grants R01-DK-062290 (to S. L.), R01-DK-58845 and R01-DK-088078 (to Y.S.) from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 60 TC 18 Z9 19 U1 3 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD JUN PY 2015 VL 64 IS 6 BP 756 EP 764 DI 10.1016/j.metabol.2015.01.013 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG7ZW UT WOS:000353527400013 PM 25749468 ER PT J AU Vajda, S Rangoni, Y Cecotti, H AF Vajda, Szilard Rangoni, Yves Cecotti, Hubert TI Semi-automatic ground truth generation using unsupervised clustering and limited manual labeling: Application to handwritten character recognition SO PATTERN RECOGNITION LETTERS LA English DT Article DE Character recognition; Classifier combination; Clustering; Feature selection AB For training supervised classifiers to recognize different patterns, large data collections with accurate labels are necessary. In this paper, we propose a generic, semi-automatic labeling technique for large handwritten character collections. In order to speed up the creation of a large scale ground truth, the method combines unsupervised clustering and minimal expert knowledge. To exploit the potential discriminant complementarities across features, each character is projected into five different feature spaces. After clustering the images in each feature space, the human expert labels the cluster centers. Each data point inherits the label of its cluster's center. A majority (or unanimity) vote decides the label of each character image. The amount of human involvement (labeling) is strictly controlled by the number of clusters - produced by the chosen clustering approach. To test the efficiency of the proposed approach, we have compared, and evaluated three state-of-the art clustering methods (k-means, self-organizing maps, and growing neural gas) on the MNIST digit data set, and a Lampung Indonesian character data set, respectively. Considering a k-nn classifier, we show that labeling manually only 1.3% (MNIST), and 3.2% (Lampung) of the training data, provides the same range of performance than a completely labeled data set would. Published by Elsevier B.V. C1 [Vajda, Szilard] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Rangoni, Yves] Henri Tudor Publ Res Ctr, L-1855 Kirchberg, Luxembourg. [Cecotti, Hubert] Univ Ulster, Fac Comp & Engn, Londonderry BT48 7JL, North Ireland. RP Vajda, S (reprint author), NIH, Natl Lib Med, Bethesda, MD 20894 USA. EM szilard.vajda@nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 33 TC 4 Z9 4 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8655 EI 1872-7344 J9 PATTERN RECOGN LETT JI Pattern Recognit. Lett. PD JUN 1 PY 2015 VL 58 BP 23 EP 28 DI 10.1016/j.patrec.2015.02.001 PG 6 WC Computer Science, Artificial Intelligence SC Computer Science GA CG5RA UT WOS:000353350300004 PM 25870463 ER PT J AU Shah, NN Stevenson, MS Yuan, CM Richards, K Delbrook, C Kreitman, RJ Pastan, I Wayne, AS AF Shah, Nirali N. Stevenson, Maryalice Stetler Yuan, Constance M. Richards, Kelly Delbrook, Cindy Kreitman, Robert J. Pastan, Ira Wayne, Alan S. TI Characterization of CD22 Expression in Acute Lymphoblastic Leukemia SO PEDIATRIC BLOOD & CANCER LA English DT Article DE CD22; monoclonal antibody; acute lymphoblastic leukemia; relapse ID HAIRY-CELL LEUKEMIA; RECOMBINANT IMMUNOTOXIN; FLOW-CYTOMETRY; SIGNAL-TRANSDUCTION; T-CELLS; B-CELLS; RECEPTOR; CHEMOIMMUNOTHERAPY; ADHESION; ANTIBODY AB BackgroundCD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL). ProcedureProperties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL. ResultsCD22 expression was demonstrated in all subjects (n=163) with detection on at least 90% of blasts in 155 cases. Median antigen site density of surface CD22 was 3,470 sites/cell (range 349-19,653, n=160). Blasts from patients with known 11q23 (MLL) rearrangement had lower site density (median 1,590 sites/cell, range 349-3,624, n=20 versus 3,853 sites/cell, range 451-19,653, n=140; P=<0.0001) and 6 of 21 cases had sub-populations of blasts lacking CD22 expression (22%-82% CD22+). CD22 expression was maintained in serial studies of 73 subjects, including those treated with anti-CD22 targeted therapy. The levels of soluble CD22 in blood and marrow by ELISA were low and not expected to influence the pharmacokinetics of anti-CD22 directed agents. ConclusionsThese characteristics make CD22 an excellent potential therapeutic target in patients with relapsed and chemotherapy-refractory ALL, although cases with MLL rearrangement require close study to exclude the presence of a CD22-negative blast population. Pediatr Blood Cancer Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Shah, Nirali N.; Richards, Kelly; Delbrook, Cindy; Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stevenson, Maryalice Stetler; Yuan, Constance M.] NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Kreitman, Robert J.; Pastan, Ira; Wayne, Alan S.] NCI, Mol Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis,Div Hematol Oncol, Los Angeles, CA 90033 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Nirali.Shah@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Warren Grant Magnuson Clinical Center FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Grant sponsor: Warren Grant Magnuson Clinical Center NR 30 TC 14 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2015 VL 62 IS 6 BP 964 EP 969 DI 10.1002/pbc.25410 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CG4DC UT WOS:000353231500008 PM 25728039 ER PT J AU Kolb, EA Gorlick, R Keir, ST Maris, JM Kang, MH Reynolds, CP Lock, RB Carol, H Wu, JR Kurmasheva, RT Houghton, PJ Smith, MA AF Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Maris, John M. Kang, Min H. Reynolds, C. Patrick Lock, Richard B. Carol, Hernan Wu, Jianrong Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. TI Initial Testing (Stage 1) of BAL101553, a Novel Tubulin Binding Agent, by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; microtubule-binding agents; preclinical testing; vascular-disrupting agents ID ONCOLOGY-GROUP; PHASE-II; PACLITAXEL; CHILDREN; MODELS; ABT-751; TUMORS AB BAL101553 is a highly water soluble prodrug of BAL27862 that arrests tumor cell proliferation and induces cell death in cancer cells through disruption of the microtubule network. In vitro BAL27862 demonstrated potent activity, with the median relative IC50 (rIC(50)) of 13.8nM (range 5.4-25.2nM). The in vitro activity of BAL27862 against the PPTP cell lines is distinctive from that previously described for vincristine. BAL101553 induced significant differences in EFS distribution compared to control in 16 of 30 (53%) solid tumor xenografts and in two of four (67%) of the evaluable ALL xenografts. No objective responses were observed. Pediatr Blood Cancer 2015;62:1106-1109. (c) 2014 Wiley Periodicals, Inc. C1 [Kolb, E. Anders] Nemours AI duPont Hosp Children, Wilmington, DE 19803 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Lock, Richard B.; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Kolb, EA (reprint author), Nemours AI duPont Hosp Children, Dept Oncol, 1600 Rockland Rd, Wilmington, DE 19803 USA. EM eakolb@nemours.org RI Lock, Richard/G-4253-2013; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786]; Basilea Pharmaceutica International Ltd [BAl101553, BAL27862] FX Grant sponsor: National Cancer Institute; Grant number: NO1-CM-42216, CA21765, CA108786; Grant sponsor: Basilea Pharmaceutica International Ltd,; Grant number: BAl101553, BAL27862 NR 15 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2015 VL 62 IS 6 BP 1106 EP 1109 DI 10.1002/pbc.25329 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CG4DC UT WOS:000353231500039 PM 25407467 ER PT J AU Nesterova, G Williams, C Bernardini, I Gahl, WA AF Nesterova, Galina Williams, Caitlyn Bernardini, Isa Gahl, William A. TI Cystinosis: renal glomerular and renal tubular function in relation to compliance with cystine-depleting therapy SO PEDIATRIC NEPHROLOGY LA English DT Article DE Nephropathic cystinosis; Cystine; Fanconi syndrome; Cysteamine; End-stage renal disease ID NEPHROPATHIC CYSTINOSIS; CYSTEAMINE THERAPY; HUMAN-FIBROBLASTS; EPITHELIAL-CELLS; FANCONI-SYNDROME; ORAL CYSTEAMINE; CHILDREN; FAILURE; PROTEIN; LYSOSOMES AB Nephropathic cystinosis is a lysosomal storage disorder characterized by renal tubular Fanconi syndrome in infancy and glomerular damage leading to renal failure at similar to 10 years of age. Therapy with the cystine-depleting agent cysteamine postpones renal failure, but the degree of compliance with this treatment has not been correlated with preservation of kidney function. We assessed leucocyte cystine depletion by cysteamine and created the composite compliance score that incorporates the extent of leucocyte cystine depletion, as well as duration of cysteamine treatment, into a single integer. Age at renal failure was used to gauge preservation of renal function, and the Fanconi syndrome index (FSI), a measure of aminoaciduria, was used to assess renal tubular Fanconi syndrome. Age at renal failure varied directly and linearly with the composite compliance score (y = 0.3x +8.8; R-2 = 0.61). The slope indicated that for every year of excellent cystine depletion, nearly 1 year of renal function was preserved. Age at renal failure correlated roughly with mean leucocyte cystine level, but not with mean cysteamine dosage. There was no correlation between the FSI and the composite compliance score. Greater compliance with oral cysteamine therapy yields greater preservation of renal glomerular, but not tubular, function. Oral cysteamine therapy should be given at the maximum tolerated dose, within the recommended limits. C1 [Nesterova, Galina; Williams, Caitlyn; Bernardini, Isa; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Nesterova, G (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM nesterovag@mail.nih.gov NR 32 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUN PY 2015 VL 30 IS 6 BP 945 EP 951 DI 10.1007/s00467-014-3018-x PG 7 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA CG4YY UT WOS:000353296700010 PM 25526929 ER PT J AU Raran-Kurussi, S Keefe, K Waugh, DS AF Raran-Kurussi, Sreejith Keefe, Karina Waugh, David S. TI Positional effects of fusion partners on the yield and solubility of MBP fusion proteins SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Gateway cloning; Fusion protein; Inclusion bodies; MBP; Solubility enhancer ID MALTOSE-BINDING PROTEIN; ETCH VIRUS PROTEASE; ESCHERICHIA-COLI; TYROSINE-PHOSPHATASE; MAMMALIAN PROTEINS; EXPRESSION; PURIFICATION; SPECIFICITY AB Escherichia coli maltose-binding protein (MBP) is exceptionally effective at promoting the solubility of its fusion partners. However, there are conflicting reports in the literature claiming that (1) MBP is an effective solubility enhancer only when it is joined to the N-terminus of an aggregation-prone passenger protein, and (2) MBP is equally effective when fused to either end of the passenger. Here, we endeavor to resolve this controversy by comparing the solubility of a diverse set of MBP fusion proteins that, unlike those analyzed in previous studies, are identical in every way except for the order of the two domains. The results indicate that fusion proteins with an N-terminal MBP provide an excellent solubility advantage along with more robust expression when compared to analogous fusions in which MBP is the C-terminal fusion partner. We find that only intrinsically soluble passenger proteins (i.e., those not requiring a solubility enhancer) are produced as soluble fusions when they precede MBP. We also report that even subtle differences in inter-domain linker sequences can influence the solubility of fusion proteins. Published by Elsevier Inc. C1 [Raran-Kurussi, Sreejith; Keefe, Karina; Waugh, David S.] NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM waughd@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Werner H. Kirsten Student Intern Program (W.H.K. SIP), Office of the Director, NCI-Frederick FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Karina Keefe was supported in part by the Werner H. Kirsten Student Intern Program (W.H.K. SIP), Office of the Director, NCI-Frederick. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 20 TC 5 Z9 7 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD JUN PY 2015 VL 110 BP 159 EP 164 DI 10.1016/j.pep.2015.03.004 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA CG5EI UT WOS:000353313500023 PM 25782741 ER PT J AU Wang, AT Chandra, K Xu, RH Sun, JF AF Wang, Antai Chandra, Krishnendu Xu, Ruihua Sun, Junfeng TI The Identifiability of Dependent Competing Risks Models Induced by Bivariate Frailty Models SO SCANDINAVIAN JOURNAL OF STATISTICS LA English DT Article DE Archimedean copula models; bivariate frailty models; competing risks models; discrete covariates; identifiability ID ARCHIMEDEAN COPULA; MARGINAL SURVIVAL; DISTRIBUTIONS AB In this paper, we propose to use a special class of bivariate frailty models to study dependent censored data. The proposed models are closely linked to Archimedean copula models. We give sufficient conditions for the identifiability of this type of competing risks models. The proposed conditions are derived based on a property shared by Archimedean copula models and satisfied by several well-known bivariate frailty models. Compared with the models studied by Heckman and Honore and Abbring and van den Berg, our models are more restrictive but can be identified with a discrete (even finite) covariate. Under our identifiability conditions, expectation-maximization (EM) algorithm provides us with consistent estimates of the unknown parameters. Simulation studies have shown that our estimation procedure works quite well. We fit a dependent censored leukaemia data set using the Clayton copula model and end our paper with some discussions. C1 [Wang, Antai] New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. [Chandra, Krishnendu] Columbia Univ, Dept Biostat, New York, NY 10027 USA. [Xu, Ruihua] NHGRI, NIH, Bethesda, MD USA. [Sun, Junfeng] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Wang, AT (reprint author), New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. EM aw224@njit.edu FU National Science Foundation [DMS1106608, DMS1343889] FX The authors would like to thank the Editor, an Associate Editor and two anonymous reviewers of this paper for a thorough review and for their valuable comments that led to great improvement of this paper. The research was supported by grant nos. DMS1106608 and DMS1343889 from the National Science Foundation. NR 15 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6898 EI 1467-9469 J9 SCAND J STAT JI Scand. J. Stat. PD JUN PY 2015 VL 42 IS 2 BP 427 EP 437 DI 10.1111/sjos.12114 PG 11 WC Statistics & Probability SC Mathematics GA CG8FS UT WOS:000353543300007 ER PT J AU Yeung, M Hurren, R Nemr, C Wang, XM Hershenfeld, S Gronda, M Liyanage, S Wu, Y Augustine, J Lee, EA Spagnuolo, PA Southall, N Chen, C Zheng, W Jeyaraju, DV Minden, MD Laposa, R Schimmer, AD AF Yeung, ManTek Hurren, Rose Nemr, Carine Wang, Xiaoming Hershenfeld, Samantha Gronda, Marcela Liyanage, Sanduni Wu, Yan Augustine, Jeevan Lee, Eric A. Spagnuolo, Paul A. Southall, Noel Chen, Catherine Zheng, Wei Jeyaraju, Danny V. Minden, Mark D. Laposa, Rebecca Schimmer, Aaron D. TI Mitochondrial DNA damage by bleomycin induces AML cell death SO APOPTOSIS LA English DT Article DE AML; Mitochondria; Mitochondrial DNA; Mitochondrial DNA damage; Bleomycin ID RADICAL SURGERY; REPAIR; CANCER; INHIBITION; CARCINOMA; LEUKEMIA AB Mitochondria contain multiple copies of their own 16.6 kb circular genome. To explore the impact of mitochondrial DNA (mtDNA) damage on mitochondrial (mt) function and viability of AML cells, we screened a panel of DNA damaging chemotherapeutic agents to identify drugs that could damage mtDNA. We identified bleomycin as an agent that damaged mtDNA in AML cells at concentrations that induced cell death. Bleomycin also induced mtDNA damage in primary AML samples. Consistent with the observed mtDNA damage, bleomycin reduced mt mass and basal oxygen consumption in AML cells. We also demonstrated that the observed mtDNA damage was functionally important for bleomycin-induced cell death. Finally, bleomycin delayed tumor growth in xenograft mouse models of AML and anti-leukemic concentrations of the drug induced mtDNA damage in AML cells preferentially over normal lung tissue. Taken together, mtDNA-targeted therapy may be an effective strategy to target AML cells and bleomycin could be useful in the treatment of this disease. C1 [Yeung, ManTek; Hurren, Rose; Nemr, Carine; Wang, Xiaoming; Hershenfeld, Samantha; Gronda, Marcela; Liyanage, Sanduni; Wu, Yan; Augustine, Jeevan; Jeyaraju, Danny V.; Minden, Mark D.; Schimmer, Aaron D.] Univ Hlth Network, Ontario Canc Inst, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Lee, Eric A.; Spagnuolo, Paul A.] Univ Waterloo, Sch Pharm, Kitchener, ON, Canada. [Southall, Noel; Chen, Catherine; Zheng, Wei] NIH, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. [Laposa, Rebecca] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada. RP Schimmer, AD (reprint author), Univ Hlth Network, Ontario Canc Inst, Princess Margaret Canc Ctr, Room 7-116,610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM aaron.schimmer@utoronto.ca RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU Canadian Stem Cell Network; LLSC FX This work was supported by the Canadian Stem Cell Network and a Grant from the LLSC to PAS. We thank Jill Flewelling for administrative assistance and Bhozena Jhas for help in preparing the manuscript. NR 26 TC 2 Z9 2 U1 1 U2 20 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1360-8185 EI 1573-675X J9 APOPTOSIS JI Apoptosis PD JUN PY 2015 VL 20 IS 6 BP 811 EP 820 DI 10.1007/s10495-015-1119-z PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CF8EW UT WOS:000352789700005 PM 25820141 ER PT J AU Kwak, JT Xu, S Wood, BJ AF Kwak, Jin Tae Xu, Sheng Wood, Bradford J. TI Efficient data mining for local binary pattern in texture image analysis SO EXPERT SYSTEMS WITH APPLICATIONS LA English DT Article DE Local binary pattern; Frequent pattern mining; Texture image; Feature selection; Classification ID MULTIRESOLUTION GRAY-SCALE; FACE RECOGNITION; FACIAL EXPRESSION; CLASSIFICATION; FEATURES; IDENTIFICATION; DESCRIPTORS; RETRIEVAL; WAVELET AB Local binary pattern (LBP) is a simple gray scale descriptor to characterize the local distribution of the gray levels in an image. Multi-resolution LBP and/or combinations of the LBPs have shown to be effective in texture image analysis. However, it is unclear what resolutions or combinations to choose for texture analysis. Examining all the possible cases is impractical and intractable due to the exponential growth in a feature space. This limits the accuracy and time- and space-efficiency of LBP. Here, we propose a data mining approach for LBP, which efficiently explores a high-dimensional feature space and finds a relatively smaller number of discriminative features. The features can be any combinations of LBPs. These may not be achievable with conventional approaches. Hence, our approach not only fully utilizes the capability of LBP but also maintains the low computational complexity. We incorporated three different descriptors (LBP, local contrast measure, and local directional derivative measure) with three spatial resolutions and evaluated our approach using two comprehensive texture databases. The results demonstrated the effectiveness and robustness of our approach to different experimental designs and texture images. Published by Elsevier Ltd. C1 [Kwak, Jin Tae; Xu, Sheng; Wood, Bradford J.] NIH, Hlth Clin Ctr, Ctr Intervent Oncol, Bethesda, MD 20892 USA. RP Kwak, JT (reprint author), 10 Ctr Dr, Bethesda, MD 20892 USA. EM jintae.kwak@nih.gov; xus2@cc.nih.gov; bwood@cc.nih.gov FU National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institutes of Health. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). NR 74 TC 2 Z9 2 U1 3 U2 41 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0957-4174 EI 1873-6793 J9 EXPERT SYST APPL JI Expert Syst. Appl. PD JUN 1 PY 2015 VL 42 IS 9 BP 4529 EP 4539 DI 10.1016/j.eswa.2015.01.055 PG 11 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic; Operations Research & Management Science SC Computer Science; Engineering; Operations Research & Management Science GA CF7PN UT WOS:000352748900031 PM 25767332 ER PT J AU Rodgers, MM Pai, VM Conroy, RS AF Rodgers, Mary M. Pai, Vinay M. Conroy, Richard S. TI Recent Advances in Wearable Sensors for Health Monitoring SO IEEE SENSORS JOURNAL LA English DT Article DE Wearable sensors; biomedical and environmental monitoring; sensor systems; accelerometers; patient monitoring ID PARKINSONS-DISEASE; FLEXIBLE ELECTRONICS; STRETCHABLE ELECTRONICS; EPIDERMAL ELECTRONICS; PHYSICAL-ACTIVITY; SUBACUTE STROKE; MOTOR FUNCTION; SYSTEM; DEVICES; SKIN AB Wearable sensor technology continues to advance and provide significant opportunities for improving personalized healthcare. In recent years, advances in flexible electronics, smart materials, and low-power computing and networking have reduced barriers to technology accessibility, integration, and cost, unleashing the potential for ubiquitous monitoring. This paper discusses recent advances in wearable sensors and systems that monitor movement, physiology, and environment, with a focus on applications for Parkinson's disease, stroke, and head and neck injuries. C1 [Rodgers, Mary M.; Pai, Vinay M.; Conroy, Richard S.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Rodgers, Mary M.] Univ Maryland, Sch Med, Dept Phys Therapy & Rehabil Sci, Baltimore, MD 21201 USA. RP Rodgers, MM (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM mary.rodgers@nih.gov; vinay.pai@nih.gov; richard.conroy@nih.gov RI Conroy, Richard/D-1979-2009 OI Conroy, Richard/0000-0002-8896-6090 NR 76 TC 12 Z9 14 U1 13 U2 132 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1530-437X EI 1558-1748 J9 IEEE SENS J JI IEEE Sens. J. PD JUN PY 2015 VL 15 IS 6 BP 3119 EP 3126 DI 10.1109/JSEN.2014.2357257 PG 8 WC Engineering, Electrical & Electronic; Instruments & Instrumentation; Physics, Applied SC Engineering; Instruments & Instrumentation; Physics GA CG3AS UT WOS:000353149400004 ER PT J AU Sandoval-Jaime, C Green, KY Sosnovtsev, SV AF Sandoval-Jaime, Carlos Green, Kim Y. Sosnovtsev, Stanislav V. TI Recovery of murine norovirus and feline calicivirus from plasmids encoding EMCV IRES in stable cell lines expressing T7 polymerase SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Murine norovirus; Feline calicivirus; Reverse genetics system; T7 RNA polymerase; EMCV IRES ID REVERSE GENETICS SYSTEM; HEMORRHAGIC-DISEASE VIRUS; MAMMALIAN-CELLS; TISSUE-CULTURE; LINKED PROTEIN; RNA-POLYMERASE; VPG; CDNA; REPLICATION; TRANSLATION AB Reverse genetics systems constitute one of the most important and powerful tools to study the molecular biology of viruses. We developed a new strategy for the recovery of murine norovirus from a single plasmid in which a bacteriophage T7 RNA polymerase (T7pol) promoter for transcription and an EMCV IRES for efficient translation were engineered immediately upstream of the viral genome. Infectious noroviruses were recovered following transfection of the newly designed plasmid into nonpermissive BHK-21 and HEK293T cell lines that were engineered to express T7pol constitutively. Recovery of the virus did not require the presence of a ribozyme at the 3 '-end of the virus genome. The strategy worked also for the efficient recovery of feline calicivirus in these normally nonpermissive cell types. This simplified reverse genetics approach may be broadly applicable to other caliciviruses. Published by Elsevier B.V. C1 [Sandoval-Jaime, Carlos; Green, Kim Y.; Sosnovtsev, Stanislav V.] NIAID, Caliciviruses Sect, Infect Dis Lab, NIH,DHHS, Bethesda, MD 20892 USA. RP Sosnovtsev, SV (reprint author), South Dr MSC8007,Bldg 50,Room 6314, Bethesda, MD 20892 USA. EM ss216m@nih.gov FU Intramural Research Program of the NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 32 TC 0 Z9 0 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD JUN 1 PY 2015 VL 217 BP 1 EP 7 DI 10.1016/j.jviromet.2015.02.003 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA CG2FV UT WOS:000353091200001 PM 25698463 ER PT J AU Sakkhachornphop, S Kijak, GH Beyrer, C Razak, MH Sanders-Buell, E Jittiwutikarn, J Suriyanon, V Robb, ML Kim, JH Celentano, DD McCutchan, FE Tovanabutra, S AF Sakkhachornphop, Supachai Kijak, Gustavo H. Beyrer, Chris Razak, Myat Htoo Sanders-Buell, Eric Jittiwutikarn, Jaroon Suriyanon, Vinai Robb, Merlin L. Kim, Jerome H. Celentano, David D. McCutchan, Francine E. Tovanabutra, Sodsai TI An effective tool for identifying HIV-1 subtypes B, C, CRF01_AE, their recombinant forms, and dual infections in Southeast Asia by the multi-region subtype specific PCR (MSSP) assay SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1; Subtyping; MSSP assay; Subtype specific PCR; Southeast Asia ID IMMUNODEFICIENCY-VIRUS TYPE-1; HETERODUPLEX MOBILITY ASSAY; POLYMERASE-CHAIN-REACTION; THAI DRUG-USERS; MOLECULAR EPIDEMIOLOGY; DISEASE PROGRESSION; NORTHERN THAILAND; GENOTYPING ASSAY; VACCINE EFFICACY; HIGH-THROUGHPUT AB The RV144 Thai vaccine trial has been the only vaccine study to show efficacy in preventing HIV infection. Ongoing molecular surveillance of HIV-1 in Southeast Asia is vital for vaccine development and evaluation. In this study a novel tool, the multi-region subtype specific PCR (MSSP) assay, that was able to identify subtypes B, C, CRF01_AE for Thailand, other Southeast Asian countries, India and China is described. The MSSP assay is based on a nested PCR strategy and amplifies eight short regions distributed along the HIV-1 genome using subtype-specific primers. A panel of 41 clinical DNA samples obtained primarily from opiate users in northern Thailand was used to test the assay performance. The MSSP assay provided 73-100% sensitivity and 100% specificity for the three subtypes in each genome region. The assay was then field-tested on 337 sera from HIV infected northern Thai drug users collected between 1999 and 2002. Subtype distribution was CRF01_AE 77.4% (n=261), subtype B 33% (n =11), CRFOLAE/B recombinant 12.2% (n= 41), CRF01_AE/C recombinant 0.6% (n = 2), and non-typeable 6.5% (n =22). The MSSP assay is a simple, cost-effective, and accurate genotyping tool for laboratory settings with limited resources and is sensitive enough to capture the recombinant genomes and dual infections. (C) 2015 Elsevier B.V. All rights reserved. C1 [Sakkhachornphop, Supachai; Suriyanon, Vinai] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50200, Thailand. [Kijak, Gustavo H.; Sanders-Buell, Eric; Robb, Merlin L.; McCutchan, Francine E.; Tovanabutra, Sodsai] US Mil HIV Res Program MHRP, Henry M Jackson Fdn Adv Mil Med, Silver Spring, MD 20910 USA. [Beyrer, Chris; Celentano, David D.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Razak, Myat Htoo] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Jittiwutikarn, Jaroon] Northern Drug Treatment Ctr, Chiang Mai 50200, Thailand. [Kim, Jerome H.] US Mil HIV Res Program MHRP, Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. RP Tovanabutra, S (reprint author), Walter Reed Army Inst Res, MHRP & Henry M Jackson Fdn Adv Mil Med HJF, 503 Robert Grant Ave,Room 2N25, Silver Spring, MD 20910 USA. EM stovanabutra@hivresearch.org FU Fogarty AIDS International for Research and Training Program; Johns Hopkins Bloomberg School of Public Health [D43TW000010-25]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-11-2-0174]; U.S. Department of Defense (DOD); National Research University Project under Thailand's Office of the Higher Education Commission FX We are very grateful to the subjects for their participation in this study. The authors thank staff members at the Henry M. Jackson Foundation for technical advice, the research staffs at Northern Drug Treatment Center and RIHES for Cohort building and specimen collections. We extend our gratitude to Dr. Thira Sirisanthana, Dr. Namtip Srirak, Mr. Kittipong Rungruengthanakit, Mr. Rassamee Keawvichit, Mrs. Kanlaya Wongworapat and Mr. Peter Lange for their advice and supports on conducting the study. We are indebted to Ms. Meera Bose and Mr. Peter Phuc Pham for HIV-1 sequence analysis. This study was supported by the Fogarty AIDS International for Research and Training Program, Johns Hopkins Bloomberg School of Public Health, grants number D43TW000010-25 and a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). We wish to thank the National Research University Project under Thailand's Office of the Higher Education Commission for partial financial support. NR 49 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD JUN 1 PY 2015 VL 217 BP 70 EP 78 DI 10.1016/j.jviromet.2015.02.015 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA CG2FV UT WOS:000353091200012 PM 25725414 ER PT J AU Rao, VK Price, S Similuk, M Niemela, J McElwee, J Rosenzweig, S Su, H Milner, J Uzel, G Lenardo, M AF Rao, V. Koneti Price, Susan Similuk, Morgan Niemela, Julie McElwee, Joshua Rosenzweig, Sergio Su, Helen Milner, Joshua Uzel, Gulbu Lenardo, Michael TI EXTENDED GENETIC TESTING OF ALPS AND ALPS LIKE DISORDERS REVEALS NOVEL DISORDERS OF IMMUNE DYSFUNCTION, INCLUDING DEFECTS IN CTLA4, PI3KCD, AND STAT3 GENES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Rao, V. Koneti; Price, Susan; Similuk, Morgan; Niemela, Julie; McElwee, Joshua; Rosenzweig, Sergio; Su, Helen; Milner, Joshua; Uzel, Gulbu; Lenardo, Michael] NIH, Bethesda, MD 20892 USA. RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2015 VL 62 SU 2 BP 23 EP 23 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CF9BD UT WOS:000352855600012 ER PT J AU Farrar, J O'Brien, K Anderson, S Atsidaftos, E Lipton, J Ellis, S Bodine, D Vlachos, A AF Farrar, Jason O'Brien, Kelly Anderson, Stacie Atsidaftos, Eva Lipton, Jeffrey Ellis, Steven Bodine, David Vlachos, Adrianna TI ERYTHROID CELLS FROM DIAMOND BLACKFAN ANEMIA (DBA) PATIENTS WITH GATA1 AND RIBOSOMAL PROTEIN (RP) MUTATIONS SHOW MARKED DIFFERENCES IN RNA EXPRESSION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Farrar, Jason; O'Brien, Kelly; Anderson, Stacie; Atsidaftos, Eva; Lipton, Jeffrey; Ellis, Steven; Bodine, David; Vlachos, Adrianna] NHGRI, 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2015 VL 62 SU 2 BP 28 EP 28 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CF9BD UT WOS:000352855600029 ER PT J AU Akshintala, S Dombi, E Glod, J Fox, E Lodish, M Whitcomb, P Balis, F Widemann, B AF Akshintala, Srivandana Dombi, Eva Glod, John Fox, Elizabeth Lodish, Maya Whitcomb, Patricia Balis, Frank Widemann, Brigitte TI RESPONSE AND RESISTANCE TO THE RECEPTOR TYROSINE KINASE INHIBITOR (TKI) VANDETANIB IN PEDIATRIC PATIENTS WITH MEDULLARY THYROID CARCINOMA (MTC) SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Akshintala, Srivandana; Dombi, Eva; Glod, John; Fox, Elizabeth; Lodish, Maya; Whitcomb, Patricia; Balis, Frank; Widemann, Brigitte] Natl Canc Inst, Pediat Oncol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2015 VL 62 SU 2 MA 750 BP 102 EP 102 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CF9BD UT WOS:000352855600281 ER PT J AU Bradford, D Akshintala, S Chen, C Jung, S Jones, E Dombi, E Whatley, M Glod, J Whitcomb, T Widemann, B AF Bradford, Diana Akshintala, Srivandana Chen, Clara Jung, Seungyeon Jones, Elizabeth Dombi, Eva Whatley, Millie Glod, John Whitcomb, Trish Widemann, Brigitte TI THE ROLE OF 18F-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY (18F-FDG PET) IN PEDIATRIC MEDULLARY THYROID CARCINOMA (MTC) SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Bradford, Diana; Akshintala, Srivandana; Chen, Clara; Jung, Seungyeon; Jones, Elizabeth; Dombi, Eva; Whatley, Millie; Glod, John; Whitcomb, Trish; Widemann, Brigitte] Natl Canc Inst, Bethesda, 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2015 VL 62 SU 2 MA 752 BP 103 EP 103 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CF9BD UT WOS:000352855600283 ER PT J AU Damiano, DL Leonard, R AF Damiano, Diane L. Leonard, Rebecca TI 5 2014 Section on Pediatrics Knowledge Translation Lecture: Clinicians and Researchers on the Same Path Toward Facilitating Family Goals for Mobility and Participation SO PEDIATRIC PHYSICAL THERAPY LA English DT Article DE cerebral palsy; knowledge translation; lecture; physical therapy; research design ID CEREBRAL-PALSY; CHILDREN AB Background: The knowledge translation (KT) lecture at the Combined Sections Meeting 2014 was a personal perspective from a researcher who had been a therapist and a longtime clinician, now a PhD candidate. Objective: To better integrate research and clinical care, KT is a seamless rather than separate process. Key Points: Knowledge translation can be enhanced by improved receptivity to evidence, and increasing use of research designs that encourage and even require clinician involvement, from single-subject designs to large-scale pragmatic trials. Clinical practice databases and hiring therapists to provide intervention in research efforts also serve to integrate research and clinical care. Limitations of applying mean group research results to an individual patient were also discussed and suggest an important unanswered topic for future research. Conclusion: We all need to assume responsibility for the researcher-clinician partnership, making our jobs more joyful and fulfilling, and hopefully the biggest beneficiaries will be our current and future patients. C1 [Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Leonard, Rebecca] Early Intervent Associates, Rockville, MD USA. RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, 10 Ctr Dr,Room 1-1469, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Intramural Research Program at the NIH Clinical Center FX Grant Funding: The Intramural Research Program at the NIH Clinical Center funded this work. NR 17 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0898-5669 EI 1538-005X J9 PEDIATR PHYS THER JI Pediatr. Phys. Ther. PD SUM PY 2015 VL 27 IS 2 BP 105 EP 112 DI 10.1097/PEP.0000000000000147 PG 8 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA CE8EW UT WOS:000352075400002 PM 25822350 ER PT J AU Roy, K Wu, YZ Meitzler, JL Juhasz, A Liu, H Jiang, GJ Lu, JM Antony, S Doroshow, JH AF Roy, Krishnendu Wu, Yongzhong Meitzler, Jennifer L. Juhasz, Agnes Liu, Han Jiang, Guojian Lu, Jiamo Antony, Smitha Doroshow, James H. TI NADPH oxidases and cancer SO CLINICAL SCIENCE LA English DT Review DE cancer; cytokine; NADPH oxidase; oxidative stress; reactive oxygen species. ID NF-KAPPA-B; EPITHELIAL-MESENCHYMAL TRANSITION; ESOPHAGEAL ADENOCARCINOMA CELLS; SUPEROXIDE-PRODUCING ENZYME; NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; HUMAN COLON CANCERS; PANCREATIC-CANCER; GROWTH-FACTOR; CHRONIC INFLAMMATION AB The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1-5 and dual oxidases DUOX1/2) which are structural homologues of gp91(phox), the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-gamma, tumour necrosis factor a, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies. C1 [Roy, Krishnendu; Liu, Han; Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Wu, Yongzhong; Meitzler, Jennifer L.; Juhasz, Agnes; Jiang, Guojian; Lu, Jiamo; Antony, Smitha; Doroshow, James H.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU federal funds from the Center for Cancer Research; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health FX d This work was supported by federal funds from the Center for Cancer Research and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services. NR 136 TC 19 Z9 22 U1 3 U2 37 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0143-5221 EI 1470-8736 J9 CLIN SCI JI Clin. Sci. PD JUN PY 2015 VL 128 IS 12 BP 863 EP 875 DI 10.1042/CS20140542 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CE6CP UT WOS:000351924000002 PM 25818486 ER PT J AU Wargon, V Riggio, M Giulianelli, S Sequeira, GR Rojas, P May, M Polo, ML Gorostiaga, MA Jacobsen, B Molinolo, A Novaro, V Lanari, C AF Wargon, Victoria Riggio, Marina Giulianelli, Sebastian Sequeira, Gonzalo R. Rojas, Paola May, Maria Polo, Maria L. Gorostiaga, Maria A. Jacobsen, Britta Molinolo, Alfredo Novaro, Virginia Lanari, Claudia TI Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; progesterone receptor isoforms; antiprogestins; mifepristone; AIB1; SMRT; cyclin D1; MYC; antiprogestin therapy; hormone responsiveness ID MAMMARY-GLAND DEVELOPMENT; RECEPTOR ISOFORM RATIO; CELL-CYCLE PROGRESSION; B-ISOFORM; PROXIMITY LIGATION; TUMOR XENOGRAFTS; GENE-REGULATION; IN-SITU; PR-A; EXPRESSION AB There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters. What's new? There is emerging interest in understanding the role of progesterone receptors (PRs)of which two isoforms have been described, PRA and PRBin breast cancer. This study investigates the proliferative effect of antiprogestins depending on the relative expression of PRA and PRB. The results provide mechanistic evidence that the responsiveness of breast cancer to antiprogestin treatment is determined by the ratio of expression of PRA and PRB isoforms. Antiprogestins selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters. The results may pave the way for a personalized use of antiprogestins in breast cancer treatment. C1 [Wargon, Victoria; Riggio, Marina; Giulianelli, Sebastian; Sequeira, Gonzalo R.; Rojas, Paola; May, Maria; Polo, Maria L.; Gorostiaga, Maria A.; Novaro, Virginia; Lanari, Claudia] Consejo Nacl Invest Cient & Tecn, Inst Expt Biol & Med IBYME, Lab Hormonal Carcinogenesis, RA-1033 Buenos Aires, DF, Argentina. [Jacobsen, Britta] Univ Colorado, Aurora, CO USA. [Molinolo, Alfredo] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Lanari, C (reprint author), IBYME CONICET, Vuelta Obligado 2490,C1428ADN, Buenos Aires, DF, Argentina. EM lanari.claudia@gmail.com FU ANAPCYT [PICT2007/932, PICT2007/939, PICT2012/1091, PICT2012/1244]; CONICET [PIP2010/692]; Fundacion Sales, Intramural Research Program, NIDCR, NIH; CONICET FX Grant sponsor: ANAPCYT; Grant numbers: PICT2007/932 and 939 and PICT2012/1091 and 1244; Grant sponsor: CONICET; Grant number: PIP2010/692; Grant sponsor: Fundacion Sales, Intramural Research Program, NIDCR, NIH and CONICET NR 55 TC 8 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2015 VL 136 IS 11 BP 2680 EP 2692 DI 10.1002/ijc.29304 PG 13 WC Oncology SC Oncology GA CD8PL UT WOS:000351357700019 PM 25363551 ER PT J AU Bang, J Huh, JH Na, JW Lu, Q Carlson, BA Tobe, R Tsuji, PA Gladyshev, VN Hatfield, DL Lee, BJ AF Bang, Jeyoung Huh, Jang Hoe Na, Ji-Woon Lu, Qiao Carlson, Bradley A. Tobe, Ryuta Tsuji, Petra A. Gladyshev, Vadim N. Hatfield, Dolph L. Lee, Byeong Jae TI Cell Proliferation and Motility Are Inhibited by G1 Phase Arrest in 15-kDa Selenoprotein-Deficient Chang Liver Cells SO MOLECULES AND CELLS LA English DT Article DE 15-kDa selenoprotein; cell cycle arrest; cell proliferation; cyclin E; selenium ID HUMAN HEALTH; SELENIUM; SEP15; PROTEIN; SEQUENCE; BINDING; FAMILY; GROWTH; ROLES AB The 15-kDa selenoprotein (Sep15) is a selenoprotein residing in the lumen of the endoplasmic reticulum (ER) and implicated in quality control of protein folding. Herein, we established an inducible RNAi cell line that targets Sep15 mRNA in Chang liver cells. RNAi-induced Sep15 deficiency led to inhibition of cell proliferation, whereas cell growth was resumed after removal of the knockdown inducer. Sep15-deficient cells were arrested at the G1 phase by upregulating p21 and p27, and these cells were also characterized by ER stress. In addition, Sep15 deficiency led to the relocation of focal adhesions to the periphery of the cell basement and to the decrease of the migratory and invasive ability. All these changes were reversible depending on Sep15 status. Rescuing the knockdown state by expressing a silent mutant Sep15 mRNA that is resistant to siRNA also reversed the phenotypic changes. Our results suggest that SEP15 plays important roles in the regulation of the G1 phase during the cell cycle as well as in cell motility in Chang liver cells, and that this selenoprotein offers a novel functional link between the cell cycle and cell motility. C1 [Bang, Jeyoung; Huh, Jang Hoe; Na, Ji-Woon; Lu, Qiao; Lee, Byeong Jae] Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. [Bang, Jeyoung; Lee, Byeong Jae] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Lee, Byeong Jae] Seoul Natl Univ, Inst Mol Biol & Genet, Seoul 151742, South Korea. [Carlson, Bradley A.; Tobe, Ryuta; Hatfield, Dolph L.] NCI, Mouse Canc Genet Program, NIH, Bethesda, MD 20892 USA. [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD 21252 USA. [Gladyshev, Vadim N.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. EM imbglmg@snu.ac.kr FU Priority Research Centers Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2010-0029694]; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0012947]; Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Ministry of Science, ICT & Future Planning [2012M3A9D1054622]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; NIH [CA080946] FX This work was supported by the Priority Research Centers Program (Grant No. 2010-0029694) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant No. 2011-0012947), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (2012M3A9D1054622) to BJL, and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research to DLH and NIH CA080946 to VNG. NR 31 TC 2 Z9 2 U1 0 U2 1 PU KOREAN SOC MOLECULAR & CELLULAR BIOLOGY PI SEOUL PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1016-8478 EI 0219-1032 J9 MOL CELLS JI Mol. Cells PD MAY 31 PY 2015 VL 38 IS 5 BP 457 EP 465 DI 10.14348/molcells.2015.0007 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CJ5VB UT WOS:000355558800011 PM 25728752 ER PT J AU Park, O Ki, SH Xu, MJ Wang, H Feng, DC Tam, J Osei-Hyiaman, D Kunos, G Gao, B AF Park, Ogyi Ki, Sung Hwan Xu, Mingjiang Wang, Hua Feng, Dechun Tam, Joseph Osei-Hyiaman, Douglas Kunos, George Gao, Bin TI Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences SO CELL AND BIOSCIENCE LA English DT Article DE Obesity; Insulin resistance; Hyperglycemia; Cytokine; Liver ID HEPATOCELLULAR-CARCINOMA; LIVER INFLAMMATION; IL-22; MICE; CYTOKINES; PANCREATITIS; HEPATOCYTES; ACTIVATION; FIBROSIS; IMMUNITY AB Background: Interleukin-22 (IL-22), a cytokine with important functions in anti-microbial defense and tissue repair, has been recently suggested to have beneficial effects in obesity and metabolic syndrome in some but not in other studies. Here, we re-examined the effects of IL-22 on obesity, insulin resistance, and hepatic glucose metabolism. Results: Genetic deletion of IL-22 did not affect high-fat-diet (HFD)-induced obesity and insulin resistance. IL-22 transgenic mice with relatively high levels of circulating IL-22 (similar to 600 pg/ml) were completely resistant to Concanavalin A-induced liver injury but developed the same degree of high fat diet (HFD)-induced obesity, insulin resistance, and fatty liver as the wild-type littermate controls. Similarly, chronic treatment with recombinant mouse IL-22 (rmIL-22) protein did not affect HFD-induced obesity and the associated metabolic syndrome. In vivo treatment with a single dose of rmIL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis and reduced blood glucose levels both in HFD-fed and streptozotocin (STZ)-treated mice without affecting insulin production. In vitro exposure of mouse primary hepatocytes to IL-22 suppressed glucose production and the expression of gluconeogenic genes. These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway. Conclusion: Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome. Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes. C1 [Park, Ogyi; Ki, Sung Hwan; Xu, Mingjiang; Wang, Hua; Feng, Dechun; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Tam, Joseph; Osei-Hyiaman, Douglas; Kunos, George] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Ki, Sung Hwan] Chosun Univ, Coll Pharm, Lab Toxicol, Gwangju, South Korea. [Tam, Joseph] Hebrew Univ Jerusalem, Fac Med, Sch Pharm, Obes & Metab Lab,Inst Drug Res, IL-91120 Jerusalem, Israel. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI Feng, Dechun/Q-5962-2016 NR 39 TC 6 Z9 6 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD MAY 30 PY 2015 VL 5 AR 25 DI 10.1186/s13578-015-0015-0 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK0OE UT WOS:000355903700001 PM 26064446 ER PT J AU Bentley, AR Divers, J Shriner, D Doumatey, AP Gutierrez, OM Adeyemo, AA Freedman, BI Rotimi, CN AF Bentley, Amy R. Divers, Jasmin Shriner, Daniel Doumatey, Ayo P. Gutierrez, Orlando M. Adeyemo, Adebowale A. Freedman, Barry I. Rotimi, Charles N. TI APOL1 G1 genotype modifies the association between HDLC and kidney function in African Americans SO BMC GENOMICS LA English DT Article DE Apolipoprotein L1; High-density lipoprotein cholesterol; African ancestry; Glomerular filtration rate ID GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HIGH-DENSITY-LIPOPROTEINS; CARDIOVASCULAR-DISEASE; GENETIC-VARIANTS; SERUM CREATININE; RISK; ATHEROSCLEROSIS; CHOLESTEROL AB Background: Despite evidence of an association between variants at the apolipoprotein L1 gene (APOL1) locus and a spectrum of related kidney diseases, underlying biological mechanisms remain unknown. An earlier preliminary study published by our group showed that an APOL1 variant (rs73885319) modified the association between high-density lipoprotein cholesterol (HDLC) and estimated glomerular filtration rate (eGFR) in African Americans. To further understand this relationship, we evaluated the interaction in two additional large cohorts of African Americans for a total of 3,592 unrelated individuals from the Howard University Family Study (HUFS), the Natural History of APOL1-Associated Nephropathy Study (NHAAN), and the Atherosclerosis Risk in Communities Study (ARIC). The association between HDLC and eGFR was determined using linear mixed models, and the interaction between rs73885319 genotype and HDLC was evaluated using a multiplicative term. Results: Among individuals homozygous for the risk genotype, a strong inverse HDLC-eGFR association was observed, with a positive association in others (p for the interaction of the rs73885319 x HDLC =0.0001). The interaction was similar in HUFS and NHAAN, and attenuated in ARIC. Given that ARIC participants were older, we investigated an age effect; age was a significant modifier of the observed interaction. When older individuals were excluded, the interaction in ARIC was similar to that in the other studies. Conclusions: Based on these findings, it is clear that the relationship between HDLC and eGFR is strongly influenced by the APOL1 rs73885319 kidney risk genotype. Moreover, the degree to which this variant modifies the association may depend on the age of the individual. More detailed physiological studies are warranted to understand how rs73885319 may affect the relationship between HDLC and eGFR in individuals with and without disease and across the lifespan. C1 [Bentley, Amy R.; Shriner, Daniel; Doumatey, Ayo P.; Adeyemo, Adebowale A.; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Divers, Jasmin] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Gutierrez, Orlando M.] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL USA. [Freedman, Barry I.] Wake Forest Sch Med, Dept Internal Med Nephrol, Winston Salem, NC USA. RP Rotimi, CN (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [S06GM008016-320107, S06GM008016-380111]; NIGMS/MBRS/SCORE Program; National Center for Research Resources, a component of the National Institutes of Health [2M01RR010284]; Intramural Research Program of the National Human Genome Research Institute in the Center for Research in Genomics and Global Health [CRGGH-Z01HG200362]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Center for Information Technology; Office of the Director at the National Institutes of Health; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01HG004402]; [DK084149]; [DK070941] FX The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. The study was supported by National Institutes of Health grants S06GM008016-320107 to C. Rotimi and S06GM008016-380111 to A. Adeyemo, both from the NIGMS/MBRS/SCORE Program. Participant enrollment was carried out at the Howard University General Clinical Research Center, which is supported by grant 2M01RR010284 from the National Center for Research Resources, a component of the National Institutes of Health. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute in the Center for Research in Genomics and Global Health (CRGGH-Z01HG200362). CRGGH is also supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Center for Information Technology, and the Office of the Director at the National Institutes of Health. 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). The authors thank the staff and participants of the ARIC study for their important contributions. Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (Eric Boerwinkle). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The NHAAN study is supported by RO1 grants DK084149 and DK070941 to B.I. Freedman. NR 40 TC 3 Z9 4 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 30 PY 2015 VL 16 AR 421 DI 10.1186/s12864-015-1645-7 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CJ2GU UT WOS:000355303000001 PM 26025194 ER PT J AU Ramalho-Ortigao, M Coutinho-Abreu, IV Balbino, VQ Figueiredo, CAS Mukbel, R Dayem, H Hanafi, HA El-Hossary, SS Fawaz, EEDY Abo-Shehada, M Hoel, DF Stayback, G Wadsworth, M Shoue, DA Abrudan, J Lobo, NF Mahon, AR Emrich, SJ Kamhawi, S Collins, FH McDowell, MA AF Ramalho-Ortigao, Marcelo Coutinho-Abreu, Iliano V. Balbino, Valdir Q. Figueiredo, Carlos Alberto S., Jr. Mukbel, Rami Dayem, Hussan Hanafi, Hanafi A. El-Hossary, Shabaan S. Fawaz, Emad El-Din Y. Abo-Shehada, Mahmoud Hoel, David F. Stayback, Gwen Wadsworth, Mariha Shoue, Douglas A. Abrudan, Jenica Lobo, Neil F. Mahon, Andrew R. Emrich, Scott J. Kamhawi, Shaden Collins, Frank H. McDowell, Mary Ann TI Phlebotomus papatasi SP15: mRNA expression variability and amino acid sequence polymorphisms of field populations SO PARASITES & VECTORS LA English DT Article DE Sand fly; Saliva; PpSP15; Leishmaniasis; Vaccine; Expression variability; MHC class II epitopes ID SAND FLY VECTOR; LEISHMANIA AMAZONENSIS INFECTION; LUTZOMYIA-LONGIPALPIS COMPLEX; ANTI-MOSQUITO ANTIBODIES; SALIVARY-GLAND PROTEINS; SOUTHERN JORDAN-VALLEY; T-CELL RECOGNITION; CUTANEOUS LEISHMANIASIS; WILD-CAUGHT; VISCERAL LEISHMANIASIS AB Background: The Phlebotomus papatasi salivary protein PpSP15 was shown to protect mice against Leishmania major, suggesting that incorporation of salivary molecules in multi-component vaccines may be a viable strategy for anti-Leishmania vaccines. Methods: Here, we investigated PpSP15 predicted amino acid sequence variability and mRNA profile of P. papatasi field populations from the Middle East. In addition, predicted MHC class II T-cell epitopes were obtained and compared to areas of amino acid sequence variability within the secreted protein. Results: The analysis of PpSP15 expression from field populations revealed significant intra-and interpopulation variation.. In spite of the variability detected for P. papatasi populations, common epitopes for MHC class II binding are still present and may potentially be used to boost the response against Le. major infections. Conclusions: Conserved epitopes of PpSP15 could potentially be used in the development of a salivary gland antigen-based vaccine. C1 [Ramalho-Ortigao, Marcelo] Kansas State Univ, Dept Entomol, Manhattan, KS 66506 USA. [Coutinho-Abreu, Iliano V.; Kamhawi, Shaden] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Balbino, Valdir Q.; Figueiredo, Carlos Alberto S., Jr.] Univ Fed Pernambuco, Dept Genet, Recife, PE, Brazil. [Mukbel, Rami; Dayem, Hussan; Hanafi, Hanafi A.; Abo-Shehada, Mahmoud] Jordan Univ Sci & Technol, Fac Vet Med, Irbid 22110, Jordan. [Fawaz, Emad El-Din Y.] NAMRU 3, US Naval Med Res Unit 3, Vector Biol Res Program, Cairo, Egypt. [Hoel, David F.] Uniformed Serv Univ Hlth Sci, Dept Biostat, Bethesda, MD 20814 USA. [Stayback, Gwen; Wadsworth, Mariha; Shoue, Douglas A.; Lobo, Neil F.; Emrich, Scott J.; Collins, Frank H.; McDowell, Mary Ann] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Abrudan, Jenica] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Mahon, Andrew R.] Cent Michigan Univ, Dept Biol, Detroit, MI 48859 USA. [Emrich, Scott J.; Collins, Frank H.] Univ Notre Dame, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA. RP McDowell, MA (reprint author), Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. EM mcdowell.11@nd.edu FU Department of Defense (DoD) Defense Advanced Research Projects Agency (DARPA) [W911NF0410380]; National Institute of Allergy and Infectious Diseases [R01AI074691] FX We are grateful to the Egyptian Ministry of Health for their aid and in sand fly collections and the Multi National Force and Observers (MFO) military units for transportation in the Sinai Peninsula. Special gratitude goes to Ms. Maria Badra for her organizational skills and support of the work in Eygpt. We are also indebted to the Sand Fly Genome Consortium and allowed us to submit our mapping results prior to the completion and publication of the sand fly genome analysis. This project was supported by contract # W911NF0410380 from the Department of Defense (DoD) Defense Advanced Research Projects Agency (DARPA) awarded to MAM. MR-O was supported by a grant from the National Institute of Allergy and Infectious Diseases (R01AI074691). NR 74 TC 2 Z9 2 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD MAY 29 PY 2015 VL 8 AR 298 DI 10.1186/s13071-015-0914-2 PG 14 WC Parasitology SC Parasitology GA CL0XL UT WOS:000356666300001 PM 26022221 ER PT J AU Tin, A Kottgen, A Folsom, AR Maruthur, NM Tajuddin, SM Nalls, MA Evans, MK Zonderman, AB Friedrich, CA Boerwinkle, E Coresh, J Kao, WHL AF Tin, Adrienne Koettgen, Anna Folsom, Aaron R. Maruthur, Nisa M. Tajuddin, Salman M. Nalls, Mike A. Evans, Michele K. Zonderman, Alan B. Friedrich, Christopher A. Boerwinkle, Eric Coresh, Josef Kao, Wen Hong Linda TI Genetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study SO BMC GENETICS LA English DT Article DE Gene-environment interaction; Serum magnesium; MUC1; TRPM6 ID DIAGNOSING INSULIN-RESISTANCE; GENOME-WIDE ASSOCIATION; DIETARY MAGNESIUM; EXPRESSION; METAANALYSIS; POPULATION; DISEASE AB Background: Low serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression. Results: The GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta = -0.013, p = 6.1x10(-9)). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta = -0.028, p = 7.3x10(-5)) than in those without any hormone use (beta = -0.011, p = 7.0x10(-8), p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (<80pmol/L: beta = -0.013, p = 1.6x10(-7); >= 80pmol/L: beta = -0.008, p = 1.8x10(-2), p for interaction 0.03). Conclusions: We identified three loci that explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. Following-up on functional studies of gene expression identified gene-environment interactions between progestin use and MUC1 and between insulin and TRPM6 on serum magnesium concentration in ARIC European-American participants. These results extend our understanding of the metabolism of serum magnesium. C1 [Tin, Adrienne; Koettgen, Anna; Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Koettgen, Anna] Univ Med Ctr Freiburg, Freiburg, Germany. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Maruthur, Nisa M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Tajuddin, Salman M.; Nalls, Mike A.; Evans, Michele K.; Zonderman, Alan B.] NIA, NIH, Bethesda, MD 20892 USA. [Friedrich, Christopher A.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Boerwinkle, Eric; Kao, Wen Hong Linda] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. RP Tin, A (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM atin1@jhu.edu OI Zonderman, Alan B/0000-0002-6523-4778; Tajuddin, Salman M./0000-0002-7919-8528 FU NIH/NIDDK Renal Disease Epidemiology Training Program [T32 DK007732]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; Emmy Noether Programme of the German Research Foundation [KO 3598/2-1] FX Dr. Tin is supported by the NIH/NIDDK T32 DK007732 Renal Disease Epidemiology Training Program.; 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). AK was supported by the Emmy Noether Programme of the German Research Foundation (KO 3598/2-1). NR 32 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD MAY 29 PY 2015 VL 16 AR 56 DI 10.1186/s12863-015-0219-7 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CJ8ZD UT WOS:000355791100001 PM 26058915 ER PT J AU Eichelberger, L Murphy, G Etemadi, A Abnet, CC Islami, F Shakeri, R Malekzadeh, R Dawsey, SM AF Eichelberger, Laura Murphy, Gwen Etemadi, Arash Abnet, Christian C. Islami, Farhad Shakeri, Ramin Malekzadeh, Reza Dawsey, Sanford M. TI Risk of Gastric Cancer by Water Source: Evidence from the Golestan Case-Control Study SO PLOS ONE LA English DT Article ID HELICOBACTER-PYLORI INFECTION; STOMACH-CANCER; MULTIPLEX SEROLOGY; ESOPHAGEAL CANCER; DRINKING-WATER; TRANSMISSION; IRAN; EPIDEMIOLOGY; SEROPREVALENCE; ADENOCARCINOMA AB Background Gastric cancer (GC) is the world's fifth most common cancer, and the third leading cause of cancer-related death. Over 70% of incident cases and deaths occur in developing countries. We explored whether disparities in access to improved drinking water sources were associated with GC risk in the Golestan Gastric Cancer Case Control Study. Methods and Findings 306 cases and 605 controls were matched on age, gender, and place of residence. We conducted unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, gender, ethnicity, marital status, education, head of household education, place of birth and residence, homeownership, home size, wealth score, vegetable consumption, and H. pylori seropositivity. Fully-adjusted ORs were 0.23 (95% CI: 0.05-1.04) for chlorinated well water, 4.58 (95% CI: 2.07-10.16) for unchlorinated well water, 4.26 (95% CI: 1.81-10.04) for surface water, 1.11 (95% CI: 0.61-2.03) for water from cisterns, and 1.79 (95% CI: 1.20-2.69) for all unpiped sources, compared to in-home piped water. Comparing unchlorinated water to chlorinated water, we found over a two-fold increased GC risk (OR 2.37, 95% CI: 1.56-3.61). Conclusions Unpiped and unchlorinated drinking water sources, particularly wells and surface water, were significantly associated with the risk of GC. C1 [Eichelberger, Laura] Univ Texas San Antonio, Dept Anthropol, San Antonio, TX 78249 USA. [Eichelberger, Laura; Murphy, Gwen; Etemadi, Arash; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Etemadi, Arash; Islami, Farhad; Shakeri, Ramin; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Oncol Res Ctr, Digest Dis Res Inst, Tehran, Iran. [Islami, Farhad] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30303 USA. RP Eichelberger, L (reprint author), Univ Texas San Antonio, Dept Anthropol, One UTSA Circle, San Antonio, TX 78249 USA. EM laura.eichelberger@utsa.edu RI Murphy, Gwen/G-7443-2015; Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016 OI , Ramin/0000-0003-0487-3629; Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Digestive Disease Research Institute of Tehran University of Medical Sciences [82-603]; Cancer Research UK [C20/A5860]; 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, National Institutes of Health; the Digestive Disease Research Institute of Tehran University of Medical Sciences (grant No 82-603); Cancer Research UK (C20/A5860); and by the International Agency for Research on Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 3 Z9 3 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 29 PY 2015 VL 10 IS 5 AR e0128491 DI 10.1371/journal.pone.0128491 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ2MQ UT WOS:000355319400094 PM 26023788 ER PT J AU Hinnebusch, AG AF Hinnebusch, Alan G. TI Blocking stress response for better memory? SO SCIENCE LA English DT Editorial Material ID NUCLEOTIDE EXCHANGE FACTOR; EIF2B COMPLEX; EIF2-ALPHA; INITIATION; SUBUNIT; PROTEIN; TERM C1 NIH, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NIH, Lab Gene Regulat & Dev, Bldg 10, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov NR 13 TC 0 Z9 0 U1 1 U2 18 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 29 PY 2015 VL 348 IS 6238 BP 967 EP 968 DI 10.1126/science.aac4832 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ1WU UT WOS:000355276600021 PM 26023119 ER PT J AU Mahanty, S Prigent, A Garraud, O AF Mahanty, Siddhartha Prigent, Antoine Garraud, Olivier TI Immunogenicity of infectious pathogens and vaccine antigens SO BMC IMMUNOLOGY LA English DT Review DE Immunogenicity; Infection; Pathogen; Antigen presentation; Vaccine; Antibody isotype ID ANTIBODY-RESPONSES; IMMUNE-RESPONSE; MALARIA; PLASMODIUM; SELECTION; MOLECULES; FUTURE AB The concept of the immunogenicity of an antigen is frequently encountered in the context of vaccine development, an area of intense interest currently due to the emergence or re-emergence of infectious pathogens with the potential for worldwide spread. However, the theoretical notion of immunogenicity as discussed in older textbooks of immunology needs reconsideration due to advances in our understanding of immunologic responses. Immunogenicity is a property that can either be a desirable attribute, for example in the generation of an effective protective immunity against infectious pathogens or an undesirable trait, for example when it relates to novel therapeutic compounds and drugs, where an immune response needs to be prevented or inhibited. In this Forum Article, we aimed to revisit the issue of immunogenicity to discuss a series of simple questions relevant to the concept that are frequently rephrased but incompletely resolved in the immunologic literature. C1 [Mahanty, Siddhartha] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Prigent, Antoine] EFS, F-42023 St Etienne, France. [Prigent, Antoine; Garraud, Olivier] Univ Lyon, EA3064, F-42023 St Etienne, France. [Garraud, Olivier] Inst Natl Transfus Sanguine, F-75015 Paris, France. RP Garraud, O (reprint author), Univ Lyon, EA3064, F-42023 St Etienne, France. EM ogarraud@ints.fr OI Mahanty, Siddhartha/0000-0003-1068-0524 FU National Institute of Allergy and Infectious Diseases, NIH FX This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 36 TC 5 Z9 5 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD MAY 29 PY 2015 VL 16 AR 31 DI 10.1186/s12865-015-0095-y PG 6 WC Immunology SC Immunology GA CJ0EJ UT WOS:000355146900001 PM 26021448 ER PT J AU Braunschweig, T Chung, JY Choi, CH Cho, H Chen, QR Xie, R Perry, C Khan, J Hewitt, SM AF Braunschweig, Till Chung, Joon-Yong Choi, Chel Hun Cho, Hanbyoul Chen, Qing-Rong Xie, Ran Perry, Candice Khan, Javed Hewitt, Stephen M. TI Assessment of a panel of tumor markers for the differential diagnosis of benign and malignant effusions by well-based reverse phase protein array SO DIAGNOSTIC PATHOLOGY LA English DT Article DE Cytodiagnosis; Tumor biomarkers; Neoplasms; Mucin 1; Epithelial membrane antigen; Pleural effusion ID EPITHELIAL MEMBRANE ANTIGEN; ASCITES ALBUMIN GRADIENT; PLEURAL FLUID; CARCINOEMBRYONIC ANTIGEN; MONOCLONAL-ANTIBODIES; CELL CARCINOMA; CLINICAL-VALUE; LUNG-CANCER; E-CADHERIN; SERUM AB Background: The differential diagnosis of benign and malignant effusion is often hampered by low cell content or insufficiently preserved tumor cells. In this study, we evaluated the combined diagnostic value of six tumor markers measured by well-based reverse-phase protein array (RPPA) for diagnosis of malignant effusion. Methods: A total of 114 patients (46 with malignant effusions, 32 with probable malignant effusions, and 36 with benign effusions) were enrolled. Expressional levels of MUC1, EMA, Pan-CK, HSP90, TGF-beta and CA125 were determined by well-based RPPA. Results: Median relative expression of MUC1, Pan-CK and EMA were significantly higher in malignant effusion than those in probable malignant or benign (p < 0.001, p = 0.003, p < 0.001, respectively), whereas the level of TGF-beta in malignant effusions were significantly lower than that in the other groups (p = 0.005). For predicting malignancy, EMA presented the best areas under the curve of 0.728 followed by MUC1 of 0.701. The sensitivity of 52.0% for MUC1 and 48.0% for EMA were not better than cytology. However, sensitivity, negative predictive value, and accuracy of the tumor marker panel were better than cytology by 14.7%, 7.5%, and 6.1%, respectively. Conclusions: Tumor marker panel measured by well-based RPPA showed values in the differential diagnosis between benign and malignant effusions. Further large scale studies need to be performed to evaluate the utility of this panel of markers. C1 [Braunschweig, Till; Chung, Joon-Yong; Choi, Chel Hun; Cho, Hanbyoul; Xie, Ran; Perry, Candice; Hewitt, Stephen M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Braunschweig, Till] Rhein Westfal TH Aachen, Inst Pathol, D-52074 Aachen, Germany. [Choi, Chel Hun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, Seoul 135710, South Korea. [Cho, Hanbyoul] Yonsei Univ, Gangnam Severance Hosp, Coll Med, Dept Obstet & Gynecol, Seoul 135720, South Korea. [Chen, Qing-Rong; Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Perry, Candice] Leidos Biomed Res Inc, Adv Technol Program, Antibody Characterizat Lab, Frederick, MD USA. RP Hewitt, SM (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU National Institutes of Health National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute, Center for Cancer Research. NR 46 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-1596 J9 DIAGN PATHOL JI Diagn. Pathol. PD MAY 29 PY 2015 VL 10 AR 53 DI 10.1186/s13000-015-0290-4 PG 10 WC Pathology SC Pathology GA CJ0OQ UT WOS:000355176500002 PM 26022333 ER PT J AU Wright, FA Lu, JP Sliter, DA Dupre, N Rouleau, GA Wojcikiewicz, RJH AF Wright, Forrest A. Lu, Justine P. Sliter, Danielle A. Dupre, Nicolas Rouleau, Guy A. Wojcikiewicz, Richard J. H. TI A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate Receptor-mediated Ca2+ Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETICULUM-ASSOCIATED DEGRADATION; ER-ASSOCIATED DEGRADATION; SPINOCEREBELLAR ATAXIAS; RELEASE CHANNELS; SYSTEM; ERLIN2; PROTEASOME; TOPOLOGY; RESIDUES; DOMAINS AB RNF170 is an endoplasmic reticulum membrane ubiquitin ligase that contributes to the ubiquitination of activated inositol 1,4,5-trisphosphate (IP3) receptors, and also, when point mutated (arginine to cysteine at position 199), causes autosomal dominant sensory ataxia (ADSA), a disease characterized by neurodegeneration in the posterior columns of the spinal cord. Here we demonstrate that this point mutation inhibits RNF170 expression and signaling via IP3 receptors. Inhibited expression of mutant RNF170 was seen in cells expressing exogenous RNF170 constructs and in ADSA lymphoblasts, and appears to result from enhanced RNF170 autoubiquitination and proteasomal degradation. The basis for these effects was probed via additional point mutations, revealing that ionic interactions between charged residues in the transmembrane domains of RNF170 are required for protein stability. In ADSA lymphoblasts, platelet-activating factor-induced Ca2+ mobilization was significantly impaired, whereas neither Ca2+ store content, IP3 receptor levels, nor IP3 production were altered, indicative of a functional defect at the IP3 receptor locus, which may be the cause of neurodegeneration. CRISPR/Cas9-mediated genetic deletion of RNF170 showed that RNF170 mediates the addition of all of the ubiquitin conjugates known to become attached to activated IP3 receptors (monoubiquitin and Lys(48)-and Lys(63)-linked ubiquitin chains), and that wild-type and mutant RNF170 have apparently identical ubiquitin ligase activities toward IP3 receptors. Thus, the Ca2+ mobilization defect seen in ADSA lymphoblasts is apparently not due to aberrant IP3 receptor ubiquitination. Rather, the defect likely reflects abnormal ubiquitination of other substrates, or adaptation to the chronic reduction in RNF170 levels. C1 [Wright, Forrest A.; Lu, Justine P.; Wojcikiewicz, Richard J. H.] SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA. [Sliter, Danielle A.] NINDS, NIH, Bethesda, MD 20892 USA. [Dupre, Nicolas] Univ Laval, CHU Quebec, Neuromuscular & Neurogenet Dis Clin, Quebec City, PQ G1J 1Z4, Canada. [Rouleau, Guy A.] McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ H3A 2B4, Canada. [Rouleau, Guy A.] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. RP Wojcikiewicz, RJH (reprint author), 750 E Adams St, Syracuse, NY 13210 USA. EM wojcikir@upstate.edu RI Regan, Clinton/E-6250-2012 FU National Institutes of Health [DK049194]; National Ataxia Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grant DK049194 and the National Ataxia Foundation. NR 47 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 29 PY 2015 VL 290 IS 22 BP 13948 EP 13957 DI 10.1074/jbc.M115.655043 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ2KK UT WOS:000355313000026 PM 25882839 ER PT J AU Stolzenberg, S Quick, M Zhao, CF Gotfryd, K Khelashvili, G Gether, U Loland, CJ Javitch, JA Noskov, S Weinstein, H Shi, L AF Stolzenberg, Sebastian Quick, Matthias Zhao, Chunfeng Gotfryd, Kamil Khelashvili, George Gether, Ulrik Loland, Claus J. Javitch, Jonathan A. Noskov, Sergei Weinstein, Harel Shi, Lei TI Mechanism of the Association between Na+ Binding and Conformations at the Intracellular Gate in Neurotransmitter: Sodium Symporters SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOPAMINE TRANSPORTER; MOLECULAR-DYNAMICS; BACTERIAL HOMOLOG; ION SELECTIVITY; OCCLUDED STATE; OUTWARD-OPEN; LEUT; SUBSTRATE; PROTEIN; SITE AB Neurotransmitter: sodium symporters (NSSs) terminate neurotransmission by Na+-dependent reuptake of released neurotransmitters. Previous studies suggested that Na+-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. We describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two different perturbations disrupting Na+ binding and transport (i.e. replacing Na+ with Li+ or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na+ cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na+ dependence. Thus, the detailed AIN generated from our method is shown to connect Na+ binding with global conformational changes that are critical for the transport mechanism. That the AIN between the Na+ binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function. C1 [Stolzenberg, Sebastian; Khelashvili, George; Weinstein, Harel; Shi, Lei] Cornell Univ, Dept Physiol & Biophys, New York, NY 10065 USA. [Weinstein, Harel; Shi, Lei] Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10065 USA. [Stolzenberg, Sebastian] Cornell Univ, Dept Phys, Ithaca, NY 14850 USA. [Quick, Matthias; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. [Quick, Matthias; Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Zhao, Chunfeng; Noskov, Sergei] Univ Calgary, Ctr Mol Simulat, Calgary, AB T2N 1N4, Canada. [Zhao, Chunfeng; Noskov, Sergei] Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada. [Gotfryd, Kamil; Gether, Ulrik; Loland, Claus J.] Univ Copenhagen, Dept Neurosci & Pharmacol, Copenhagen, Denmark. [Shi, Lei] NIDA, Computat Chem & Mol Biophys Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Weinstein, H (reprint author), Weill Cornell Med Coll, 1300 York Ave,Box 75, New York, NY 10065 USA. EM haw2002@med.cornell.edu; les2007@med.cornell.edu OI Gether, Ulrik/0000-0002-0020-3807; Loland, Claus/0000-0002-1773-1446 FU United States Department of Energy Office of Science User Facility [DE-AC05-00OR22725] FX We thank MiEstrella Miller-Cruz and Trang Nguyen for the preparation of bacterial membrane vesicles and the purification of LeuT variants and Lone Rosenquist for technical assistance in the hDAT experiments. Computations were performed on Ranger at the Texas Advanced Computing Center (TG-MCB090022); the resources of the Oak Ridge Leadership Computing Facility, which is a United States Department of Energy Office of Science User Facility supported under Contract DE-AC05-00OR22725; the West-Grid/Compute Canada facilities; and the local Tielemann, Noskov, and Kusalik cluster supported by the Canadian Foundation for Innovation. NR 42 TC 16 Z9 16 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 29 PY 2015 VL 290 IS 22 BP 13992 EP 14003 DI 10.1074/jbc.M114.625343 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ2KK UT WOS:000355313000030 PM 25869126 ER PT J AU Maeda, A Ono, M Holmbeck, K Li, L Kilts, TM Kram, V Noonan, ML Yoshioka, Y McNerny, EMB Tantillo, MA Kohn, DH Lyons, KM Robey, PG Young, MF AF Maeda, Azusa Ono, Mitsuaki Holmbeck, Kenn Li, Li Kilts, Tina M. Kram, Vardit Noonan, Megan L. Yoshioka, Yuya McNerny, Erin M. B. Tantillo, Margaret A. Kohn, David H. Lyons, Karen M. Robey, Pamela G. Young, Marian F. TI WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TISSUE GROWTH-FACTOR; CCN FAMILY PROTEINS; OSTEOBLAST DIFFERENTIATION; SKELETAL DEVELOPMENT; CAUSES OSTEOPENIA; MICE; OSTEOGENESIS; EXPRESSION; PATHWAYS; GENES AB WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1(-/-)) mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total bone mineral density of Wisp1(-/-) mice was significantly lower than that of WT mice. Further investigation by micro-computed tomography showed that female Wisp1(-/-) mice had decreased trabecular bone volume/total volume and that both male and female Wisp1(-/-) mice had decreased cortical bone thickness accompanied by diminished biomechanical strength. The molecular basis for decreased bone mass in Wisp1(-/-) mice arises from reduced bone formation likely caused by osteogenic progenitors that differentiate poorly compared with WT cells. Osteoclast precursors from Wisp1(-/-) mice developed more tartrate-resistant acid phosphatase-positive cells in vitro and in transplants, suggesting that WISP1 is also a negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy, Wisp1(-/-) mice had lower bone mineral density compared WT mice, confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1(-/-) bone marrow stromal cells had reduced expression of beta-catenin and its target genes, potentially caused by WISP1 inhibition of SOST binding to LRP6. Taken together, our data suggest that the decreased bone mass found in Wisp1(-/-) mice could potentially be caused by an insufficiency in the osteodifferentiation capacity of bone marrow stromal cells arising from diminished Wnt signaling, ultimately leading to altered bone turnover and weaker biomechanically compromised bones. C1 [Maeda, Azusa; Ono, Mitsuaki; Holmbeck, Kenn; Li, Li; Kilts, Tina M.; Kram, Vardit; Noonan, Megan L.; Yoshioka, Yuya; Robey, Pamela G.; Young, Marian F.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [McNerny, Erin M. B.; Tantillo, Margaret A.; Kohn, David H.] Univ Michigan, Biol & Mat Sci, Ann Arbor, MI 48109 USA. [McNerny, Erin M. B.; Tantillo, Margaret A.; Kohn, David H.] Univ Michigan, Div Prosthodont, Ann Arbor, MI 48109 USA. [Lyons, Karen M.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Orthoped Hosp, Los Angeles, CA 90095 USA. [Lyons, Karen M.] Univ Calif Los Angeles, Orthoped Hosp, Dept Orthoped Surg, Los Angeles, CA 90095 USA. [Maeda, Azusa; Ono, Mitsuaki; Yoshioka, Yuya] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Oral Rehabil & Regenerat Med, Okayama, Okayama 7008558, Japan. RP Young, MF (reprint author), NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Rm 225, Bethesda, MD 20892 USA. EM myoung@dir.nidcr.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU National Institutes of Health from NIDCR [1 Z01 DE000379-21]; NIAMS [R01 AR056657, AR052686]; NIDCR [T32 DE007057]; Japan Society for the Promotion of Science FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program Grant 1 Z01 DE000379-21 from NIDCR (to M. O., K. H., L. L., T. M. K., V. K., M. L. N., P. G. R., and M. F. Y.), Award R01 AR056657 from NIAMS and Award T32 DE007057 from NIDCR (to E. M., B. M., M. A. T., and D. H. K.), and Award AR052686 from NIAMS (to K. M. L.). This work was also supported by a fellowship from the Japan Society for the Promotion of Science (to A. M.). NR 27 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 29 PY 2015 VL 290 IS 22 BP 14004 EP 14018 DI 10.1074/jbc.M114.628818 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ2KK UT WOS:000355313000031 PM 25864198 ER PT J AU Huang, SYN Ghosh, S Pommier, Y AF Huang, Shar-yin Naomi Ghosh, Sanchari Pommier, Yves TI Topoisomerase I Alone Is Sufficient to Produce Short DNA Deletions and Can Also Reverse Nicks at Ribonucleotide Sites SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VACCINIA TOPOISOMERASE; GENOME INTEGRITY; EXCISION-REPAIR; LEADING-STRAND; DUPLEX DNA; COMPLEXES; CLEAVAGE; MECHANISMS; COVALENT; YEAST AB Ribonucleotide monophosphates (rNMPs) are among the most frequent form of DNA aberration, as high ratios of ribonucleotide triphosphate: deoxyribonucleotide triphosphate pools result in approximately two misincorporated rNMPs/kb of DNA. The main pathway for the removal of rNMPs is by RNase H2. However, in a RNase H2 knock-out yeast strain, a topoisomerase I (Top1)-dependent mutator effect develops with accumulation of short deletions within tandem repeats. Proposed models for these deletions implicated processing of Top1-generated nicks at rNMP sites and/or sequential Top1 binding, but experimental support has been lacking thus far. Here, we investigated the biochemical mechanism of the Top1-induced short deletions at the rNMP sites by generating nicked DNA substrates bearing 2',3'-cyclic phosphates at the nick sites, mimicking the Top1-induced nicks. We demonstrate that a second Top1 cleavage complex adjacent to the nick and subsequent faulty Top1 religation led to the short deletions. Moreover, when acting on the nicked DNA substrates containing 2',3'-cyclic phosphates, Top1 generated not only the short deletion, but also a full-length religated DNA product. Acatalytically inactive Top1 mutant (Top1-Y723F) also induced the full-length products, indicating that Top1 binding independent of its enzymatic activity promotes the sealing of DNA backbones via nucleophilic attacks by the 5'-hydroxyl on the 2',3'-cyclic phosphate. The resealed DNA would allow renewed attempt for repair by the error-free RNase H2-dependent pathway in vivo. Our results provide direct evidence for the generation of short deletions by sequential Top1 cleavage events and for the promotion of nick religation at rNMP sites by Top1. C1 [Pommier, Yves] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU National Institutes of Health from the Center for Cancer Research, NCI [Z01 BC006161] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Program Grant Z01 BC006161 from the Center for Cancer Research, NCI. NR 50 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 29 PY 2015 VL 290 IS 22 BP 14068 EP 14076 DI 10.1074/jbc.M115.653345 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CJ2KK UT WOS:000355313000036 PM 25887397 ER PT J AU Ueda, T Nagamachi, A Takubo, K Yamasaki, N Matsui, H Kanai, A Nakata, Y Ikeda, K Konuma, T Oda, H Wolff, L Honda, Z Wu, XD Helin, K Iwama, A Suda, T Inaba, T Honda, H AF Ueda, Takeshi Nagamachi, Akiko Takubo, Keiyo Yamasaki, Norimasa Matsui, Hirotaka Kanai, Akinori Nakata, Yuichiro Ikeda, Kenichiro Konuma, Takaaki Oda, Hideaki Wolff, Linda Honda, Zen-ichiro Wu, Xudong Helin, Kristian Iwama, Atsushi Suda, Toshio Inaba, Toshiya Honda, Hiroaki TI Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2 SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; OXIDATIVE-PHOSPHORYLATION; EMBRYONIC FIBROBLASTS; CANCER METABOLISM; EXPRESSION; STRESS; FAMILY; PROLIFERATION; MALIGNANCIES; MUTATIONS AB We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for -7/7q- syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. C1 [Ueda, Takeshi; Yamasaki, Norimasa; Nakata, Yuichiro; Ikeda, Kenichiro; Honda, Hiroaki] Hiroshima Univ, Dept Dis Model, Res Inst Radiat Biol & Med, Hiroshima 7348553, Japan. [Nagamachi, Akiko; Matsui, Hirotaka; Kanai, Akinori; Inaba, Toshiya] Hiroshima Univ, Dept Mol Oncol, Res Inst Radiat Biol & Med, Hiroshima 7348553, Japan. [Takubo, Keiyo; Suda, Toshio] Keio Univ, Sch Med, Dept Cell Differentiat, Sakaguchi Lab Dev Biol, Tokyo, Japan. [Konuma, Takaaki; Iwama, Atsushi] Chiba Univ, Dept Cellular & Mol Med, Grad Sch Med, Chiba, Japan. [Oda, Hideaki] Tokyo Womens Med Univ, Dept Pathol, Tokyo, Japan. [Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Honda, Zen-ichiro] Ochanomizu Univ, Hlth Care Ctr, Tokyo 112, Japan. [Honda, Zen-ichiro] Ochanomizu Univ, Grad Sch Humanities & Sci, Inst Environm Sci Human Life, Tokyo 112, Japan. [Wu, Xudong; Helin, Kristian] Univ Copenhagen, BRIC, Copenhagen, Denmark. [Wu, Xudong; Helin, Kristian] Univ Copenhagen, Ctr Epigenet, Copenhagen, Denmark. RP Ueda, T (reprint author), Hiroshima Univ, Dept Dis Model, Res Inst Radiat Biol & Med, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. EM takeshiueda@hiroshima-u.ac.jp; hhonda@hiroshima-u.ac.jp RI Suda, Toshio/H-6761-2013; OI Suda, Toshio/0000-0001-7540-1771; Helin, Kristian/0000-0003-1975-6097 FU Ministry of Education, Science and Culture of Japan FX This work was in part supported by a Grant in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan. NR 44 TC 7 Z9 7 U1 2 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 28 PY 2015 VL 125 IS 22 BP 3437 EP 3446 DI 10.1182/blood-2014-03-562694 PG 10 WC Hematology SC Hematology GA CK1PR UT WOS:000355979800015 PM 25872778 ER PT J AU Lynn, RC Poussin, M Kalota, A Feng, Y Low, PS Dimitrov, DS Powell, DJ AF Lynn, Rachel C. Poussin, Mathilde Kalota, Anna Feng, Yang Low, Philip S. Dimitrov, Dimiter S. Powell, Daniel J., Jr. TI Targeting of folate receptor beta on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells SO BLOOD LA English DT Article ID TRANS-RETINOIC ACID; IN-VIVO PERSISTENCE; OVARIAN-CANCER; ANTITUMOR-ACTIVITY; VITAMIN-A; RHEUMATOID-ARTHRITIS; CLINICAL-TRIAL; PHASE-I; INDUCTION; TUMOR AB T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate receptor beta (FR beta) is a myeloid-lineage antigen expressed on 70% of acute myeloid leukemia (AML) patient samples. Here, we describe the development and evaluation of the first CARs specific for human FR beta (m909) in vitro and in vivo. m909 CAR T cells exhibited selective activation and lytic function against engineered C30-FR beta as well as endogenous FR beta(+) AML cell lines in vitro. In mouse models of human AML, m909 CAR T cells mediated the regression of engrafted FR beta(+) THP1 AML in vivo. In addition, we demonstrated that treatment of AML with all-trans retinoic acid (ATRA) enhanced FR beta expression, resulting in improved immune recognition by m909 CAR T cells. Because many cell surface markers are shared between AML blasts and healthy hematopoietic stem and progenitor cells (HSCs), we evaluated FR beta expression and recognition of HSCs by CAR T cells. m909 CAR T cells were not toxic against healthy human CD34(+) HSCs in vitro. Our results indicate that FR beta is a promising target for CAR T-cell therapy of AML, which may be augmented by combination with ATRA. C1 [Lynn, Rachel C.; Poussin, Mathilde; Powell, Daniel J., Jr.] Univ Penn, Perelman Sch Med, Ovarian Canc Res Ctr, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Kalota, Anna] Univ Penn, Div Hematol Oncol, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Feng, Yang; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Expt Immunol Lab, Canc & Inflammat Program,Ctr Canc Res, Frederick, MD 21701 USA. [Low, Philip S.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Powell, Daniel J., Jr.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Powell, DJ (reprint author), Univ Penn, Perelman Sch Med, Smilow Ctr, 3400 Civ Ctr Blvd,Bldg 421,Room 08-103, Philadelphia, PA 19104 USA. EM poda@mail.med.upenn.edu FU National Institutes of Health National Cancer Institute (NCI) [RO1-CA168900]; National Institute of Allergy and Infectious Diseases [T32-AI070099]; Joint Fox Chase Cancer Center and University of Pennsylvania Ovarian Cancer Specialized Program of Research Excellence NCI [P50 CA083638]; Intramural Research Program at the NCI Center for Cancer Research; NCI [CA016520] FX This work was supported by the National Institutes of Health National Cancer Institute (NCI) grant RO1-CA168900 (D.J.P.), National Institute of Allergy and Infectious Diseases grant T32-AI070099 (R.C.L.), Joint Fox Chase Cancer Center and University of Pennsylvania Ovarian Cancer Specialized Program of Research Excellence NCI grant P50 CA083638 (D.J.P.), the Intramural Research Program at the NCI Center for Cancer Research (D.S.D.), and NCI grant CA016520, which supported imaging at the University of Pennsylvania Small Animal Imaging Facility Optical/Bioluminescence Core. NR 59 TC 18 Z9 19 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 28 PY 2015 VL 125 IS 22 BP 3466 EP 3476 DI 10.1182/blood-2014-11-612721 PG 11 WC Hematology SC Hematology GA CK1PR UT WOS:000355979800018 PM 25887778 ER PT J AU Palardy, G Chitnis, AB AF Palardy, Gregory Chitnis, Ajay B. TI Identification of the Mind Bomb1 Interaction Domain in Zebrafish DeltaD SO PLOS ONE LA English DT Article ID RECEPTOR INTERNALIZATION; JUXTAMEMBRANE DOMAIN; PRIMARY NEUROGENESIS; UBIQUITIN LIGASE; NOTCH; ENDOCYTOSIS; ACTIVATION; DROSOPHILA; INHIBITION; HOMOLOG AB Ubiquitylation promotes endocytosis of the Notch ligands like Delta and Serrate and is essential for them to effectively activate Notch in a neighboring cell. The RING E3 ligase Mind bomb1 (Mib1) ubiquitylates DeltaD to facilitate Notch signaling in zebrafish. We have identified a domain in the intracellular part of the zebrafish Notch ligand DeltaD that is essential for effective interactions with Mib1. We show that elimination of the Mind bomb1 Interaction Domain (MID) or mutation of specific conserved motifs in this domain prevents effective Mib1-mediated ubiquitylation and internalization of DeltaD. Lateral inhibition mediated by Notch signaling regulates early neurogenesis in zebrafish. In this context, Notch activation suppresses neurogenesis, while loss of Notch-mediated lateral inhibition results in a neurogenic phenotype, where too many cells are allowed to become neurons. While Mib1-mediated endocytosis of DeltaD is essential for effective activation of Notch in a neighboring cell (in trans) it is not required for DeltaD to inhibit function of Notch receptors in the same cell (in cis). As a result, forms of DeltaD that have the MID can activate Notch in trans and suppress early neurogenesis when mRNA encoding it is ectopically expressed in zebrafish embryos. On the other hand, when the MID is eliminated/mutated in DeltaD, its ability to activate Notch in trans fails but ability to inhibit in cis is retained. As a result, ectopic expression of DeltaD lacking an effective MID results in a failure of Notch-mediated lateral inhibition and a neurogenic phenotype. C1 [Palardy, Gregory; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Chitnis, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM chitnisa@mail.nih.gov FU Eunice Kennedy Shriver National Insitute of Child Health and Human Development [1ZIAHD001012] FX This research was funded by the intramural program of the Eunice Kennedy Shriver National Insitute of Child Health and Human Development 1ZIAHD001012. NR 25 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 28 PY 2015 VL 10 IS 5 AR e0127864 DI 10.1371/journal.pone.0127864 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0SC UT WOS:000355187300060 PM 26020642 ER PT J AU Prasad, R Dyrkheeva, N Williams, J Wilson, SH AF Prasad, Rajendra Dyrkheeva, Nadezhda Williams, Jason Wilson, Samuel H. TI Mammalian Base Excision Repair: Functional Partnership between PARP-1 and APE1 in AP-Site Repair SO PLOS ONE LA English DT Article ID DNA-POLYMERASE-BETA; STRAND BREAK REPAIR; APURINIC APYRIMIDINIC SITES; CELL NUCLEAR ANTIGEN; POLY(ADP-RIBOSE) POLYMERASE-1; APURINIC/APYRIMIDINIC ENDONUCLEASE-1; MOUSE FIBROBLASTS; PROTEIN XRCC1; LIGASE-III; IN-VITRO AB The apurinic/apyrimidinic-(AP-) site in genomic DNA arises through spontaneous base loss and base removal by DNA glycosylases and is considered an abundant DNA lesion in mammalian cells. The base excision repair (BER) pathway repairs the AP-site lesion by excising and replacing the site with a normal nucleotide via template directed gap-filling DNA synthesis. The BER pathway is mediated by a specialized group of proteins, some of which can be found in multiprotein complexes in cultured mouse fibroblasts. Using a DNA polymerase (pol) beta immunoaffinity-capture technique to isolate such a complex, we identified five tightly associated and abundant BER factors in the complex: PARP-1, XRCC1, DNA ligase III, PNKP, and Tdp1. AP endonuclease 1 (APE1), however, was not present. Nevertheless, the complex was capable of BER activity, since repair was initiated by PARP-1's AP lyase strand incision activity. Addition of purified APE1 increased the BER activity of the pol beta complex. Surprisingly, the pol beta complex stimulated the strand incision activity of APE1. Our results suggested that PARP-1 was responsible for this effect, whereas other proteins in the complex had no effect on APE1 strand incision activity. Studies of purified PARP-1 and APE1 revealed that PARP-1 was able to stimulate APE1 strand incision activity. These results illustrate roles of PARP-1 in BER including a functional partnership with APE1. C1 [Prasad, Rajendra; Dyrkheeva, Nadezhda; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Williams, Jason] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences [Z01ES050158, Z01ES050159]; Eli Lilly and Co.; United States Department of State, United States-Russia FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences, project numbers Z01ES050158 and Z01ES050159. ND is supported in part by Eli Lilly and Co. and the United States Department of State, as part of the United States-Russia Collaboration in the Biomedical Sciences NIH Visiting Fellows Program. NR 79 TC 4 Z9 4 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 28 PY 2015 VL 10 IS 5 AR e0124269 DI 10.1371/journal.pone.0124269 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0SC UT WOS:000355187300007 PM 26020771 ER PT J AU Puetz, TW Youngstedt, SD Herring, MP AF Puetz, Timothy W. Youngstedt, Shawn D. Herring, Matthew P. TI Effects of Pharmacotherapy on Combat-Related PTSD, Anxiety, and Depression: A Systematic Review and Meta-Regression Analysis SO PLOS ONE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; OF-VETERANS-AFFAIRS; SYMPTOMS; METAANALYSIS; EXERCISE; QUALITY; TRIALS; COMORBIDITY; PREVALENCE; GUIDELINES AB The efficacy of pharmacotherapy for PTSD, anxiety, and depression among combat veterans is not well-established. Objectives To estimate the effect of pharmacotherapy on PTSD, anxiety, and depression among combat veterans; to determine whether the effects varied according to patient and intervention characteristics; and to examine differential effects of pharmacotherapy on outcomes. Materials and Methods Google Scholar, PILOTS, PsycINFO, PubMed, and Web of Science databases were searched through November 2014. Searches resulted in eighteen double-blind, placebo controlled trials of 773 combat veterans diagnosed with PTSD and included only validated pre- and post-intervention PTSD and anxiety or depression measures. Authors extracted data on effect sizes, moderators, and study quality. Hedges' d effect sizes were computed and random effects models estimated sampling error and population variance. The Johnson-Neyman procedure identified the critical points in significant interactions to define regions of significance. Results Pharmacotherapy significantly reduced (Delta, 95% CI) PTSD (0.38, 0.23-0.52), anxiety (0.42, 0.30-0.54), and depressive symptoms (0.52, 0.35-0.70). The effects of SSRIs and tricyclic antidepressants on PTSD were greater than other medications independent of treatment duration. The effect of SSRIs and tricyclic antidepressants were greater than other medications up to 5.2 and 13.6 weeks for anxiety and depression, respectively. The magnitude of the effect of pharmacotherapy on concurrently-measured PTSD, anxiety, and depression did not significantly differ. Conclusions Pharmacotherapy reduced PTSD, anxiety, and depressive symptoms in combat veterans. The effects of SSRIs and tricyclic antidepressants were greater for PTSD and occurred quicker for anxiety and depression than other medications. C1 [Puetz, Timothy W.] NIH, Ctr Clin, Off Director, Bethesda, MD 20892 USA. [Youngstedt, Shawn D.] Arizona State Univ, Coll Nursing & Hlth Innovat, Phoenix, AZ USA. [Youngstedt, Shawn D.] Arizona State Univ, Sch Nutr & Hlth Promot, Phoenix, AZ USA. [Youngstedt, Shawn D.] Phoenix VA Hlth Care Syst, Phoenix, AZ USA. [Herring, Matthew P.] Univ Limerick, Dept Phys Educ & Sport Sci, Limerick, Ireland. RP Herring, MP (reprint author), Univ Limerick, Dept Phys Educ & Sport Sci, Limerick, Ireland. EM matthew.herring@ul.ie RI Herring, Matthew/O-2265-2014 OI Herring, Matthew/0000-0002-6835-5321 FU National Institutes of Health [R01 HL095799] FX Funding for this work was provided by the National Institutes of Health under grant R01 HL095799. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 1 Z9 2 U1 3 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 28 PY 2015 VL 10 IS 5 AR e0126529 DI 10.1371/journal.pone.0126529 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0SC UT WOS:000355187300025 PM 26020791 ER PT J AU Cohen, JI AF Cohen, Jeffrey I. TI A New Vaccine to Prevent Herpes Zoster SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID VARICELLA; RECIPIENTS; EFFICACY C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NR 10 TC 6 Z9 6 U1 1 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 28 PY 2015 VL 372 IS 22 BP 2149 EP 2150 DI 10.1056/NEJMe1505050 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CJ0EI UT WOS:000355146800013 PM 25916342 ER PT J AU Lack, G Plaut, M Sayre, PH AF Lack, Gideon Plaut, Marshall Sayre, Peter H. TI Peanut Consumption in Infants at Risk for Peanut Allergy REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Lack, Gideon] Kings Coll London, London WC2R 2LS, England. [Plaut, Marshall] NIAID, Bethesda, MD 20892 USA. [Sayre, Peter H.] Immune Tolerance Network, San Francisco, CA USA. RP Lack, G (reprint author), Kings Coll London, London WC2R 2LS, England. EM gideon.lack@kcl.ac.uk NR 5 TC 1 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 28 PY 2015 VL 372 IS 22 BP 2165 EP 2166 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CJ0EI UT WOS:000355146800021 PM 26017828 ER PT J AU Carter, BD Freedman, ND Jacobs, EJ AF Carter, Brian D. Freedman, Neal D. Jacobs, Eric J. TI Smoking and Mortality - Beyond Established Causes REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Carter, Brian D.; Jacobs, Eric J.] Amer Canc Soc, Atlanta, GA 30329 USA. [Freedman, Neal D.] NCI, Bethesda, MD 20892 USA. RP Carter, BD (reprint author), Amer Canc Soc, Atlanta, GA 30329 USA. EM brian.carter@cancer.org RI Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 NR 2 TC 5 Z9 5 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 28 PY 2015 VL 372 IS 22 BP 2170 EP 2170 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CJ0EI UT WOS:000355146800029 PM 26017836 ER PT J AU Grady, C AF Grady, Christine TI Enduring and Emerging Challenges of Informed Consent REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM cgrady@nih.gov NR 5 TC 4 Z9 4 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 28 PY 2015 VL 372 IS 22 BP 2172 EP 2172 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CJ0EI UT WOS:000355146800032 PM 26017840 ER PT J AU Liang, X He, Y Salmeron, BJ Gu, H Stein, EA Yang, YH AF Liang, Xia He, Yong Salmeron, Betty Jo Gu, Hong Stein, Elliot A. Yang, Yihong TI Interactions between the Salience and Default-Mode Networks Are Disrupted in Cocaine Addiction SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain circuits; cocaine addiction; modularity analysis; network interactions; resting fMRI ID STATE FUNCTIONAL CONNECTIVITY; TORONTO-ALEXITHYMIA-SCALE; ANTERIOR CINGULATE CORTEX; SUBSTANCE USE DISORDERS; BRAIN NETWORKS; DRUG-ADDICTION; GLOBAL SIGNAL; HEAD MOTION; INSULA; USERS AB Cocaine dependence is a complex neuropsychiatric disorder manifested as dysregulation of multiple behavioral, emotional, and cognitive constructs. Neuroimaging studies have begun to identify specific neurobiological circuit impairments in cocaine-dependent (CD) individuals that may underlie these symptoms. However, whether, where, and how the interactions within and between these circuits are disrupted remain largely unknown. We used resting-state fMRI and modularity network analysis to identify brain modules of a priori interest (default-mode network [DMN], salience network [SN], executive control network [ECN], medial temporal lobe [MTL], and striatum) in 47 CD and 47 matched healthy control (HC) participants and explored alterations within and between these brain modules as a function of addiction. At the module level, intermodule connectivity decreased between DMN and SN in CD. At the nodal level, several regions showed decreased connections with multiple modules in CD: the rostral anterior cingulate connection strength was reduced with SN and MTL; the posterior cingulate had reduced connections with ECN; and the bilateral insula demonstrated decreased connections with DMN. Furthermore, alexithymia, a personality trait previously associated with addiction, correlated negatively with intramodule connectivity within SN only in cocaine users. Our results indicate that cocaine addiction is associated with disrupted interactions among DMN, MTL, and SN, which have been implicated, respectively, in self-referential functions, emotion and memory, and coordinating between internal and external stimuli, providing novel and important insights into the neurobiological mechanisms of cocaine addiction. C1 [Liang, Xia; Salmeron, Betty Jo; Gu, Hong; Stein, Elliot A.; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Liang, Xia; He, Yong] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. [Liang, Xia; He, Yong] Beijing Normal Univ, IDG McGovern Inst Brain Res, Beijing 100875, Peoples R China. RP Yang, YH (reprint author), NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. EM yihongyang@intra.nida.nih.gov RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 FU National Institute on Drug Abuse, National Institutes of Health; Natural Science Foundation of China [81030028, 31221003]; National Science Fund for Distinguished Young Scholars [81225012] FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. Y.H. was supported by Natural Science Foundation of China Grants 81030028 and 31221003 and National Science Fund for Distinguished Young Scholars Grant 81225012. NR 73 TC 7 Z9 7 U1 3 U2 21 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 27 PY 2015 VL 35 IS 21 BP 8081 EP 8090 DI 10.1523/JNEUROSCI.3188-14.2015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CL1AB UT WOS:000356673100005 PM 26019326 ER PT J AU Li, X Rubio, FJ Zeric, T Bossert, JM Kambhampati, S Cates, HM Kennedy, PJ Liu, QR Cimbro, R Hope, BT Nestler, EJ Shaham, Y AF Li, Xuan Rubio, F. Javier Zeric, Tamara Bossert, Jennifer M. Kambhampati, Sarita Cates, Hannah M. Kennedy, Pamela J. Liu, Qing-Rong Cimbro, Raffaello Hope, Bruce T. Nestler, Eric J. Shaham, Yavin TI Incubation of Methamphetamine Craving Is Associated with Selective Increases in Expression of Bdnf and Trkb, Glutamate Receptors, and Epigenetic Enzymes in Cue-Activated Fos-Expressing Dorsal Striatal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dorsal striatum; epigenetics; FACS; glutamate; methamphetamine; relapse ID CONTEXT-INDUCED REINSTATEMENT; ANXIOGENIC DRUG YOHIMBINE; VENTRAL TEGMENTAL AREA; COCAINE-SEEKING; NUCLEUS-ACCUMBENS; PREFRONTAL CORTEX; DORSOLATERAL STRIATUM; NEUROTROPHIC FACTOR; MOLECULAR ALTERATIONS; INDUCED RELAPSE AB Cue-induced methamphetamine seeking progressively increases after withdrawal (incubation of methamphetamine craving), but the underlying mechanisms are largely unknown. We determined whether this incubation is associated with alterations in candidate genes in dorsal striatum (DS), a brain area implicated in cue-and context-induced drug relapse. We first measured mRNA expression of 24 candidate genes in whole DS extracts after short (2 d) or prolonged (1 month) withdrawal in rats following extended-access methamphetamine or saline (control condition) self-administration (9 h/d, 10 d). We found minimal changes. Next, using fluorescence-activated cell sorting, we compared gene expression in Fos-positive dorsal striatal neurons, which were activated during "incubated" cue-induced drug-seeking tests after prolonged withdrawal, with nonactivated Fos-negative neurons. We found significant increases in mRNA expression of immediate early genes (Arc, Egr1), Bdnf and its receptor (Trkb), glutamate receptor subunits (Gria1, Gria3, Grm1), and epigenetic enzymes (Hdac3, Hdac4, Hdac5, GLP, Dnmt3a, Kdm1a) in the Fos-positive neurons only. Using RNA scope to determine striatal subregion and cell-type specificity of the activated neurons, we measured colabeling of Fos with Drd1 and Drd2 in three DS subregions. Fos expression was neither subregion nor cell-type specific (52.5 and 39.2% of Fos expression colabeled with Drd1 and Drd2, respectively). Finally, we found that DS injections of SCH23390 (C17H18ClNO), a D1-family receptor antagonist known to block cue-induced Fos induction, decreased incubated cue-induced methamphetamine seeking after prolonged withdrawal. Results demonstrate a critical role of DS in incubation of methamphetamine craving and that this incubation is associated with selective gene-expression alterations in cue-activated D1- and D2-expressing DS neurons. C1 [Li, Xuan; Rubio, F. Javier; Zeric, Tamara; Bossert, Jennifer M.; Kambhampati, Sarita; Liu, Qing-Rong; Hope, Bruce T.; Shaham, Yavin] US Dept Hlth & Human Serv, Behav Neurosci Res Branch, Intramural Res Program, NIDA,NIH, Baltimore, MD 21224 USA. [Cates, Hannah M.; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Cates, Hannah M.; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Kennedy, Pamela J.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Cimbro, Raffaello] Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD 21224 USA. RP Li, X (reprint author), US Dept Hlth & Human Serv, Behav Neurosci Res Branch, Intramural Res Program, NIDA,NIH, Baltimore, MD 21224 USA. EM anna.li@nih.gov; yavin.shaham@nih.gov RI Hope, Bruce/A-9223-2010; Liu, Qing-Rong/A-3059-2012; OI Hope, Bruce/0000-0001-5804-7061; Liu, Qing-Rong/0000-0001-8477-6452; Cates, Hannah/0000-0002-9413-0847; Cimbro, Raffaello/0000-0002-6251-5160 FU NIDA [P01DA008227]; NIDA Intramural Research Program; National Institutes of Health; Becas-Chile scholarship; Universidad de los Andes, Santiago, Chile; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health [P30AR053503] FX This work was supported by the intramural (Y.S., B.T.H.) and extramural (P01DA008227; E.J.N.) divisions of the NIDA, and an intramural-extramural award from the NIDA Intramural Research Program (Y.S., X.L., E.J.N.). F.J.R. was supported by an appointment to the NIDA Research Participation Program sponsored by the National Institutes of Health and administered by the Oak Ridge Institute for Science and Education, and received additional financial support from a Becas-Chile scholarship managed by CONICYT and the Universidad de los Andes, Santiago, Chile. The Johns Hopkins FACS Core facility was supported by Award P30AR053503 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health. NR 70 TC 20 Z9 20 U1 2 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 27 PY 2015 VL 35 IS 21 BP 8232 EP 8244 DI 10.1523/JNEUROSCI.1022-15.2015 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CL1AB UT WOS:000356673100017 PM 26019338 ER PT J AU Shalaeva, DN Dibrova, DV Galperin, MY Mulkidjanian, AY AF Shalaeva, Daria N. Dibrova, Daria V. Galperin, Michael Y. Mulkidjanian, Armen Y. TI Modeling of interaction between cytochrome c and the WD domains of Apaf-1: bifurcated salt bridges underlying apoptosome assembly SO BIOLOGY DIRECT LA English DT Article DE Apoptosis; WD40 domains; Hydrogen bond; Salt bridge; Apoptosis; Protein-protein interactions; Caspase; Molecular dynamics simulations; Sequence analysis; Evolution ID ELECTRON-TRANSFER; CRYSTAL-STRUCTURE; CELL-DEATH; MITOCHONDRIAL PATHWAY; GLOBULAR-PROTEINS; WD40-REPEAT PROTEINS; APOPTOTIC ACTIVITY; BC(1) COMPLEX; PREDICTION; BINDING AB Background: Binding of cytochrome c, released from the damaged mitochondria, to the apoptotic protease activating factor 1 (Apaf-1) is a key event in the apoptotic signaling cascade. The binding triggers a major domain rearrangement in Apaf-1, which leads to oligomerization of Apaf-1/cytochrome c complexes into an apoptosome. Despite the availability of crystal structures of cytochrome c and Apaf-1 and cryo-electron microscopy models of the entire apoptosome, the binding mode of cytochrome c to Apaf-1, as well as the nature of the amino acid residues of Apaf-1 involved remain obscure. Results: We investigated the interaction between cytochrome c and Apaf-1 by combining several modeling approaches. We have applied protein-protein docking and energy minimization, evaluated the resulting models of the Apaf-1/cytochrome c complex, and carried out a further analysis by means of molecular dynamics simulations. We ended up with a single model structure where all the lysine residues of cytochrome c that are known as functionally-relevant were involved in forming salt bridges with acidic residues of Apaf-1. This model has revealed three distinctive bifurcated salt bridges, each involving a single lysine residue of cytochrome c and two neighboring acidic resides of Apaf-1. Salt bridge-forming amino acids of Apaf-1 showed a clear evolutionary pattern within Metazoa, with pairs of acidic residues of Apaf-1, involved in bifurcated salt bridges, reaching their highest numbers in the sequences of vertebrates, in which the cytochrome c-mediated mechanism of apoptosome formation seems to be typical. Conclusions: The reported model of an Apaf-1/cytochrome c complex provides insights in the nature of protein-protein interactions which are hard to observe in crystallographic or electron microscopy studies. Bifurcated salt bridges can be expected to be stronger than simple salt bridges, and their formation might promote the conformational change of Apaf-1, leading to the formation of an apoptosome. Combination of structural and sequence analyses provides hints on the evolution of the cytochrome c-mediated apoptosis. C1 [Shalaeva, Daria N.; Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. [Shalaeva, Daria N.; Mulkidjanian, Armen Y.] Sch Bioengn & Bioinformat, Moscow 117999, Russia. [Dibrova, Daria V.; Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physico Chem Biol, Moscow 117999, Russia. [Galperin, Michael Y.] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Mulkidjanian, AY (reprint author), Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. EM amulkid@uos.de RI Mulkidjanian, Armen/J-8086-2013 OI Mulkidjanian, Armen/0000-0001-5844-3064 FU Osnabrueck University, Germany; German Academic Exchange Service; Russian Science Foundation [14-14-00592, 14-50-00029]; Development Program of the Lomonosov Moscow State University, Russia; Intramural Research Program of the National Institutes of Health at the National Library of Medicine, USA FX The authors are grateful to Prof. V.P. Skulachev for drawing their attention to the potential key role of the residues of Apaf-1 in the formation of an apoptosome. The research of the authors was supported in part by the Osnabrueck University, Germany and a fellowship from the German Academic Exchange Service (DNS), grants from the Russian Science Foundation (14-14-00592, AYM, molecular modeling of apoptosome formation, and 14-50-00029, DVD, AYM, phylogenomic analysis of cytochrome c), by the Development Program of the Lomonosov Moscow State University, Russia (access to the supercomputer facility), and by the Intramural Research Program of the National Institutes of Health at the National Library of Medicine, USA (MYG). NR 96 TC 1 Z9 1 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 27 PY 2015 VL 10 AR 29 DI 10.1186/s13062-015-0059-4 PG 28 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CJ0JH UT WOS:000355161100001 PM 26014357 ER PT J AU Thomas, A Chen, YB Yu, TH Jakopovic, M Giaccone, G AF Thomas, Anish Chen, Yuanbin Yu, Tinghui Jakopovic, Marko Giaccone, Giuseppe TI Trends and characteristics of young non-small cell lung cancer patients in the United States SO FRONTIERS IN ONCOLOGY LA English DT Article DE non-small cell lung cancer; SEER; young; population-based studies; disparities ID AGE; SMOKING; EPIDEMIOLOGY; SURVEILLANCE; CARCINOMA; DIAGNOSIS; OUTCOMES; ADULTS; TUMORS; RATES AB Background: Although the median age at diagnosis of non-small cell lung cancer (NSCLC) is 70 years, a subset of patients with NSCLC present at a younger age (<40 years). Little is known about the time-trends in incidence of NSCLC in the young, their characteristics and outcomes. Methods: The surveillance, epidemiology, and end results database was used to extract NSCLC cases from 1978 to 2010. Yearly incidence rates in various age groups, race, site of disease, histology, treatment patterns, and outcomes were assessed. We modeled Kaplan Meyer survival curves stratified by age of presentation. Results: Young patients represented 0.6% of incident NSCLC from 1978 to 2010. The incidence of young NSCLC declined significantly during this time-period. Young NSCLCs had a higher proportion of women (51%), Asians or Pacific Islanders (14%), adenocarcinoma histology (59%) and were more likely to present with distant metastases (68%). The young had better all cause and lung cancer-specific survival than the older patients (median survival for localized, regional, and distant disease: not reached, 28, 9 vs. 46, 17, 5 months; p <0.001 for all groups). Male sex, non-adenocarcinoma histology, and main bronchial primary were independent negative prognostic factors among the young. In contrast to the overall population, black race was a poor prognostic factor among the young. Conclusion: The incidence of NSCLC in the young decreased from 1978 to 2010. The clinical characteristics of NSCLC in the young, including demographic distribution, treatment, and outcomes are different from those observed in the older patients. C1 [Thomas, Anish; Chen, Yuanbin] NCI, Natl Inst Hlth, Med Oncol Branch, Bethesda, MD 20892 USA. [Yu, Tinghui] Fed Drug Adm, Off Surveillance & Biometr Devices & Radiol, Silver Spring, MD USA. [Jakopovic, Marko] Univ Zagreb, Univ Hosp Ctr Zagreb, Sch Med, Dept Resp Dis, Zagreb 41000, Croatia. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Canc Ctr, Res Bldg RoomW503,3970Reservoir Rd NW, Washington, DC 20057 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 NR 37 TC 9 Z9 10 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD MAY 26 PY 2015 VL 5 AR 113 DI 10.3389/fonc.2015.00113 PG 7 WC Oncology SC Oncology GA CO4OE UT WOS:000359139500001 PM 26075181 ER PT J AU Cheng, Y Lu, F Lee, SK Kong, DH Ha, KS Wang, B Sattabongkot, J Tsuboi, T Han, ET AF Cheng, Yang Lu, Feng Lee, Seong-Kyun Kong, Deok-Hoon Ha, Kwon-Soo Wang, Bo Sattabongkot, Jetsumon Tsuboi, Takafumi Han, Eun-Taek TI Characterization of Plasmodium vivax Early Transcribed Membrane Protein 11.2 and Exported Protein 1 SO PLOS ONE LA English DT Article ID HOST-CELL CYTOPLASM; MALARIA PARASITE; ERYTHROCYTE-MEMBRANE; VACUOLAR MEMBRANE; FALCIPARUM; INVASION; FAMILY; INFECTION; ANTIGEN; RHOPTRY AB In Plasmodium, the membrane of intracellular parasites is initially formed during invasion as an invagination of the red blood cell surface, which forms a barrier between the parasite and infected red blood cells in asexual blood stage parasites. The membrane proteins of intracellular parasites of Plasmodium species have been identified such as early-transcribed membrane proteins (ETRAMPs) and exported proteins (EXPs). However, there is little or no information regarding the intracellular parasite membrane in Plasmodium vivax. In the present study, recombinant PvETRAMP11.2 (PVX_003565) and PvEXP1 (PVX_091700) were expressed and evaluated antigenicity tests using sera from P. vivax-infected patients. A large proportion of infected individuals presented with IgG antibody responses against PvETRAMP11.2 (76.8%) and PvEXP1 (69.6%). Both of the recombinant proteins elicited high antibody titers capable of recognizing parasites of vivax malaria patients. PvETRAMP11.2 partially co-localized with PvEXP1 on the intracellular membranes of immature schizont. Moreover, they were also detected at the apical organelles of newly formed merozoites of mature schizont. We first proposed that these proteins might be synthesized in the preceding schizont stage, localized on the parasite membranes and apical organelles of infected erythrocytes, and induced high IgG antibody responses in patients. C1 [Cheng, Yang; Lu, Feng; Lee, Seong-Kyun; Wang, Bo; Han, Eun-Taek] Kangwon Natl Univ, Sch Med, Dept Med Environm Biol & Trop Med, Chunchon, Gangwon Do, South Korea. [Cheng, Yang] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Lu, Feng] Jiangsu Inst Parasit Dis, Minist Hlth, Key Lab Parasit Dis Control & Prevent, Wuxi, Jiangsu, Peoples R China. [Lu, Feng] Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite Mol Biol, Wuxi, Jiangsu, Peoples R China. [Kong, Deok-Hoon; Ha, Kwon-Soo] Kangwon Natl Univ, Sch Med, Dept Mol & Cellular Biochem, Chunchon, Gangwon Do, South Korea. [Wang, Bo] Anhui Med Univ, Affiliated Hosp 1, Dept Clin Lab, Hefei, Anhui, Peoples R China. [Sattabongkot, Jetsumon] Mahidol Univ, Fac Trop Med, Mahidol Vivax Res Unit, Bangkok 10700, Thailand. [Tsuboi, Takafumi] Ehime Univ, Proteosci Ctr, Div Malaria Res, Matsuyama, Ehime, Japan. RP Tsuboi, T (reprint author), Ehime Univ, Proteosci Ctr, Div Malaria Res, Matsuyama, Ehime, Japan. EM tsuboi.takafumi.mb@ehime-u.ac.jp; ethan@kangwon.ac.kr FU National Research Foundation (NRF) of Korea Grant - Korean government (MEST) [2011-0016401]; Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A121180]; MEXT KAKENHI [23117008]; JSPS KAKENHI in Japan [23406007] FX This work was supported by National Research Foundation (NRF) of Korea Grant funded by the Korean government (MEST) (2011-0016401) and a grant from the Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A121180). This work was also supported in part by MEXT KAKENHI (23117008) and JSPS KAKENHI (23406007) in Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0127500 DI 10.1371/journal.pone.0127500 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900099 ER PT J AU Fujita, R Otake, K Arimura, Y Horikoshi, N Miya, Y Shiga, T Osakabe, A Tachiwana, H Ohzeki, J Larionov, V Masumoto, H Kurumizaka, H AF Fujita, Risa Otake, Koichiro Arimura, Yasuhiro Horikoshi, Naoki Miya, Yuta Shiga, Tatsuya Osakabe, Akihisa Tachiwana, Hiroaki Ohzeki, Jun-ichirou Larionov, Vladimir Masumoto, Hiroshi Kurumizaka, Hitoshi TI Stable complex formation of CENP-B with the CENP-A nucleosome SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN CENTROMERE PROTEIN; CELL-CYCLE; CRYSTAL-STRUCTURE; DNA-BINDING; MOLECULAR ARCHITECTURE; CHROMOSOME SEGREGATION; OUTER KINETOCHORE; HISTONE VARIANT; BUDDING YEAST; ALPHOID DNA AB CENP-A and CENP-B are major components of centromeric chromatin. CENP-A is the histone H3 variant, which forms the centromere-specific nucleosome. CENP-B specifically binds to the CENP-B box DNA sequence on the centromere-specific repetitive DNA. In the present study, we found that the CENP-A nucleosome more stably retains human CENP-B than the H3.1 nucleosome in vitro. Specifically, CENP-B forms a stable complex with the CENP-A nucleosome, when the CENP-B box sequence is located at the proximal edge of the nucleosome. Surprisingly, the CENP-B binding was weaker when the CENP-B box sequence was located in the distal linker region of the nucleosome. This difference in CENP-B binding, depending on the CENP-B box location, was not observed with the H3.1 nucleosome. Consistently, we found that the DNA-binding domain of CENP-B specifically interacted with the CENP-A-H4 complex, but not with the H3.1-H4 complex, in vitro. These results suggested that CENP-B forms a more stable complex with the CENP-A nucleosome through specific interactions with CENP-A, if the CENP-B box is located proximal to the CENP-A nucleosome. Our in vivo assay also revealed that CENP-B binding in the vicinity of the CENP-A nucleosome substantially stabilizes the CENP-A nucleosome on alphoid DNA in human cells. C1 [Fujita, Risa; Arimura, Yasuhiro; Horikoshi, Naoki; Miya, Yuta; Shiga, Tatsuya; Osakabe, Akihisa; Tachiwana, Hiroaki; Kurumizaka, Hitoshi] Waseda Univ, Grad Sch Adv Sci & Engn, Lab Struct Biol, Shinjuku Ku, Tokyo 1628480, Japan. [Otake, Koichiro; Ohzeki, Jun-ichirou; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Frontier Res, Lab Cell Engn, Kisarazu, Chiba 2920818, Japan. [Larionov, Vladimir] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Kurumizaka, H (reprint author), Waseda Univ, Grad Sch Adv Sci & Engn, Lab Struct Biol, Shinjuku Ku, 2-2 Wakamatsu Cho, Tokyo 1628480, Japan. EM kurumizaka@waseda.jp OI Horikoshi, Naoki/0000-0003-1842-6934 FU MEXT KAKENHI [25116002, 23247030, 23114008]; MEXT, Japan; Waseda Research Institute for Science and Engineering; Uehara Foundation; Naito Foundation; Japan Society for the Promotion of Science [25-3931]; Kazusa DNA Research Institute Foundation; Intramural Research Program of the NIH, NCI, CCR FX MEXT KAKENHI [25116002 to H.K., 23247030 and 23114008 to H.M.]; Platform for Drug Discovery, Informatics and Structural Life Science from MEXT, Japan [to H.K.]. H.K. was also supported by the Waseda Research Institute for Science and Engineering, and by the Uehara Foundation and the Naito Foundation. Y.A. was supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists [25-3931]. H.M. was also supported by the Kazusa DNA Research Institute Foundation. V.L. received support from the Intramural Research Program of the NIH, NCI, CCR. Funding for open access charge: Waseda University. NR 70 TC 7 Z9 7 U1 5 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 MAY 26 PY 2015 VL 43 IS 10 BP 4909 EP 4922 DI 10.1093/nar/gkv405 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK0XO UT WOS:000355929200017 PM 25916850 ER PT J AU Zong, DL Callen, E Pegoraro, G Lukas, C Lukas, J Nussenzweig, A AF Zong, Dali Callen, Elsa Pegoraro, Gianluca Lukas, Claudia Lukas, Jiri Nussenzweig, Andre TI Ectopic expression of RNF168 and 53BP1 increases mutagenic but not physiological non-homologous end joining SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CLASS-SWITCH RECOMBINATION; DOUBLE-STRAND BREAKS; DNA-DAMAGE-RESPONSE; HOMOLOGOUS RECOMBINATION; UBIQUITIN LIGASE; SOMATIC HYPERMUTATION; OVARIAN-CARCINOMA; BRCA1 DEFICIENCY; CANCER GENOMICS; REPAIR PROTEINS AB DNA double strand breaks (DSBs) formed during S phase are preferentially repaired by homologous recombination (HR), whereas G(1) DSBs, such as those occurring during immunoglobulin class switch recombination (CSR), are repaired by non-homologous end joining (NHEJ). The DNA damage response proteins 53BP1 and BRCA1 regulate the balance between NHEJ and HR. 53BP1 promotes CSR in part by mediating synapsis of distal DNA ends, and in addition, inhibits 5' end resection. BRCA1 antagonizes 53BP1 dependent DNA end-blocking activity during S phase, which would otherwise promote mutagenic NHEJ and genome instability. Recently, it was shown that supra-physiological levels of the E3 ubiquitin ligase RNF168 results in the hyper-accumulation of 53BP1/BRCA1 which accelerates DSB repair. Here, we ask whether increased expression of RNF168 or 53BP1 impacts physiological versus mutagenic NHEJ. We find that the anti-resection activities of 53BP1 are rate-limiting for mutagenic NHEJ but not for physiological CSR. As heterogeneity in the expression of RNF168 and 53BP1 is found in human tumors, our results suggest that deregulation of the RNF168/53BP1 pathway could alter the chemosensitivity of BRCA1 deficient tumors. C1 [Zong, Dali; Callen, Elsa; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Pegoraro, Gianluca] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lukas, Claudia; Lukas, Jiri] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen, Denmark. RP Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov OI Pegoraro, Gianluca/0000-0003-2843-9464 FU Intramural Research Program of the National Institutes of Health; Department of Defense grant [BCRP DOD Idea Expansion Award] [11557134]; Novo Nordisk Foundation [NNF14CC0001]; National Cancer Institute; Center for Cancer Research FX Intramural Research Program of the National Institutes of Health, the National Cancer Institute, the Center for Cancer Research; Department of Defense grant [BCRP DOD Idea Expansion Award, 11557134 to A.N.]; Novo Nordisk Foundation [NNF14CC0001 to J.L. and C.L.]. Funding for open access charge: NIH Intramural Research Program. NR 58 TC 4 Z9 4 U1 0 U2 4 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 MAY 26 PY 2015 VL 43 IS 10 BP 4950 EP 4961 DI 10.1093/nar/gkv336 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK0XO UT WOS:000355929200020 PM 25916843 ER PT J AU Billioux, A Nakigozi, G Newell, K Chang, LW Quinn, TC Gray, RH Ndyanabo, A Galiwango, R Kiggundu, V Serwadda, D Reynolds, SJ AF Billioux, Alexander Nakigozi, Gertrude Newell, Kevin Chang, Larry W. Quinn, Thomas C. Gray, Ron H. Ndyanabo, Anthony Galiwango, Ronald Kiggundu, Valerian Serwadda, David Reynolds, Steven J. TI Durable Suppression of HIV-1 after Virologic Monitoring-Based Antiretroviral Adherence Counseling in Rakai, Uganda SO PLOS ONE LA English DT Article ID SUB-SAHARAN AFRICA; VIRAL LOAD; SOUTH-AFRICA; THERAPY; INFECTION; OUTCOMES; COHORT; ADULTS; METAANALYSIS; PREDICTORS AB Objectives HIV viral load is recommended for monitoring antiretroviral treatment and identifying treatment failure. We assessed the durability of viral suppression after viral load-triggered adherence counseling among patients with HIV viremia 6 months after ART initiation. Design Observational cohort enrolled in an antiretroviral treatment program in rural Uganda. Methods Participants who underwent routine viral load determination every 24 weeks and had at least 48 weeks of follow-up were included in this analysis. Patients with viral loads > 400 copies/ml at 24 weeks of treatment were given additional adherence counseling, and all patients were followed to assess the duration of viral suppression and development of virologic failure. Results 1,841 participants initiating antiretroviral therapy were enrolled in the Rakai Health Sciences Program between June 2005 and June 2011 and were followed with viral load monitoring every 24 weeks. 148 (8%) of patients did not achieve viral suppression at 24 weeks and were given additional adherence counseling. 85 (60%) of these patients had undetectable viral loads at 48 weeks, with a median duration of viral suppression of 240 weeks (IQR 193-288 weeks). Failure to achieve an undetectable viral load at 48 weeks was associated with age < 30 years and 24 week viral load > 2,000 copies/ml in multivariate logistic regression analysis. Conclusions The majority of patients with persistent viremia who were provided adherence counseling achieved robust viral suppression for a median 4.6 years. Access to virologic monitoring and adherence counseling is a priority in resource-limited settings. C1 [Billioux, Alexander; Chang, Larry W.; Quinn, Thomas C.; Reynolds, Steven J.] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. [Billioux, Alexander; Nakigozi, Gertrude; Chang, Larry W.; Quinn, Thomas C.; Ndyanabo, Anthony; Galiwango, Ronald; Kiggundu, Valerian; Serwadda, David; Reynolds, Steven J.] Rakai Hlth Sci Program, Rakai, Uganda. [Newell, Kevin] Leidos Biomed Res Inc, Clin Monitoring Res Program, Clin Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, NIH, Bethesda, MD 20892 USA. [Chang, Larry W.; Gray, Ron H.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda. RP Reynolds, SJ (reprint author), Johns Hopkins Sch Med, Baltimore, MD 21205 USA. EM sjr@jhmi.edu FU National Cancer Institute [HHSN261200800001E]; National Institute of Mental Health [K23MH086338]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Leidos Biomedical Research, Inc. FX This project has been funded in whole or in part with federal funds from the National Cancer Institute under Contract No. HHSN261200800001E, the National Institute of Mental Health under contract K23MH086338, and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. 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. Leidos Biomedical Research, Inc., provided support in the form of a salary for author KN, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the 'author contributions' section. NR 29 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0127235 DI 10.1371/journal.pone.0127235 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900074 PM 26011158 ER PT J AU Gross, JA Bureau, A Croteau, J Galfalvy, H Oquendo, MA Haghighi, F Merette, C Giegling, I Hodgkinson, C Goldman, D Rujescu, D Mann, JJ Turecki, G AF Gross, Jeffrey A. Bureau, Alexandre Croteau, Jordie Galfalvy, Hanga Oquendo, Maria A. Haghighi, Fatemeh Merette, Chantal Giegling, Ina Hodgkinson, Colin Goldman, David Rujescu, Dan Mann, J. John Turecki, Gustavo TI A Genome-Wide Copy Number Variant Study of Suicidal Behavior SO PLOS ONE LA English DT Article ID BIPOLAR DISORDER; PARKINSONS-DISEASE; LRRK2; POPULATION; PHOSPHORYLATION; RESOLUTION; MUTATIONS; LINKAGE; RISK; CNVS AB Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior. C1 [Gross, Jeffrey A.; Turecki, Gustavo] Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Montreal, PQ, Canada. [Bureau, Alexandre; Croteau, Jordie; Merette, Chantal] Univ Laval, Inst Univ Sante Mentale Quebec, Ctr Rech, Quebec City, PQ, Canada. [Galfalvy, Hanga; Haghighi, Fatemeh] Columbia Univ, Dept Psychiat, Div Biostat, New York, NY USA. [Oquendo, Maria A.; Mann, J. John] Columbia Univ, Dept Psychiat, Mol Imaging & Neuropathol Div, New York, NY USA. [Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Giegling, Ina; Rujescu, Dan] Univ Halle Wittenberg, Psychiat Clin, D-06108 Halle, Saxony Anhalt, Germany. RP Turecki, G (reprint author), Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Montreal, PQ, Canada. EM gustavo.turecki@mcgill.ca RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Bureau, Alexandre/0000-0001-8220-9999 FU NIH [R01MH082188] FX Support was provided by NIH grant R01MH082188 to GT, JJM, and DR (http://projectreporter.nih.gov/project_info_description.cfm?aid=7527841 &icde=21862620&ddparam=&ddvalue=&ddsub=&cr=5&csb=default&cs=ASC). NR 38 TC 4 Z9 4 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0128369 DI 10.1371/journal.pone.0128369 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900230 PM 26010658 ER PT J AU Navarathna, DHMLP Stein, EV Lessey-Morillon, EC Nayak, D Martin-Manso, G Roberts, DD AF Navarathna, Dhammika H. M. L. P. Stein, Erica V. Lessey-Morillon, Elizabeth C. Nayak, Debasis Martin-Manso, Gema Roberts, David D. TI CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis SO PLOS ONE LA English DT Article ID T-CELL-ACTIVATION; DENDRITIC CELLS; SIRP-ALPHA; NEUTROPHIL TRANSMIGRATION; CYTOKINE EXPRESSION; FUNGAL-INFECTIONS; IN-VIVO; ALBICANS; RESPONSES; THROMBOSPONDIN-1 AB CD47 is a widely expressed receptor that regulates immunity by engaging its counter-receptor SIRP alpha on phagocytes and its secreted ligand thrombospondin-1. Mice lacking CD47 can exhibit enhanced or impaired host responses to bacterial pathogens, but its role in fungal immunity has not been examined. cd47(-/-) mice on a C57BL/6 background showed significantly increased morbidity and mortality following Candida albicans infection when compared with wild-type mice. Despite normal fungal colonization at earlier times, cd47(-/-) mice at four days post-infection had increased colonization of brain and kidneys accompanied by stronger inflammatory reactions. Neutrophil and macrophage numbers were significantly elevated in kidneys and neutrophils in the brains of infected cd47(-/-) mice. However, no defect in phagocytic activity towards C. albicans was observed in cd47(-/-) bone-marrow-derived macrophages, and neutrophil and macrophage killing of C. albicans was not impaired. CD47-deficiency did not alter the early humoral immune response to C. albicans. Th1, Th2, and Th17 population of CD4(+) T cells were expanded in the spleen, and gene expression profiles of spleen and kidney showed stronger pro-inflammatory signaling in infected cd47(-/-) mice. The chemoattractant chemokines MIP-2 alpha and MIP-2 beta were highly expressed in infected spleens of cd47(-/-) mice. G-CSF, GM-CSF, and the inflammasome component NLRP3 were more highly expressed in infected cd47(-/-) kidneys than in infected wild-type controls. Circulating pro-(TNF-alpha, IL-6) and anti-inflammatory cytokines (IL-10) were significantly elevated, but IL-17 was decreased. These data indicate that CD47 plays protective roles against disseminated candidiasis and alters pro-inflammatory and immunosuppressive pathways known to regulate innate and T cell immunity. C1 [Navarathna, Dhammika H. M. L. P.; Stein, Erica V.; Lessey-Morillon, Elizabeth C.; Martin-Manso, Gema; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Nayak, Debasis] NINDS, NIH, Bethesda, MD 20892 USA. [Stein, Erica V.] George Washington Univ, Microbiol & Immunol Program, Inst Biomed Sci, Dept Microbiol, Washington, DC 20037 USA. [Stein, Erica V.] George Washington Univ, Microbiol & Immunol Program, Inst Biomed Sci, Dept Immunol, Washington, DC 20037 USA. [Nayak, Debasis] George Washington Univ, Microbiol & Immunol Program, Inst Biomed Sci, Dept Trop Med, Washington, DC 20037 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NIH, National Cancer Institute, Center for Cancer Research; National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (DDR) and the National Institute of Neurological Disorders and Stroke (DN). NR 73 TC 3 Z9 3 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0128220 DI 10.1371/journal.pone.0128220 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900208 PM 26010544 ER PT J AU Sepanlou, SG Malekzadeh, R Poustchi, H Sharafkhah, M Ghodsi, S Malekzadeh, F Etemadi, A Pourshams, A Pharoah, PD Abnet, CC Brennan, P Boffetta, P Dawsey, SM Kamangar, F AF Sepanlou, Sadaf G. Malekzadeh, Reza Poustchi, Hossein Sharafkhah, Maryam Ghodsi, Saeed Malekzadeh, Fatemeh Etemadi, Arash Pourshams, Akram Pharoah, Paul D. Abnet, Christian C. Brennan, Paul Boffetta, Paolo Dawsey, Sanford M. Kamangar, Farin TI The Clinical Performance of an Office-Based Risk Scoring System for Fatal Cardiovascular Diseases in North-East of Iran SO PLOS ONE LA English DT Article ID CORONARY-HEART-DISEASE; GLOBAL BURDEN; PRIMARY PREVENTION; GOLESTAN COHORT; PREDICTION; POPULATION; PROFILE; VALIDATION; HEALTH; MORTALITY AB Background Cardiovascular diseases (CVD) are becoming major causes of death in developing countries. Risk scoring systems for CVD are needed to prioritize allocation of limited resources. Most of these risk score algorithms have been based on a long array of risk factors including blood markers of lipids. However, risk scoring systems that solely use office-based data, not including laboratory markers, may be advantageous. In the current analysis, we validated the office-based Framingham risk scoring system in Iran. Methods The study used data from the Golestan Cohort in North-East of Iran. The following risk factors were used in the development of the risk scoring method: sex, age, body mass index, systolic blood pressure, hypertension treatment, current smoking, and diabetes. Cardiovascular risk functions for prediction of 10-year risk of fatal CVDs were developed. Results A total of 46,674 participants free of CVD at baseline were included. Predictive value of estimated risks was examined. The resulting Area Under the ROC Curve (AUC) was 0.774 (95% CI: 0.762-0.787) in all participants, 0.772 (95% CI: 0.753-0.791) in women, and 0.763 (95% CI: 0.747-0.779) in men. AUC was higher in urban areas (0.790, 95% CI: 0.766-0.815). The predicted and observed risks of fatal CVD were similar in women. However, in men, predicted probabilities were higher than observed. Conclusion The AUC in the current study is comparable to results of previous studies while lipid profile was replaced by body mass index to develop an office-based scoring system. This scoring algorithm is capable of discriminating individuals at high risk versus low risk of fatal CVD. C1 [Sepanlou, Sadaf G.; Malekzadeh, Reza; Poustchi, Hossein; Sharafkhah, Maryam; Ghodsi, Saeed; Malekzadeh, Fatemeh; Etemadi, Arash; Pourshams, Akram; Kamangar, Farin] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran, Iran. [Etemadi, Arash; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran, Iran. EM malek@ams.ac.ir RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; Sepanlou, Sadaf/H-9343-2016 OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Sepanlou, Sadaf/0000-0002-3669-5129 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH; Digestive Disease Research Institute of Tehran University of Medical Sciences [82-603]; Cancer Research UK (CRUK); International Agency for Research on Cancer FX This study was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH, by the Digestive Disease Research Institute of Tehran University of Medical Sciences (grant No 82-603), by Cancer Research UK (CRUK), and by the International Agency for Research on Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 2 Z9 2 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0126779 DI 10.1371/journal.pone.0126779 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900041 PM 26011607 ER PT J AU Wang, LM Lu, HB Brown, PL Rea, W Vaupel, B Yang, YH Stein, E Shepard, PD AF Wang, Leiming Lu, Hanbing Brown, P. Leon Rea, William Vaupel, Bruce Yang, Yihong Stein, Elliot Shepard, Paul D. TI Manganese-Enhanced MRI Reflects Both Activity-Independent and Activity-Dependent Uptake within the Rat Habenulomesencephalic Pathway SO PLOS ONE LA English DT Article ID CEREBRAL GLUCOSE-UTILIZATION; RESONANCE-IMAGING MEMRI; HABENULO-INTERPEDUNCULAR PATHWAY; IN-VIVO; GLUTAMATE RECEPTORS; CALCIUM-CHANNELS; TRANSFERRIN RECEPTOR; CA2+ PERMEABILITY; NEURONAL-ACTIVITY; BRAIN ACTIVATION AB Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful technique for assessing the functional connectivity of neurons within the central nervous system. Despite the widely held proposition that MEMRI signal is dependent on neuronal activity, few studies have directly tested this implicit hypothesis. In the present series of experiments, MnCl2 was injected into the habenula of urethane-anesthetized rats alone or in combination with drugs known to alter neuronal activity by modulating specific voltage-and/or ligand-gated ion channels. Continuous quantitative T1 mapping was used to measure Mn2+ accumulation in the interpeduncular nucleus, a midline structure in which efferents from the medial habenula terminate. Microinjection of MnCl2 into the habenular complex using a protocol that maintained spontaneous neuronal activity resulted in a time-dependent increase in MEMRI signal intensity in the interpeduncular nucleus consistent with fast axonal transport of Mn2+ between these structures. Co-injection of the excitatory amino-acid agonist AMPA, increased the Mn2+-enhanced signal intensity within the interpeduncular nucleus. AMPA-induced increases in MEMRI signal were attenuated by co-injection of either the sodium channel blocker, TTX, or broad-spectrum Ca2+ channel blocker, Ni2+, and were occluded in the presence of both channel blockers. However, neither Ni2+ nor TTX, alone or in combination, attenuated the increase in signal intensity following injection of Mn2+ into the habenula. These results support the premise that changes in neuronal excitability are reflected by corresponding changes in MEMRI signal intensity. However, they also suggest that basal rates of Mn2+ uptake by neurons in the medial habenula may also occur via activity-independent mechanisms. C1 [Wang, Leiming; Lu, Hanbing; Rea, William; Vaupel, Bruce; Yang, Yihong; Stein, Elliot] Natl Inst Drug Abuse, Neuroimaging Res Branch, IRP, Baltimore, MD 21224 USA. [Wang, Leiming; Brown, P. Leon; Shepard, Paul D.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21228 USA. [Wang, Leiming; Brown, P. Leon; Shepard, Paul D.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. RP Shepard, PD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21228 USA. EM shepard.paul@gmail.com FU Intramural Research Program of the National Institute on Drug Abuse, NIDA Residential Research Support Services [N01DA-5-9909]; National Institute of Mental Health [MH-094489] FX This work was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, NIDA Residential Research Support Services Contract N01DA-5-9909 and a grant from the National Institute of Mental Health (MH-094489). NR 62 TC 1 Z9 1 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0127773 DI 10.1371/journal.pone.0127773 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900142 PM 26009889 ER PT J AU Williams, RJ Tse, T DiPiazza, K Zarin, DA AF Williams, Rebecca J. Tse, Tony DiPiazza, Katelyn Zarin, Deborah A. TI Terminated Trials in the ClinicalTrials.gov Results Database: Evaluation of Availability of Primary Outcome Data and Reasons for Termination SO PLOS ONE LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; CLINICAL-TRIALS; PUBLICATION; REGISTRATION; PREVALENCE; INSTITUTE; BENEFIT; UPDATE; IMPACT; ISSUES AB Background Clinical trials that end prematurely (or "terminate") raise financial, ethical, and scientific concerns. The extent to which the results of such trials are disseminated and the reasons for termination have not been well characterized. Methods and Findings A cross-sectional, descriptive study of terminated clinical trials posted on the ClinicalTrials.gov results database as of February 2013 was conducted. The main outcomes were to characterize the availability of primary outcome data on ClinicalTrials.gov and in the published literature and to identify the reasons for trial termination. Approximately 12% of trials with results posted on the ClinicalTrials. gov results database (905/7,646) were terminated. Most trials were terminated for reasons other than accumulated data from the trial (68%; 619/905), with an insufficient rate of accrual being the lead reason for termination among these trials (57%; 350/619). Of the remaining trials, 21% (193/905) were terminated based on data from the trial (findings of efficacy or toxicity) and 10% (93/905) did not specify a reason. Overall, data for a primary outcome measure were available on ClinicalTrials. gov and in the published literature for 72% (648/905) and 22% (198/905) of trials, respectively. Primary outcome data were reported on the ClinicalTrials. gov results database and in the published literature more frequently (91% and 46%, respectively) when the decision to terminate was based on data from the trial. Conclusions Trials terminate for a variety of reasons, not all of which reflect failures in the process or an inability to achieve the intended goals. Primary outcome data were reported most often when termination was based on data from the trial. Further research is needed to identify best practices for disseminating the experience and data resulting from terminated trials in order to help ensure maximal societal benefit from the investments of trial participants and others involved with the study. C1 [Williams, Rebecca J.; Tse, Tony; Zarin, Deborah A.] NIH, Natl Lib Med, DHHS, Bethesda, MD 20892 USA. [DiPiazza, Katelyn] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Williams, RJ (reprint author), NIH, Natl Lib Med, DHHS, Bldg 10, Bethesda, MD 20892 USA. EM williamsre@mail.nih.gov FU Intramural Research Program of the 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). The views expressed in this article are those of the authors and do not necessarily reflect the positions of the NIH. NLM had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript and decision to submit the manuscript for publication. NLM reviewed and approved the manuscript prior to publication. NR 40 TC 10 Z9 10 U1 4 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0127242 DI 10.1371/journal.pone.0127242 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900075 PM 26011295 ER PT J AU Yang, Z Li, JJ Liu, QS Yuan, TT Zhang, YY Chen, LQ Lou, Q Sun, ZH Ying, HZ Xu, JQ Dimitrov, DS Zhang, MY AF Yang, Zheng Li, Jingjing Liu, Qingsheng Yuan, Tingting Zhang, Yanyu Chen, Li-Qing Lou, Qi Sun, Zehua Ying, Huazhong Xu, Jianqing Dimitrov, Dimiter S. Zhang, Mei-Yun TI Identification of Non-HIV Immunogens That Bind to Germline b12 Predecessors and Prime for Elicitation of Cross-clade Neutralizing HIV-1 Antibodies SO PLOS ONE LA English DT Article ID B-CELL RECEPTORS; POTENT NEUTRALIZATION; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; VACCINE DESIGN; BROAD; GP120; ANTIGEN; VIRUS; EPITOPE AB A fundamental challenge for developing an effective and safe HIV-1 vaccine is to identify vaccine immunogens that can initiate and maintain immune responses leading to elicitation of broadly neutralizing HIV-1 antibodies (bnAbs) through complex maturation pathways. We have previously found that HIV-1 envelope glycoproteins (Env) lack measurable binding to putative germline predecessors of known bnAbs and proposed to search for non-HIV immunogens that could initiate their somatic maturation. Using bnAb b12 as a model bnAb and yeast display technology, we isolated five (poly) peptides from plant leaves, insects, E. coli strains, and sea water microbes that bind to b12 putative germline and intermediate antibodies. Rabbit immunization with the (poly) peptides alone induced high titers of cross-reactive antibodies that neutralized HIV-1 isolates SF162 and JRFL. Priming rabbits with the (poly) peptides followed by boosts with trimeric gp140(SF162) and then resurfaced Env (RSC3) induced antibodies that competed with mature b12 and neutralized tier 1 and 2 viruses from clade B, C and E, while control rabbits without (poly) peptide priming induced antibodies that did not compete with mature b12 and neutralized fewer isolates. The degree of competition with mature b12 for binding to gp140SF162 correlated with the neutralizing activity of the rabbit IgG. Reversing the order of the two boosting immunogens significantly affected the binding profile and neutralization potency of the rabbit IgG. Our study is the first to provide evidence that appears to support the concept that non-HIV immunogens may initiate immune responses leading to elicitation of cross-clade neutralizing antibodies. C1 [Yang, Zheng; Li, Jingjing; Liu, Qingsheng; Yuan, Tingting; Zhang, Yanyu; Sun, Zehua; Zhang, Mei-Yun] Univ Hong Kong, Li Ka Shing Fac Med, AIDS Inst, Dept Microbiol, Pok Fu Lam, Hong Kong, Peoples R China. [Chen, Li-Qing; Lou, Qi; Ying, Huazhong] Zhejiang Acad Med Sci, Ctr Lab Anim, Shanghai, Zhejiang, Peoples R China. [Xu, Jianqing] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Inst Biomed Sci, Shanghai 201508, Peoples R China. [Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Immunol Lab, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Zhang, Mei-Yun] Shenzhen Third Peoples Hosp, Liver Dis Inst, Shenzhen 518112, Peoples R China. RP Zhang, MY (reprint author), Univ Hong Kong, Li Ka Shing Fac Med, AIDS Inst, Dept Microbiol, Pok Fu Lam, Hong Kong, Peoples R China. EM zhangmy2014@hotmail.com OI Yang, Zheng/0000-0003-0217-6694 FU General Research Fund (GRF) from Hong Kong Research Grants Consuls (RGC) [785112]; China 12th 5-year Mega project for HIV/AIDS [2012ZX10001006] FX This work was supported by a General Research Fund (GRF) (#785112) from Hong Kong Research Grants Consuls (RGC) (http://www.ugc.edu.hk/eng/rgc/index.htm) and the China 12th 5-year Mega project for HIV/AIDS (#2012ZX10001006) (http://www.most.gov.cn/tztg/index.htm) to M-Y Z. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 1 Z9 1 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 26 PY 2015 VL 10 IS 5 AR e0126428 DI 10.1371/journal.pone.0126428 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ0QZ UT WOS:000355183900028 PM 26010511 ER PT J AU Qian, X Brinton, LA Schairer, C Matthews, CE AF Qian, X. Brinton, L. A. Schairer, C. Matthews, C. E. TI Reply to 'Sleep duration and breast cancer risk in the breast cancer detection demonstration project follow-up cohort: true associations or bias?' SO BRITISH JOURNAL OF CANCER LA English DT Letter C1 [Qian, X.; Matthews, C. E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Brinton, L. A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Schairer, C.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Qian, X (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM qian.xiao@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 7 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 26 PY 2015 VL 112 IS 11 BP 1839 EP 1840 DI 10.1038/bjc.2015.131 PG 4 WC Oncology SC Oncology GA CJ0EQ UT WOS:000355148100025 PM 25897672 ER PT J AU Blum, MR Bauer, DC Collet, TH Fink, HA Cappola, AR da Costa, BR Wirth, CD Peeters, RP Asvold, BO den Elzen, WPJ Luben, RN Imaizumi, M Bremner, AP Gogakos, A Eastell, R Kearney, PM Strotmeyer, ES Wallace, ER Hoff, M Ceresini, G Rivadeneira, F Uitterlinden, AG Stott, DJ Westendorp, RGJ Khaw, KT Langhammer, A Ferrucci, L Gussekloo, J Williams, GR Walsh, JP Juni, P Aujesky, D Rodondi, N AF Blum, Manuel R. Bauer, Douglas C. Collet, Tinh-Hai Fink, Howard A. Cappola, Anne R. da Costa, Bruno R. Wirth, Christina D. Peeters, Robin P. Asvold, Bjorn O. den Elzen, Wendy P. J. Luben, Robert N. Imaizumi, Misa Bremner, Alexandra P. Gogakos, Apostolos Eastell, Richard Kearney, Patricia M. Strotmeyer, Elsa S. Wallace, Erin R. Hoff, Mari Ceresini, Graziano Rivadeneira, Fernando Uitterlinden, Andre G. Stott, David J. Westendorp, Rudi G. J. Khaw, Kay-Tee Langhammer, Arnuf Ferrucci, Luigi Gussekloo, Jacobijn Williams, Graham R. Walsh, John P. Jueni, Peter Aujesky, Drahomir Rodondi, Nicolas CA Thyroid Studies Collaboration TI Subclinical Thyroid Dysfunction and Fracture Risk A Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; PARTICIPANT DATA-ANALYSIS; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; STIMULATING HORMONE; SYSTEMATIC REVIEWS; RANDOMIZED-TRIALS; FOLLOW-UP; HYPERTHYROIDISM AB IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH >= 4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age-and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidismwas 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HRwas 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HRwas 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HRwas 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSHwas associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HRwas 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HRwas 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HRwas 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HRwas 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures. C1 [Blum, Manuel R.; Wirth, Christina D.; Aujesky, Drahomir; Rodondi, Nicolas] Univ Hosp Bern, Inselspital, Dept Gen Internal Med, CH-3010 Bern, Switzerland. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Collet, Tinh-Hai] Univ Lausanne Hosp, Serv Endocrinol Diabet & Metab, Lausanne, Switzerland. [Fink, Howard A.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Fink, Howard A.] VA Med Ctr, Geriatr Res Educ & Clin Ctr, Minneapolis, MN USA. [Cappola, Anne R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [da Costa, Bruno R.] Florida Int Univ, Nicole Wertheim Coll Nursing & Hlth Sci, Dept Phys Therapy, Miami, FL 33199 USA. [Peeters, Robin P.; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Peeters, Robin P.; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Asvold, Bjorn O.; Hoff, Mari; Langhammer, Arnuf] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway. [Asvold, Bjorn O.] Univ Trondheim Hosp, St Olavs Hosp, Dept Endocrinol, Trondheim, Norway. [den Elzen, Wendy P. J.; Gussekloo, Jacobijn] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands. [Luben, Robert N.; Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Imaizumi, Misa] Radiat Effects Res Fdn, Nagasaki, Japan. [Bremner, Alexandra P.] Univ Western Australia, Sch Populat Hlth, Crawley, WA, Australia. [Gogakos, Apostolos; Williams, Graham R.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Eastell, Richard] Univ Sheffield, Dept Human Metab, Sheffield, S Yorkshire, England. [Kearney, Patricia M.] Natl Univ Ireland Univ Coll Cork, Dept Epidemiol & Publ Hlth, Cork, Ireland. [Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Wallace, Erin R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Hoff, Mari] Nord Trondelag Hosp Trust, Levanger Hosp, Levanger, Norway. [Ceresini, Graziano] Univ Hosp Parma, Dept Clin & Expt Med, Geriatr Endocrine Unit, Parma, Italy. [Stott, David J.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. [Westendorp, Rudi G. J.] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Walsh, John P.] Univ Western Australia, Crawley, WA, Australia. [Walsh, John P.] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia. [Jueni, Peter] Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. RP Rodondi, N (reprint author), Univ Bern, Inselspital, Dept Gen Internal Med, CH-3010 Bern, Switzerland. EM nicolas.rodondi@insel.ch RI Rivadeneira, Fernando/O-5385-2015; OI Rivadeneira, Fernando/0000-0001-9435-9441; Schmidt, Christina Doris/0000-0003-2604-6253; Strotmeyer, Elsa/0000-0002-4093-6036; Luben, Robert/0000-0002-5088-6343; Blum, Manuel/0000-0003-4638-775X; R. da Costa, Bruno/0000-0002-1786-6332; Collet, Tinh-Hai/0000-0002-3243-1222 FU Swiss National Science Foundation [SNSF 320030-138267, 320030-150025]; Swiss Heart Foundation; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); NIA [R01AG023629, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; American Heart Association; NINR [R01-NR012459]; Medical Research Council UK; Cancer Research UK; NIH; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01AG027810, U01AG042124, U01AG042139, U01AG042140, U01AG042143, U01AG042145, U01AG042168, U01AR066160, UL1TR000128]; Wallac Oy (Turku, Finland); Dutch Ministry of Health, Welfare and Sports; Bristol-Myers Squibb; Erasmus MC; Erasmus University, Rotterdam, the Netherlands; Netherlands Organisation for Scientific Research (NWO); Netherlands Organisation for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Dutch Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; sanofi-aventis; Eli Lilly; Novartis; Pfizer; Procter & Gamble Pharmaceuticals; Roche; Netherlands Organization for Scientific Research [NGI/NWO 911-03-016]; Swiss National Science Foundation; Swiss Foundation for Grants in Biology and Medicine [PBLAP3-145870, P3SMP3-155318] FX This project was supported by grants from the Swiss National Science Foundation (SNSF 320030-138267 and 320030-150025) and partially supported by a grant from the Swiss Heart Foundation (Dr Rodondi). The Cardiovascular Health Study was supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) (HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and grant U01HL080295) with an additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by the NIA (R01AG023629). The thyroid measurements in the Cardiovascular Health Study were supported by an American Heart Association Grant-in-Aid (Dr Fried). The Health, Aging, and Body Composition Study was supported by the NIA (contract numbers: N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; and grant R01-AG028050); and an NINR grant (R01-NR012459). The NIA funded the Health, Aging, and Body Composition Study, reviewed the manuscript, and approved its publication. This research was supported in part by the NIA. The EPIC (European Prospective Investigation of Cancer)-Norfolk Study was supported by research grants from the Medical Research Council UK and Cancer Research UK. The Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding. The following institutes provided support: the NIA, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research (grant numbers: U01AG027810, U01AG042124, U01AG042139, U01AG042140, U01AG042143, U01AG042145, U01AG042168, U01AR066160, and UL1TR000128). The Nord-Trondelag Health Study (HUNT Study) is a collaborative effort of the Faculty of Medicine, Norwegian University of Science and Technology; the Norwegian Institute of Public Health; and the Nord-Trondelag County Council. Thyroid function testing in the HUNT Study was financially supported by Wallac Oy (Turku, Finland). The Leiden 85-plus Study was partly funded by the Dutch Ministry of Health, Welfare and Sports. The original PROSPER study was supported by an unrestricted, investigator-initiated grant from Bristol-Myers Squibb. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, the Netherlands; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Dutch Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The original OPUS study was supported by sanofi-aventis, Eli Lilly, Novartis, Pfizer, Procter & Gamble Pharmaceuticals, and Roche. Dr Westendorp is supported by the Netherlands Organization for Scientific Research (NGI/NWO 911-03-016). Dr Collet reports receipt of research support from grants from the Swiss National Science Foundation and the Swiss Foundation for Grants in Biology and Medicine (PBLAP3-145870, P3SMP3-155318). NR 59 TC 30 Z9 30 U1 3 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 26 PY 2015 VL 313 IS 20 BP 2055 EP 2065 DI 10.1001/jama.2015.5161 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CJ0DC UT WOS:000355142400019 PM 26010634 ER PT J AU Nogueira, L Foerster, C Groopman, J Egner, P Koshiol, J Ferreccio, C AF Nogueira, Leticia Foerster, Claudia Groopman, John Egner, Patricia Koshiol, Jill Ferreccio, Catterina CA Gallbladder Canc Chile Working Grp TI Association of Aflatoxin With Gallbladder Cancer in Chile SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID B-1 C1 [Nogueira, Leticia; Koshiol, Jill] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Foerster, Claudia; Ferreccio, Catterina] Pontificia Univ Catolica Chile, Sch Med, Santiago, Chile. [Groopman, John; Egner, Patricia] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. RP Ferreccio, C (reprint author), Pontificia Univ Catolica Chile, Fac Med, Dept Publ Hlth, Marcoleta 434, Santiago, Chile. EM catferre@gmail.com RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU Intramural NIH HHS NR 6 TC 10 Z9 10 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 26 PY 2015 VL 313 IS 20 BP 2075 EP 2077 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CJ0DC UT WOS:000355142400023 PM 26010638 ER PT J AU Liu, R Umbach, DM Peddada, SD Xu, ZL Troster, AI Huang, XM Chen, HL AF Liu, Rui Umbach, David M. Peddada, Shyamal D. Xu, Zongli Troester, Alexander I. Huang, Xuemei Chen, Honglei TI Potential sex differences in nonmotor symptoms in early drug-naive Parkinson disease SO NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; GENDER-DIFFERENCES; DE-NOVO; RISK; MOTOR; FEATURES; COHORT; HETEROGENEITY; MULTICENTER; CONSUMPTION AB Objective:To examine potential sex differences in nonmotor symptoms (NMS) among drug-naive patients with Parkinson disease (PD), and to identify NMS that can best differentiate patients with early PD from controls.Methods:Our cross-sectional analysis included 414 newly diagnosed, untreated patients with PD (269 men and 145 women) and 188 healthy controls (121 men and 67 women) in the Parkinson's Progression Markers Initiative Study. NMS were measured using well-validated instruments covering sleep, olfactory, neurobehavioral, autonomic, and neuropsychological domains.Results:Male and female patients with PD were fairly comparable on motor presentations but differed on several nonmotor features. Male patients with PD had significantly more pronounced deficits in olfaction (p = 0.02) and in certain cognitive measurements (all p < 0.01) than female patients, whereas female cases experienced higher trait anxiety (p = 0.02). Multiple stepwise logistic regression analysis showed that the combination of NMS measuresUniversity of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), and state anxiety from the State-Trait Anxiety Inventoryeffectively differentiated patients with PD from controls with an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI]: 0.89-0.94). UPSIT, MoCA, and SCOPA-AUT were the most predictive NMS measurements in men (AUC = 0.919; 95% CI: 0.89-0.95) as compared to UPSIT, MoCA, and REM Sleep Behavior Disorder Screening Questionnaire in women (AUC = 0.903; 95% CI: 0.86-0.95).Conclusions:Our analysis revealed notable sex differences in several nonmotor features of patients with de novo PD. Furthermore, we found a parsimonious NMS combination that could effectively differentiate de novo cases from healthy controls. C1 [Liu, Rui; Xu, Zongli; Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Umbach, David M.; Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, Res Triangle Pk, NC 27709 USA. [Troester, Alexander I.] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. RP Liu, R (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM liur2@niehs.nih.gov OI xu, zongli/0000-0002-9034-8902; Chen, Honglei/0000-0003-3446-7779 FU Michael J. Fox Foundation for Parkinson's Research; AbbVie; Avid Radiopharmaceuticals; Biogen Idec; Bristol-Myers Squibb; Covance; Elan; GE Healthcare; Genentech; GSK-GlaxoSmithKline; Lilly; Merck; MSD-Meso Scale Discovery; Piramal; Pfizer; Roche; UCB; Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences [Z01-ES-101986]; NIH [NS060722, ES019672, NS08215] FX Parkinson's Progression Markers Initiative, a public-private partnership, is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including AbbVie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Elan, GE Healthcare, Genentech, GSK-GlaxoSmithKline, Lilly, Merck, MSD-Meso Scale Discovery, Piramal, Pfizer, Roche, and UCB (www.ppmi-info.org/fundingpartners). R.L., D.M.U., S.D.P., Z.X., and H.C. are supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986). H.X. is supported by NIH grants NS060722, ES019672, and NS08215. NR 40 TC 14 Z9 14 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 26 PY 2015 VL 84 IS 21 BP 2107 EP 2115 DI 10.1212/WNL.0000000000001609 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CJ2LT UT WOS:000355317000008 PM 25925983 ER PT J AU Tsai, SYA Pokrass, MJ Klauer, NR Nohara, H Su, TP AF Tsai, Shang-Yi A. Pokrass, Michael J. Klauer, Neal R. Nohara, Hiroshi Su, Tsung-Ping TI Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE sigma-1 receptor; p35; myristic acid; axon growth; cdk5 ID CYCLIN-DEPENDENT KINASE-5; ALZHEIMERS-DISEASE; CDK5 ACTIVATOR; BRAIN-DEVELOPMENT; MICE; CHAPERONES; P25; NEURODEGENERATION; GUIDANCE; CLEAVAGE AB Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t(1/2) and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t(1/2), promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25. C1 [Tsai, Shang-Yi A.; Pokrass, Michael J.; Klauer, Neal R.; Nohara, Hiroshi; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. RP Tsai, SYA (reprint author), NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. EM stsai@intra.nida.nih.gov; tsu@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services FX We thank Dr. Li-Huei Tsai for providing p35 plasmid and Dr. Peter Davies for providing mouse MC-1 and mouse PHF-1 antibodies. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services. NR 59 TC 12 Z9 13 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 2015 VL 112 IS 21 BP 6742 EP 6747 DI 10.1073/pnas.1422001112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ1AJ UT WOS:000355213200062 PM 25964330 ER PT J AU Reveley, C Seth, AK Pierpaoli, C Silva, AC Yu, D Saunders, RC Leopold, DA Ye, FQ AF Reveley, Colin Seth, Anil K. Pierpaoli, Carlo Silva, Afonso C. Yu, David Saunders, Richard C. Leopold, David A. Ye, Frank Q. TI Superficial white matter fiber systems impede detection of long-range cortical connections in diffusion MR tractography SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diffusion MRI; tractography; neuroanatomy; white matter; connectome ID MACAQUE MONKEY; HUMAN BRAIN; CEREBRAL-CORTEX; PATHWAYS; TISSUE; AREAS; RECONSTRUCTION; NEUROANATOMY; VALIDATION; PRINCIPLES AB In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure-function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is used increasingly to infer long-range anatomical connections of the cortex. Because axonal projections originate and terminate in the gray matter but travel mainly through the deep white matter, the success of tractography hinges on the capacity to follow fibers across this transition. Here we demonstrate that the complex arrangement of white matter fibers residing just under the cortical sheet poses severe challenges for long-range tractography over roughly half of the brain. We investigate this issue by comparing dMRI from very-high-resolution ex vivo macaque brain specimens with histological analysis of the same tissue. Using probabilistic tracking from pure gray and white matter seeds, we found that similar to 50% of the cortical surface was effectively inaccessible for long-range diffusion tracking because of dense white matter zones just beneath the infragranular layers of the cortex. Analysis of the corresponding myelin-stained sections revealed that these zones colocalized with dense and uniform sheets of axons running mostly parallel to the cortical surface, most often in sulcal regions but also in many gyral crowns. Tracer injection into the sulcal cortex demonstrated that at least some axonal fibers pass directly through these fiber systems. Current and future high-resolution dMRI studies of the human brain will need to develop methods to overcome the challenges posed by superficial white matter systems to determine long-range anatomical connections accurately. C1 [Reveley, Colin; Seth, Anil K.] Univ Sussex, Sch Engn & Informat, Sackler Ctr Consciousness Sci, Brighton BN1 9QJ, E Sussex, England. [Pierpaoli, Carlo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Silva, Afonso C.] NINDS, Cerebral Microcirculat Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Yu, David; Leopold, David A.; Ye, Frank Q.] NINDS, Neurophysiol Imaging Facil, NIMH, Bethesda, MD 20892 USA. [Yu, David; Leopold, David A.; Ye, Frank Q.] NEI, NIH, Bethesda, MD 20892 USA. [Saunders, Richard C.; Leopold, David A.] NIMH, Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. RP Leopold, DA (reprint author), NINDS, Neurophysiol Imaging Facil, NIMH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM LeopoldD@mail.nih.gov OI Leopold, David/0000-0002-1345-6360 FU National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Eye Institute; School of Informatics at the University of Sussex; Dr. Mortimer and Theresa Sackler Foundation FX We thank Dr. Cibu Thomas for critical comments on the manuscript and Drs. Donna Dierker, Tim Coalson, and Matt Glasser for advice and discussion, and Drs. Hellmut Merkle, Daniel Papoti, and Charles Zhu for technical assistance. This work was supported by the Intramural Research Programs of the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and the National Eye Institute. C.R. and A.K.S. received support from the School of Informatics at the University of Sussex and the Dr. Mortimer and Theresa Sackler Foundation. NR 57 TC 42 Z9 42 U1 3 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 26 PY 2015 VL 112 IS 21 BP E2820 EP E2828 DI 10.1073/pnas.1418198112 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ1AJ UT WOS:000355213200014 PM 25964365 ER PT J AU Murley, A Sarsam, RD Toulmay, A Yamada, J Prinz, WA Nunnari, J AF Murley, Andrew Sarsam, Reta D. Toulmay, Alexandre Yamada, Justin Prinz, William A. Nunnari, Jodi TI Ltc1 is an ER-localized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; REPEAT PROTEINS; YEAST; COMPLEX; IMPORT; VAC8P; INHERITANCE; RECEPTOR; BINDING AB Organelle contact sites perform fundamental functions in cells, including lipid and ion homeostasis, membrane dynamics, and signaling. Using a forward proteomics approach in yeast, we identified new ER-mitochondria and ER-vacuole contacts specified by an uncharacterized protein, Ylr072w. Ylr072w is a conserved protein with GRAM and VASt domains that selectively transports sterols and is thus termed Ltc1, for Lipid transfer at contact site 1. Ltc1 localized to ER-mitochondria and ER-vacuole contacts via the mitochondrial import receptors Tom70/71 and the vacuolar protein Vac8, respectively. At mitochondria, Ltc1 was required for cell viability in the absence of Mdm34, a subunit of the ER -mitochondria encounter structure. At vacuoles, Ltc1 was required for sterol-enriched membrane domain formation in response to stress. Increasing the proportion of Ltc1 at vacuoles was sufficient to induce sterol-enriched vacuolar domains without stress. Thus, our data support a model in which Ltc1 is a sterol-dependent regulator of organelle and cellular homeostasis via its dual localization to ER- mitochondria and ER-vacuole contact sites. C1 [Murley, Andrew; Sarsam, Reta D.; Yamada, Justin; Nunnari, Jodi] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. [Toulmay, Alexandre; Prinz, William A.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Nunnari, J (reprint author), Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. EM jmnunnari@ucdavis.edu FU National Institutes of Health (NIH) [5T32GM007377-34]; NIH [R01GM062942, R01GM097432, R01GM106019] FX A. Murley was supported by National Institutes of Health (NIH) training grant 5T32GM007377-34; J. Nunnari is supported by NIH grants R01GM062942, R01GM097432, and R01GM106019. NR 53 TC 32 Z9 35 U1 2 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAY 25 PY 2015 VL 209 IS 4 BP 539 EP 548 DI 10.1083/jcb.201502033 PG 10 WC Cell Biology SC Cell Biology GA CJ6ZO UT WOS:000355643900011 PM 25987606 ER PT J AU Carvalheiro, T Gomes, D Pinto, LA Ines, L Lopes, A Henriques, A Pedreiro, S Martinho, A Trindade, H Young, HA da Silva, JAP Paiva, A AF Carvalheiro, Tiago Gomes, Diane Pinto, Ligia A. Ines, Luis Lopes, Ana Henriques, Ana Pedreiro, Susana Martinho, Antonio Trindade, Helder Young, Howard A. Pereira da Silva, Jose Antonio Paiva, Artur TI Sera from patients with active systemic lupus erythematosus patients enhance the toll-like receptor 4 response in monocyte subsets SO JOURNAL OF INFLAMMATION-LONDON LA English DT Article DE Systemic lupus erythematosus; Serum; Cytokines; Toll like receptor 4; Classical monocytes; Non-classical monocytes; Myeloid dendritic cells ID DISEASE-ACTIVITY INDEX; BLOOD DENDRITIC CELLS; MONONUCLEAR-CELLS; IGG; PATHOGENESIS; ACTIVATION; COMPLEXES; TNF; DIFFERENTIATION; MICROPARTICLES AB Background: Systemic Lupus Erythematosus (SLE) is an auto-immune disease whose complex pathogenesis remains unraveled. Here we aim to explore the inflammatory ability of SLE patients' sera upon peripheral blood (PB) monocyte subsets and myeloid dendritic cells (mDCs) obtained from healthy donors. Methods: In this study we included 11 SLE patients with active disease (ASLE), 11 with inactive disease (ISLE) and 10 healthy controls (HC). PB from healthy donors was stimulated with patients' sera, toll-like receptor (TLR) 4 ligand lipopolysaccharide or both. The intracellular production of TNF-alpha was evaluated in classical, non-classical monocytes and mDCs, using flow cytometry. TNF-alpha mRNA expression was assessed in all these purified cells, after sera treatment. Results: We found that sera of SLE patients did not change spontaneous TNF-alpha production by monocytes or dendritic cells. However, upon stimulation of TLR4, the presence of sera from ASLE patients, but not ISLE, significantly increased the intracellular expression of TNF-alpha in classical and non-classical monocytes. This ability was related to titers anti-double stranded DNA antibodies in the serum. High levels of anti-TNF-alpha in the patients' sera were associated with increased TNF-alpha expression by co-cultured mDCs. No relationship was found with the levels of a wide variety of other pro-inflammatory cytokines. A slight increase of TNF-alpha mRNA expression was observed in these purified cells when they were cultured only in the presence of SLE serum. Conclusions: Our data suggest that SLE sera induce an abnormal in vitro TLR4 response in classical and non-classical monocytes, reflected by a higher TNF-alpha intracellular expression. These effects may be operative in the pathogenesis of SLE. C1 [Carvalheiro, Tiago; Lopes, Ana; Pedreiro, Susana; Martinho, Antonio; Trindade, Helder; Paiva, Artur] Portuguese Inst Blood & Transplantat, Blood & Transplantat Ctr Coimbra, P-3041861 Coimbra, Portugal. [Gomes, Diane; Paiva, Artur] Coll Hlth Technol Coimbra, P-3046854 Coimbra, Portugal. [Pinto, Ligia A.] Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD 21702 USA. [Ines, Luis; Pereira da Silva, Jose Antonio] Ctr Hosp & Univ Coimbra, Dept Rheumatol, P-3000075 Coimbra, Portugal. [Ines, Luis; Henriques, Ana; Pereira da Silva, Jose Antonio] Univ Coimbra, Fac Med, P-3000548 Coimbra, Portugal. [Ines, Luis] Univ Beira Interior, Sch Hlth Sci, P-6200506 Covilha, Portugal. [Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Paiva, A (reprint author), Portuguese Inst Blood & Transplantat, Blood & Transplantat Ctr Coimbra, P-3041861 Coimbra, Portugal. EM artur.paiva@ipst.min-saude.pt OI Henriques, Ana/0000-0002-5096-791X; Da Silva, Jose/0000-0002-2782-6780 FU Portuguese Society of Rheumatology (SPR): "Bolsa de Investigacao na area das Doencas Reumaticas Inflamatorias - Bolsa SPR/MSD"; Intramural Research Program of the NIH, National Cancer Institute FX This work was partially supported by research grant from the Portuguese Society of Rheumatology (SPR): "Bolsa de Investigacao na area das Doencas Reumaticas Inflamatorias - Bolsa SPR/MSD 2014" and by the Intramural Research Program of the NIH, National Cancer Institute. NR 46 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-9255 J9 J INFLAMM-LOND JI J. Inflamm.-Lond. PD MAY 23 PY 2015 VL 12 AR 38 DI 10.1186/s12950-015-0083-2 PG 9 WC Immunology SC Immunology GA CJ3QJ UT WOS:000355398600001 PM 26038677 ER PT J AU Russ, DE Ho, KY Longo, NS AF Russ, Daniel E. Kwan-Yuet Ho Longo, Nancy S. TI HTJoinSolver: Human immunoglobulin VDJ partitioning using approximate dynamic programming constrained by conserved motifs SO BMC BIOINFORMATICS LA English DT Article ID MEMORY B-CELLS; SOMATIC HYPERMUTATION; HUMAN-ANTIBODY; SEQUENCES; IDENTIFICATION; ALGORITHM; ALIGNMENT; DATABASE; HIV-1 AB Background: Partitioning the human immunoglobulin variable region into variable (V), diversity (D), and joining (J) segments is a common sequence analysis step. We introduce a novel approximate dynamic programming method that uses conserved immunoglobulin gene motifs to improve performance of aligning V-segments of rearranged immunoglobulin (Ig) genes. Our new algorithm enhances the former JOINSOLVER algorithm by processing sequences with insertions and/or deletions (indels) and improves the efficiency for large datasets provided by high throughput sequencing. Results: In our simulations, which include rearrangements with indels, the V-matching success rate improved from 61% for partial alignments of sequences with indels in the original algorithm to over 99% in the approximate algorithm. An improvement in the alignment of human VDJ rearrangements over the initial JOINSOLVER algorithm was also seen when compared to the Stanford. S22 human Ig dataset with an online VDJ partitioning software evaluation tool. Conclusions: HTJoinSolver can rapidly identify V- and J-segments with indels to high accuracy for mutated sequences when the mutation probability is around 30% and 20% respectively. The D-segment is much harder to fit even at 20% mutation probability. For all segments, the probability of correctly matching V, D, and J increases with our alignment score. C1 [Russ, Daniel E.; Kwan-Yuet Ho] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Longo, Nancy S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Russ, DE (reprint author), NIH, Div Computat Biosci, Ctr Informat Technol, 12 South Dr, Bethesda, MD 20892 USA. EM druss@mail.nih.gov OI Russ, Daniel/0000-0003-4040-4416 FU Intramural Research Programs of the Center for Information Technology; National Institutes of Health; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors wish to thank Dr. John Mascola for the opportunity to develop HTJoinSolver. This work was supported by the Intramural Research Programs of the Center for Information Technology [DER, K-YH], National Institutes of Health and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health [NSL]. NR 21 TC 2 Z9 2 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAY 23 PY 2015 VL 16 AR 170 DI 10.1186/s12859-015-0589-x PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CI7GH UT WOS:000354930500001 PM 26001675 ER PT J AU Khor, B Gagnon, JD Goel, G Roche, MI Conway, KL Tran, K Aldrich, LN Sundberg, TB Paterson, AM Mordecai, S Dombkowski, D Schirmer, M Tan, PH Bhan, AK Roychoudhuri, R Restifo, NP O'Shea, JJ Medoff, BD Shamji, AF Schreiber, SL Sharpe, AH Shaw, SY Xavier, RJ AF Khor, Bernard Gagnon, John D. Goel, Gautam Roche, Marly I. Conway, Kara L. Tran, Khoa Aldrich, Leslie N. Sundberg, Thomas B. Paterson, Alison M. Mordecai, Scott Dombkowski, David Schirmer, Melanie Tan, Pauline H. Bhan, Atul K. Roychoudhuri, Rahul Restifo, Nicholas P. O'Shea, John J. Medoff, Benjamin D. Shamji, Alykhan F. Schreiber, Stuart L. Sharpe, Arlene H. Shaw, Stanley Y. Xavier, Ramnik J. TI The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells SO ELIFE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; PATHOGENIC T(H)17 CELLS; RETINOIC-ACID; TRANSCRIPTIONAL SIGNATURE; FOXP3 EXPRESSION; GENE-EXPRESSION; SMALL MOLECULES; NUCLEAR FACTOR; DOWN-SYNDROME; REG-CELLS AB The balance between Th17 and T regulatory (T-reg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosinephosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of T-reg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of T-reg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. C1 [Khor, Bernard; Conway, Kara L.; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. [Khor, Bernard; Conway, Kara L.; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA USA. [Khor, Bernard; Goel, Gautam; Conway, Kara L.; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Khor, Bernard; Gagnon, John D.; Conway, Kara L.; Aldrich, Leslie N.; Sundberg, Thomas B.; Schirmer, Melanie; Shamji, Alykhan F.; Schreiber, Stuart L.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Khor, Bernard; Mordecai, Scott; Dombkowski, David; Bhan, Atul K.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Roche, Marly I.; Medoff, Benjamin D.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Tran, Khoa; Tan, Pauline H.; Shaw, Stanley Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Aldrich, Leslie N.; Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Paterson, Alison M.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Paterson, Alison M.; Sharpe, Arlene H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Roychoudhuri, Rahul; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Xavier, RJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. EM xavier@molbio.mgh.harvard.edu RI Roychoudhuri, Rahul/A-7442-2010; OI Roychoudhuri, Rahul/0000-0002-5392-1853; Gagnon, John/0000-0001-6208-5781; Schirmer, Melanie/0000-0001-6456-3679; Khor, Bernard/0000-0003-4689-5092; Restifo, Nicholas P./0000-0003-4229-4580 NR 84 TC 5 Z9 5 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 22 PY 2015 VL 4 AR e05920 DI 10.7554/eLife.05920 PG 27 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ5QI UT WOS:000374264300001 ER PT J AU Newman, DJ Cragg, GM AF Newman, David J. Cragg, Gordon M. TI Endophytic and epiphytic microbes as "sources" of bioactive agents SO FRONTIERS IN CHEMISTRY LA English DT Review DE endophyte; epiphyte; natural product sources; ultured microbes; novel sources ID TUNICATE ECTEINASCIDIA-TURBINATA; FUNGUS RHIZOPUS-MICROSPORUS; NATURAL-PRODUCTS; HUPERZIA-SERRATA; BACTERIAL ENDOSYMBIONT; ALKALOID SWAINSONINE; ANTICANCER AGENTS; GENE-CLUSTER; SAFRAMYCIN-A; DIDEMNIN-B AB Beginning with the report by Stierle and Strobel in 1993 on taxol(R) production by an endophytic fungus (Stierle et al., 1993), it is possible that a number of the agents now used as leads to treatments of diseases in man, are not produced by the plant or invertebrate host from which they were first isolated and identified. They are probably the product of a microbe in, on or around the macroorganism. At times there is an intricate "dance" between a precursor produced by a microbe, and interactions within the macroorganism, or in certain cases, a fungus, that ends up with the production of a novel agent that has potential as a treatment for a human disease. This report will give examples from insects, plants, and marine invertebrates. C1 [Newman, David J.; Cragg, Gordon M.] NCI, Nat Prod Branch, Frederick, MD 21701 USA. EM djnewman664@verizon.net NR 87 TC 10 Z9 10 U1 17 U2 41 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND EI 2296-2646 J9 FRONT CHEM JI Front. Chem. PD MAY 22 PY 2015 VL 3 AR 34 DI 10.3389/fchem.2015.00034 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA DI2WL UT WOS:000373359700001 PM 26052511 ER PT J AU Earl, J Rico, D Carrillo-de-Santa-Pau, E Rodriguez-Santiago, B Mendez-Pertuz, M Auer, H Gomez, G Grossman, HB Pisano, DG Schulz, WA Perez-Jurado, LA Carrato, A Theodorescu, D Chanock, S Valencia, A Real, FX AF Earl, Julie Rico, Daniel Carrillo-de-Santa-Pau, Enrique Rodriguez-Santiago, Benjamin Mendez-Pertuz, Marinela Auer, Herbert Gomez, Gonzalo Grossman, Herbert Barton Pisano, David G. Schulz, Wolfgang A. Perez-Jurado, Luis A. Carrato, Alfredo Theodorescu, Dan Chanock, Stephen Valencia, Alfonso Real, Francisco X. TI The UBC-40 Urothelial Bladder Cancer cell line index: a genomic resource for functional studies SO BMC GENOMICS LA English DT Article DE Urothelial bladder cancer; Cell line; Genomics; Mutation; Oncogene; Tumor suppressor ID COPY NUMBER ALTERATIONS; FGFR3 MUTATIONS; IN-VIVO; CARCINOMA; P53; EXPRESSION; HYBRIDIZATION; PROGRESSION; PROMOTER; VARIANTS AB Background: Urothelial bladder cancer is a highly heterogeneous disease. Cancer cell lines are useful tools for its study. This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression. Results: Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1 12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events. Conclusions: Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing. C1 [Earl, Julie; Carrillo-de-Santa-Pau, Enrique; Mendez-Pertuz, Marinela; Real, Francisco X.] Spanish Natl Canc Res Ctr, CNIO, F BBVA Canc Cell Biol Programme, Epithelial Carcinogenesis Grp, Madrid, Spain. [Earl, Julie; Valencia, Alfonso] Hosp Ramon & Cajal, Med Oncol Serv, E-28034 Madrid, Spain. [Rico, Daniel; Valencia, Alfonso] Spanish Natl Canc Res Ctr, CNIO, Struct Biol & Biocomp Programme, Struct Computat Biol Grp, Madrid, Spain. [Rodriguez-Santiago, Benjamin] qGenomics, Quantitat Genom Med Lab, Barcelona, Spain. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Rodriguez-Santiago, Benjamin; Perez-Jurado, Luis A.] Ctr Invest Biomed Red Enfermedades Raras, Barcelona, Spain. [Auer, Herbert] Parc Cient Barcelona, Inst Recerca Biomed Barcelona, Barcelona, Spain. [Gomez, Gonzalo; Pisano, David G.] Spanish Natl Canc Res Ctr, CNIO, Struct Biol & Biocomp Programme, Bioinformat Unit, Madrid, Spain. [Grossman, Herbert Barton] Univ Texas Houston, MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Schulz, Wolfgang A.] Univ Dusseldorf, Dept Urol, Dusseldorf, Germany. [Theodorescu, Dan] Univ Colorado, Ctr Comprehens Canc, Aurora, CO 80045 USA. [Chanock, Stephen] NCI, Translat Genom Lab, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Real, Francisco X.] Ctr Nacl Invest Oncol, Canc Cell Biol Programme, Madrid 28029, Spain. RP Real, FX (reprint author), Spanish Natl Canc Res Ctr, CNIO, F BBVA Canc Cell Biol Programme, Epithelial Carcinogenesis Grp, Madrid, Spain. EM preal@cnio.es RI Valencia, Alfonso/I-3127-2015; Perez Jurado, Luis Alberto/M-7706-2015; Gomez-Lopez, Gonzalo/D-9123-2016; Pisano, David/N-5817-2014; OI Valencia, Alfonso/0000-0002-8937-6789; Gomez-Lopez, Gonzalo/0000-0002-4146-0551; Pisano, David/0000-0002-4895-4124; Rodriguez-Santiago, Benjamin/0000-0003-1167-3852; Rico, Daniel/0000-0002-6561-2310 FU Consolider ONCOBIO, Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [SAF2011-15934-E]; Asociacion Espanola Contra el Cancer; NIH [CA089715]; National Institutes of Health [CA075115, CA104106]; [EU-FP7-201663] FX This work was supported, in part, by grants Consolider ONCOBIO, SAF2011-15934-E, Red Tematica de Investigacion Cooperativa en Cancer (RTICC)]; Asociacion Espanola Contra el Cancer, EU-FP7-201663, and NIH RO-1 (CA089715); and National Institutes of Health grants CA075115 and CA104106 (to D.T.). NR 49 TC 13 Z9 13 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 22 PY 2015 VL 16 AR 403 DI 10.1186/s12864-015-1450-3 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CK7IH UT WOS:000356405500001 PM 25997541 ER PT J AU Kirtland, KA Saaddine, JB Geiss, LS Thompson, TJ Cotch, MF Lee, PP AF Kirtland, Karen A. Saaddine, Jinan B. Geiss, Linda S. Thompson, Ted J. Cotch, Mary F. Lee, Paul P. TI Geographic Disparity of Severe Vision Loss - United States, 2009-2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID VISUAL IMPAIRMENT; US ADULTS; HEALTH C1 [Kirtland, Karen A.; Saaddine, Jinan B.; Geiss, Linda S.; Thompson, Ted J.] CDC, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Cotch, Mary F.] NEI, NIH, Bethesda, MD USA. [Lee, Paul P.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. RP Kirtland, KA (reprint author), CDC, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM kkirtland@cdc.gov FU Intramural NIH HHS [Z99 EY999999] NR 10 TC 1 Z9 1 U1 1 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD MAY 22 PY 2015 VL 64 IS 19 BP 513 EP 517 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI7PV UT WOS:000354957300002 PM 25996092 ER PT J AU Finkel, T Menazza, S Holmstrom, KM Parks, RJ Liu, JL Sun, JH Liu, J Pan, X Murphy, E AF Finkel, Toren Menazza, Sara Holmstroem, Kira M. Parks, Randi J. Liu, Julia Sun, Junhui Liu, Jie Pan, Xin Murphy, Elizabeth TI The Ins and Outs of Mitochondrial Calcium SO CIRCULATION RESEARCH LA English DT Review DE calcium signaling; cell death; mitochondria ID PERMEABILITY TRANSITION PORE; CYTOSOLIC FREE CALCIUM; MEDIATED CELL-DEATH; CA2+ UPTAKE; HEART-MITOCHONDRIA; OXIDATIVE-PHOSPHORYLATION; ESSENTIAL COMPONENT; CYCLOSPORINE-A; ISCHEMIA/REPERFUSION INJURY; CARDIAC MITOCHONDRIA AB Calcium is thought to play an important role in regulating mitochondrial function. Evidence suggests that an increase in mitochondrial calcium can augment ATP production by altering the activity of calcium-sensitive mitochondrial matrix enzymes. In contrast, the entry of large amounts of mitochondrial calcium in the setting of ischemia-reperfusion injury is thought to be a critical event in triggering cellular necrosis. For many decades, the details of how calcium entered the mitochondria remained a biological mystery. In the past few years, significant progress has been made in identifying the molecular components of the mitochondrial calcium uniporter complex. Here, we review how calcium enters and leaves the mitochondria, the growing insight into the topology, stoichiometry and function of the uniporter complex, and the early lessons learned from some initial mouse models that genetically perturb mitochondrial calcium homeostasis. C1 [Finkel, Toren; Holmstroem, Kira M.; Liu, Julia; Liu, Jie] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Menazza, Sara; Parks, Randi J.; Sun, Junhui; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Pan, Xin] Natl Ctr Biomed Anal, Cell Biol Lab, Beijing, Peoples R China. RP Finkel, T (reprint author), 10 Ctr Dr,Bldg 10 CRC 5-3330, Bethesda, MD 20892 USA. EM finkelt@nih.gov; murphy1@mail.nih.gov OI Holmstrom, Kira/0000-0001-6434-7909 FU NHLBI; Leducq Foundation FX This work was supported by NHLBI Intramural funds and a grant from the Leducq Foundation. NR 79 TC 23 Z9 23 U1 3 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAY 22 PY 2015 VL 116 IS 11 BP 1810 EP 1819 DI 10.1161/CIRCRESAHA.116.305484 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA CI6IE UT WOS:000354861500013 PM 25999421 ER PT J AU Lungu, C Muegge, K Jeltsch, A Jurkowska, RZ AF Lungu, Cristiana Muegge, Kathrin Jeltsch, Albert Jurkowska, Renate Z. TI An ATPase-Deficient Variant of the SNF2 Family Member HELLS Shows Altered Dynamics at Pericentromeric Heterochromatin SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article ID DNA METHYLATION; CELLULAR PROLIFERATION; HISTONE METHYLATION; MOLECULAR MACHINES; SILENT CHROMATIN; MAMMALIAN-CELLS; REPEAT ELEMENTS; GENE-EXPRESSION; SNF2-LIKE GENE; NUCLEAR-MATRIX AB The HELLS (helicase, lymphoid specific, also known as lymphoid-specific helicase) protein is related to the SNF2 (sucrose non-fermentable 2) family of chromatin remodeling ATPases. It is required for efficient DNA methylation in mammals, particularly at heterochromatin-located repetitive sequences. In this study, we investigated the interaction of HELLS with chromatin and used an ATPase-deficient HELLS variant to address the role of ATP hydrolysis in this process. Chromatin fractionation experiments demonstrated that, in the absence of the ATPase activity, HELLS is retained at the nuclear matrix compartment, defined in part by lamin B1. Microscopy studies revealed a stronger association of the ATPase-deficient mutant with heterochromatin. These results were further supported by fluorescence recovery after photobleaching measurements, which showed that, at heterochromatic sites, wild-type HELLS is very dynamic, with a recovery half-time of 0.8 s and a mobile protein fraction of 61%. In contrast, the ATPase-deficient mutant displayed 4.5-s recovery half-time and a reduction in the mobile fraction to 30%. We also present evidence suggesting that, in addition to the ATPase activity, a functional H3K9me3 signaling pathway contributes to an efficient release of HELLS from pericentromeric chromatin. Overall, our results show that a functional ATPase activity is not required for the recruitment of HELLS to heterochromatin, but it is important for the release of the enzyme from these sites. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Lungu, Cristiana; Jeltsch, Albert; Jurkowska, Renate Z.] Univ Stuttgart, Inst Biochem, D-70569 Stuttgart, Germany. [Muegge, Kathrin] NCI, Mouse Canc Genet Program, Basic Sci Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA. RP Jurkowska, RZ (reprint author), Univ Stuttgart, Inst Biochem, Pfaffenwaldring 55, D-70569 Stuttgart, Germany. EM renata.jurkowska@ibc.uni-stuttgart.de RI Jeltsch, Albert/O-7404-2014 OI Jeltsch, Albert/0000-0001-6113-9290 FU Carl Zeiss foundation; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX C.L. and R.Z.J. have been financed by fellowships from the Carl Zeiss foundation. K.M. has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 62 TC 1 Z9 1 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 22 PY 2015 VL 427 IS 10 BP 1903 EP 1915 DI 10.1016/j.jmb.2015.03.014 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CH6KH UT WOS:000354145000005 PM 25823553 ER PT J AU Dey, S Scullen, T Noguchi, CT AF Dey, Soumyadeep Scullen, Tyler Noguchi, Constance Toni TI Erythropoietin negatively regulates pituitary ACTH secretion SO BRAIN RESEARCH LA English DT Article DE Erythropoietin; Adrenocorticotropic hormone; Pituitary gland ID CORTISOL METABOLISM; HEMODIALYZED PATIENTS; MESSENGER-RNA; HUMAN OBESITY; ADRENAL AXIS; RECEPTOR; EXPRESSION; STRESS; BRAIN; CELLS AB Erythropoietin (Epo) and Epo-receptor (EpoR) signaling, in addition to its classical role in erythropoiesis, exhibit a protective response in non-hematopoietic tissues. Mice with EpoR expression restricted to only hematopoietic tissues (Delta EpoR(E)), become obese, have low energy expenditure, and are glucose intolerant and insulin resistant. In the arcuate nucleus of the mouse hypothalamus, EpoR expression co-localizes in proopiomelanocortin (POMC) neurons. In vivo high-dose Epo treatment increases hypothalamus POMC, reduces food intake and fat mass accumulation. Here we report that Epo treatment also decreases plasma concentration of the pituitary derived POMC peptide, adrenocorticotropic hormone (ACTH). Conversely, Delta EpoR(E) mice show reduced hypothalamus POMC and high plasma concentrations of ACTH. In the pituitary, POMC is synthesized in the corticotroph cells, and here we examine Epo effect on pituitary POMC expression using the AtT-20 mouse corticotroph pituitary cell line. In AtT-20 cells, enzyme immunoassay analysis showed that Epo inhibits ACTH secretion. This effect is post-translational, as Epo treatment did not affect POMC mRNA expression but increased intracellular levels of ACTH peptide. Moreover, Epo reduced the basal intracellular calcium (Ca2+) levels, suggesting an effect in the Ca2+-signaling pathway. In summary, our studies suggest a novel regulatory pathway of ACTH secretion in the pituitary via EpoR-signaling. The higher plasma ACTH level in Delta EpoR(E) mice also suggests a possible mechanism of deregulated pituitary function with loss of Epo-signaling. Published by Elsevier B.V. C1 [Dey, Soumyadeep; Scullen, Tyler; Noguchi, Constance Toni] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Noguchi, CT (reprint author), Mol Med Branch, 10 Ctr Dr,Room 9N319,MSC-1822, Bethesda, MD 20892 USA. EM cnoguchi@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health [ZIA DK025061, ZIA DK025102] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (ZIA DK025061 and ZIA DK025102) at the National Institutes of Health. NR 37 TC 1 Z9 2 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD MAY 22 PY 2015 VL 1608 BP 14 EP 20 DI 10.1016/j.brainres.2015.02.052 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CG8YH UT WOS:000353601100002 PM 25765155 ER PT J AU Zhao, HY Ghirlando, R Alfonso, C Arisaka, F Attali, I Bain, DL Bakhtina, MM Becker, DF Bedwell, GJ Bekdemir, A Besong, TMD Birck, C Brautigam, CA Brennerman, W Byron, O Bzowska, A Chaires, JB Chaton, CT Colfen, H Connaghan, KD Crowley, KA Curth, U Daviter, T Dean, WL Diez, AI Ebel, C Eckert, DM Eisele, LE Eisenstein, E England, P Escalante, C Fagan, JA Fairman, R Finn, RM Fischle, W de la Torre, JG Gor, J Gustafsson, H Hall, D Harding, SE Cifre, JGH Herr, AB Howell, EE Isaac, RS Jao, SC Jose, D Kim, SJ Kokona, B Kornblatt, JA Kosek, D Krayukhina, E Krzizike, D Kusznir, EA Kwon, H Larson, A Laue, TM Le Roy, A Leech, AP Lilie, H Luger, K Luque-Ortega, JR Ma, J May, CA Maynard, EL Modrak-Wojcik, A Mok, YF Mucke, N Nagel-Steger, L Narlikar, GJ Noda, M Nourse, A Obsil, T Park, CK Park, JK Pawelek, PD Perdue, EE Perkins, SJ Perugini, MA Peterson, CL Peverelli, MG Piszczek, G Prag, G Prevelige, PE Raynal, BDE Rezabkova, L Richter, K Ringel, AE Rosenberg, R Rowe, AJ Rufer, AC Scott, DJ Seravalli, JG Solovyova, AS Song, RJ Staunton, D Stoddard, C Stott, K Strauss, HM Streicher, WW Sumida, JP Swygert, SG Szczepanowski, RH Tessmer, I Toth, RT Tripathy, A Uchiyama, S Uebel, SFW Unzai, S Gruber, AV von Hippel, PH Wandrey, C Wang, SH Weitzel, SE Wielgus-Kutrowska, B Wolberger, C Wolff, M Wright, E Wu, YS Wubben, JM Schuck, P AF Zhao, Huaying Ghirlando, Rodolfo Alfonso, Carlos Arisaka, Fumio Attali, Ilan Bain, David L. Bakhtina, Marina M. Becker, Donald F. Bedwell, Gregory J. Bekdemir, Ahmet Besong, Tabot M. D. Birck, Catherine Brautigam, Chad A. Brennerman, William Byron, Olwyn Bzowska, Agnieszka Chaires, Jonathan B. Chaton, Catherine T. Coelfen, Helmut Connaghan, Keith D. Crowley, Kimberly A. Curth, Ute Daviter, Tina Dean, William L. Diez, Ana I. Ebel, Christine Eckert, Debra M. Eisele, Leslie E. Eisenstein, Edward England, Patrick Escalante, Carlos Fagan, Jeffrey A. Fairman, Robert Finn, Ron M. Fischle, Wolfgang Garcia de la Torre, Jose Gor, Jayesh Gustafsson, Henning Hall, Damien Harding, Stephen E. Hernandez Cifre, Jose G. Herr, Andrew B. Howell, Elizabeth E. Isaac, Richard S. Jao, Shu-Chuan Jose, Davis Kim, Soon-Jong Kokona, Bashkim Kornblatt, Jack A. Kosek, Dalibor Krayukhina, Elena Krzizike, Daniel Kusznir, Eric A. Kwon, Hyewon Larson, Adam Laue, Thomas M. Le Roy, Aline Leech, Andrew P. Lilie, Hauke Luger, Karolin Luque-Ortega, Juan R. Ma, Jia May, Carrie A. Maynard, Ernest L. Modrak-Wojcik, Anna Mok, Yee-Foong Muecke, Norbert Nagel-Steger, Luitgard Narlikar, Geeta J. Noda, Masanori Nourse, Amanda Obsil, Tomas Park, Chad K. Park, Jin-Ku Pawelek, Peter D. Perdue, Erby E. Perkins, Stephen J. Perugini, Matthew A. Peterson, Craig L. Peverelli, Martin G. Piszczek, Grzegorz Prag, Gali Prevelige, Peter E. Raynal, Bertrand D. E. Rezabkova, Lenka Richter, Klaus Ringel, Alison E. Rosenberg, Rose Rowe, Arthur J. Rufer, Arne C. Scott, David J. Seravalli, Javier G. Solovyova, Alexandra S. Song, Renjie Staunton, David Stoddard, Caitlin Stott, Katherine Strauss, Holger M. Streicher, Werner W. Sumida, John P. Swygert, Sarah G. Szczepanowski, Roman H. Tessmer, Ingrid Toth, Ronald T. Tripathy, Ashutosh Uchiyama, Susumu Uebel, Stephan F. W. Unzai, Satoru Gruber, Anna Vitlin von Hippel, Peter H. Wandrey, Christine Wang, Szu-Huan Weitzel, Steven E. Wielgus-Kutrowska, Beata Wolberger, Cynthia Wolff, Martin Wright, Edward Wu, Yu-Sung Wubben, Jacinta M. Schuck, Peter TI A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation SO PLOS ONE LA English DT Article ID FLUORESCENCE-DETECTED SEDIMENTATION; SIZE-EXCLUSION CHROMATOGRAPHY; FIELD-FLOW FRACTIONATION; SPINCO ULTRACENTRIFUGE; BEAD MODELS; VELOCITY; AGGREGATION; PROTEINS; BIOPHARMACEUTICALS; HYDRODYNAMICS AB Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 +/- 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of +/- 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies. C1 [Zhao, Huaying; Ma, Jia; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, Dynam Macromol Assembly Sect, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Alfonso, Carlos; Luque-Ortega, Juan R.] CSIC, Ctr Invest Biol, Analyt Ultracentrifugac & Light Scattering Facil, E-28040 Madrid, Spain. [Arisaka, Fumio] Nihon Univ, Life Sci Res Ctr, Coll Bioresource Sci, Fujisawa, Kanagawa 2520880, Japan. [Attali, Ilan; Prag, Gali; Gruber, Anna Vitlin] Tel Aviv Univ, Dept Biochem & Mol Biol, IL-69978 Tel Aviv, Israel. [Bain, David L.; Connaghan, Keith D.] Univ Colorado Denver, Dept Pharmaceut Sci, Aurora, CO 80045 USA. [Bakhtina, Marina M.] Ohio State Univ, Ctr Retrovirus Res, Dept Chem & Biochem, Columbus, OH 43210 USA. [Bakhtina, Marina M.] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. [Becker, Donald F.; Seravalli, Javier G.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Bedwell, Gregory J.; Prevelige, Peter E.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Bekdemir, Ahmet] Ecole Polytech Fed Lausanne, Inst Mat, Supramol Nanomat & Interfaces Lab, CH-1015 Lausanne, Switzerland. [Besong, Tabot M. D.; Harding, Stephen E.; Rowe, Arthur J.] Univ Nottingham, Sch Biosci, Natl Ctr Macromol Hydrodynam, Loughborough LE12 5RD, Leics, England. [Birck, Catherine] Struct Biol Platform IGBMC, F-67400 Illkirch Graffenstaden, France. [Brautigam, Chad A.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Brennerman, William; Perdue, Erby E.] Beckman Coulter Inc, Div Life Sci, Indianapolis, IN 46268 USA. [Byron, Olwyn] Univ Glasgow, Sch Life Sci, Glasgow G37 TT, Lanark, Scotland. [Bzowska, Agnieszka; Modrak-Wojcik, Anna; Wielgus-Kutrowska, Beata] Univ Warsaw, Inst Expt Phys, Fac Phys, Div Biophys, PL-02089 Warsaw, Poland. [Chaires, Jonathan B.; Dean, William L.] Univ Louisville, JG Brown Canc Ctr, Louisville, KY 40202 USA. [Chaton, Catherine T.; Herr, Andrew B.] Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. [Coelfen, Helmut; Rosenberg, Rose] Univ Konstanz, Phys Chem, D-78457 Constance, Germany. [Crowley, Kimberly A.; Peterson, Craig L.; Swygert, Sarah G.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Curth, Ute] Hannover Med Sch, Inst Biophys Chem, D-30625 Hannover, Germany. [Daviter, Tina] Univ London, Biol Biophys Ctr, Inst Struct & Mol, London WC1E 7HX, England. [Daviter, Tina] UCL, London WC1E 7HX, England. [Diez, Ana I.; Garcia de la Torre, Jose; Hernandez Cifre, Jose G.] Univ Murcia, Dept Phys Chem, Murcia 30071, Spain. [Ebel, Christine; Le Roy, Aline] Univ Grenoble Alpes, IBS, F-38044 Grenoble, France. [Ebel, Christine; Le Roy, Aline] CNRS, IBS, F-38044 Grenoble, France. [Ebel, Christine; Le Roy, Aline] CEA, IBS, F-38044 Grenoble, France. [Eckert, Debra M.] Univ Utah, Sch Med, Dept Biochem, Prot Interact Core, Salt Lake City, UT 84112 USA. [Eisele, Leslie E.; Song, Renjie] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12208 USA. [Eisenstein, Edward] Univ Maryland, Fischell Dept Bioengn, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [England, Patrick; Raynal, Bertrand D. E.] Inst Pasteur, Ctr Biophys Macromol & Interact, F-75724 Paris, France. [Escalante, Carlos] Virginia Commonwealth Univ, Sch Med, Dept Physiol & Biophys, Richmond, VA 23220 USA. [Fagan, Jeffrey A.] Natl Inst Stand & Technol, Mat Sci & Engn Lab, Gaithersburg, MD 20899 USA. [Fairman, Robert; Kokona, Bashkim] Haverford Coll, Dept Biol, Haverford, PA 19041 USA. [Finn, Ron M.; Fischle, Wolfgang] Max Planck Inst Biophys Chem, Lab Chromatin Biochem, D-37077 Gottingen, Germany. [Gor, Jayesh; Perkins, Stephen J.] UCL, Dept Struct & Mol Biol, London WC1E 6BT, England. [Gustafsson, Henning; Strauss, Holger M.] Novo Nordisk AS, Diabet Biophys, DK-2760 Malov, Denmark. [Hall, Damien] Australian Natl Univ, Sect Biol Chem, Res Sch Chem, Acton, ACT 0200, Australia. [Howell, Elizabeth E.; Wright, Edward] Univ Tennessee, Biochem Cell & Mol Biol Dept, Knoxville, TN 37996 USA. [Isaac, Richard S.; Larson, Adam; Narlikar, Geeta J.; Stoddard, Caitlin] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. [Isaac, Richard S.; Larson, Adam; Stoddard, Caitlin] Univ Calif San Francisco, Tetrad Grad Program, San Francisco, CA 94158 USA. [Jao, Shu-Chuan] Acad Sinica, Inst Biol Chem, Taipei 115, Taiwan. [Jao, Shu-Chuan; Wang, Szu-Huan] Acad Sinica, Sci Instrument Ctr, Biophys Core Facil, Taipei 115, Taiwan. [Jose, Davis; von Hippel, Peter H.; Weitzel, Steven E.] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. [Jose, Davis; von Hippel, Peter H.; Weitzel, Steven E.] Univ Oregon, Dept Chem & Biochem, Eugene, OR 97403 USA. [Kim, Soon-Jong] Mokpo Natl Univ, Dept Chem, Muan 534729, South Korea. [Kornblatt, Jack A.] Concordia Univ, Enzyme Res Grp, Montreal, PQ H4B 1R6, Canada. [Kosek, Dalibor; Obsil, Tomas] Charles Univ Prague, Fac Sci, Dept Phys & Macromol Chem, Prague 12843, Czech Republic. [Krayukhina, Elena; Noda, Masanori; Uchiyama, Susumu] Osaka Univ, Grad Sch Engn, Dept Biotechnol, Suita, Osaka 5650871, Japan. [Krzizike, Daniel; Luger, Karolin] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Kusznir, Eric A.; Rufer, Arne C.] F Hoffmann LaRoche Ltd, Roche Innovat Ctr Basel, Pharma Res & Early Dev, CH-4070 Basel, Switzerland. [Kwon, Hyewon; Sumida, John P.] Univ Washington, Analyt Biopharm Core, Seattle, WA 98195 USA. [Laue, Thomas M.; May, Carrie A.] Univ New Hampshire, Dept Biochem, Durham, NH 03824 USA. [Leech, Andrew P.] Univ York, Dept Biol, Technol Facil, York YO10 5DD, N Yorkshire, England. [Lilie, Hauke] Univ Halle Wittenberg, Inst Biochem & Biotechnol, D-06120 Halle, Germany. [Maynard, Ernest L.] Uniformed Serv Univ Hlth Sci, Dept Biochem, Bethesda, MD 20814 USA. [Mok, Yee-Foong] Univ Melbourne, Dept Biochem & Mol Biol Inst Mol Sci & Biotechnol, Parkville, Vic 3010, Australia. [Muecke, Norbert] German Canc Res Ctr, Biophys Macromol, D-69120 Heidelberg, Germany. [Nagel-Steger, Luitgard; Wolff, Martin] Res Ctr Juelich, ICS 6, Struct Biochem, D-52428 Julich, Germany. [Nourse, Amanda] St Jude Childrens Res Hosp, Mol Interact Anal Shared Resource, Memphis, TN 38105 USA. [Park, Chad K.] Univ Arizona, Dept Chem & Biochem, Analyt Biophys & Mat Characterizat, Tucson, AZ 85721 USA. [Park, Jin-Ku] Mokpo Natl Univ, Cent Instrument Ctr, Muan 534729, South Korea. [Pawelek, Peter D.] Concordia Univ, Dept Chem & Biochem, Montreal, PQ H4B 1R6, Canada. [Perugini, Matthew A.; Peverelli, Martin G.; Wubben, Jacinta M.] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem, Melbourne, Vic 3086, Australia. [Piszczek, Grzegorz] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Rezabkova, Lenka] Paul Scherrer Inst, Dept Biol & Chem, Lab Biomol Res, CH-5232 Villigen, Switzerland. [Richter, Klaus] Tech Univ Munich, Dept Chem, D-85748 Garching, Germany. [Richter, Klaus] Tech Univ Munich, Ctr Integrated Prot Sci, D-85748 Garching, Germany. [Ringel, Alison E.; Wolberger, Cynthia] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Scott, David J.] Rutherford Appleton Lab, Didcot OX11 0FA, Oxon, England. [Solovyova, Alexandra S.] Newcastle Univ, Proteome & Prot Anal, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Staunton, David] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England. [Stott, Katherine] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. [Streicher, Werner W.] Novo Nordisk Fdn Ctr Prot Res, Prot Funct & Interact, DK-2200 Copenhagen, Denmark. [Szczepanowski, Roman H.] Int Inst Mol & Cell Biol, Core Facil, PL-02109 Warsaw, Poland. [Tessmer, Ingrid] Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, D-97080 Wurzburg, Germany. [Toth, Ronald T.] Univ Kansas, Macromol & Vaccine Stabilizat Ctr, Lawrence, KS 66047 USA. [Tripathy, Ashutosh] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Uebel, Stephan F. W.] Max Planck Inst Biochem, Biochem Core Facil, D-82152 Martinsried, Germany. [Unzai, Satoru] Yokohama City Univ, Grad Sch Med Life Sci, Drug Design Lab, Yokohama, Kanagawa 2300045, Japan. [Wandrey, Christine] Ecole Polytech Fed Lausanne, Lab Med Regenerat & Pharmacobiol, CH-1015 Lausanne, Switzerland. [Wu, Yu-Sung] Univ Delaware, Dept Chem & Biomol Engn, Newark, DE 19716 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, Dynam Macromol Assembly Sect, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov RI Alfonso, Carlos/K-1316-2014; Obsil, Tomas/B-7142-2012; Richter, Klaus/A-2673-2010; Hall, Damien/D-9927-2012; Nagel-Steger, Luitgard/H-6415-2013; OI Perugini, Matthew/0000-0001-8052-5584; Fagan, Jeffrey/0000-0003-1483-5554; Alfonso, Carlos/0000-0001-7165-4800; Obsil, Tomas/0000-0003-4602-1272; Hall, Damien/0000-0003-1538-7618; Nagel-Steger, Luitgard/0000-0001-5232-2149; Schuck, Peter/0000-0002-8859-6966; kornblatt, jack/0000-0002-9802-8321; Herr, Andrew/0000-0002-3598-3399; Harding, Stephen E./0000-0002-7798-9692 FU Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health; Max Planck Society; Rudolf Virchow Center for Experimental Biomedicine - German Research Council (Deutsche Forschungsgemeinschaft, DFG) [FZ 82]; National Cancer Institute [CA35635]; National Institute of General Medical Sciences [GM 095822, GM 109102, GM 094363, P30GM103519]; MINECO-Spain/FEDER [CTQ2012-33717]; Centre for Preclinical Research and Technology (CePT) - European Union [POIG.02.02.00-14-024/08-00]; FRISBI [ANR-10-INSB-05-02]; GRAL within the Grenoble Partnership for Structural Biology (PSB) [ANR-10-LABX-49-01]; NIH [GM-15792, GM-29158, GM82545, GM067777, F31GM105363]; NSF; French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]; Instruct, European Strategy Forum on Research Infrastructures (ESFRI); European Regional Development Fund within the Innovation Economy Operational Program [POIG.02.02.00-00025/09]; National Research Foundation of Korea [2011-0010437]; EMBO long-term fellowship; Marie Curie IEF fellowship; A.N.U. Senior Research Fellowship FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, the National Heart, Lung, and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health; the Max Planck Society; and the Rudolf Virchow Center for Experimental Biomedicine by the German Research Council (Deutsche Forschungsgemeinschaft, DFG) FZ 82. Further, this work was supported by National Cancer Institute grant CA35635, grants from the National Institute of General Medical Sciences (GM 095822, GM 109102, GM 094363, and P30GM103519), and by grant CTQ2012-33717 from MINECO-Spain/FEDER. The purchase of the XL-I AUC instrument for IIMCB Warsaw was supported by Centre for Preclinical Research and Technology (CePT) - European Union POIG.02.02.00-14-024/08-00 project. This work used the platforms of the Grenoble Instruct centre (ISBG; UMS 3518 CNRS-CEA-UJF-EMBL) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology (PSB). This work was supported in part by NIH research grants GM-15792 and GM-29158 and by a Shared Instrument Proposal grant from NSF (P. H. von Hippel, Principle Investigator). The work in the Strasbourg centre was supported by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01, and Instruct as part of the European Strategy Forum on Research Infrastructures (ESFRI). Some of the experiments in the present study were performed in the NanoFun laboratories co-financed by the European Regional Development Fund within the Innovation Economy Operational Program, Project No. POIG.02.02.00-00025/09. S-JK acknowledges support from National Research Foundation of Korea (2011-0010437). LR acknowledges the receipt of EMBO long-term and Marie Curie IEF fellowships. DH acknowledges the receipt of an A.N.U. Senior Research Fellowship. DME and the University of Utah Protein Interaction Core Facility are supported by NIH Grant GM82545. KL acknowledges NIH grant GM067777, and DK acknowledges NIH grant F31GM105363. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 7 Z9 7 U1 4 U2 35 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 21 PY 2015 VL 10 IS 5 AR e0126420 DI 10.1371/journal.pone.0126420 PG 30 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK7VW UT WOS:000356444000024 PM 25997164 ER PT J AU Jin, DJ Cagliero, C Martin, CM Izard, J Zhou, YN AF Jin, Ding J. Cagliero, Cedric Martin, Carmen M. Izard, Jerome Zhou, Yan N. TI The dynamic nature and territory of transcriptional machinery in the bacterial chromosome SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE RNA polymerase; bacterial nucleolus; replisome; chromosome territories; growth rate regulation; stress responses; superresolution imaging; E. coli ID ESCHERICHIA-COLI CHROMOSOME; RIBOSOMAL-RNA TRANSCRIPTION; NUCLEOID-ASSOCIATED PROTEINS; SALMONELLA-TYPHIMURIUM; ACTIVE TRANSCRIPTION; SPATIAL-ORGANIZATION; STRINGENT RESPONSE; DNA-REPLICATION; BALANCED GROWTH; SEQA PROTEIN AB Our knowledge of the regulation of genes involved in bacterial growth and stress responses is extensive; however, we have only recently begun to understand how environmental cues influence the dynamic, three-dimensional distribution of RNA polymerase (RNAP) in Escherichia coli on the level of single cell, using wide-field fluorescence microscopy and state-of-the-art imaging techniques. Live-cell imaging using either an agarose-embedding procedure or a microfluidic system further underscores the dynamic nature of the distribution of RNAP in response to changes in the environment and highlights the challenges in the study. A general agreement between live-cell and fixed-cell images has validated the formaldehyde-fixing procedure, which is a technical breakthrough in the study of the cell biology of RNAP. In this review we use a systems biology perspective to summarize the advances in the cell biology of RNAP in E. coli, including the discoveries of the bacterial nucleolus, the spatial compartmentalization of the transcription machinery at the periphery of the nucleoid, and the segregation of the chromosome territories for the two major cellular functions of transcription and replication in fast-growing cells. Our understanding of the coupling of transcription and bacterial chromosome (or nucleoid) structure is also summarized. Using E. coli as a simple model system, co-imaging of RNAP with DNA and other factors during growth and stress responses will continue to be a useful tool for studying bacterial growth and adaptation in changing environment. C1 [Jin, Ding J.; Cagliero, Cedric; Martin, Carmen M.; Izard, Jerome; Zhou, Yan N.] NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. RP Jin, DJ (reprint author), NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, POB B, Frederick, MD 21702 USA. EM jind@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. DJJ would like to thank the four reviewers and the editor for critical reading of the manuscript and productive interactions in the reviewing process. NR 77 TC 3 Z9 3 U1 2 U2 9 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD MAY 21 PY 2015 VL 6 AR 497 DI 10.3389/fmicb.2015.00497 PG 14 WC Microbiology SC Microbiology GA CK5MC UT WOS:000356267800001 PM 26052320 ER PT J AU Barrett, AJ Ito, S AF Barrett, A. John Ito, Sawa TI The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century SO BLOOD LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC GRANULOCYTIC-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; BCR-ABL TRANSCRIPTS; VERSUS-HOST-DISEASE; 1ST CHRONIC PHASE; CRYOPRESERVED AUTOLOGOUS MARROW; CHROMOSOME-POSITIVE LEUKEMIA; DONOR LEUKOCYTE TRANSFUSIONS; IMATINIB MESYLATE TREATMENT AB The introduction of tyrosine kinase inhibitors (TKIs), a treatment of chronic myelogenous leukemia (CML), has largely replaced curative strategies based on allogeneic stem cell transplantation (SCT). Nevertheless, SCT still remains an option for accelerated/blastic-phase and selected chronic-phase CML. Transplant outcomes can be optimized by peritransplant TKIs, conditioning regimen, BCR-ABL monitoring, and relapse management. Controversies exist in transplant timing, pediatric CML, alternative donors, and economics. SCT continues to serve as a platform of "operational cure" for CML with TKIs and immunotherapies. C1 [Barrett, A. John; Ito, Sawa] NHLBI, Stem Cell Allotransplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov FU National Institutes of Health Intramural Research Program at the National Heart, Lung, and Blood Institute FX This study was supported by the National Institutes of Health Intramural Research Program at the National Heart, Lung, and Blood Institute. NR 93 TC 7 Z9 8 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 21 PY 2015 VL 125 IS 21 BP 3230 EP 3235 DI 10.1182/blood-2014-10-567784 PG 6 WC Hematology SC Hematology GA CJ7QF UT WOS:000355691700006 PM 25852053 ER PT J AU Garnham, CP Vemu, A Wilson-Kubalek, EM Yu, I Szyk, A Lander, GC Milligan, RA Roll-Mecak, A AF Garnham, Christopher P. Vemu, Annapurna Wilson-Kubalek, Elizabeth M. Yu, Ian Szyk, Agnieszka Lander, Gabriel C. Milligan, Ronald A. Roll-Mecak, Antonina TI Multivalent Microtubule Recognition by Tubulin Tyrosine Ligase-like Family Glutamylases SO CELL LA English DT Article ID ALPHA-BETA-TUBULIN; STRUCTURAL BASIS; IN-VITRO; POSTTRANSLATIONAL MODIFICATIONS; POLYGLUTAMYLATION; PROTEIN; MOTILITY; BINDING; RESOLUTION; BRAIN AB Glutamylation, the most prevalent tubulin posttranslational modification, marks stable microtubules and regulates recruitment and activity of microtubule-interacting proteins. Nine enzymes of the tubulin tyrosine ligase-like (TTLL) family catalyze glutamylation. TTLL7, the most abundant neuronal glutamylase, adds glutamates preferentially to the beta-tubulin tail. Coupled with ensemble and single-molecule biochemistry, our hybrid X-ray and cryo-electron microscopy structure of TTLL7 bound to the microtubule delineates a tripartite microtubule recognition strategy. The enzyme uses its core to engage the disordered anionic tails of alpha-and beta-tubulin, and a flexible cationic domain to bind the microtubule and position itself for beta-tail modification. Furthermore, we demonstrate that all single-chain TTLLs with known glutamylase activity utilize a cationic microtubule-binding domain analogous to that of TTLL7. Therefore, our work reveals the combined use of folded and intrinsically disordered substrate recognition elements as the molecular basis for specificity among the enzymes primarily responsible for chemically diversifying cellular microtubules. C1 [Garnham, Christopher P.; Vemu, Annapurna; Yu, Ian; Szyk, Agnieszka; Roll-Mecak, Antonina] NINDS, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Wilson-Kubalek, Elizabeth M.; Lander, Gabriel C.; Milligan, Ronald A.] Scripps Res Inst, La Jolla, CA 92037 USA. [Roll-Mecak, Antonina] NHLBI, Bethesda, MD 20892 USA. RP Roll-Mecak, A (reprint author), NINDS, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. EM antonina@mail.nih.gov FU NIGMS [P41 GM103310]; NINDS postdoctoral fellowship; Damon Runyon Cancer Research Foundation (DFS) [07-13]; Pew Scholars program; Searle Scholars program; NIH [DP2 EB020402, GM-052468, GM095573]; Searle Scholar program; National Institute of Neurological Disorders and Stroke; National Heart, Lung and Blood Institute FX We thank staff at beamlines 24-ID (Advanced Photon Source) and 5.0.1 and 5.0.2 (Advanced Light Source) for support, D.-Y. Lee for access to mass spectrometers, and A. Ferre-D'Amare, E. Giniger, and S. Gottesman for critical reading of the manuscript. TEM studies were conducted at the National Resource for Automated Molecular Microscopy, supported by NIGMS (P41 GM103310). C.P.G. is supported by an NINDS postdoctoral fellowship. G.C.L. is supported by the Damon Runyon Cancer Research Foundation (DFS-#07-13), the Pew Scholars program, the Searle Scholars program, and NIH (DP2 EB020402). R.A.M. is supported by NIH (GM-052468). E.M.W.-K is partly supported by NIH (GM095573). A.R.-M. is supported by the Searle Scholar program and the intramural programs of the National Institute of Neurological Disorders and Stroke and National Heart, Lung and Blood Institute. NR 53 TC 11 Z9 15 U1 2 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 21 PY 2015 VL 161 IS 5 BP 1112 EP 1123 DI 10.1016/j.cell.2015.04.003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CJ0GA UT WOS:000355152600018 PM 25959773 ER PT J AU Canela, A Stanlie, A Nussenzweig, A AF Canela, Andres Stanlie, Andre Nussenzweig, Andre TI Collateral DNA Damage Produced by Genome-Editing Drones: Exception or Rule? SO MOLECULAR CELL LA English DT Editorial Material ID OFF-TARGET CLEAVAGE; CHROMOSOMAL TRANSLOCATIONS; SEQUENCING REVEALS; REARRANGEMENTS; NUCLEASES; BREAKS; CELLS AB In the recent issue of Nature Biotechnology, Frock et al. (2015) developed an elegant technique to capture translocation partners that can be utilized to determine off-target regions of genome-editing endonucleases as well as endogenous mutators at nucleotide resolution. C1 [Canela, Andres; Stanlie, Andre; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD MAY 21 PY 2015 VL 58 IS 4 BP 565 EP 567 DI 10.1016/j.molcel.2015.05.012 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CJ0GO UT WOS:000355154000004 PM 26000841 ER PT J AU Zhang, YF Phung, Y Gao, W Kawa, S Hassan, R Pastan, I Ho, M AF Zhang, Yi-Fan Phung, Yen Gao, Wei Kawa, Seiji Hassan, Raffit Pastan, Ira Ho, Mitchell TI New High Affinity Monoclonal Antibodies Recognize Non-Overlapping Epitopes On Mesothelin For Monitoring And Treating Mesothelioma SO SCIENTIFIC REPORTS LA English DT Article ID MALIGNANT PLEURAL MESOTHELIOMA; ANTIMESOTHELIN IMMUNOTOXIN SS1P; OVARIAN-CANCER PATIENTS; SERUM MESOTHELIN; POTENTIATING FACTOR; CELL-SURFACE; IMMUNOTHERAPY; COMBINATION; DIAGNOSIS; THERAPY AB Mesothelin is an emerging cell surface target in mesothelioma and other solid tumors. Most antibody drug candidates recognize highly immunogenic Region I (296-390) on mesothelin. Here, we report a group of high-affinity non-Region I rabbit monoclonal antibodies. These antibodies do not compete for mesothelin binding with the immunotoxin SS1P that binds Region I of mesothelin. One pair of antibodies (YP218 and YP223) is suitable to detect soluble mesothelin in a sandwich ELISA with high sensitivity. The new assay can also be used to measure serum mesothelin concentration in mesothelioma patients, indicating its potential use for monitoring patients treated with current antibody therapies targeting Region I. The antibodies are highly specific and sensitive in immunostaining of mesothelioma. To explore their use in tumor therapy, we have generated the immunotoxins based on the Fv of these antibodies. One immunotoxin (YP218 Fv-PE38) exhibits potent anti-tumor cytotoxicity towards primary mesothelioma cell lines in vitro and an NCI-H226 xenograft tumor in mice. Furthermore, we have engineered a humanized YP218 Fv that retains full binding affinity for mesothelin-expressing cancer cells. In conclusion, with their unique binding properties, these antibodies may be promising candidates for monitoring and treating mesothelioma and other mesothelin-expressing cancers. C1 [Zhang, Yi-Fan; Phung, Yen; Gao, Wei; Kawa, Seiji; Pastan, Ira; Ho, Mitchell] Natl Canc Inst, Ctr Canc Res, Mol Biol Lab, Bethesda, MD 20892 USA. [Hassan, Raffit] Natl Canc Inst, Ctr Canc Res, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. RP Ho, M (reprint author), Natl Canc Inst, Ctr Canc Res, Mol Biol Lab, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Zhang, Yifan/O-9621-2015 OI Zhang, Yifan/0000-0002-0629-0200 FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research. This work was also possible by the Mesothelioma Applied Research Foundation Craig Kozicki Memorial Grant to M Ho. 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. We thank Miriam Anver and the staff in Pathology/Histotechnology Laboratory, SAIC (Frederick, MD), for helping with in vivo toxicity test and immunohistochemistry analysis and Jingli Zhang (NCI) for helping with the cytotoxicity assays using primary patient cell lines. We also thank the NIH Fellows Editorial Board for editorial assistance. The vehicle and SS1P groups used as control groups in the study (Fig. 7B) have been previously published in: Kim H, Gao W, Ho M. Novel immunocytokine IL12-SS1 (Fv) inhibits mesothelioma tumor growth in nude mice. NR 38 TC 3 Z9 3 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 21 PY 2015 VL 5 AR 09928 DI 10.1038/srep09928 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5BL UT WOS:000355502300001 PM 25996440 ER PT J AU Contijoch, F Witschey, WRT Rogers, K Rears, H Hansen, M Yushkevich, P Gorman, J Gorman, RC Han, YC AF Contijoch, Francisco Witschey, Walter R. T. Rogers, Kelly Rears, Hannah Hansen, Michael Yushkevich, Paul Gorman, Joseph, III Gorman, Robert C. Han, Yuchi TI User-initialized active contour segmentation and golden-angle real-time cardiovascular magnetic resonance enable accurate assessment of LV function in patients with sinus rhythm and arrhythmias SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Real-time CMR; Arrhythmia; Temporal resolution ID NONLINEAR INVERSE RECONSTRUCTION; LEFT-VENTRICULAR FUNCTION; K-SPACE; RADIAL FLASH; TEMPORAL RESOLUTION; BALANCED SSFP; CARDIAC MRI; T SENSE; TRAJECTORIES; EXERCISE AB Background: Data obtained during arrhythmia is retained in real-time cardiovascular magnetic resonance (rt-CMR), but there is limited and inconsistent evidence to show that rt-CMR can accurately assess beat-to-beat variation in left ventricular (LV) function or during an arrhythmia. Methods: Multi-slice, short axis cine and real-time golden-angle radial CMR data was collected in 22 clinical patients (18 in sinus rhythm and 4 patients with arrhythmia). A user-initialized active contour segmentation (ACS) software was validated via comparison to manual segmentation on clinically accepted software. For each image in the 2D acquisitions, slice volume was calculated and global LV volumes were estimated via summation across the LV using multiple slices. Real-time imaging data was reconstructed using different image exposure times and frame rates to evaluate the effect of temporal resolution on measured function in each slice via ACS. Finally, global volumetric function of ectopic and non-ectopic beats was measured using ACS in patients with arrhythmias. Results: ACS provides global LV volume measurements that are not significantly different from manual quantification of retrospectively gated cine images in sinus rhythm patients. With an exposure time of 95.2 ms and a frame rate of > 89 frames per second, golden-angle real-time imaging accurately captures hemodynamic function over a range of patient heart rates. In four patients with frequent ectopic contractions, initial quantification of the impact of ectopic beats on hemodynamic function was demonstrated. Conclusion: User-initialized active contours and golden-angle real-time radial CMR can be used to determine time-varying LV function in patients. These methods will be very useful for the assessment of LV function in patients with frequent arrhythmias. C1 [Contijoch, Francisco] Univ Penn, Smilow Ctr Translat Res, Dept Bioengn, Philadelphia, PA 19104 USA. [Witschey, Walter R. T.; Rears, Hannah; Yushkevich, Paul] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Rogers, Kelly; Han, Yuchi] Univ Penn, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. [Hansen, Michael] NHLBI, NIH, Bethesda, MD 20892 USA. [Gorman, Joseph, III; Gorman, Robert C.] Univ Penn, Dept Surg, Philadelphia, PA USA. RP Contijoch, F (reprint author), Univ Penn, Smilow Ctr Translat Res, Dept Bioengn, 3400 Civ Ctr Blvd,Bldg 421,7th Floor,Rm 103, Philadelphia, PA 19104 USA. EM fcont@seas.upenn.edu RI Hansen, Michael/J-5391-2015; OI Hansen, Michael/0000-0002-8087-8731; Contijoch, Francisco/0000-0001-9616-3274 FU National Institutes of Health [F31-HL120580, R00-HL108157, R01-EB014346, R01-HL103723, R01-HL63954, T32-HL007954, T32-EB009384] FX We would like to acknowledge the National Institutes of Health for support through grants: F31-HL120580, R00-HL108157, R01-EB014346, R01-HL103723, R01-HL63954, T32-HL007954, T32-EB009384. NR 28 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY 21 PY 2015 VL 17 AR 37 DI 10.1186/s12968-015-0146-9 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CI7JU UT WOS:000354940300001 PM 25994390 ER PT J AU Klein, HG Cortes-Puch, I Natanson, C AF Klein, Harvey G. Cortes-Puch, Irene Natanson, Charles TI Blood-transfusion decisions not simple SO NATURE LA English DT Letter C1 [Klein, Harvey G.; Cortes-Puch, Irene; Natanson, Charles] NIH, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM hklein@dtm.cc.nih.gov NR 3 TC 2 Z9 2 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 21 PY 2015 VL 521 IS 7552 BP 289 EP 289 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI5RM UT WOS:000354816500035 PM 25993950 ER PT J AU Chen, ZS Shojaee, S Buchner, M Geng, HM Lee, J Klemm, L Titz, B Graeber, TG Park, E Tan, YX Satterthwaite, A Paietta, E Hunger, SP Willman, CL Melnick, A Loh, ML Jung, JU Coligan, JE Bolland, S Mak, TW Limnander, A Jumaa, H Reth, M Weiss, A Lowell, CA Muschen, M AF Chen, Zhengshan Shojaee, Seyedmehdi Buchner, Maike Geng, Huimin Lee, JaeWoong Klemm, Lars Titz, Boern Graeber, Thomas G. Park, Eugene Tan, Ying Xim Satterthwaite, Anne Paietta, Elisabeth Hunger, Stephen P. Willman, Cheryl L. Melnick, Ari Loh, Mignon L. Jung, Jae U. Coligan, John E. Bolland, Silvia Mak, Tak W. Limnander, Andre Jumaa, Hassan Reth, Michael Weiss, Arthur Lowell, Clifford A. Mueschen, Markus TI Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia SO NATURE LA English DT Article ID IN-VIVO; RECEPTOR; DELETION; ACTIVATION; MOTIFS AB B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum(for example, non-functional BCR)(1) or hyperactivation above maximum (for example, self-reactive BCR)(2,3) thresholds of signalling strength causes negative selection. In similar to 25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling(4,5). Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival(6). We tested the hypothesis that targeted hyperactivation-above a maximum threshold-will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1)(9), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL. C1 [Chen, Zhengshan; Shojaee, Seyedmehdi; Buchner, Maike; Geng, Huimin; Lee, JaeWoong; Klemm, Lars; Park, Eugene; Lowell, Clifford A.; Mueschen, Markus] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Titz, Boern; Graeber, Thomas G.] Univ Calif Los Angeles, Crump Inst Mol Imaging, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Tan, Ying Xim; Weiss, Arthur] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Med,Div Rheumatol, Rosalind Russell Ephraim P Engleman Med Res Ctr A, San Francisco, CA 94143 USA. [Satterthwaite, Anne] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Paietta, Elisabeth] Albert Einstein Coll Med, Dept Med, Bronx, NY 10466 USA. [Hunger, Stephen P.] Childrens Hosp Philadelphia, Div Pediat Oncol, Philadelphia, PA 19104 USA. [Hunger, Stephen P.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Willman, Cheryl L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87102 USA. [Melnick, Ari] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Melnick, Ari] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA. [Loh, Mignon L.] Univ Calif San Francisco, Pediat Hematol Oncol, San Francisco, CA 94143 USA. [Jung, Jae U.] Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Bolland, Silvia] NIAID, Autoimmun & Funct Genom Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Mak, Tak W.] Univ Hlth Network, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2M9, Canada. [Limnander, Andre] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Jumaa, Hassan] Univ Clin Ulm, Inst Immunol, D-89081 Ulm, Germany. [Reth, Michael] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany. [Reth, Michael] Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany. [Reth, Michael] MPI Immunbiol & Epigenet, D-79104 Freiburg, Germany. RP Muschen, M (reprint author), Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. EM markus.muschen@ucsf.edu OI Titz, Bjoern/0000-0003-4414-4105; Graeber, Thomas/0000-0001-8574-9181 FU National Institutes of Health/National Cancer Institute [R01CA137060, R01CA139032, R01CA169458, R01CA172558, R01CA157644]; ECOG-ACRIN [CA180820, CA180794]; Leukemia and Lymphoma Society; California Institute for Regenerative Medicine [TR02-1816]; William Lawrence and Blanche Hughes Foundation; DFG [EXC294, TRR130, SFB746] FX We thank R. W. Hendriks for encouragement and critical discussions, A. Park and C. Lin and all the members of the Muschen laboratory, L. Tian and B. Scott for their support. This work is supported by grants from the National Institutes of Health/National Cancer Institute through R01CA137060, R01CA139032, R01CA169458, R01CA172558 and R01CA157644 (to M.M.), ECOG-ACRIN grants CA180820 and CA180794 (to E.P.), grants from the Leukemia and Lymphoma Society (to M.M.), the California Institute for Regenerative Medicine through TR02-1816 (M.M.), and the William Lawrence and Blanche Hughes Foundation. M.M. is a Scholar of The Leukemia and Lymphoma Society and a Senior Investigator of the Wellcome Trust. M.R. is supported by the DFG through EXC294, TRR130 and SFB746. NR 22 TC 24 Z9 24 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 21 PY 2015 VL 521 IS 7552 BP 357 EP + DI 10.1038/nature14231 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI5RM UT WOS:000354816500057 PM 25799995 ER PT J AU Xu, H Rahimpour, S Nesvick, CL Zhang, X Ma, JY Zhang, M Zhang, G Wang, L Yang, C Hong, CS Germanwala, AV Elder, JB Ray-Chaudhury, A Yao, Y Gilbert, MR Lonser, RR Heiss, JD Brady, RO Mao, Y Qin, JH Zhuang, ZP AF Xu, Hui Rahimpour, Shervin Nesvick, Cody L. Zhang, Xu Ma, Jingyun Zhang, Min Zhang, Ge Wang, Li Yang, Chunzhang Hong, Christopher S. Germanwala, Anand V. Elder, J. Bradley Ray-Chaudhury, Abhik Yao, Yu Gilbert, Mark R. Lonser, Russell R. Heiss, John D. Brady, Roscoe O. Mao, Ying Qin, Jianhua Zhuang, Zhengping TI Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy SO ONCOTARGET LA English DT Article DE glioblastoma; bevacizumab; epithelial-mesenchymal transition; pathologic angiogenesis; hypoxia-inducible factor ID ENDOTHELIAL GROWTH-FACTOR; EPITHELIAL-MESENCHYMAL TRANSITION; RECURRENT MALIGNANT GLIOMA; RECEPTOR INHIBITOR SU5416; ANTI-ANGIOGENIC THERAPY; INDUCIBLE FACTOR-I; STEM-CELLS; PHASE-II; GLIOBLASTOMA-MULTIFORME; TUMOR PROGRESSION AB Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), can attenuate tumor-associated edema and improve patient symptoms but based on magnetic resonance imaging, is associated with non-enhancing tumor progression and possibly gliosarcoma differentiation. To gain insight into these findings, we investigated the role of hypoxia and epithelial-mesenchymal transition (EMT)-associated proteins in GBM. Tumor markers of hypoxia and EMT were upregulated in bevacizumab-treated tumors from GBM patients compared to untreated counterparts. Exposure of glioma cells to 1% oxygen tension increased cell proliferation, expression of EMT-associated proteins and enhanced cell migration in vitro. These phenotypic changes were significantly attenuated by pharmacologic knockdown of hypoxia-inducible Factor 1 alpha (HIF1 alpha) or HIF2 alpha, indicating that HIFs represent a therapeutic target for mesenchymal GBM cells. These findings provide insights into potential development of novel therapeutic targeting of angiogenesis-specific pathways in GBM. C1 [Xu, Hui; Zhang, Xu; Ma, Jingyun; Zhang, Min; Wang, Li; Qin, Jianhua] Chinese Acad Sci, Dalian Inst Chem Phys, Div Biotechnol, Dalian, Peoples R China. [Rahimpour, Shervin; Nesvick, Cody L.; Yang, Chunzhang; Hong, Christopher S.; Ray-Chaudhury, Abhik; Heiss, John D.; Brady, Roscoe O.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Zhang, Ge] Dalian Med Univ, Dept Immunol, Dalian, Peoples R China. [Germanwala, Anand V.] Loyola Univ, Med Ctr, Dept Neurol Surg, Chicago, IL 60611 USA. [Elder, J. Bradley; Lonser, Russell R.] Ohio State Univ, Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. [Yao, Yu; Mao, Ying] Fudan Univ, Dept Neurosurg, Huashan Hosp, Shanghai Med Coll, Shanghai 200433, Peoples R China. [Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Dept Neuro Oncol, Div Canc Med, Houston, TX 77030 USA. RP Mao, Y (reprint author), Fudan Univ, Dept Neurosurg, Huashan Hosp, Shanghai Med Coll, Shanghai 200433, Peoples R China. EM yingmao168@hotmail.com; jhqin@dicp.ac.cn; zhuangp@ninds.nih.gov RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU National Nature Science Foundation of China [11161160552, 91227123]; Key Projects in the National Science & Technology Pillar Program in the Twelfth Five-Year Plan Period of China [2012BAK02B00, 2012BAK02B03]; Intramural Research Program at the National Institutes of Health (NIH), National Cancer Institute; NIH Medical Research Scholars Program - NIH FX This work was supported by the National Nature Science Foundation of China (grant nos. 91227123 and 11161160552), Key Projects in the National Science & Technology Pillar Program in the Twelfth Five-Year Plan Period of China (grant nos. 2012BAK02B00 and 2012BAK02B03), Intramural Research Program at the National Institutes of Health (NIH), National Cancer Institute, and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH through Pfizer, Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 49 TC 12 Z9 12 U1 3 U2 10 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 20 PY 2015 VL 6 IS 14 BP 11882 EP 11893 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2SZ UT WOS:000359008200013 PM 25957416 ER PT J AU Castro, NP Fedorova-Abrams, ND Merchant, AS Rangel, MC Nagaoka, T Karasawa, H Klauzinska, M Hewitt, SM Biswas, K Sharan, SK Salomon, DS AF Castro, Nadia P. Fedorova-Abrams, Natalie D. Merchant, Anand S. Rangel, Maria Cristina Nagaoka, Tadahiro Karasawa, Hideaki Klauzinska, Malgorzata Hewitt, Stephen M. Biswas, Kajal Sharan, Shyam K. Salomon, David S. TI Cripto-1 as a novel therapeutic target for triple negative breast cancer SO ONCOTARGET LA English DT Article DE cripto-1; notch4; epithelial-mesenchymal plasticity; mouse model; triple-negative breast cancer ID EPITHELIAL-MESENCHYMAL TRANSITION; GAMMA-SECRETASE INHIBITORS; GENE-EXPRESSION; STEM-CELLS; CARCINOMA; PROGRESSION; METASTASIS; TUMORS; NOTCH; MOUSE AB Triple-negative breast cancer (TNBC) presents the poorest prognosis among the breast cancer subtypes and no current standard therapy. Here, we performed an in-depth molecular analysis of a mouse model that establishes spontaneous lung metastasis from JygMC(A) cells. These primary tumors resembled the triple-negative breast cancer (TNBC) both phenotypically and molecularly. Morphologically, primary tumors presented both epithelial and spindle-like cells but displayed only adenocarcinoma-like features in lung parenchyma. The use of laser-capture microdissection combined with Nanostring mRNA and microRNA analysis revealed overexpression of either epithelial and miRNA-200 family or mesenchymal markers in adenocarcinoma and mesenchymal regions, respectively. Cripto-1, an embryonic stem cell marker, was present in spindle-like areas and its promoter showed activity in primary tumors. Cripto-1 knockout by the CRISPR-Cas9 system inhibited tumor growth and pulmonary metastasis. Our findings show characterization of a novel mouse model that mimics the TNBC and reveal Cripto-1 as a TNBC target hence may offer alternative treatment strategies for TNBC. C1 [Castro, Nadia P.; Rangel, Maria Cristina; Nagaoka, Tadahiro; Karasawa, Hideaki; Klauzinska, Malgorzata; Salomon, David S.] NIH, Tumor Growth Factor Sect, Mouse Canc Genet Program, Frederick, MD 20892 USA. [Fedorova-Abrams, Natalie D.; Merchant, Anand S.] NIH, CCRIFX Bioinformat Core, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NIH, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Biswas, Kajal; Sharan, Shyam K.] NIH, Genet Canc Susceptibil Sect, Mouse Canc Genet Program, Frederick, MD USA. RP Salomon, DS (reprint author), NIH, Tumor Growth Factor Sect, Mouse Canc Genet Program, Frederick, MD 20892 USA. EM castron2@mail.nih.gov; salomond@mail.nih.gov RI Rangel, Maria Cristina/P-7216-2014; Abrams, Natalie/F-4845-2011; OI Rangel, Maria Cristina/0000-0002-8002-9617; Abrams, Natalie/0000-0001-9698-2819; Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the NIH, National Cancer Institute FX The study was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 53 TC 8 Z9 9 U1 1 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 20 PY 2015 VL 6 IS 14 BP 11910 EP 11929 PG 20 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2SZ UT WOS:000359008200015 PM 26059540 ER PT J AU Terry, S El-Sayed, IY Destouches, D Maille, P Nicolaiew, N Ploussard, G Semprez, F Pimpie, C Beltran, H Londono-Vallejo, A Allory, Y de la Taille, A Salomon, DS Vacherot, F AF Terry, Stephane El-Sayed, Ihsan Y. Destouches, Damien Maille, Pascale Nicolaiew, Nathalie Ploussard, Guillaume Semprez, Fannie Pimpie, Cynthia Beltran, Himisha Londono-Vallejo, Arturo Allory, Yves de la Taille, Alexandre Salomon, David S. Vacherot, Francis TI CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities SO ONCOTARGET LA English DT Article DE prostate cancer; CRIPTO; mesenchymal-like cancer cells; EMT; FGFR; AKT ID MAMMARY EPITHELIAL-CELLS; CANCER STEM-CELLS; SIGNALING PATHWAY; TUMOR PROGRESSION; BREAST-CANCER; GENE FUSIONS; TRANSITION; EXPRESSION; RECEPTOR; MORPHOGENESIS AB Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors. C1 [Terry, Stephane; El-Sayed, Ihsan Y.; Destouches, Damien; Nicolaiew, Nathalie; Ploussard, Guillaume; Semprez, Fannie; Pimpie, Cynthia; Allory, Yves; de la Taille, Alexandre; Vacherot, Francis] Inserm, U955, Equipe 7, Creteil, France. [Terry, Stephane; El-Sayed, Ihsan Y.; Destouches, Damien; Nicolaiew, Nathalie; Semprez, Fannie; Pimpie, Cynthia; Allory, Yves; de la Taille, Alexandre; Vacherot, Francis] Univ Paris Est, UMR S955, UPEC, F-94000 Creteil, France. [Terry, Stephane; Londono-Vallejo, Arturo] CNRS, Inst Curie, Ctr Rech, UMR 3244, F-75248 Paris, France. [Terry, Stephane] Inserm, U753, Inst Cancerol Gustave Roussy, F-94805 Villejuif, France. [El-Sayed, Ihsan Y.] Univ Libanaise, EDST PRASE, Fac Sci, Beirut, Lebanon. [Destouches, Damien] CNRS, Lab Rech Croissance Cellulaire, Reparat & Regenerat Tissulaires CRRET, F-94010 Creteil, France. [Maille, Pascale; Allory, Yves] Hop Henri Mondor, AP HP, Dept pathol, F-94000 Creteil, France. [Beltran, Himisha] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Ploussard, Guillaume; Vacherot, Francis] Hop Henri Mondor, AP HP, Serv Urol, F-94000 Creteil, France. [Salomon, David S.] Frederick Natl Lab Canc Res, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Terry, S (reprint author), Inserm, U955, Equipe 7, Creteil, France. EM stephane.terry@gmail.com RI Terry, Stephane/K-5351-2013; OI Terry, Stephane/0000-0003-3089-7886; Londono Vallejo, Arturo/0000-0003-3535-7563 FU INSERM; CNRS; Association pour la Recherche sur les Tumeurs de la Prostate; Institut National du Cancer FX We are grateful to Caterina Bianco, Alyson Baker, Sylvain Loric, Ahmad Daher, Laurent Salomon, Bruno Goud for providing material and/or advice, and to Laurence Kheuang, Pascale Soyeux and Vianney Barris for technical assistance. We appreciate the contribution of Sandy Azoulay, Corine Matar, Nanor Sirab, Philippe Fontanges, Rachid Souktani, Eric Huet and Raquel Esgueva for their input in the preliminary work. This work was supported by INSERM and CNRS intramural fundings and in part by grants from "Association pour la Recherche sur les Tumeurs de la Prostate" (to ST) and "Institut National du Cancer" (to ALV and YA) NR 66 TC 3 Z9 3 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 20 PY 2015 VL 6 IS 14 BP 11994 EP 12008 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2SZ UT WOS:000359008200020 PM 25596738 ER PT J AU Butz, H Szabo, PM Khella, HWZ Nofech-Mozes, R Patocs, A Yousef, GM AF Butz, Henriett Szabo, Peter M. Khella, Heba W. Z. Nofech-Mozes, Roy Patocs, Attila Yousef, George M. TI miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1 SO ONCOTARGET LA English DT Article DE renal cell carcinoma; miR-124-3p; integrated analysis; CAV1; FLOT1 ID BREAST-CANCER; TUMOR PROGRESSION; GENE-EXPRESSION; PROSTATE-CANCER; DOWN-REGULATION; MESSENGER-RNA; UP-REGULATION; CAVEOLIN-1; PROLIFERATION; METASTASIS AB Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with frequent metastatic rate and poor survival. Integrated analyses allow understanding the interplay between different levels of molecular alterations. We integrated miRNA and gene expression data from 458 ccRCC and 254 normal kidney specimens to construct a miRNA-target interaction network. We identified the downregulated miR-124-3p, -30a-5p and -200c-3p as the most influential miRNAs in RCC pathogenesis. miR-124-3p and miR-200c-3p expression showed association with patient survival, miR-30a-5p was downregulated in metastases compared to primary tumors. We used an independent set of 87 matched samples for validation. We confirmed the functional impact of these miRNAs by in vitro assays. Restoration of these miRNAs reduced migration, invasion and proliferation. miR-124-3p decreased the S phase of cell cycle, as well. We compared transcriptome profiling before and after miRNA overexpression, and validated CAV1 and FLOT1 as miR-124-3p targets. Patients with higher CAV1 and FLOT1 had lower miR-124-3p expression and shorter overall survival. We hypothesize that these three miRNAs are fundamental contributing to ccRCC aggressive/metastatic behavior; and miR-124-3p especially has a key role through regulating CAV1 and FLOT1 expression. Restoration of the levels of these miRNAs could be considered as a potential therapeutic strategy for ccRCC. C1 [Butz, Henriett; Khella, Heba W. Z.; Nofech-Mozes, Roy; Yousef, George M.] St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Butz, Henriett; Khella, Heba W. Z.; Nofech-Mozes, Roy; Yousef, George M.] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON M5B 1W8, Canada. [Butz, Henriett; Khella, Heba W. Z.; Yousef, George M.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Szabo, Peter M.] NCI, NIH, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Patocs, Attila] Hungarian Acad Sci, HAS SE Lendulet Hereditary Endocrine Tumors Res G, H-1051 Budapest, Hungary. RP Yousef, GM (reprint author), St Michaels Hosp, Dept Lab Med, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM yousefg@smh.ca FU Canadian Institute of Health Research [MOP 119606]; Kidney Foundation of Canada [KFOC130030]; Kidney Cancer Research Network of Canada; Prostate Cancer Canada Movember Discovery Grants [D2013-39] FX GMY is supported by grants from Canadian Institute of Health Research (MOP 119606), Kidney Foundation of Canada (KFOC130030), the Kidney Cancer Research Network of Canada, and Prostate Cancer Canada Movember Discovery Grants (D2013-39). NR 50 TC 8 Z9 9 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 20 PY 2015 VL 6 IS 14 BP 12543 EP 12557 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2SZ UT WOS:000359008200059 PM 26002553 ER PT J AU Albiges, L Murray, B Brooks, A Cherniack, A Berger, A Creighton, CJ Ricketts, C Bottaro, DP Srinivasan, R Schmidt, LS Meyerson, M Spellman, P Linehan, WM Choueiri, TK AF Albiges, Laurence Murray, Bradley Brooks, Angela Cherniack, Andrew Berger, Alice Creighton, Chad J. Ricketts, Christopher Bottaro, Donald P. Srinivasan, Ramaprasad Schmidt, Laura S. Meyerson, Matthew Spellman, Paul Linehan, W. Marston Choueiri, Toni K. CA Canc Genome Atlas TCGA Kidney TI Distinct MET alterations to induce a common phenotype and to define a MET-driven subset of papillary RCC: Results from the Cancer Genome Atlas (TCGA) Kidney Renal Papillary (KIRP) Working Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Broad Inst, Boston, MA USA. Broad Inst, Cambridge, MA USA. Baylor Coll Med, Houston, TX 77030 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dana Farber Canc Inst,Brigham & Womens Hosp,Broad, Boston, MA USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NCI, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 4521 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900989 ER PT J AU Allette, K Pattanayak, P Steinberg, SM Parnes, H Jackson, G Francis, D Lamping, E Folio, L Apolo, AB AF Allette, Kimaada Pattanayak, Puskar Steinberg, Seth M. Parnes, Howard Jackson, Gloria Francis, Deneise Lamping, Elizabeth Folio, Les Apolo, Andrea Borghese TI Assessment of treatment response using Computed Tomography (CT) tumor volume measurements and lesion number in metastatic urothelial carcinoma (mUC) patients (pts) receiving cabozantinib. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NIH, Radiol & Imaging Sci, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. NCI, Med 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e15503 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903053 ER PT J AU Apolo, AB Lee, MJ Tomita, Y Lee, S Agarwal, PK Jackson, G Francis, DC Lamping, E Buford, L Tomita, S Mackall, K Parnes, HL Dahut, WL Gulley, JL Trepel, JB AF Apolo, Andrea Borghese Lee, Min-Jung Tomita, Yusuke Lee, Sunmin Agarwal, Piyush K. Jackson, Gloria Francis, Deneise C. Lamping, Elizabeth Buford, Lauren Tomita, Saori Mackall, Katherine Parnes, Howard L. Dahut, William L. Gulley, James L. Trepel, Jane B. TI Evaluation of a new circulating tumor cell (CTC) platform to predict response and survival in metastatic urothelial carcinoma (UC) patients receiving cabozantinib (cabo). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, Ctr Canc Res, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e15501 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903052 ER PT J AU Aren, OR Silva, R Cerda, H Arancibia, JM Rojas, C Reyes, M Ascui, RA Banchero, P Pichun, MEB AF Aren, Osvaldo Rudy Silva, Ricardo Cerda, Humberto Arancibia, Jorge M. Rojas, Carlos Reyes, Mauricio Ascui, Rodrigo Andres Banchero, Patricia Pichun, Mauricio Emmanuel Burotto TI Single institution experience with 75 mg dose of erlotinib in Latin American patients with mutated metastatic non-small cell lung cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Ctr Int Estudios Clin, Santiago, Chile. Inst Nacl Canc, Santiago, Chile. Hosp Reg Concepcion, Concepcion, Chile. Univ Chile, Santiago, Chile. 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 8075 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901787 ER PT J AU Bates, SE Lindenberg, ML Bryla, C Pichun, MEB Patronas, N Amiri-Kordestani, L Gonzalez, EM Fojo, T Balasubramaniam, S Choyke, PL AF Bates, Susan Elaine Lindenberg, Maria Liza Bryla, Christine Pichun, Mauricio Emmanuel Burotto Patronas, Nicholas Amiri-Kordestani, Laleh Gonzalez, Esther Mena Fojo, Tito Balasubramaniam, Sanjeeve Choyke, Peter L. TI ANG1005 for brain metastases from breast cancer: 18F-FLT-PET and MRI as complementary approaches to response assessment. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NIH, Dept Radiol, Bethesda, MD 20892 USA. US FDA, Bethesda, MD 20014 USA. Johns Hopkins Univ, Div Nucl Med, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 2552 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900585 ER PT J AU Bell-McGuinn, KM Brady, WE Schilder, RJ Fracasso, PM Moore, KN Walker, JL Duska, LR Mathews, CA Chen, A Shepherd, SP Giranda, VL Aghajanian, C AF Bell-McGuinn, Katherine M. y Brady, William E. Schilder, Russell J. Fracasso, Paula M. Moore, Kathleen N. Walker, Joan L. Duska, Linda R. Mathews, Cara Amanda Chen, Alice Shepherd, Stacie Peacock Giranda, Vincent L. Aghajanian, Carol TI A phase I study of continuous veliparib in combination with IV carboplatin/paclitaxel or IV/IP paclitaxel/cisplatin and bevacizumab in newly diagnosed patients with previously untreated epithelial ovarian, fallopian tube, or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Weill Cornell Med Coll, New York, NY USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. OUHSC, Stephenson Canc Ctr, Oklahoma City, OK USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. AbbVie, N Chicago, IL USA. NR 0 TC 3 Z9 3 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 5507 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901165 ER PT J AU Bhaumik, S Stewart, D Pemov, A Choyke, PL Dombi, E Glod, J Miettinen, M Khan, J Steinberg, SM Goodwin, A Baldwin, A Widemann, BC AF Bhaumik, Sucharita Stewart, Douglas Pemov, Alexander Choyke, Peter L. Dombi, Eva Glod, John Miettinen, Markku Khan, Javed Steinberg, Seth M. Goodwin, Anne Baldwin, Andrea Widemann, Brigitte C. TI Early detection of transformation of plexiform neurofibromas to malignant peripheral nerve sheath tumors in neurofibromatosis type 1. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. NCI, Bethesda, MD 20892 USA. NCI, Clin Genet Branch, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS10083 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904650 ER PT J AU Blakeslee, SB Parker, PA Gunn, CM Bandos, H Bevers, TB Battaglia, TA Fagerlin, A McCaskill-Stevens, WJ Holmberg, C AF Blakeslee, Sarah B. Parker, Patricia A. Gunn, Christine M. Bandos, Hanna Bevers, Therese Bartholomew Battaglia, Tracy Ann Fagerlin, Angela McCaskill-Stevens, Worta J. Holmberg, Christine TI Decision-making in breast cancer risk reduction: Results from a nested qualitative study from NRG Oncology/NSABP protocol DMP-1 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Charite, Berlin Sch Publ Hlth, D-13353 Berlin, Germany. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NRG Oncol NSABP, Boston, MA USA. Boston Univ, Med Ctr, Boston, MA USA. NRG Oncol, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. NRG Oncol NSABP, Houston, TX USA. Boston Med Ctr, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Ann Arbor VA Healthcare Syst, Ann Arbor, MI USA. NCI, Rockville, MD USA. Charite, Berlin Sch Publ Hlth, D-13353 Berlin, Germany. 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17569 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903537 ER PT J AU Bot, A Kochenderfer, J Mardiros, A Perez, A Navale, L Chang, R Yueh, WS Yoder, S Jia, XC Rosenberg, SA Go, WY Wiezorek, JS Roberts, M Chang, DD AF Bot, Adrian Kochenderfer, James Mardiros, Armen Perez, Arianne Navale, Lynn Chang, Richard Yueh Wei-Shen Yoder, Sean Jia Xiao-Chi Rosenberg, Steven A. Go, William Y. Wiezorek, Jeffrey S. Roberts, Margo Chang, David D. TI Biomarker analysis of patients treated with anti-CD19 chimeric antigen receptor (CAR) T cells. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Kite Pharma Inc, Santa Monica, CA USA. NCI, Bethesda, MD 20892 USA. Kite Pharma, Santa Monica, CA USA. NR 0 TC 0 Z9 0 U1 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 3028 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900662 ER PT J AU Bottaro, DP Lee, YH Wright, CE Wong, TK Agarwal, PK Apolo, AB AF Bottaro, Donald P. Lee, Young H. Wright, Cara E. Wong, Tiffany K. Agarwal, Piyush K. Apolo, Andrea Borghese TI Signaling by Met and related receptor tyrosine kinases in urothelial carcinoma of the bladder. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e15511 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903061 ER PT J AU Burris, HA Giaccone, G Im, SA Bauer, TM Oh, DY Jones, SF Nordstrom, JL Li, H Carlin, DA Baughman, JE Lechleider, RJ Bang, YJ AF Burris, Howard A. Giaccone, Giuseppe Im, Seock-Ah Bauer, Todd Michael Oh, Do-Youn Jones, Suzanne Fields Nordstrom, Jeffrey L. Li, Hua Carlin, David A. Baughman, Jan E. Lechleider, Robert Joseph Bang, Yung-Jue TI Updated findings of a first-in-human, phase I study of margetuximab (M), an Fc-optimized chimeric monoclonal antibody (MAb), in patients (pts) with HER2-positive advanced solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. NCI, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Med, Seoul, South Korea. Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. MacroGenics Inc, Rockville, MD USA. MacroGenics Inc, San Francisco, CA 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 523 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901130 ER PT J AU Chavez-Mac Gregor, M Barlow, WE Pusztai, L Goetz, MP Rastogi, P Ganz, PA Mamounas, EP Paik, S Bandos, H Gralow, J Lew, DL Hortobagyi, GN AF Chavez-Mac Gregor, Mariana Barlow, William E. Pusztai, Lajos Goetz, Matthew P. Rastogi, Priya Ganz, Patricia A. Mamounas, Eleftherios P. Paik, Soonmyung Bandos, Hanna Gralow, Julie Lew, Danika L. Hortobagyi, Gabriel N. TI Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy plus /- one year of everolimus in patients with high-risk, hormone receptor (HR) positive and HER2-negative breast cancer (BC): SWOG/NRG/Alliance S1207 (NCT01674140). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Canc Rsrch & Biostats, Seattle, WA USA. Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT USA. Mayo Clin, Rochester, MN USA. NRG Oncol NSABP, Pittsburgh, PA USA. UPMC Canc Ctr, Pittsburgh, PA USA. UCLA Jonsson Comprehens Canc Ctr, Los Angeles, CA USA. Natl Surg Adjuvant Breast & Bowel Project, Orlando, FL USA. UF Hlth Canc Ctr Orlando Hlth, Orlando, FL USA. Yonsei Univ, Coll Med, NRG Oncol NSABP, Pittsburgh, PA USA. NRG Oncol NSABP, Pittsburgh, PA USA. Severance BioMed Sci Inst, Pittsburgh, PA USA. Yonsei Univ, Coll Med, Pittsburgh, PA USA. NRG Oncol, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. SWOG Stat Ctr, Seattle, WA 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS637 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904829 ER PT J AU Chiou, VL Kohn, EC Annunziata, CM Minasian, LM Lipkowitz, S Yu, M Gordon, N Houston, ND Lee, JM AF Chiou, Victoria L. Kohn, Elise C. Annunziata, Christina M. Minasian, Lori M. Lipkowitz, Stan Yu, Minshu Gordon, Nicolas Houston, Nicole D. Lee, Jung-min TI Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in heavily pretreated high-grade serous ovarian cancer (HGSOC) at low genetic risk (NCT01445418). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 1 Z9 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 5514 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901173 ER PT J AU Chun, D Lynch, JA DuVall, SL Filipski, KK Kelley, MJ Berse, B Venne, V AF Chun, Danielle Lynch, Julie Ann DuVall, Scott L. Filipski, Kelly Kristin Kelley, Michael J. Berse, Brygida Venne, Vickie TI Utilization of BRCA1/BRCA2 testing in Veterans Health Administration. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Utah, Sch Med, Salt Lake City, UT USA. Vet Healthcare Adm, Lincoln, MA USA. NCI, Bethesda, MD 20892 USA. Duke Univ, Chapel Hill, NC USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Vet Healthcare Adm, Salt Lake City, UT 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17510 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903484 ER PT J AU Connolly, RM Zhao, FM Miller, K Tevaarwerk, A Wagner, LI Lee, MJ Murray, J Gray, RJ Piekarz, R Zujewski, JA Sparano, JA AF Connolly, Roisin M. Zhao, Fengmin Miller, Kathy Tevaarwerk, Amye Wagner, Lynne I. Lee, Min-Jung Murray, Judy Gray, Robert James Piekarz, Richard Zujewski, Jo Anne Sparano, Joseph A. TI E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. Dana Farber Canc Inst, Malden, MA USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. Northwestern Univ, Feinberg Sch, Chicago, IL 60611 USA. NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS636 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904828 ER PT J AU Couvillon, A Turkbey, B Lindenberg, ML Choyke, PL Kaushal, A Citrin, DE Krauze, AV McNally, D McKinney, Y Martinez, M Han, H Karzai, F Parnes, HL Pinto, PA Gulley, JL Dahut, WL Madan, RA AF Couvillon, Anna Turkbey, Baris Lindenberg, Maria Liza Choyke, Peter L. Kaushal, Aradhana Citrin, Deborah E. Krauze, Andra V. McNally, Deborah McKinney, Yolanda Martinez, Mirna Han, Hui Karzai, Fatima Parnes, Howard L. Pinto, Peter A. Gulley, James L. Dahut, William L. Madan, Ravi Amrit TI Association of NaF PET/CT findings with PSA and alkaline phosphatase in untreated castration-sensitive prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Ctr Canc Res, Mol Imaging Program, Bethesda, MD USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. NCI, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e16118 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903283 ER PT J AU Coyne, GHO Kummar, S Do, KT Holbeck, S Hollingshead, MG Horneffer, Y Juwara, L Srivastava, AK Rubinstein, L Piekarz, R Sharon, E Streicher, H Conley, BA Antony, R Collins, JM Chen, A Doroshow, JH AF Coyne, Geraldine Helen O'Sullivan Kummar, Shivaani Khanh Tu Do Holbeck, Susan Hollingshead, Melinda G. Horneffer, Yvonne Juwara, Lamin Srivastava, Apurva K. Rubinstein, Larry Piekarz, Richard Sharon, Elad Streicher, Howard Conley, Barbara A. Antony, Ramya Collins, Jerry M. Chen, Alice Doroshow, James H. TI Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Early Clin Trials Dev Program, Bethesda, MD USA. Stanford Univ, Sch Med, Phase Clin Res Program 1, Stanford, CA 94305 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Frederick, MD 21701 USA. NCI, Bethesda, MD 20892 USA. Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. Div Canc Treatment & Diag, Bethesda, MD USA. NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. Leidos Biomed Res Inc, Frederick, MD USA. NCI, DCTD, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 6 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS2614 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904692 ER PT J AU Deeken, JF Wang, HK Smaglo, BG Hwang, JJ He, AR Weiner, LM Marshall, J Giaccone, G Liu, SV Luecht, J Urso, C Spiegel, JY Cheema, A Pishvaian, MJ AF Deeken, John F. Wang, Hongkun Smaglo, Brandon George Hwang, Jimmy J. He, Aiwu Ruth Weiner, Louis M. Marshall, John Giaccone, Giuseppe Liu, Stephen V. Luecht, Jim Urso, Christina Spiegel, Jay Y. Cheema, Amrita Pishvaian, Michael J. TI A phase I study of intravenous artesunate (IV AS) in patients with solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Inova Comprehens Canc & Res Inst, Mclean, VA USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Med & Oncol, Washington, DC USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Innovat Ctr Biomed Informat, Washington, DC USA. NCI, NIH, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 2535 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900568 ER PT J AU Denicoff, A Massett, HA Mishkin, GE Bangs, R Berlin, J Bischoff, MB DeSanto, F Duli, A Horvath, LE Katz, MS Lambersky, R Mann, BS McCaskill-Stevens, WJ Seibel, N Stine, SH Williams, W Mooney, MM Abrams, JS AF Denicoff, Andrea Massett, Holly A. Mishkin, Grace E. Bangs, Rick Berlin, Jordan Bischoff, Miriam B. DeSanto, Frank Duli, Anne Horvath, Laura E. Katz, Michael S. Lambersky, Ruth Mann, Bhupinder Singh McCaskill-Stevens, Worta J. Seibel, Nita Stine, Sharon Hartson Williams, Wade Mooney, Margaret M. Abrams, Jeffrey S. TI Creating a national collaborative strategy to enhance trial accrual in NCI's National Clinical Trials Network (NCTN) in the era of precision medicine SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. SWOG, San Antonio, TX USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Stanford Canc Ctr, Stanford, CA USA. SWOG, Ann Arbor, MI USA. Case Comprehens Canc Ctr, Cleveland, OH USA. Alliance Clin Trials Oncol, Naperville, IL USA. ECOG ACRIN, North Hollywood, CA USA. ECOG ACRIN, Philadelphia, PA USA. NCI, Rockville, MD USA. NRG Oncol, Merchantville, NJ USA. Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Oklahoma City, OK 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 6589 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901503 ER PT J AU Disis, ML Patel, MR Pant, S Infante, JR Lockhart, AC Kelly, K Beck, JT Gordon, MS Weiss, GJ Ejadi, S Taylor, MH von Heydebreck, A Chin, KM Cuillerot, JM Gulley, JL AF Disis, Mary L. Patel, Manish R. Pant, Shubham Infante, Jeffrey R. Lockhart, A. Craig Kelly, Karen Beck, Joseph Thaddeus Gordon, Michael S. Weiss, Glen J. Ejadi, Samuel Taylor, Matthew Hiram von Heydebreck, Anja Chin, Kevin M. Cuillerot, Jean-Marie Gulley, James L. TI Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Washington, Sch Med, Seattle, WA USA. Florida Canc Specialists, Sarah Cannon Res Inst, Sarasota, FL USA. Peggy & Charles Stephenson Oklahoma Canc Ctr, Oklahoma City, OK USA. Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA. Washington Univ, Sch Med, St Louis, MO USA. UC Davis Comprehens Canc Ctr, Sacramento, CA USA. Highlands Oncol Grp, Rogers, AR USA. Pinnacle Oncol Hematol, Scottsdale, AZ USA. Canc Treatment Centers Amer, Western Reg Med Ctr, Goodyear, AZ USA. Virginia G Piper Canc Ctr, Scottsdale, AZ USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Merck KGaA, Darmstadt, Germany. EMD Serono, Billerica, MA USA. NCI, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 6 Z9 6 U1 5 U2 11 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 5509 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901167 ER PT J AU Dix, DB Gratias, EJ Seibel, N Anderson, JR Mullen, EA Geller, JI Khanna, G Kalapurakal, JA Perlman, EJ Ehrlich, PF Malogolowkin, MH Grundy, PE Dome, JS AF Dix, David B. Gratias, Eric J. Seibel, Nita Anderson, James Robert Mullen, Elizabeth Anne Geller, James I. Khanna, Geetika Kalapurakal, John A. Perlman, Elizabeth Jones Ehrlich, Peter F. Malogolowkin, Marcio H. Grundy, Paul Edward Dome, Jeffrey S. TI Omission of lung radiation in patients with stage IV favorable histology Wilms Tumor (FHWT) showing complete lung nodule response after chemotherapy: A report from Children's Oncology Group study AREN0533. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. TC Thompson Childrens Hosp, Chattanooga, TN USA. NCI, Bethesda, MD 20892 USA. Frontier Sci Madison, Madison, WI USA. Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. Washington Univ, Sch Med St Louis, St Louis, MO USA. Northwestern Univ, Lurie Comp Canc Ctr, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. Alberta Hlth Svcs, Edmonton, AB, Canada. Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 1 Z9 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10011 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900015 ER PT J AU Dix, DB Fernandez, CV Chi, YY Anderson, JR Mullen, EA Geller, JI Gratias, EJ Khanna, G Kalapurakal, JA Perlman, EJ Seibel, N Ehrlich, PF Malogolowkin, MH Gow, KW Hamilton, TE Grundy, PE Dome, J AF Dix, David B. Fernandez, Conrad Vincent Chi, Yueh-Yun Anderson, James Robert Mullen, Elizabeth Anne Geller, James I. Gratias, Eric J. Khanna, Geetika Kalapurakal, John A. Perlman, Elizabeth Jones Seibel, Nita Ehrlich, Peter F. Malogolowkin, Marcio H. Gow, Kenneth William Hamilton, Thomas Edward Grundy, Paul Edward Dome, Jeffrey TI Augmentation of therapy for favorable-histology Wilms Tumor with combined loss of heterozygosity of chromosomes 1p and 16q: A report from the Children's Oncology Group studies AREN0532 and AREN0533. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. IWK Hlth Ctr, Halifax, NS, Canada. Dept Biostat, Gainesville, FL USA. Frontier Sci Madison, Madison, WI USA. Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. TC Thompson Childrens Hosp, Chattanooga, TN USA. Washington Univ, Sch Med, St Louis, MO USA. Northwestern Univ, Lurie Comp Canc Ctr, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. NCI, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. Seattle Childrens Hosp, Seattle, WA USA. Boston Childrens Hosp, Boston, MA USA. Alberta Hlth Svcs, Edmonton, AB, Canada. Childrens Natl Med Ctr, Washington, DC USA. NR 0 TC 1 Z9 1 U1 2 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10009 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900012 ER PT J AU Doros, LA Turner, J Williams, GM Rossi, C Schultz, KAP Stewart, D Dehner, LP Messinger, YH Hill, DA AF Doros, Leslie Ann Turner, Joyce Williams, Gretchen M. Rossi, Christopher Schultz, Kris Ann Pinekenstein Stewart, Douglas Dehner, Louis P. Messinger, Yoav H. Hill, D. Ashley TI The DICER1 syndrome: Genotype-phenotype correlation in PPB patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Childrens Natl Med Ctr, Arlington, VA USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. NCI, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO USA. Childrens Hosp & Clin, Minneapolis, MN USA. NR 0 TC 1 Z9 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10022 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900027 ER PT J AU Drilon, AE Eaton, A Schindler, K Gounder, MM Smith, GL Vulih, D Harris, PJ Spriggs, DR Ivy, P Iasonos, A Lacouture, ME Hyman, DM AF Drilon, Alexander E. Eaton, Anne Schindler, Katja Gounder, Mrinal M. Smith, Gary L. Vulih, Diana Harris, Pamela Jo Spriggs, David R. Ivy, Percy Iasonos, Alexia Lacouture, Mario E. Hyman, David Michael TI Dermatologic toxicities of 3,517 solid tumor patients on phase I clinical trials of the National Institutes of Health Cancer Therapy Evaluation Program (CTEP). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Med Univ Vienna, Vienna, Austria. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Theradex Syst Inc, Princeton, NJ USA. NCI, Canc Therapeut Evaluat Program, Bethesda, MD 20892 USA. Weill Cornell Med Coll, New York, NY 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 2546 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900579 ER PT J AU Duffy, AG Makarova-Rusher, OV Kerkar, SP Kleiner, DE Fioravanti, S Walker, M Carey, S Figg, WD Steinberg, SM Anderson, V Abi-Jaoudeh, N Levi, E Wood, BJ Greten, TF AF Duffy, Austin G. Makarova-Rusher, Oxana V. Kerkar, Sid P. Kleiner, David E. Fioravanti, Suzanne Walker, Melissa Carey, Stephanie Figg, William Douglas Steinberg, Seth M. Anderson, Victoria Abi-Jaoudeh, Nadine Levi, Elliot Wood, Bradford J. Greten, Tim F. TI A pilot study of tremelimumab - a monoclonal antibody against CTLA-4-in combination with either trans catheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Gastrointestinal Malignancies Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NIH, Radiol & Imaging Sci, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, NIH, Bethesda, MD USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 1 Z9 2 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 4081 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900919 ER PT J AU Duffy, AG Ma, C Ulahannan, SV Makarova-Rusher, OV Fioravanti, S Walker, M Turkbey, B Trepel, J Cao, L Steinberg, SM Figg, WD Greten, TF AF Duffy, Austin G. Ma, Chi Ulahannan, Susanna Varkey Makarova-Rusher, Oxana V. Fioravanti, Suzanne Walker, Melissa Turkbey, Baris Trepel, Jane Cao, Liang Steinberg, Seth M. Figg, William Douglas Greten, Tim F. TI A phase 1/2 study of TRC105 in combination with sorafenib in hepatocellular carcinoma (HCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. Canc & Blood Care PC, Ponca City, OK USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 4083 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900921 ER PT J AU Eaton, A Iasonos, A Gounder, MM Pamer, E Drilon, AE Vulih, D Smith, GL Ivy, P Spriggs, DR Hyman, DM AF Eaton, Anne Iasonos, Alexia Gounder, Mrinal M. Pamer, Erika Drilon, Alexander E. Vulih, Diana Smith, Gary L. Ivy, Percy Spriggs, David R. Hyman, David Michael TI Physician toxicity attribution in phase I trials: Evaluating the effect of dose on the frequency of 11,909 toxicities. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Theradex Syst Inc, Princeton, NJ USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Weill Cornell Med Coll, New York, NY 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17674 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903626 ER PT J AU Feng, LR Wolff, BS Lukkahatai, N Saligan, LN AF Feng, Li Rebekah Wolff, Brian S. Lukkahatai, Nada Saligan, Leorey N. TI Immunological predictors of fatigue outcomes in prostate cancer patients receiving radiation therapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NIH, Bethesda, MD 20892 USA. Univ Nevada, Las Vegas, NV 89154 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e16130 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903293 ER PT J AU George, A Hoang, AN Rais-Bahrami, S Walton-Diaz, A Rastinehad, A Siddiqui, MM Shakir, NA Ho, R Fascelli, M Abboud, SF Chelluri, R Merino, MJ Choyke, PL Turkbey, B Wood, BJ Pinto, PA AF George, Arvin Hoang, Anthony N. Rais-Bahrami, Soroush Walton-Diaz, Annerleim Rastinehad, Ardeshir Siddiqui, Mohummad Minhaj Shakir, Nabeel Ahmad Ho, Richard Fascelli, Michele Abboud, Steven F. Chelluri, Raju Merino, Maria J. Choyke, Peter L. Turkbey, Baris Wood, Bradford J. Pinto, Peter A. TI Magnetic resonance imaging-guided focal laser ablation for prostate cancer: A phase I trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Hofstra North Shore LIJ Sch Med, New Hyde Pk, NY USA. NIH, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, NIH, Bethesda, MD USA. NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e16128 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903291 ER PT J AU Gerber, DE Oxnard, GR Mandrekar, SJ Dahlberg, SE Malik, SM Mooney, MM Abrams, JS Janne, PA Li, TH Ramalingam, SS Vokes, EE Govindan, R AF Gerber, David E. Oxnard, Geoffrey R. Mandrekar, Sumithra J. Dahlberg, Suzanne Eleanor Malik, Shakun M. Mooney, Margaret M. Abrams, Jeffrey S. Janne, Pasi A. Li, Tianhong Ramalingam, Suresh S. Vokes, Everett E. Govindan, Ramaswamy TI ALCHEMIST: a clinical trial platform to bring genomic discovery and molecularly targeted therapies to early-stage lung cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. Clin Invest Branch CTEP DCTD, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. UC Davis Comprehens Canc Ctr, Sacramento, CA USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Washington Univ, Sch Med, St Louis, MO 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS7583 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904847 ER PT J AU Goey, AKL Trepel, JB Sissung, TM Peer, CJ Lee, MJ Tomita, Y Ehrlich, S Bryla, C Berman, AW Balasubramaniam, S Piekarz, R Rajan, A Steinberg, SM Giaccone, G Figg, WD Bates, SE AF Goey, Andrew K. L. Trepel, Jane B. Sissung, Tristan M. Peer, Cody J. Lee, Min-Jung Tomita, Yusuke Ehrlich, Sheryl Bryla, Christine Berman, Arlene W. Balasubramaniam, Sanjeeve Piekarz, Richard Rajan, Arun Steinberg, Seth M. Giaccone, Giuseppe Figg, William Douglas Bates, Susan Elaine TI UGT1A1 genotype effects on PK, PD and toxicities of belinostat administered by 48 h continuous infusion. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Program, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e13581 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902574 ER PT J AU Goncalves, PH Soubani, AO Heilbrun, LK Smith, DW Villegas, J LoRusso, P AF Goncalves, Priscila Hermont Soubani, Ayman O. Heilbrun, Lance K. Smith, Daryn W. Villegas, Juan LoRusso, Patricia TI Pulmonary function tests (PFT) results in a phase 1 (Ph1) oncology patient (pt) population. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Mt Sinai Hosp, Chicago, IL USA. Yale Canc Ctr, New Haven, CT 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17759 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903699 ER PT J AU Gulley, JL Giacchino, JL Breitmeyer, JB Franzusoff, AJ Panicali, D Schlom, J Kantoff, PW AF Gulley, James L. Giacchino, Jeannie Lorraine Breitmeyer, James Bradley Franzusoff, Alexis J. Panicali, Dennis Schlom, Jeffrey Kantoff, Philip W. TI Prospect: A randomized double-blind phase 3 efficacy study of PROSTVAC-VF immunotherapy in men with asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. Bavarian Nord AS, Mountain View, CA USA. Bavarian Nord Inc, Mountain View, CA USA. Bavarian Nord Inc, Mountain View, CA USA. NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS5081 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904790 ER PT J AU Gulley, JL Madan, RA Singh, H Gray, TE Trager, JB Sheikh, NA Mccoy, C McNeel, DG AF Gulley, James L. Madan, Ravi Amrit Singh, Harpreet Gray, Todd E. Trager, James B. Sheikh, Nadeem A. Mccoy, Candice McNeel, Douglas G. TI The impact of age on sipuleucel-T-induced immune responses. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Washington, DC USA. Dendreon Corp, Seattle, WA USA. Univ Wisconsin, Madison, WI 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e16009 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903186 ER PT J AU Gulley, JL Spigel, D Kelly, K Chandler, JC Rajan, A Hassan, R Wong, DJL Leach, J Edenfield, WJ Wang, D Vrindavanam, N Weiss, GJ Gurtler, JS Grote, HJ von Heydebreck, A Chin, KM Iannotti, N AF Gulley, James L. Spigel, David Kelly, Karen Chandler, Jason Claud Rajan, Arun Hassan, Raffit Wong, Deborah Jean Lee Leach, Joseph Edenfield, William Jeffery Wang, Ding Vrindavanam, Nandagopal Weiss, Glen J. Gurtler, Jayne S. Grote, Hans Juergen von Heydebreck, Anja Chin, Kevin M. Iannotti, Nicholas TI Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. UC Davis Comprehens Canc Ctr, Sacramento, CA USA. West Clin, Memphis, TN USA. NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD USA. Univ Calif Los Angeles, Los Angeles, CA USA. Virginia Piper Canc Inst, Minneapolis, MN USA. Inst Translat Oncol Res, Greenville, SC USA. Henry Ford Hlth Syst, Detroit, MI USA. Signal Point Clin Res Ctr LLC, Middletown, OH USA. Canc Treatment Ctr Amer, Western Reg Med Ctr, Goodyear, AZ USA. Metairie Oncologist LLC, Metairie, LA USA. Merck KGaA, Darmstadt, Germany. EMD Serono, Billerica, MA USA. Hematol Oncol Associates Treasure Coast, Port St Lucie, FL USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 2 Z9 2 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 8034 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901747 ER PT J AU Halpern, MT Urato, M Schwartz, M Kent, EE AF Halpern, Michael T. Urato, Matthew Schwartz, Margot Kent, Erin E. TI Healthcare plan and provider ratings among cancer survivors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Arizona, Coll Publ Hlth, Tucson, AZ USA. RTI Int, Res Triangle Pk, NC USA. RTI Int, Waltham, MA USA. NCI, Rockville, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 9579 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902074 ER PT J AU Hamilton, EP Birrer, MJ DiCarlo, BA Gaillard, S Martin, LP Nemunaitis, JJ Perez, RP Schilder, RJ Annunziata, CM Begley, CG Hager, SJ AF Hamilton, Erika Paige Birrer, Michael J. DiCarlo, Brian Anthony Gaillard, Stephanie Martin, Lainie P. Nemunaitis, John J. Perez, Raymond P. Schilder, Russell J. Annunziata, Christina M. Begley, Colin G. Hager, Steven Jeffrey TI A phase 1b, open-label, non-randomized multicenter study of birinapant in combination with conatumumab in subjects with relapsed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. Massachusetts Gen Hosp, Dana Farber Canc Ctr, Boston, MA 02114 USA. Coastal Integrat Canc Care, San Luis Obispo, CA USA. Duke Canc Inst, Durham, NC USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Mary Crowley Canc Res Ctr, Dallas, TX USA. Univ Kansas, Fairway, KS USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. NCI, NIH, Bethesda, MD 20892 USA. TetraLog Pharmaceut, Westlake Village, CA USA. Calif Canc Associates Res & Excellence, Fresno, CA USA. RI Annunziata, Christina/L-3219-2016; Perez, Raymond/R-6159-2016 OI Annunziata, Christina/0000-0003-2033-6532; Perez, Raymond/0000-0002-7432-2411 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 5571 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901236 ER PT J AU Hassan, R Antonia, SJ Alley, EW Kindler, HL Jahan, T Grous, JJ Honarmand, S McDougall, K Whiting, CC Nair, N Lemmens, E Murphy, AL Thomas, A Brockstedt, DG AF Hassan, Raffit Antonia, Scott Joseph Alley, Evan W. Kindler, Hedy Lee Jahan, Thierry Grous, John J. Honarmand, Somayeh McDougall, Katherine Whiting, Chan C. Nair, Nitya Lemmens, Ed Murphy, Aimee L. Thomas, Anish Brockstedt, Dirk G. TI Mesothelin-targeted immunotherapy CRS-207 in combination with standard of care chemotherapy as treatment for malignant pleural mesothelioma (MPM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Chicago, Chicago, IL 60637 USA. UC San Francisco, San Francisco, CA USA. Aduro BioTech Inc, Berkeley, CA USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 7565 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901695 ER PT J AU Heery, CR Infante, JR Iannotti, N Kelly, K Nikolinakos, P von Heydebreck, A Chin, KM Gulley, JL AF Heery, Christopher Ryan Infante, Jeffrey R. Iannotti, Nicholas Kelly, Karen Nikolinakos, Petros von Heydebreck, Anja Chin, Kevin M. Gulley, James L. TI Phase I expansion cohort trial to investigate the safety and clinical activity of avelumab (MSB0010718C) in patients with metastatic or locally advanced solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA. Hematol Oncol Associates Treasure Coast, Port St Lucie, FL USA. UC Davis Comprehens Canc Ctr, Sacramento, CA USA. Northeast Georgia Canc Care, Athens, GA USA. Merck KGaA, Darmstadt, Germany. EMD Serono, Billerica, MA USA. NCI, Genitourinary Malignancies 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 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS3101 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904717 ER PT J AU Heery, CR Coyne, GHO Marte, JL Singh, H Cordes, LM Madan, RA Donahue, RN Grenga, I Lepone, L Neuteboom, B Speit, I Chin, KM Schlom, J Gulley, JL AF Heery, Christopher Ryan Coyne, Geraldine Helen O'Sullivan Marte, Jennifer L. Singh, Harpreet Cordes, Lisa M. Madan, Ravi Amrit Donahue, Renee Nicole Grenga, Italia Lepone, Lauren Neuteboom, Berend Speit, Isabell Chin, Kevin M. Schlom, Jeffrey Gulley, James L. TI Pharmacokinetic profile and receptor occupancy of avelumab (MSB0010718C), an anti-PD-L1 monoclonal antibody, in a phase I, open-label, dose escalation trial in patients with advanced solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD USA. NCI, NIH, Washington, DC USA. NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD USA. EMD Serono, Billerica, MA USA. Merck KGaA, Darmstadt, Germany. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 3055 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900689 ER PT J AU Heske, C Mendoza, A Yeung, C Proia, DA Neckers, L Helman, LJ AF Heske, Christine Mendoza, Arnulfo Yeung, Choh Proia, David A. Neckers, Len Helman, Lee J. TI Activity of Hsp90-inhibitor drug conjugate (HDC) STA-12-8666 in preclinical models of pediatric sarcoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Synta Pharmaceut, Lexington, MA USA. NCI, Urol Oncol Branch, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10025 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900030 ER PT J AU Hobday, TJ Yin, J Pettinger, A Strosberg, JR Reidy, DL Chen, HX Erlichman, C AF Hobday, Timothy J. Yin, Jun Pettinger, Adam Strosberg, Jonathan R. Reidy, Diane Lauren Chen, Helen X. Erlichman, Charles TI Multicenter prospective phase II trial of bevacizumab (bev) for progressive pancreatic neuroendocrine tumor (PNET) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mayo Clin, Coll Med, Dept Oncol, Rochester, MN USA. Mayo Clin, Rochester, MN USA. Mayo Clin, Coll Med, Rochester, MN USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Weill Cornell Med Coll, New York, NY USA. NCI, Canc Therapy Evaluat Program, Rockville, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 4096 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900934 ER PT J AU Hyman, DM Sill, M Cho, JK Lankes, HA Piekarz, R Hensley, ML AF Hyman, David Michael Sill, Michael Cho, Jonathan K. Lankes, Heather A. Piekarz, Richard Hensley, Martee Leigh TI A phase II study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group Study (GOG-0231D). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Stat & Data Ctr, Gynecol Oncol Grp, Buffalo, NY USA. Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. Gyn Onc Grp, Buffalo, NY USA. NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. Weill Cornell Med Coll, New York, NY 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e16512 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903309 ER PT J AU Jacobsen, PB Rowland, JH Paskett, ED Van Leeuwen, F Moskowitz, CS Katta, S Wollins, D Robison, LL AF Jacobsen, Paul B. Rowland, Julia Howe Paskett, Electra D. Van Leeuwen, Flora Moskowitz, Chaya S. Katta, Sweatha Wollins, Dana Robison, Leslie L. TI Results of the ASCO survey of cancer survivorship research: Summary and implications. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. NCI, NIH, Bethesda, MD USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Netherlands Canc Inst, Dept Psychosocial Oncol & Epidemiol, Amsterdam, Netherlands. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Amer Soc Clin Oncol, Alexandria, VA USA. St Jude Childrens Res Hosp, Memphis, TN 38105 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 9567 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902062 ER PT J AU Jang, S Zheng, CY Tsai, HT Fu, AZ Barac, A Atkins, MB Freeman, AN Minasian, LM Potosky, AL AF Jang, Sekwon Zheng, Chaoyi Tsai, Huei-Ting Fu, Alex Z. Barac, Ana Atkins, Michael B. Freeman, Andrew N. Minasian, Lori M. Potosky, Arnold L. TI Cardiovascular toxicity following anti-angiogenic therapy in persons over age 65 with advanced renal cell carcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Inova Comprehens Canc & Res Inst, Fairfax, VA USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. MedStar Washington Hosp Ctr, Washington, DC USA. Lombardi Comprehens Canc Ctr, Washington, DC USA. NCI, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 4544 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901015 ER PT J AU Ji, JPJ Zhang, YP Redon, CE Chen, A Holbeck, S Hollingshead, MG Parchment, RE Pommier, Y Tomaszewski, JE Doroshow, JH Bonner, W AF Ji, Jiuping Jay Zhang, Yiping Redon, Christophe E. Chen, Alice Holbeck, Susan Hollingshead, Melinda G. Parchment, Ralph E. Pommier, Yves Tomaszewski, Joseph E. Doroshow, James H. Bonner, William TI Using gamma-H2AX and H2AX quantitative ELISA for monitoring DNA damage induced by chemotherapeutic agents and irradiation exposure. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Frederick Natl Lab Canc Res, Natl Clin Target Validat Lab, Frederick, MD USA. NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Frederick, MD 21701 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 2559 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900592 ER PT J AU Jochems, C Kwilas, A Kim, YS Brechbiel, MW Hodge, JW Newton, RC Schlom, J Tsang, KY AF Jochems, Caroline Kwilas, Anna Kim, Young-Seung Brechbiel, Martin W. Hodge, James W. Newton, Robert Charles Schlom, Jeffrey Tsang, Kwong-Yok TI The IDO inhibitor INCB024360 to enhance dendritic cell immunogenicity and anti-tumor immunity in vitro. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, CCR, NIH, Bethesda, MD 20892 USA. NCI, Radioimmune & Chem Sect, CCR, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Incyte Corp, Avondale, PA USA. NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e14012 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902603 ER PT J AU Karzai, F Madan, RA Theoret, MR Arlen, PM Strauss, J Chun, G Couvillon, A Harold, N Chen, C Dawson, NA Apolo, AB Steinberg, SM Trepel, JB Wright, JJ Price, DK Gulley, JL Figg, WD Dahut, WL AF Karzai, Fatima Madan, Ravi Amrit Theoret, Marc Robert Arlen, Philip M. Strauss, Julius Chun, Guinevere Couvillon, Anna Harold, Nancy Chen, Clara Dawson, Nancy Ann Apolo, Andrea Borghese Steinberg, Seth M. Trepel, Jane B. Wright, John Joseph Price, Douglas K. Gulley, James L. Figg, William Douglas Dahut, William L. TI Overcoming resistance mechanisms in a study of 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 Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. Lombardi Comprehens Canc Ctr, Washington, DC USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Clin Pharmacol Program, 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 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e16032 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903207 ER PT J AU Kazandjian, DG Blumenthal, GM Fernandes, L Mathieu, LN Tang, SH Sridhara, R Kluetz, PG Keegan, P Pazdur, R AF Kazandjian, Dickran Gano Blumenthal, Gideon Michael Fernandes, Laura Mathieu, Luckson Noe Tang, Shenghui Sridhara, Rajeshwari Kluetz, Paul Gustav Keegan, Patricia Pazdur, Richard TI The relationship of delay in time to deterioration of chest pain, cough and dyspnea with radiographic response with targeted therapies (TT) and chemotherapy (CT) in NSCLC. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 US FDA, Rockville, MD 20857 USA. NIH, Potomac, MD USA. US FDA, Silver Spring, MD USA. US FDA, Silver Spring, MD USA. FDA, Kensington, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e19052 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903906 ER PT J AU Kelly, K Patel, MR Infante, JR Iannotti, N Nikolinakos, P Leach, J Wang, D Chandler, JC Jerusalem, GHM Gurtler, JS Arkenau, HT Speit, I von Heydebreck, A Chin, KM Heery, CR Gulley, JL AF Kelly, Karen Patel, Manish R. Infante, Jeffrey R. Iannotti, Nicholas Nikolinakos, Petros Leach, Joseph Wang, Ding Chandler, Jason Claud Jerusalem, Guy Heinrich Maria Gurtler, Jayne S. Arkenau, Hendrik-Tobias Speit, Isabell von Heydebreck, Anja Chin, Kevin M. Heery, Christopher Ryan Gulley, James L. TI Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic or locally advanced solid tumors: assessment of safety and tolerability in a phase I, open-label expansion study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 UC Davis Comprehens Canc Ctr, Sacramento, CA USA. Florida Canc Specialists, Sarah Cannon Res Inst, Sarasota, FL USA. Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA. Hematol Oncol Associates Treasure Coast, Port St Lucie, FL USA. Univ Canc & Blood Ctr LLC, Athens, GA USA. Virginia Piper Canc Inst, Minneapolis, MN USA. Henry Ford Hlth Syst, Detroit, MI USA. West Clin, Memphis, TN USA. Ctr Hosp Univ, Liege, Belgium. Metairie Oncologist LLC, Metairie, LA USA. Sarah Cannon Res United Kingdom, London, England. Merck KGaA, Darmstadt, Germany. EMD Serono, Billerica, MA USA. NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 4 Z9 4 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 3044 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900678 ER PT J AU Koshkin, VS Bolejack, V Schwartz, LH Zhao, BS Chugh, R Wahl, RL Reinke, DK Helman, LJ Patel, S Schuetze, S Baker, LH AF Koshkin, Vadim S. Bolejack, Vanessa Schwartz, Lawrence H. Zhao, Binsheng Chugh, Rashmi Wahl, Richard L. Reinke, Denise K. Helman, Lee J. Patel, Shreyaskumar Schuetze, Scott Baker, Laurence H. TI The who and what of imaging in sarcoma and correlation with survival SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Michigan, Ann Arbor, MI 48109 USA. Canc Res & Biostat, Seattle, WA USA. Columbia Univ Med Ctr, New York Presbyterian Hosp, New York, NY USA. Columbia Univ Med Ctr, Dept Radiol, New York, NY USA. Univ Michigain Hlth Syst, Ann Arbor, MI USA. Mallinckrodt Inst Rad, St Louis, MO USA. SARC, Ann Arbor, MI USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10511 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900146 ER PT J AU Kothari, S Gustafson, D Killian, K Costello, J Edelman, DC Walling, J Meltzer, PS Theodorescu, D Apolo, AB AF Kothari, Shalin Gustafson, Daniel Killian, Keith Costello, James Edelman, Daniel C. Walling, Jennifer Meltzer, Paul S. Theodorescu, Dan Apolo, Andrea Borghese TI COXEN prediction of antineoplastic drug sensitivity in bladder cancer patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 SUNY Upstate Med Univ, Syracuse, NY 13210 USA. Colorado State Univ, Ft Collins, CO 80523 USA. NCI, Bethesda, MD 20892 USA. Univ Colorado, Aurora, CO USA. Ctr Canc Res, Bethesda, MD USA. Univ Virginia, Charlottesville, VA 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e15533 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903081 ER PT J AU Kreitman, RJ Arons, E Still, K Tallman, MS Stetler-Stevenson, M Yuan, C FitzGerald, DJP Pastan, I AF Kreitman, Robert J. Arons, Evgeny Still, Katherine Tallman, Martin S. Stetler-Stevenson, Maryalice Yuan, Constance FitzGerald, David J. P. Pastan, Ira TI Moxetumomab pasudotox and minimal residual disease in hairy cell leukemia. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Ctr Canc Res, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 7079 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901615 ER PT J AU Kumar, A Burton, JK Suman, VJ Qin, R Erlichman, C Haluska, P Harris, PJ Bible, KC AF Kumar, Aditi Burton, Jill K. Suman, Vera J. Qin, Rui Erlichman, Charles Haluska, Paul Harris, Pamela Jo Bible, Keith Christopher TI Effects of pazopanib therapy on mean corpuscular volume in patients enrolled in MC1112: Analysis of correlation with time to disease progression in solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mayo Clin, Rochester, MN USA. Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA. NCI, Canc Therapeut Evaluat Program, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e13596 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902587 ER PT J AU Kumar, NB Pow-Sang, J Egan, K Spiess, PE Dickinson, SI Salup, R Helal, M McLarty, J Williams, CR Schreiber, FJ Parnes, H Sebti, S Kazi, A Kang, L Quinn, GP Smith, T Yue, BL Chornokur, G Crocker, T Schell, MJ AF Kumar, Nagi B. Pow-Sang, Julio Egan, Kathleen Spiess, Philippe E. Dickinson, Shohreh I. Salup, Raoul Helal, Mohamed McLarty, Jerry Williams, Christopher R. Schreiber, Fred James Parnes, Howard Sebti, Said Kazi, Aslam Kang, Loveleen Quinn, Gwendolyn P. Smith, Tiffany Yue, Binglin Chornokur, Ganna Crocker, Theresa Schell, Michael J. TI Effect of green tea catechins in prostate cancer chemoprevention. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr, Tampa, FL USA. H Lee Moffitt Canc Ctr & Res Inst, Dept Genitourinary Oncol, Tampa, FL USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. James A Haley Vet Adm Hosp, Tampa, FL USA. US Virgin Isl, Tampa Urol, Tampa, FL USA. Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA 71105 USA. Univ Florida, Div Urol, Shands Hosptial, Jacksonville, FL USA. Watson Clin, Lakeland, FL USA. NIH, Bethesda, MD 20892 USA. H Lee Moffitt Canc Ctr & Res Inst Inc, Tampa, FL USA. James A Haley Vet Hosp, Tampa, FL USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. USF Hlth Byrd Alzheimers Inst, Tampa, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 9 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 1572 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900439 ER PT J AU Kummar, S Do, KT Coyne, GHO Turkbey, B Meltzer, PS Polley, E Horneffer, Y Juwara, L Antony, R Choyke, PL Mitchell, SA Helman, LJ Chen, A Doroshow, JH AF Kummar, Shivaani Do, Khanh Tu Coyne, Geraldine Helen O'Sullivan Turkbey, Baris Meltzer, Paul S. Polley, Eric Horneffer, Yvonne Juwara, Lamin Antony, Ramya Choyke, Peter L. Mitchell, Sandra A. Helman, Lee J. Chen, Alice Doroshow, James H. TI Phase II trial of PF-03084014 in adults with desmoid tumors/aggressive fibromatosis. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Stanford Univ, Sch Med, Phase Clin Res Program 1, Stanford, CA 94305 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Early Clin Trials Dev Program, Bethesda, MD USA. NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. Ctr Canc Res, Bethesda, MD USA. NCI, Div Canc Treatment & Diag, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. Leidos Biomed Res Inc, Frederick, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Div Canc Treatment & Diag, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10563 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900203 ER PT J AU Lagmay, JP Krailo, MD Dang, H Kim, A Hawkins, DS Beaty, O Widemann, BC Zwerdling, T Bomgaars, L Langevin, AM Grier, HE Weigel, B Blaney, S Gorlick, RG Janeway, KA AF Lagmay, Joanne P. Krailo, Mark D. Dang, Ha Kim, AeRang Hawkins, Douglas S. Beaty, Orren Widemann, Brigitte C. Zwerdling, Theodore Bomgaars, Lisa Langevin, Anne-Marie Grier, Holcombe E. Weigel, Brenda Blaney, Susan Gorlick, Richard Greg Janeway, Katherine A. TI Outcome of recurrent osteosarcoma patients enrolled in seven phase II trials through CCG, POG, and COG: Learning from the past to move forward. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Florida, Shands Hosp Children, Gainesville, FL USA. Childrens Onc Grp, Arcadia, CA USA. Childrens Oncol Grp, Arcadia, CA USA. Ctr Canc & Blood Disorders, Washington, DC USA. Seattle Childrens Hosp, Seattle, WA USA. Mission Hosp, Fairview, NC USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Calif Davis, Sacramento, CA USA. Texas Childrens Canc Ctr, Houston, TX USA. Univ Texas Med Hlth Ctr San Antonio, San Antonio, TX USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Minnesota, Minneapolis, MN USA. Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. Childrens Hosp, Bronx, NY 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10042 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900049 ER PT J AU Lai, C Pittaluga, S Shovlin, M Steinberg, SM Roschewski, MJ Jaffe, ES Wilson, WH Dunleavy, K AF Lai, Catherine Pittaluga, Stefania Shovlin, Margaret Steinberg, Seth M. Roschewski, Mark J. Jaffe, Elaine S. Wilson, Wyndham Hopkins Dunleavy, Kieron TI The outcome of ALK positive and ALK negative anaplastic large cell lymphoma (ALCL) following DA-EPOCH SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 8564 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901876 ER PT J AU Land, SR Warren, GW Moinpour, C Ostroff, JS Crafts, J Folz, J Gulley, JL Szabo, E Chollette, V Brandon, TH Duffy, S Hatsukami, DK Dresler, CM Gritz, ER Schnoll, R Sarna, L Rigotti, N Buckner, JC Mitchell, SA Toll, B AF Land, Stephanie R. Warren, Graham Walter Moinpour, Carol Ostroff, Jamie S. Crafts, Jennifer Folz, Jasmine Gulley, James L. Szabo, Eva Chollette, Veronica Brandon, Thomas H. Duffy, Sonia Hatsukami, Dorothy K. Dresler, Carolyn M. Gritz, Ellen R. Schnoll, Robert Sarna, Linda Rigotti, Nancy Buckner, Jan C. Mitchell, Sandra A. Toll, Benjamin TI Standardizing measurement of tobacco use in cancer clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Westat Corp, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Potomac, MD USA. NCI, Rockville, MD USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. Univ Michigan, Ann Arbor, MI 48109 USA. Masonic Canc Ctr, Minneapolis, MN USA. Tobacco Cessat & Control Subcomm, Rockville, MD USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. Yale Univ, New Haven, CT 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 9550 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902045 ER PT J AU Lheureux, S Weberpals, JI Hendrickson, AEW Fleming, GF Olawaiye, A Brana, I Mackay, H Dhani, NC Wilson, MK Rodriguez-Freixinos, V Martin-Lorente, C Ward, J Chang, K Wang, L Speers, V Karakasis, K Bowering, VL Chen, A Brenton, J Oza, AM AF Lheureux, Stephanie Weberpals, Johanne Ingrid Hendrickson, Andrea Elisabeth Wahner Fleming, Gini F. Olawaiye, Alexander Brana, Irene Mackay, Helen Dhani, Neesha C. Wilson, Michelle K. Rodriguez-Freixinos, Victor Martin-Lorente, Cristina Ward, Jacklyn Chang, Karen Wang, Lisa Speers, Vanessa Karakasis, Katherine Bowering, Valerie Lydia Chen, Alice Brenton, James Oza, Amit M. TI A randomized, placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with AZD 1775 (MK 1775) in women with recurrent, platinum-resistant epithelial ovarian, primary peritoneal, or Fallopian tube cancers: Trial of Princess Margaret, Mayo, Chicago, and California consortia. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Princess Margaret Canc Ctr, Toronto, ON, Canada. Ottawa Gen Hosp, Ottawa, ON K1H 8L6, Canada. Mayo Clin, Rochester, MN USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Massachusetts Gen Hosp, Chestnut Hill, MA USA. UHN Princess Margaret Hosp, Cambridge, ON, Canada. Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. Univ Toronto, Princess Margaret Canc Ctr, Univ Hlth Network, Div Med Oncol & Hematol,Dept Med, Toronto, ON, Canada. Princess Margaret Canc Ctr, Dept Biostat, Toronto, ON, Canada. Univ Hlth Network, Toronto, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England. NR 0 TC 0 Z9 0 U1 2 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS5613 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904802 ER PT J AU Lheureux, S Ledermann, JA Runswick, S Hodgson, DR Timms, K Lanchbury, JS Kaye, SB Gourley, C Bowtell, D Kohn, EC Scott, CL Matulonis, U Panzarella, T Dougherty, BA Barrett, JC Lai, ZW O'Connor, M Robertson, JD Ho, TW Oza, AM AF Lheureux, Stephanie Ledermann, Jonathan A. Runswick, Sarah Hodgson, Darren R. Timms, Kirsten Lanchbury, Jerry S. Kaye, Stanley B. Gourley, Charlie Bowtell, David Kohn, Elise C. Scott, Clare L. Matulonis, Ursula Panzarella, Tony Dougherty, Brian Andrew Barrett, J. Carl Lai, Zhongwu O'Connor, Mark Robertson, Jane D. Ho, Tony Weishiu Oza, Amit M. TI Genomic characterization of long-term responders to olaparib. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Princess Margaret Canc Ctr, Toronto, ON, Canada. UCL, Inst Canc, London, England. AstraZeneca, Macclesfield, Cheshire, England. Myriad Genet Inc, Salt Lake City, UT USA. Inst Canc Res, London SW3 6JB, England. Royal Marsden NHS Fdn Trust, London, England. Univ Edinburgh, Canc Res UK Ctr, Edinburgh, Midlothian, Scotland. Peter MacCallum Canc Ctr, East Melbourne, Australia. NIH, NCI, Bethesda, MD 20892 USA. Royal Melbourne Hosp, Parkville, Vic 3050, Australia. Dana Farber Canc Inst, Boston, MA 02115 USA. Princess Margaret Hosp, Dept Biostat, Toronto, ON M4X 1K9, Canada. Univ Toronto, Toronto, ON, Canada. AstraZeneca, Waltham, MA USA. Astra Zeneca, Wilmington, DE USA. Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 5566 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901230 ER PT J AU Lheureux, S Butler, MO Clarke, B Cristea, MC Martin, LP Tonkin, KS Fleming, GF Tinker, A Hirte, HW Tsoref, D Mackay, H Dhani, NC Ghatage, P Pham, NA Motta, V Wang, L Karakasis, K Udagani, S Streicher, H Oza, AM AF Lheureux, Stephanie Butler, Marcus O. Clarke, Blaise Cristea, Mihaela C. Martin, Lainie P. Tonkin, Katia Sonia Fleming, Gini F. Tinker, Anna Hirte, Hal W. Tsoref, Daliah Mackay, Helen Dhani, Neesha C. Ghatage, Prafull Nhu-An Pham Motta, Vinicius Wang, Lisa Karakasis, Katherine Udagani, Smitha Streicher, Howard Oza, Amit M. TI A phase I/II study of ipilimumab in women with metastatic or recurrent cervical carcinoma: A study of the Princess Margaret and Chicago N01 Consortia. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Princess Margaret Canc Ctr, Toronto, ON, Canada. Univ Hlth Network, Dept Pathol & Lab Med, Toronto, ON, Canada. City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. Univ Toronto, Dept Med, Div Med Oncol & Hematol, Princess Margaret Canc Ctr,Univ Hlth Network, Toronto, ON, Canada. Tom Baker Canc Clin, Calgary, AB, Canada. Univ Toronto, Lab Med & Pathobiol, Toronto, ON, Canada. Princess Margaret Canc Ctr, Dept Biostat, Toronto, ON, Canada. Univ Hlth Network, Toronto, ON, Canada. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 3061 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900695 ER PT J AU Liu, J Lee, JM Luo, WX Birrer, MJ Whalen, C Houston, ND Obermayer, E Spagnoletti, T Barry, WT Kohn, EC Ivy, SP Matulonis, U AF Liu, Joyce Lee, Jung-min Luo, Weixiu Birrer, Michael J. Whalen, Christin Houston, Nicole D. Obermayer, Elizabeth Spagnoletti, Tatum Barry, William Thomas Kohn, Elise C. Ivy, S. Percy Matulonis, Ursula TI A phase 1 study optimizing the dosing of olaparib tablet formulation combined with cediranib in recurrent ovarian cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Newton, MA USA. NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dana Farber Canc Ctr, Boston, MA 02114 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, CTEP, Rockville, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 5559 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901222 ER PT J AU Liu, SV Powderly, JD Camidge, DR Ready, N Heist, RS Hodi, FS Giaccone, G Liu, B Wallin, J Funke, RP Waterkamp, D Gettinger, SN AF Liu, Stephen V. Powderly, John D. Camidge, D. Ross Ready, Neal Heist, Rebecca Suk Hodi, F. Stephen Giaccone, Giuseppe Liu, Bo Wallin, Jeffrey Funke, Roel Peter Waterkamp, Daniel Gettinger, Scott N. TI Safety and efficacy of MPDL3280A (anti-PDL1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Georgetown Univ Hosp, Washington, DC 20007 USA. Carolina BioOncol Inst, Huntersville, NC USA. Univ Colorado, Ctr Canc, Aurora, CO USA. Duke Univ, Med Ctr, Chapel Hill, NC USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Genentech Inc, San Francisco, CA 94080 USA. F Hoffmann La Roche Ltd, Basel, Switzerland. Yale Sch Med, New Haven, CT USA. NR 0 TC 20 Z9 20 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 8030 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901743 ER PT J AU Lopez-Chavez, A Evbuomwan, M Xi, LQ Chun, G Vidaurre, T Arrieta, O Oblitas, G Oton, AB Calvo, AR Rajan, A Amarapurkar, P Raffeld, M Steinberg, SM Arze-Aimaretti, L Giaccone, G AF Lopez-Chavez, Ariel Evbuomwan, Moses Xi, Liqiang Chun, Guinevere Vidaurre, Tatiana Arrieta, Oscar Oblitas, George Oton, Ana Belen Calvo, Alejandro R. Rajan, Arun Amarapurkar, Pooja Raffeld, Mark Steinberg, Seth M. Arze-Aimaretti, Lorena Giaccone, Giuseppe TI EGFR mutations in Latinos from the United States and Latin America. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. INEN, Lima, Peru. Inst Nacl Cancerol INCAN, Mexico City, DF, Mexico. Hosp Oncol Luis Razetti, Caracas, Venezuela. Univ Colorado, DHMC, Denver, CO 80202 USA. Kettering Canc & Blood Spclsts, Kettering, OH USA. NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Miami, Miami, FL USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. Univ Mayor de San Simon, Cochabamba, Bolivia. 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 8070 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901782 ER PT J AU Lynch, JA Berse, B Filipski, KK Kulich, S Freedman, AN DuVall, SL Kelley, MJ AF Lynch, Julie Ann Berse, Brygida Filipski, Kelly Kristin Kulich, Scott Freedman, Andrew N. DuVall, Scott L. Kelley, Michael J. TI Epidermal growth factor receptor (EGFR) testing among veterans diagnosed with lung cancer in the VA SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Vet Healthcare Adm, Lincoln, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NCI, Bethesda, MD 20892 USA. Vet Hlth Adm, Pittsburgh, PA USA. NCI, Epidemiol & Genom Res Program, Bethesda, MD USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Duke Univ, Chapel Hill, NC 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17582 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903548 ER PT J AU Lynch, JA Berse, B Filipski, KK Freedman, AN DuVall, S Venne, V Kelley, MJ AF Lynch, Julie Ann Berse, Brygida Filipski, Kelly Kristin Freedman, Andrew N. DuVall, Scott Venne, Vickie Kelley, Michael J. TI Implementation of gene expression testing for breast cancer patients within the Veterans Health Administration. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Vet Healthcare Adm, Lincoln, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NCI, Bethesda, MD 20892 USA. NCI, Epidemiol & Genom Res Program, Bethesda, MD 20892 USA. Vet Healthcare Adm, Salt Lake City, UT USA. Duke Univ, Chapel Hill, NC 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17511 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903485 ER PT J AU Makarova-Rusher, OV Erokhina, KA Duffy, AG Ulahannan, SV Greten, TF AF Makarova-Rusher, Oxana V. Erokhina, Katerina A. Duffy, Austin G. Ulahannan, Susanna Varkey Greten, Tim F. TI Racial/ethnic disparities in hepatocellular carcinoma treatment and survival: Are we making progress? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. West Palm Hosp, W Palm Beach, FL 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17591 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903557 ER PT J AU Malik, SM Korn, E Thomas, A AF Malik, Shakun M. Korn, Ed Thomas, Anish TI Small cell lung cancer: Why has it become an orphan disease? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Clin Invest Branch CTEP DCTD, Rockville, MD USA. NCI, NIH, Rockville, MD USA. NCI, Med Oncol Branch, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 7578 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901708 ER PT J AU Mansfield, AS Vulih, D Smith, GL Harris, PJ Ivy, SP AF Mansfield, Aaron Scott Vulih, Diana Smith, Gary L. Harris, Pamela Jo Ivy, S. Percy TI Patterns of hepatic impairment in phase I clinical trials. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mayo Clinc, Rochester, MN USA. Theradex Syst Inc, Princeton, NJ USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NCI, CTEP, Rockville, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 2567 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900600 ER PT J AU Massett, HA Godwin, E Rubinstein, L Ivy, P DiPiazza, K Zwiebel, J Friedman, S Denicoff, A Mishkin, GE Abrams, J AF Massett, Holly A. Godwin, Elizabeth Rubinstein, Lawrence Ivy, Percy DiPiazza, Kate Zwiebel, James Friedman, Steve Denicoff, Andrea Mishkin, Grace E. Abrams, Jeffrey TI An analysis of corrective action plans to address slow accruing NCI-held IND early phase trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. NCI, Rockville, MD USA. NCI, Canc Therapy Evaluat Program, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 6577 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901491 ER PT J AU May, M Rojas, P Sequeira, G Elia, A Vazquez, PM Gonzalez, P Abba, MC Molinolo, A Hewitt, SM Perou, CM Gass, H Lanari, C AF May, Maria Rojas, Paola Sequeira, Gonzalo Elia, Andres Vazquez, Paula Martinez Gonzalez, Pedro Abba, Martin C. Molinolo, Alfredo Hewitt, Stephen M. Perou, Charles M. Gass, Hugo Lanari, Claudia TI Progesterone receptor isoform ratio to define the molecular signature of luminal breast cancers and their antiprogestin responsiveness. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 IBYME CONICET, Buenos Aires, DF, Argentina. Hosp Gen Pacheco, Tigre, Argentina. CINIBA, La Plata, Buenos Aires, Argentina. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 11016 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900275 ER PT J AU Merchant, MS Cristea, MC Stadtmauer, EA Tap, WD D'Angelo, SP Grupp, SA Holdich, T Binder-Scholl, G Jakobsen, BK Odunsi, K Rapoport, A Mackall, C AF Merchant, Melinda S. Cristea, Mihaela C. Stadtmauer, Edward A. Tap, William D. D'Angelo, Sandra P. Grupp, Stephan A. Holdich, Tom Binder-Scholl, Gwendolyn Jakobsen, Bent K. Odunsi, Kunle Rapoport, Aaron Mackall, Crystal TI Genetically engineered NY-ESO-1 specific T cells in HLA-A201+patients with advanced cancers. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Adaptimmune, Abingdon, Oxon, England. Adaptimmune LLC, Philadelphia, PA USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Greenebaum Canc Ctr, Baltimore, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 3 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS3102 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904718 ER PT J AU Naing, A Fu, SQ Habra, MA Chugh, R Kebebew, E Russell, J Welshans, D Fassnacht, M Kroiss, M Goebeler, ME Ijzerman, M Plaunt, MR Mohideen, P Phillips, M Smith, DC AF Naing, Aung Fu, Siqing Habra, Mouhammed Amir Chugh, Rashmi Kebebew, Electron Russell, Jeffrey Welshans, Dawn Fassnacht, Martin Kroiss, Matthias Goebeler, Maria-Elisabeth Ijzerman, Marian Plaunt, Marianne R. Mohideen, Pharis Phillips, Martin Smith, David C. TI ATR-101 phase 1 clinical study for adrenocortical carcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Program 1, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Div Internal Med, Houston, TX 77030 USA. Univ Michigain Hlth Syst, Ann Arbor, MI USA. NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Head & Neck & Endocrine Oncol, Tampa, FL 33612 USA. Univ Hosp Wuerzburg, Dept Internal Med 1, Endocrine Unit, Wurzburg, Germany. Uniklinikum Wurzburg, Dept Endocrinol, Wurzburg, Germany. Zentrum Innere Med, Med Klin 2, Wurzburg, Germany. Atterocor Inc, Ann Arbor, MI USA. Univ Michigan, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS4585 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904777 ER PT J AU Pahuja, S Beumer, JH Appleman, LJ Tawbi, HAH Stoller, RG Lee, JJ Lin, Y Ding, F Yu, J Belani, CP Chen, AP Giranda, VL Shepherd, SP Chu, E Puhalla, S AF Pahuja, Shalu Beumer, Jan Hendrik Appleman, Leonard Joseph Tawbi, Hussein Abdul-Hassan Stoller, Ronald G. Lee, James J. Lin, Yan Ding, Fei Yu, Jing Belani, Chandra Prakash Chen, Alice P. Giranda, Vincent L. Shepherd, Stacie Peacock Chu, Edward Puhalla, Shannon TI A phase I study of veliparib (ABT-888) in combination with weekly carboplatin and paclitaxel in advanced solid malignancies and enriched for triple-negative breast cancer (TNBC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Magee Womens Hosp UPMC, Pittsburgh, PA USA. Penn State Hershey Canc Inst, Hershey, PA USA. NCI, Potomac, MD USA. AbbVie, N Chicago, IL USA. Abbott, Abbott Pk, IL USA. Univ Pittsburgh, Med Ctr, Magee Womens Hosp UMPC, Womens Canc Program, Pittsburgh, PA USA. NR 0 TC 4 Z9 4 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 1015 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900096 ER PT J AU Park, JW Green, JE Kim, HK AF Park, Jun Won Green, Jeffrey E. Kim, Hark K. TI Establishment and characterization of Smad4-and p53-null GEM models for colorectal adenocarcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Natl Canc Ctr, Biomol Funct Res Branch, Goyang, South Korea. NCI, Transgen Oncogenesis & Genom Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. Natl Canc Ctr, Goyang, South Korea. 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e14697 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902782 ER PT J AU Pichun, MEB Thomas, A Wilkerson, J Hassan, R Fojo, AT Giaccone, G Rajan, A AF Pichun, Mauricio Emmanuel Burotto Thomas, Anish Wilkerson, Julia Hassan, Raffit Fojo, Antonio Tito Giaccone, Giuseppe Rajan, Arun TI Effect of treatment on the regression and growth rates of thymic epithelial tumors (TETs). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Rockville, MD USA. NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Thorac & Gastrointestinal Oncol Branch, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e18564 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903865 ER PT J AU Piotrowski, AF Campian, JL Hakim, F Rose, J Yan, XY Gress, R Grossman, SA AF Piotrowski, Anna F. Campian, Jian Li Hakim, Frances Rose, Jeremy Yan, Xiao-Yi Gress, Ronald Grossman, Stuart A. TI Serial evaluation of lymphocyte subsets in patients with newly diagnosed high grade gliomas treated with standard radiation and temozolomide SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Johns Hopkins Univ, Ellicott City, MD USA. Washington Univ, St Louis, MO USA. NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e22116 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904502 ER PT J AU Purev, E Srinivasan, R Aue, G Stroncek, D Khuu, H Ramos, C Cook, L Cho, E Schmitt, M Childs, RW AF Purev, Enkhtsetseg Srinivasan, Ramaprasad Aue, George Stroncek, Dave Khuu, Hahn Ramos, Caltalina Cook, Lisa Cho, Elena Schmitt, Monica Childs, Richard W. TI Outpatient allogeneic hematopoietic cell transplant following alemtuzumab based reduced intensity conditioning in patients with advanced mycosis fungoides/Sezary syndrome. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Purev, Enkhtsetseg; Srinivasan, Ramaprasad; Aue, George; Stroncek, Dave; Khuu, Hahn; Ramos, Caltalina; Cook, Lisa; Cho, Elena; Schmitt, Monica; Childs, Richard W.] 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 7089 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901625 ER PT J AU Rimando, J Larrick, S Fowler, N Castiello, L Ali, SA Sabatino, M Stroncek, D Felizardo, T Fowler, DH AF Rimando, Joseph Larrick, Steven Fowler, Nicholas Castiello, Luciano Ali, Syed Abbas Sabatino, Marianna Stroncek, Dave Felizardo, Tania Fowler, Daniel H. TI The relationship between HIF family gene expression in allogeneic T-cell products and acute graft-versus-host disease. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NIH, Bethesda, MD 20892 USA. NCI, NIH, Columbia, MD USA. NCI, Expt Transplantat & Immunol Branch, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 7026 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901562 ER PT J AU Rubinstein, MMZ Gray, RJ Sparano, JA Zujewski, J Whelan, TJ Albain, KS Hayes, DF Geyer, CE Dees, EC Perez, EA Keane, MM Vallejos, C Goggins, TF Mayer, IA Brufsky, A Toppmeyer, D Kaklamani, VG Atkins, JN Berenberg, JL Sledge, GW AF Rubinstein, Maria M. Zlobinsky Gray, Robert James Sparano, Joseph A. Zujewski, JoAnne Whelan, Timothy Joseph Albain, Kathy S. Hayes, Daniel F. Geyer, Charles E. Dees, Elizabeth Claire Perez, Edith A. Keane, Maccon M. Vallejos, Carlos Goggins, Timothy F. Mayer, Ingrid A. Brufsky, Adam Toppmeyer, Deborah Kaklamani, Virginia G. Atkins, James Norman Berenberg, Jeffrey L. Sledge, George W. TI Recurrence score and clinicopathologic characteristics of TAILORx participants by race and ethnicity. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Montefiore Med Ctr, Bronx, NY 10467 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. Canc Care Ontario, Hamilton, ON, Canada. SWOG, NRG Oncol NSABP, Maywood, IL USA. Loyola Univ, Chicago Stritch Sch Med, Maywood, IL 60153 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. Univ N Carolina, Chapel Hill, NC USA. Mayo Clin, Jacksonville, FL 32224 USA. West Ireland Canc Ctr, Galway, Ireland. Inst Nacl Enfermedades Neoplas, Lima, Peru. Fox Valley Hem Onc, Appleton, WI USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. NRG Oncol NSABP, Pittsburgh, PA USA. Magee Womens Hosp, Pittsburgh, PA USA. Canc Inst New Jersey, New Brunswick, NJ USA. Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA. Southeastern Medcl Ctr, Goldsboro, NC USA. Tripler Army Medcl Ctr, Honolulu, HI USA. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. RI Whelan, Timothy/D-3185-2017 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 533 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901140 ER PT J AU Rubinstein, WS Benson, M Chitipiralla, S Hoover, J Kattman, BL Katz, KS Maglott, DR Malheiro, AJ Tekumalla, R Lee, JM AF Rubinstein, Wendy S. Benson, Mark Chitipiralla, Shanmuga Hoover, Jeffrey Kattman, Brandi L. Katz, Kenneth S. Maglott, Donna R. Malheiro, Adriana J. Tekumalla, Radhika Lee, Jennifer M. TI The NIH Genetic Testing Registry and content tailored for oncologists. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Rubinstein, Wendy S.; Benson, Mark; Chitipiralla, Shanmuga; Hoover, Jeffrey; Kattman, Brandi L.; Katz, Kenneth S.; Maglott, Donna R.; Malheiro, Adriana J.; Tekumalla, Radhika; Lee, Jennifer M.] 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e12543 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902351 ER PT J AU Schultz, KAP Williams, GM Stewart, D Rosenberg, PS Doros, LA Dehner, LP Hill, DA Messinger, YH AF Schultz, Kris Ann Pinekenstein Williams, Gretchen M. Stewart, Douglas Rosenberg, Philip S. Doros, Leslie Ann Dehner, Louis P. Hill, D. Ashley Messinger, Yoav H. TI Association of recurrent or progressive p of form types II and III pleuropulmonary blastoma (PPB) with poor outcome: A report from the international PPB registry. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. NCI, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Arlington, VA USA. Washington Univ, Sch Med St Louis, St Louis, MO USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Childrens Hosp & Clin, Minneapolis, MN 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 10014 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900018 ER PT J AU Shirai, K Day, TA Szabo, E Van Waes, C O'Brien, PE Matheus, MG Godwin, K Sood, AJ Vick, JA Martin, D Vitale-Cross, L Molinolo, A Gutkind, JS AF Shirai, Keisuke Day, Terry A. Szabo, Eva Van Waes, Carter O'Brien, Paul E. Matheus, Maria Gisele Godwin, Kristina Sood, Amit J. Vick, Julie A. Martin, Daniel Vitale-Cross, Lynn Molinolo, Alfredo Gutkind, Jorge Silvio TI A pilot, single arm, prospective trial using neoadjuvant rapamycin prior to definitive therapy in head and neck squamous cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Med Univ S Carolina, Charleston, SC 29425 USA. Natl Canc Inst, Potomac, MD USA. Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. Medcl Univ South Carolina, Charleston, SC USA. Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. Rho Inc, Chapel Hill, NC USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NR 0 TC 1 Z9 1 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 6071 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901388 ER PT J AU Singh, H Madan, RA Dahut, WL Strauss, J Rauckhorst, M McMahon, S Heery, CR Schlom, J Gulley, JL AF Singh, Harpreet Madan, Ravi Amrit Dahut, William L. Strauss, Julius Rauckhorst, Myrna McMahon, Sheri Heery, Christopher Ryan Schlom, Jeffrey Gulley, James L. TI Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e14008 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036902600 ER PT J AU Somlo, G Frankel, PH Luu, TH Ma, CX Arun, B Garcia, AA Cigler, T Cream, L Harvey, HA Sparano, JA Nanda, R Chew, HK Moynihan, TJ Vahdat, LT Goetz, MP Hurria, A Mortimer, JE Gandara, DR Chen, AP Weitzel, JN AF Somlo, George Frankel, Paul Henry Luu, Thehang H. Ma, Cynthia X. Arun, Banu Garcia, Agustin A. Cigler, Tessa Cream, Leah Harvey, Harold A. Sparano, Joseph A. Nanda, Rita Chew, Helen K. Moynihan, Timothy Jerome Vahdat, Linda T. Goetz, Matthew P. Hurria, Arti Mortimer, Joanne E. Gandara, David R. Chen, Alice P. Weitzel, Jeffrey N. TI Efficacy of the PARP inhibitor (PI) ABT-888 (veliparib [vel]) either with carboplatin (carb) or as a single agent followed by post-progression therapy in combination with carb in patients (pts) with BRCA1- or BRCA2-(BRCA)-associated metastatic breast cancer (MBC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 City Hope Natl Med Ctr, Duarte, CA USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. Washington Univ, St Louis, MO USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ So Calif, Los Angeles Cty Hosp, Los Angeles, CA USA. Weill Cornell Breast Ctr, New York, NY USA. Penn State Coll Med, Hershey, PA USA. Penn State Milton S Hershey Med Ctr, Hershey, PA USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Calif Davis, Med Ctr, Sacramento, CA USA. Mayo Clin, Rochester, MN USA. Weill Cornell Med Coll, New York, NY USA. Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA 95817 USA. NCI, Potomac, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 520 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901127 ER PT J AU Suneja, G Lin, CC Simard, EP Han, XS Engels, EA Jemal, A AF Suneja, Gita Lin, Chun Chieh Simard, Edgar P. Han, Xuesong Engels, Eric A. Jemal, Ahmedin TI Disparities in cancer treatment among HIV-infected individuals SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Huntsman Canc Hosp, Salt Lake City, UT USA. Amer Canc Soc, Atlanta, GA 30329 USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. Amer Canc Soc, Atlanta, GA 30329 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e17592 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903558 ER PT J AU Tsang, KY Boyerinas, B Jochems, C Fantini, M Heery, CR Madan, RA Gulley, JL Schlom, J AF Tsang, Kwong-Yok Boyerinas, Benjamin Jochems, Caroline Fantini, Massimo Heery, Christopher Ryan Madan, Ravi Amrit Gulley, James L. Schlom, Jeffrey TI Antibody dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody, avelumab (MSB0010718C), on human tumor cells. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, 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 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 3038 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900672 ER PT J AU Tutt, ANJ Kaufman, B Gelber, RD Mc Fadden, E Goessl, CD Viale, G Arahmani, A Fumagalli, D Azim, HA Wu, WT Grocholewicz, A Costantino, JP Rastogi, P Garber, JE Geyer, CE AF Tutt, Andrew Nicholas James Kaufman, Bella Gelber, Richard D. Mc Fadden, Eleanor Goessl, Carsten Dietrich Viale, Giuseppe Arahmani, Amal Fumagalli, Debora Azim, Hatem Abdel Wu, Wenting Grocholewicz, Anna Costantino, Joseph P. Rastogi, Priya Garber, Judy Ellen Geyer, Charles E. TI OlympiA: A randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Kings Coll London, Sch Med, London WC2R 2LS, England. Chaim Sheba Med Ctr, Ramat Gan, Israel. Tel Aviv Univ, Sackler Fac Med, Ramat Gan, Israel. Dana Farber Canc Inst, Boston, MA 02115 USA. Frontier Sci, Kingussie, Inverness, Scotland. AstraZeneca, Gaithersburg, MD USA. European Inst Oncol, Div Pathol, Milan, Italy. Breast Int Grp, Brussels, Belgium. Inst Jules Bordet, B-1000 Brussels, Belgium. AstraZeneca, Gaithersburg, MD USA. AstraZeneca, Warsaw, Poland. NRG Oncol, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. NRG Oncol, NSABP, Pittsburgh, PA USA. UPMC, Ctr Canc, Pittsburgh, PA USA. Virginia Commonwealth Univ, Massey Canc Ctr, Pittsburgh, PA 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS1109 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904664 ER PT J AU Urbanic, JJ Case, D Baez-Diaz, L Brown, DR Strasser, J Enevold, G Naughton, M Weaver, KE Baglan, K Bryant, D Langefeld, C Lad, TE Lee, L Rine, G Curtis, AE Koprowski, CD Tomlinson, WV Lesser, GJ Shaw, EG Hu, JJ AF Urbanic, James John Case, Doug Baez-Diaz, Luis Brown, Doris R. Strasser, Jon Enevold, Gina Naughton, Michelle Weaver, Kathryn E. Baglan, Kathy Bryant, David Langefeld, Carl Lad, Thomas E. Lee, Lucille Rine, Grant Curtis, Amarinthia E. Koprowski, Christoper D. Tomlinson, W. Vic Lesser, Glenn Jay Shaw, Edward G. Hu, Jennifer J. TI A prospective evaluation of radiotherapy (RT) related skin reactions in a multi-racial/ethnic population of women with newly diagnosed breast cancer (BC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Calif San Diego, Encinitas, CA USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Natl Surg Adjuvant Breast & Bowel Project, San Juan, PR USA. CCOP San Juan, San Juan, PR USA. Helen F Graham Canc Ctr, Newark, DE USA. Ohio State Univ, Columbus, OH 43210 USA. Mercy Hosp Sanit Louis, St Louis, MO USA. Via Christi Canc Ctr, Wichita, KS USA. Cook Cty Hosp, Chicago, IL 60612 USA. North Shore LIJ Canc Inst, Lake Success, NY USA. Wesley Med Ctr, Wichita, KS USA. Upstate Carolina CCOP, Spartanburg, SC USA. Christiana Care Hlth Syst, Helen Graham Canc Ctr, Newark, DE USA. AnMed Hlth, Anderson, SC USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Wake Forest Baptist Hlth, Winston Salem, NC USA. Univ Miami, Miami, FL 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 6593 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901507 ER PT J AU Walcott, FL Land, SR Costantino, JP Midthune, D Dunn, BK AF Walcott, Farzana L. Land, Stephanie R. Costantino, Joseph P. Midthune, Doug Dunn, Barbara Karen TI Vasomotor symptoms, BMI, and adherence to tamoxifen in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Rockville, MD USA. NRG Oncol, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. NCI, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 1501 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900368 ER PT J AU Wallden, B Ferree, S Ravi, H Dowidar, N Hood, T Danaher, P Mashadi-Hossein, A Wright, G Schaper, C Storhoff, JJ AF Wallden, Brett Ferree, Sean Ravi, Harini Dowidar, Naeem Hood, Tressa Danaher, Patrick Mashadi-Hossein, Afshin Wright, George Schaper, Carl Storhoff, James Justin TI Development of the molecular diagnostic (MDx) DLBCL Lymphoma Subtyping Test (LST) on the nCounter Analysis System SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NanoString Technol Inc, Seattle, WA 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 8536 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901848 ER PT J AU Yabroff, KR Dowling, E Guy, G Banegas, M McNeel, TS Davidoff, AJ Chawla, N Hartigan, DB Han, XS Kent, EE Li, CY Virgo, KS Rodriguez, J de Moor, J Zheng, ZY Jemal, A Ekwueme, DU AF Yabroff, K. Robin Dowling, Emily Guy, Gery Banegas, Matthew McNeel, Timothy S. Davidoff, Amy J. Chawla, Neetu Hartigan, Danielle Blanch Han, Xuesong Kent, Erin E. Li, Chunyu Virgo, Katherine S. Rodriguez, Juan de Moor, Janet Zheng, Zhiyuan Jemal, Ahmedin Ekwueme, Donatus U. TI Financial hardship associated with cancer in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Rockville, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. IMS, Rockville, MD USA. Yale Univ, Sch Publ Hlth, New Haven, CT USA. Kaiser Permanente No Calif, Oakland, CA USA. Bentley Univ, Saugus, MA USA. Amer Canc Soc, Atlanta, GA 30329 USA. Emory Univ, Atlanta, GA 30322 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 6608 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901522 ER PT J AU Yellu, M Fakhrejahani, F Ying, J Mierzwa, M Malek, E Haque, S Sendilnathan, A Huth, BJ Morris, JC Karim, NA Latif, T Redmond, KP Barrett, W Videtic, GMM Sadraei, NH AF Yellu, Mahender Fakhrejahani, Farhad Ying, Jun Mierzwa, Michelle Malek, Ehsan Haque, Sulsal Sendilnathan, Arun Huth, Bradley Joseph Morris, John Charles Karim, Nagla Abdel Latif, Tahir Redmond, Kevin P. Barrett, William Videtic, Gregory M. M. Sadraei, Nooshin Hashemi TI Lymphopenia as a predictor of survival in chemoradiation (CRT)-treated stage III non-small cell lung cancer (NSCLC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Cincinnati, Cincinnati, OH USA. Natl Canc Inst, Potomac, MD USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Cincinnati, Div Hematol & Oncol, Cincinnati, OH USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Univ Cincinnati, Barrett Canc Ctr, Cincinnati, OH USA. Univ Cincinnati, Dept Med, Inst Canc, Div Hematol Oncol, Cincinnati, OH USA. Univ Cincinnati, Inst Canc, Cincinnati, OH USA. Univ Hosp, Cincinnati, OH USA. Cleveland Clin Fdn, Cleveland, OH 44195 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA e18513 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903821 ER PT J AU Yu, HA Oxnard, GR Spira, AI Horn, L Weiss, J Feng, Y West, HJ Giaccone, G Evans, TL Kelly, RJ Fleege, T Poondru, S Jie, F Aoyama, K Foley, MA Whitcomb, D Keating, AT Krivoshik, AP AF Yu, Helena Alexandra Oxnard, Geoffrey R. Spira, Alexander I. Horn, Leora Weiss, Jared Feng, Yan West, Howard Jack Giaccone, Giuseppe Evans, Tracey L. Kelly, Ronan Joseph Fleege, Tanya Poondru, Srinivasu Jie, Fei Aoyama, Koji Foley, Margaret A. Whitcomb, Debbie Keating, Anne Therese Krivoshik, Andrew P. TI Phase I dose escalation study of ASP8273, a mutant-selective irreversible EGFR inhibitor, in subjects with EGFR mutation positive NSCLC. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. US Oncol Res, Virginia Canc Specialists Res Inst, Fairfax, VA USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Case Western Reserve Univ, Univ Hosp, Broadview Hts, OH USA. Swedish Canc Inst, Seattle, WA USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Penn, Wynnewood, PA USA. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. Astellas Pharma Global Dev, Northbrook, IL USA. Astellas Pharma Inc, Northbrook, IL USA. Astellas Pharma, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 2 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 8083 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901795 ER PT J AU Zell, JA Unger, JM Anderson, GL Cook, ED Krouse, RS Lance, MP Minasian, LM Ford, L Brown, P AF Zell, Jason A. Unger, Joseph M. Anderson, Garnet L. Cook, Elise D. Krouse, Robert S. Lance, M. Peter Minasian, Lori M. Ford, Leslie Brown, Powel TI SWOG S0820/PACES (Preventing Adenomas of the Colon with Eflornithine and Sulindac): A randomized, double-blind, placebo-controlled phase III clinical trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 UC Irvine Hlth, Chao Family Comprehens Canc Ctr, Orange, CA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Southern Arizona Vet Affairs Hlth Care Syst, Tucson, AZ USA. Univ Arizona, Tucson, AZ USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA TPS3627 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036904730 ER PT J AU Zheng, ZY Jemal, A Guy, G Han, XS Banegas, M Li, CY Ekwueme, DU Yabroff, KR AF Zheng, Zhiyuan Jemal, Ahmedin Guy, Gery Han, Xuesong Banegas, Matthew Li, Chunyu Ekwueme, Donatus U. Yabroff, K. Robin TI Medical expenditures and productivity loss among colorectal, breast, and prostate cancer survivors in the US SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 Amer Canc Soc, Atlanta, GA 30329 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NCI, Rockville, MD 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 MAY 20 PY 2015 VL 33 IS 15 SU S MA 6619 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036901533 ER PT J AU Lu, VB Ikeda, SR Puhl, HL AF Lu, Van B. Ikeda, Stephen R. Puhl, Henry L., III TI A 3.7 kb Fragment of the Mouse Scn10a Gene Promoter Directs Neural Crest But Not Placodal Lineage EGFP Expression in a Transgenic Animal SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dorsal root ganglia; nodose ganglion; pain; sodium channels; transgenic ID SODIUM-CHANNEL NA(V)1.8; GRUENEBERG GANGLION NEURONS; INFLAMMATORY PAIN; MULTIPLE-SCLEROSIS; CALCIUM-CHANNELS; AFFERENT NEURONS; SENSORY NEURONS; NA+ CURRENTS; ION CHANNELS; DRG NEURONS AB Under physiological conditions, the voltage-gated sodium channel Na(v)1.8 is expressed almost exclusively in primary sensory neurons. The mechanism restricting Na(v)1.8 expression is not entirely clear, but we have previously described a 3.7 kb fragment of the Scn10a promoter capable of recapitulating the tissue-specific expression of Na(v)1.8 in transfected neurons and cell lines (Puhl and Ikeda, 2008). To validate these studies in vivo, a transgenic mouse encoding EGFP under the control of this putative sensory neuron specific promoter was generated and characterized in this study. Approximately 45% of dorsal root ganglion neurons of transgenic mice were EGFP-positive (mean diameter = 26.5 mu m). The majority of EGFP-positive neurons bound isolectin B4, although a small percentage (similar to 10%) colabeled with markers of A-fiber neurons. EGFP expression correlated well with the presence of Na(v)1.8 transcript (95%), Na(v)1.8-immunoreactivity (70%), and TTX-R I-Na (100%), although not all Na(v)1.8-expressing neurons expressed EGFP. Several cranial sensory ganglia originating from neurogenic placodes, such as the nodose ganglion, failed to express EGFP, suggesting that additional regulatory elements dictate Scn10a expression in placodal-derived sensory neurons. EGFP was also detected in discrete brain regions of transgenic mice. Quantitative PCR and Na(v)1.8-immunoreactivity confirmed Na(v)1.8 expression in the amygdala, brainstem, globus pallidus, lateral and paraventricular hypothalamus, and olfactory tubercle. TTX-R I-Na recorded from EGFP-positive hypothalamic neurons demonstrate the usefulness of this transgenic line to study novel roles of Na(v)1.8 beyond sensory neurons. Overall, Scn10a-EGFP transgenic mice recapitulate the majority of the Na(v)1.8 expression pattern in neural crest-derived sensory neurons. C1 [Lu, Van B.; Ikeda, Stephen R.; Puhl, Henry L., III] NIAAA, Sect Transmitter Signaling, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Puhl, HL (reprint author), NIAAA, Lab Mol Physiol, NIH, 5625 Fishers Lane,Room TS-06, Rockville, MD 20852 USA. EM puhlh@mail.nih.gov FU Intramural program at the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the Intramural program at the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. We thank Dr. James Pickel (National Institute of Mental Health Transgenic Core Facility) for assistance with pronuclear microinjections and Dr. Margaret Davis (Laboratory for Integrative Neuroscience/National Institute on Alcohol Abuse and Alcoholism) for technical assistance with immunohistochemistry experiments. NR 51 TC 3 Z9 3 U1 6 U2 16 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 20 PY 2015 VL 35 IS 20 BP 8021 EP 8034 DI 10.1523/JNEUROSCI.0214-15.2015 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CL0YW UT WOS:000356670000024 PM 25995484 ER PT J AU Land, SR Marcus, PM AF Land, Stephanie R. Marcus, Pamela M. TI Cancer Screening and Diagnosis: Opportunities for Smoking Cessation Intervention SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID LUNG-CANCER; UNITED-STATES; MORTALITY; PROGRAM; TOBACCO; TRIAL C1 [Land, Stephanie R.; Marcus, Pamela M.] NCI, NIH, Bethesda, MD 20892 USA. RP Land, SR (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM stephanie.land@alumni.stanford.edu NR 23 TC 6 Z9 6 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 MAY 20 PY 2015 VL 33 IS 15 BP 1631 EP + DI 10.1200/JCO.2015.61.2077 PG 4 WC Oncology SC Oncology GA CK2RW UT WOS:000356060500002 PM 25897157 ER PT J AU Lynch, C Zhao, JH Huang, RL Xiao, JW Li, LH Heyward, S Xia, MH Wang, HB AF Lynch, Caitlin Zhao, Jinghua Huang, Ruili Xiao, Jingwei Li, Linhao Heyward, Scott Xia, Menghang Wang, Hongbing TI Quantitative High-Throughput Identification of Drugs as Modulators of Human Constitutive Androstane Receptor SO SCIENTIFIC REPORTS LA English DT Article ID PREGNANE-X-RECEPTOR; ORPHAN NUCLEAR RECEPTORS; PRIMARY HUMAN HEPATOCYTES; STRUCTURAL DETERMINANTS; ENHANCER MODULE; AGONIST LIGAND; HEPG2 CELLS; CAR; ACTIVATION; METABOLISM AB The constitutive androstane receptor (CAR, NR1I3) plays a key role in governing the transcription of numerous hepatic genes that involve xenobiotic metabolism/clearance, energy homeostasis, and cell proliferation. Thus, identification of novel human CAR (hCAR) modulators may not only enhance early prediction of drug-drug interactions but also offer potentially novel therapeutics for diseases such as metabolic disorders and cancer. In this study, we have generated a double stable cell line expressing both hCAR and a CYP2B6-driven luciferase reporter for quantitative high-throughput screening (qHTS) of hCAR modulators. Approximately 2800 compounds from the NIH Chemical Genomics Center Pharmaceutical Collection were screened employing both the activation and deactivation modes of the qHTS. Activators (115) and deactivators (152) of hCAR were identified from the primary qHTS, among which 10 agonists and 10 antagonists were further validated in the physiologically relevant human primary hepatocytes for compound-mediated hCAR nuclear translocation and target gene expression. Collectively, our results reveal that hCAR modulators can be efficiently identified through this newly established qHTS assay. Profiling drug collections for hCAR activity would facilitate the prediction of metabolism-based drug-drug interactions, and may lead to the identification of potential novel therapeutics. C1 [Lynch, Caitlin; Xiao, Jingwei; Li, Linhao; Wang, Hongbing] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Zhao, Jinghua; Huang, Ruili; Xia, Menghang] NIH, NCATS, Bethesda, MD 20892 USA. [Heyward, Scott] Bioreclamat IVT, Baltimore, MD USA. RP Wang, HB (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. EM hwang@rx.umaryland.edu RI Li, Linhao/A-6348-2013 FU National Institutes of Health [DK061652, GM107058]; National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported in part by the National Institutes of Health Grants (DK061652 and GM107058), and the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. We also thank William Hedrich and Bryan Mackowiak for critical reading of the manuscript. NR 43 TC 5 Z9 5 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 20 PY 2015 VL 5 AR 10405 DI 10.1038/srep10405 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ3PC UT WOS:000355395300001 PM 25993555 ER PT J AU Vardy, E Robinson, JE Li, C Olsen, RHJ DiBerto, JF Giguere, PM Sassano, FM Huang, XP Zhu, H Urban, DJ White, KL Rittiner, JE Crowley, NA Pleil, KE Mazzone, CM Mosier, PD Song, J Kash, TL Malanga, CJ Krashes, MJ Roth, BL AF Vardy, Eyal Robinson, J. Elliott Li, Chia Olsen, Reid H. J. DiBerto, Jeffrey F. Giguere, Patrick M. Sassano, Flori M. Huang, Xi-Ping Zhu, Hu Urban, Daniel J. White, Kate L. Rittiner, Joseph E. Crowley, Nicole A. Pleil, Kristen E. Mazzone, Christopher M. Mosier, Philip D. Song, Juan Kash, Thomas L. Malanga, C. J. Krashes, Michael J. Roth, Bryan L. TI A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior SO NEURON LA English DT Article ID KAPPA-OPIOID RECEPTOR; PROTEIN-COUPLED RECEPTORS; BETA-CELL FUNCTION; IN-VIVO; SALVINORIN-A; G(Q)-COUPLED RECEPTOR; FEEDING-BEHAVIOR; REMOTE-CONTROL; ACTIVATION; LIGANDS AB DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators. C1 [Vardy, Eyal; Olsen, Reid H. J.; Giguere, Patrick M.; Sassano, Flori M.; Huang, Xi-Ping; Zhu, Hu; Urban, Daniel J.; White, Kate L.; Crowley, Nicole A.; Pleil, Kristen E.; Mazzone, Christopher M.; Song, Juan; Kash, Thomas L.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27514 USA. [Vardy, Eyal; Olsen, Reid H. J.; Giguere, Patrick M.; Sassano, Flori M.; Huang, Xi-Ping; Zhu, Hu; Urban, Daniel J.; White, Kate L.; Crowley, Nicole A.; Pleil, Kristen E.; Mazzone, Christopher M.; Song, Juan; Kash, Thomas L.; Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH, PDSP, Chapel Hill, NC 27514 USA. [Robinson, J. Elliott; DiBerto, Jeffrey F.; Malanga, C. J.] Univ N Carolina, Sch Med, Neurol Dept, Chapel Hill, NC 27514 USA. [Robinson, J. Elliott; Olsen, Reid H. J.; Rittiner, Joseph E.; Crowley, Nicole A.; Pleil, Kristen E.; Mazzone, Christopher M.; Song, Juan; Kash, Thomas L.; Malanga, C. J.; Roth, Bryan L.] Univ N Carolina, Sch Med, Curriculum Neurobiol, Chapel Hill, NC 27599 USA. [Robinson, J. Elliott; Crowley, Nicole A.; Pleil, Kristen E.; Mazzone, Christopher M.; Kash, Thomas L.; Malanga, C. J.] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [Li, Chia; Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Li, Chia; Krashes, Michael J.] NIDA, Baltimore, MD 21224 USA. [Mosier, Philip D.] Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. RP Krashes, MJ (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM michael.krashes@nih.gov; bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010; OI Robinson, J. Elliott/0000-0001-9417-3938 FU NIH BRAIN Initiative [UO1MH105892, R01 DA017204, PO1DA035764]; NIH-NIMH Psychoactive Drug Screening Program; Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases - NIDDK [DK075087, DK075089]; NARSAD Young Investigator Award [R01AA019454, R00AA017668]; [U01AA020911]; [F31AA02228001]; [R01 AA018335]; [F30 AA021312] FX This work was supported, in whole or in part, by the NIH BRAIN Initiative Grant UO1MH105892 (B.L.R. and T.L.K.) and by R01 DA017204 (B.L.R.), PO1DA035764 (B.L.R.), and the NIH-NIMH Psychoactive Drug Screening Program (B.L.R.); the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases - NIDDK; DK075087, DK075089 (M.J.K.); and by R01AA019454, R00AA017668, NARSAD Young Investigator Award, and U01AA020911 (T.L.K.); and F31AA02228001 (N.A.C.), R01 AA018335 (C.J.M.), and F30 AA021312 (J.E.R.). NR 46 TC 41 Z9 41 U1 4 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAY 20 PY 2015 VL 86 IS 4 BP 936 EP 946 DI 10.1016/j.neuron.2015.03.065 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CI6OB UT WOS:000354878400009 PM 25937170 ER PT J AU Yang, S Prentice, RL AF Yang, Song Prentice, Ross L. TI Assessing potentially time-dependent treatment effect from clinical trials and observational studies for survival data, with applications to the Women's Health Initiative combined hormone therapy trial SO STATISTICS IN MEDICINE LA English DT Article DE average hazard ratio; censored data; hazard ratio; nonproportional hazards; semiparametric analysis; simultaneous inference ID ESTROGEN PLUS PROGESTIN; HAZARD RATIO; TRANSFORMATION MODELS; PROPENSITY SCORE; CENSORED-DATA; SHORT-TERM; REGRESSION; REDUCTION; INFERENCE; CHECKING AB For risk and benefit assessment in clinical trials and observational studies with time-to-event data, the Cox model has usually been the model of choice. When the hazards are possibly non-proportional, a piece-wise Cox model over a partition of the time axis may be considered. Here, we propose to analyze clinical trials or observational studies with time-to-event data using a certain semiparametric model. The model allows for a time-dependent treatment effect. It includes the important proportional hazards model as a sub-model and can accommodate various patterns of time-dependence of the hazard ratio. After estimation of the model parameters using a pseudo-likelihood approach, simultaneous confidence intervals for the hazard ratio function are established using a Monte Carlo method to assess the time-varying pattern of the treatment effect. To assess the overall treatment effect, estimated average hazard ratio and its confidence intervals are also obtained. The proposed methods are applied to data from the Women's Health Initiative. To compare the Women's Health Initiative clinical trial and observational study, we use the propensity score in building the regression model. Compared with the piece-wise Cox model, the proposed model yields a better model fit and does not require partitioning of the time axis. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Yang, Song] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Yang, S (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr MSC 7913, Bethesda, MD 20892 USA. EM yangso@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C]; National Cancer Institute [CA53996] FX We thank the WHI Publication and Presentation Committee for reviewing and approving this article. The WHI was sponsored by the National Heart, Lung, and Blood Institute through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, and HHSN268201100003C. This work was also partially supported by National Cancer Institute grant CA53996. We would also like to thank Dr. Nancy Geller and Dr. Dong-Yun Kim for careful reviews and comments that led to the improvement of this research article. NR 35 TC 0 Z9 0 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAY 20 PY 2015 VL 34 IS 11 BP 1801 EP 1817 DI 10.1002/sim.6453 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CF5YL UT WOS:000352633200001 PM 25689356 ER PT J AU Landsman, V Lou, WYW Graubard, BI AF Landsman, V. Lou, W. Y. W. Graubard, B. I. TI Estimating survival probabilities by exposure levels: utilizing vital statistics and complex survey data with mortality follow-up SO STATISTICS IN MEDICINE LA English DT Article DE categorical exposure; Cox proportional hazard model; crude hazard rate; leave-one-out jackknife; linked mortality data; multistage surveys; Taylor deviates ID STANDARD ERRORS; UNITED-STATES; SMOKING; HAZARDS; DEATH; RISK AB We present a two-step approach for estimating hazard rates and, consequently, survival probabilities, by levels of general categorical exposure. The resulting estimator utilizes three sources of data: vital statistics data and census data are used at the first step to estimate the overall hazard rate for a given combination of gender and age group, and cohort data constructed from a nationally representative complex survey with linked mortality records, are used at the second step to divide the overall hazard rate by exposure levels. We present an explicit expression for the resulting estimator and consider two methods for variance estimation that account for complex multistage sample design: (1) the leaving-one-out jackknife method, and (2) the Taylor linearization method, which provides an analytic formula for the variance estimator. The methods are illustrated with smoking and all-cause mortality data from the US National Health Interview Survey Linked Mortality Files, and the proposed estimator is compared with a previously studied crude hazard rate estimator that uses survey data only. The advantages of a two-step approach and possible extensions of the proposed estimator are discussed. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Landsman, V.; Lou, W. Y. W.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. [Graubard, B. I.] NCI, Bethesda, MD 20852 USA. RP Landsman, V (reprint author), Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. EM victoria.landsman@utoronto.ca NR 20 TC 0 Z9 0 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAY 20 PY 2015 VL 34 IS 11 BP 1864 EP 1875 DI 10.1002/sim.6455 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CF5YL UT WOS:000352633200005 PM 25656596 ER PT J AU Hu, ZH Proschan, M AF Hu, Zonghui Proschan, Michael TI Two-part test of vaccine effect SO STATISTICS IN MEDICINE LA English DT Article DE Fisher's exact test; Lachenbruch's test; local alternative; randomization test; vaccine ID TRIALS AB Vaccine benefit is usually two-folded: (i) prevent a disease or, failing that, (ii) diminish the severity of a disease. To assess vaccine effect, we propose two adaptive tests. The weighted two-part test is a combination of two statistics, one on disease incidence and one on disease severity. More weight is given to the statistic with the larger a priori effect size, and the weights are determined to maximize testing power. The randomized test applies to the scenario where the total number of infections is relatively small. It uses information on disease severity to bolster power while preserving disease incidence as the primary interest. Properties of the proposed tests are explored asymptotically and by numerical studies. Although motivated by vaccine studies, the proposed tests apply to any trials that involve both binary and continuous outcomes for evaluating treatment effect. Published 2015. This article is a US Government work and is in the public domain in the USA. C1 [Hu, Zonghui; Proschan, Michael] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Hu, ZH (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huzo@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAY 20 PY 2015 VL 34 IS 11 BP 1904 EP 1911 DI 10.1002/sim.6412 PG 8 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CF5YL UT WOS:000352633200008 PM 25630496 ER PT J AU Westendorp, WF Nederkoorn, PJ Aksentijevich, I Hak, AE Lichtenbelt, KD Braun, KPJ AF Westendorp, Willeke F. Nederkoorn, Paul J. Aksentijevich, Ivona Hak, A. Elisabeth Lichtenbelt, Klaske D. Braun, Kees P. J. TI UNEXPLAINED EARLY-ONSET LACUNAR STROKE AND INFLAMMATORY SKIN LESIONS: CONSIDER ADA2 DEFICIENCY SO NEUROLOGY LA English DT Editorial Material C1 [Westendorp, Willeke F.; Nederkoorn, Paul J.; Hak, A. Elisabeth] Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Aksentijevich, Ivona] NHGRI, NIH, Bethesda, MD 20892 USA. [Lichtenbelt, Klaske D.; Braun, Kees P. J.] Univ Med Ctr Utrecht, Utrecht, Netherlands. RP Westendorp, WF (reprint author), Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM w.f.westendorp@amc.nl NR 2 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 19 PY 2015 VL 84 IS 20 BP 2092 EP 2093 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DD2NU UT WOS:000369760100017 PM 25888558 ER PT J AU Freeman, ZT Rice, KA Soto, PL Pate, KAM Weed, MR Ator, NA DeLeon, IG Wong, DF Zhou, Y Mankowski, JL Zink, MC Adams, RJ Hutchinson, EK AF Freeman, Z. T. Rice, K. A. Soto, P. L. Pate, K. A. M. Weed, M. R. Ator, N. A. DeLeon, I. G. Wong, D. F. Zhou, Y. Mankowski, J. L. Zink, M. C. Adams, R. J. Hutchinson, E. K. TI Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID LESCH-NYHAN-SYNDROME; BORDERLINE PERSONALITY-DISORDER; AUTISM SPECTRUM DISORDER; MACACA-MULATTA; PREFRONTAL CORTEX; RETROSPECTIVE ANALYSIS; DOPAMINE RELEASE; EXTENDED-RELEASE; WORKING-MEMORY; UP-REGULATION AB Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (r(s) = 0.662, P = 0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (r(s) = 0.563, P = 0.045 and r(s) = 0.692, P = 0.009, respectively). We also tested the efficacy of guanfacine, an alpha 2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P = 0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (r(s) = -0.761, P = 0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans. C1 [Freeman, Z. T.; Rice, K. A.; Pate, K. A. M.; Mankowski, J. L.; Zink, M. C.; Adams, R. J.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Rice, K. A.; Hutchinson, E. K.] NIH, Div Vet Resources, Bethesda, MD 21205 USA. [Soto, P. L.; Weed, M. R.; Ator, N. A.; DeLeon, I. G.; Wong, D. F.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [DeLeon, I. G.] Kennedy Krieger Inst, Dept Behav Psychol, Baltimore, MD USA. [Wong, D. F.; Zhou, Y.] Johns Hopkins Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Wong, D. F.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. RP Hutchinson, EK (reprint author), NIH, Div Vet Resources, 9000 Rockville Pike,Bldg 14A, Bethesda, MD 21205 USA. EM EricHutchinsonDVM@gmail.com FU Johns Hopkins Research Animal Resources; National Institutes of Health [U01MH075378, T32OD011089, P40OD013117, P40RR019995] FX We acknowledge Melanie Albano, Kristy Koenig, Theresa Meade, Caroline Garrett, Tracey Graham, Nicole Azene, Tori Baxter, Stacey Perry, Virginia Bogdan and Ray Smith for their valuable contributions in conducting these experiments. This project was supported by Johns Hopkins Research Animal Resources and by the following National Institutes of Health grants U01MH075378, T32OD011089, P40OD013117 and P40RR019995. NR 56 TC 3 Z9 3 U1 4 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD MAY 19 PY 2015 VL 5 AR e567 DI 10.1038/tp.2015.61 PG 7 WC Psychiatry SC Psychiatry GA DA2WH UT WOS:000367657300001 PM 25989141 ER PT J AU Hurwitz, AA Lee, S Knox, S Kohrt, H Verdeil, G Romano, E Margolin, K Urba, WJ Speiser, DE AF Hurwitz, Arthur A. Lee, Sylvia Knox, Susan Kohrt, Holbrook Verdeil, Gregory Romano, Emanuela Margolin, Kim Urba, Walter J. Speiser, Daniel E. TI 29th Annual meeting of the Society for Immunotherapy of Cancer (SITC) SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Immunotherapy; Cancer; Adaptive immunity; Innate immunity; Adoptive immunotherapy; Immune escape; Checkpoint inhibitors; Tumor immunity; Immune suppression AB The 29th annual meeting of the Society for Immunotherapy of Cancer (SITC) was held November 7-9, 2014 in National Harbor, MD and was organized by Dr. Arthur A. Hurwitz (National Cancer Institute), Dr. Kim A. Margolin (Stanford University), Dr. Daniel E. Speiser (Ludwig Center for Cancer Research, University of Lausanne) and Dr. Walter J. Urba (Earle A. Chiles Research Institute, Providence Cancer Center). This meeting included over 1,600 registered participants from 28 separate countries, making it the largest SITC meeting held to date. It highlighted significant worldwide progress in the development and application of cancer immunology to the practice of clinical oncology, including advances in diagnosis, prognosis and therapy, utilizing several immunological pathways and mechanisms for a variety of oncologic conditions. Presentations and posters demonstrated that many concepts that had been pursued preclinically in the past are now being translated into clinical practice, with clear benefits for patients. C1 [Hurwitz, Arthur A.] NCI, Frederick, MD 21701 USA. [Lee, Sylvia] Univ Washington, Seattle, WA 98195 USA. [Lee, Sylvia] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Knox, Susan; Margolin, Kim] Stanford Univ, Stanford, CA 94305 USA. [Kohrt, Holbrook] Stanford Canc Inst, Stanford, CA USA. [Verdeil, Gregory; Romano, Emanuela; Speiser, Daniel E.] Ludwig Ctr Canc Res, Lausanne, Switzerland. [Romano, Emanuela] Univ Lausanne, Med Oncol Serv, Lausanne, Switzerland. [Urba, Walter J.] Providence Canc Ctr, Earle A Chiles Res Inst, Portland, OR 97504 USA. RP Urba, WJ (reprint author), Providence Canc Ctr, Earle A Chiles Res Inst, Portland, OR 97504 USA. EM walter.urba@providence.org OI Verdeil, Gregory/0000-0001-9445-8474 NR 4 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD MAY 19 PY 2015 VL 3 AR 17 DI 10.1186/s40425-015-0062-4 PG 14 WC Oncology SC Oncology GA CU7SJ UT WOS:000363741500002 ER PT J AU Meir, M Galanty, Y Kashani, L Blank, M Khosravi, R Fernandez-Avila, MJ Cruz-Garcia, A Star, A Shochot, L Thomas, Y Garrett, LJ Chamovitz, DA Bodine, DM Kurz, T Huertas, P Ziv, Y Shiloh, Y AF Meir, Michal Galanty, Yaron Kashani, Lior Blank, Michael Khosravi, Rami Jesus Fernandez-Avila, Maria Cruz-Garcia, Andres Star, Ayelet Shochot, Lea Thomas, Yann Garrett, Lisa J. Chamovitz, Daniel A. Bodine, David M. Kurz, Thimo Huertas, Pablo Ziv, Yael Shiloh, Yosef TI The COP9 signalosome is vital for timely repair of DNA double-strand breaks SO NUCLEIC ACIDS RESEARCH LA English DT Article ID E3 UBIQUITIN LIGASES; CELLULAR-RESPONSE; DAMAGE RESPONSE; END RESECTION; GENOME STABILITY; PATHWAY CHOICE; ATM; SCF; DYNAMICS; ROLES AB The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylationdependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways-nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection-the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability. C1 [Meir, Michal; Galanty, Yaron; Kashani, Lior; Blank, Michael; Khosravi, Rami; Star, Ayelet; Shochot, Lea; Ziv, Yael; Shiloh, Yosef] Tel Aviv Univ, George S Wise Fac Life Sci, Sackler Sch Med, David & Inez Myers Lab Canc Res,Dept Human Mol Ge, IL-69978 Tel Aviv, Israel. [Jesus Fernandez-Avila, Maria; Cruz-Garcia, Andres; Huertas, Pablo] Univ Seville, Ctr Andaluz Biol Mol Med Regenerat CABIMER, Seville 41092, Spain. [Jesus Fernandez-Avila, Maria; Cruz-Garcia, Andres; Huertas, Pablo] Univ Seville, Dept Genet, Seville 41092, Spain. [Thomas, Yann; Kurz, Thimo] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. [Garrett, Lisa J.; Bodine, David M.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Chamovitz, Daniel A.] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Mol Biol & Ecol Plants, IL-69978 Tel Aviv, Israel. RP Shiloh, Y (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Sackler Sch Med, David & Inez Myers Lab Canc Res,Dept Human Mol Ge, IL-69978 Tel Aviv, Israel. EM y.galanty@gurdon.cam.ac.uk; yaelz@post.tau.ac.il; yossih@post.tau.ac.il RI Huertas, Pablo/N-2245-2016; OI Huertas, Pablo/0000-0002-1756-4449; Chamovitz, Daniel/0000-0002-2815-2909; Kurz, Thimo/0000-0003-0700-6993 FU Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Israel Cancer Research Fund; Israel Science Foundation [1900/12, 998/14]; I-CORE Program of the Planning and Budgeting Committee of the Israel Ministry of Education; Spanish Ministry of Economy and Competitivity [SAF2013-43255-P]; ERC Starting Grant (DSBRECA); ERC Starting Grant (NEDD8andCRLs); Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico FX Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Israel Cancer Research Fund; Israel Science Foundation (grants no. 1900/12 and 998/14); The I-CORE Program of the Planning and Budgeting Committee of the Israel Ministry of Education, to YS laboratory; Spanish Ministry of Economy and Competitivity (SAF2013-43255-P) and ERC Starting Grant (DSBRECA), to PH laboratory; ERC Starting Grant (NEDD8andCRLs) to TK laboratory; Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico, to A. C.-G. YS is a Research Professor of the Israel Cancer Research Fund. Funding for open access charge: Donation to our lab. NR 62 TC 8 Z9 8 U1 1 U2 2 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 MAY 19 PY 2015 VL 43 IS 9 BP 4517 EP 4530 DI 10.1093/nar/gkv270 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK0XK UT WOS:000355928800017 PM 25855810 ER PT J AU Sherpa, C Rausch, JW Le Grice, SFJ Hammarskjold, ML Rekosh, D AF Sherpa, Chringma Rausch, Jason W. Le Grice, Stuart F. J. Hammarskjold, Marie-Louise Rekosh, David TI The HIV-1 Rev response element (RRE) adopts alternative conformations that promote different rates of virus replication SO NUCLEIC ACIDS RESEARCH LA English DT Article ID VIRAL MESSENGER-RNA; GENE-EXPRESSION REQUIRES; TARGET SEQUENCE; FUNCTIONAL-ANALYSIS; ENV EXPRESSION; BINDING-SITE; PROTEIN EXPRESSION; ACTIVATION DOMAIN; TRANS-ACTIVATOR; NUCLEAR EXPORT AB The HIV Rev protein forms a complex with a 351 nucleotide sequence present in unspliced and incompletely spliced human immunodeficiency virus (HIV) mRNAs, the Rev response element (RRE), to recruit the cellular nuclear export receptor Crm1 and RanGTP. This complex facilitates nucleo-cytoplasmic export of these mRNAs. The precise secondary structure of the HIV-1 RRE has been controversial, since studies have reported alternative structures comprising either four or five stem-loops. The published structures differ only in regions that lie outside of the primary Rev binding site. Using in-gel SHAPE, we have now determined that the wt NL4-3 RRE exists as a mixture of both structures. To assess functional differences between these RRE 'conformers', we created conformationally locked mutants by site-directed mutagenesis. Using subgenomic reporters, as well as HIV replication assays, we demonstrate that the five stem-loop form of the RRE promotes greater functional Rev/ RRE activity compared to the four stem-loop counterpart. C1 [Sherpa, Chringma; Hammarskjold, Marie-Louise; Rekosh, David] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Myles H Thaler Ctr AIDS & Human Retrovirus Res, Charlottesville, VA 22908 USA. [Rausch, Jason W.; Le Grice, Stuart F. J.] NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Rekosh, D (reprint author), Univ Virginia, Dept Microbiol Immunol & Canc Biol, Myles H Thaler Ctr AIDS & Human Retrovirus Res, Charlottesville, VA 22908 USA. EM mh7g@virginia.edu; dr4u@virginia.edu FU University of Virginia and National Institute of General Medical Sciences [GM110009]; Intramural Research Program of the National Institutes of Health; University of Virginia and National Cancer Institute FX Charles H. Ross Jr and Myles H. Thaler Endowments at the University of Virginia and National Institute of General Medical Sciences [GM110009] (to M.-L. H. and D.R.); Intramural Research Program of the National Institutes of Health (to S.L.G. and J.R.). Funding for open access charge: University of Virginia and National Cancer Institute. NR 74 TC 14 Z9 14 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 MAY 19 PY 2015 VL 43 IS 9 BP 4676 EP 4686 DI 10.1093/nar/gkv313 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK0XK UT WOS:000355928800030 PM 25855816 ER PT J AU Kononenko, AV Lee, NCO Liskovykh, M Masumoto, H Earnshaw, WC Larionov, V Kouprina, N AF Kononenko, Artem V. Lee, Nicholas C. O. Liskovykh, Mikhail Masumoto, Hiroshi Earnshaw, William C. Larionov, Vladimir Kouprina, Natalay TI Generation of a conditionally self-eliminating HAC gene delivery vector through incorporation of a tTA(VP64) expression cassette SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN ARTIFICIAL CHROMOSOMES; TRANSFORMATION-ASSOCIATED RECOMBINATION; SACCHAROMYCES-CEREVISIAE; GENOMIC LOCI; STEM-CELLS; DNA; YEAST; CENTROMERE; TRANSGENE; CLONING AB Human artificial chromosome (HAC)-based vectors represent an alternative technology for gene delivery and expression with a potential to overcome the problems caused by virus-based vectors. The recently developed alphoid(tetO)-HAC has an advantage over other HAC vectors because it can be easily eliminated from cells by inactivation of the HAC kinetochore via binding of chromatin modifiers, tTA or tTS, to its centromeric tetO sequences. This provides a unique control for phenotypes induced by genes loaded into the HAC. The alphoid(tetO)-HAC elimination is highly efficient when a high level of chromatin modifiers as tetR fusion proteins is achieved following transfection of cells by a retrovirus vector. However, such vectors are potentially mutagenic and might want to be avoided under some circumstances. Here, we describe a novel system that allows verification of phenotypic changes attributed to expression of genes from the HAC without a transfection step. We demonstrated that a single copy of tTA(VP64) carrying four tandem repeats of the VP16 domain constitutively expressed from the HAC is capable to generate chromatin changes in the HAC kinetochore that are not compatible with its function. To adopt the alphoid(tetO)-HAC for routine gene function studies, we constructed a new TAR-BRV-tTA(VP64) cloning vector that allows a selective isolation of a gene of interest from genomic DNA in yeast followed by its direct transfer to bacterial cells and subsequent loading into the loxP site of the alphoid(tetO)-HAC in hamster CHO cells from where the HAC may be MMCT-transferred to the recipient human cells. C1 [Kononenko, Artem V.; Lee, Nicholas C. O.; Liskovykh, Mikhail; Larionov, Vladimir; Kouprina, Natalay] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Frontier Res, Lab Cell Engn, Kisarazu, Chiba 2920818, Japan. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. RP Kouprina, N (reprint author), NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. EM larionov@mail.nih.gov; kouprinn@mail.nih.gov RI Lee, Nicholas/F-3668-2015 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA; Kazusa DNA Research Institute Foundation; Wellcome Trust [073915]; NIH FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA (V.L., N.K.); Kazusa DNA Research Institute Foundation (H.M.); Wellcome Trust of which W.C.E. is a Principal Research Fellow [073915]. Funding for open access charge: NIH. NR 58 TC 2 Z9 2 U1 2 U2 5 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 MAY 19 PY 2015 VL 43 IS 9 AR e57 DI 10.1093/nar/gkv124 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CK0XK UT WOS:000355928800001 PM 25712097 ER PT J AU Lark, DS Kang, L Lustig, ME Bonner, JS James, FD Neufer, PD Wasserman, DH AF Lark, Daniel S. Kang, Li Lustig, Mary E. Bonner, Jeffrey S. James, Freyja D. Neufer, P. Darrell Wasserman, David H. TI Enhanced Mitochondrial Superoxide Scavenging Does Not Improve Muscle Insulin Action in the High Fat-Fed Mouse SO PLOS ONE LA English DT Article ID SKELETAL-MUSCLE; GLUCOSE-HOMEOSTASIS; DISMUTASE PROTECTS; CONSCIOUS MOUSE; TRANSGENIC MICE; H2O2 EMISSION; CELL-DEATH; RESISTANCE; OVEREXPRESSION; ANTIOXIDANT AB Improving mitochondrial oxidant scavenging may be a viable strategy for the treatment of insulin resistance and diabetes. Mice overexpressing the mitochondrial matrix isoform of superoxide dismutase (sod2(tg) mice) and/or transgenically expressing catalase within the mitochondrial matrix (mcat(tg) mice) have increased scavenging of O-2(.-) and H2O2, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcat(tg) mice. The goal of the current study was to test the hypothesis that increased O-2(._) scavenging alone or in combination with increased H2O2 scavenging (mtAO mice) enhances in vivo muscle insulin action in the HF-fed mouse. Insulin action was examined in conscious, unrestrained and unstressed wild type (WT), sod2(tg), mcattg and mtAO mice using hyperinsulinemic-euglycemic clamps (insulin clamps) combined with radioactive glucose tracers following sixteen weeks of normal chow or HF (60% calories from fat) feeding. Glucose infusion rates, whole body glucose disappearance, and muscle glucose uptake during the insulin clamp were similar in chow- and HF-fed WT and sod2(tg) mice. Consistent with our previous work, HF-fed mcat(tg) mice had improved muscle insulin action, however, an additive effect was not seen in mtAO mice. Insulin-stimulated Akt phosphorylation in muscle from clamped mice was consistent with glucose flux measurements. These results demonstrate that increased O-2(._) scavenging does not improve muscle insulin action in the HF-fed mouse alone or when coupled to increased H2O2 scavenging. C1 [Lark, Daniel S.; Kang, Li; Lustig, Mary E.; Bonner, Jeffrey S.; James, Freyja D.; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. [Neufer, P. Darrell] E Carolina Univ, Dept Physiol, Greenville, NC USA. [Neufer, P. Darrell] E Carolina Univ, East Carolina Diabet & Obes Inst, Greenville, NC USA. [Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37235 USA. RP Lark, DS (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, 221 Kirkland Hall, Nashville, TN 37235 USA. EM daniel.lark@vanderbilt.edu OI Lark, Daniel/0000-0001-8386-8478 FU National Institutes of Health [DK054902, DK059637, DK007061, DK073488] FX This work was supported by National Institutes of Health Grants DK054902 (to D.H.W.), DK059637 (Vanderbilt-NIDDK Mouse Metabolic Phenotyping Center), DK007061 (to D.S.L.) and DK073488 (to P.D.N.). The authors would also like to acknowledge the Diabetes Research and Training Center (DK20593). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 2 Z9 2 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 19 PY 2015 VL 10 IS 5 AR UNSP e0126732 DI 10.1371/journal.pone.0126732 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI7BT UT WOS:000354918600041 PM 25992608 ER PT J AU Chang, YH Chen, SL Lee, SY Chen, PS Wang, TY Lee, IH Chen, KC Yang, YK Hong, JS Lu, RB AF Chang, Yun-Hsuan Chen, Shiou-Lan Lee, Sheng-Yu Chen, Po See Wang, Tzu-Yun Lee, I. Hui Chen, Kao Chin Yang, Yen Kuang Hong, Jau-Shyong Lu, Ru-Band TI Low-dose add-on memantine treatment may improve cognitive performance and self-reported health conditions in opioid-dependent patients undergoing methadone-maintenance-therapy SO SCIENTIFIC REPORTS LA English DT Article ID OPIATE TREATMENT INDEX; RECEPTOR ANTAGONIST; DISORDERS; BUPRENORPHINE; METAANALYSIS; AMPHETAMINE; RELIABILITY; DYSFUNCTION; IMPAIRMENT; DEMENTIA AB An important interaction between opioid and dopamine systems has been indicated, and using opioids may negatively affect cognitive functioning. Memantine, a medication for Alzheimer's disease, increasingly is being used for several disorders and maybe important for cognitive improvement. Opioid-dependent patients undergoing methadone-maintenance-therapy (MMT) and healthy controls (HCs) were recruited. Patients randomly assigned to the experimental (5 mg/day memantine (MMT+M) or placebo (MMT+P) group: 57 in MMT+M, 77 in MMT+P. Those completed the cognitive tasks at the baseline and after the 12-week treatment were analyzed. Thirty-seven age- and gender-matched HCs, and 42 MMT+P and 39 MMT+M patients were compared. The dropout rates were 49.4% in the MMT+P and 26.3% in the MMT+M. Both patient groups' cognitive performances were significantly worse than that of the HCs. After the treatment, both patient groups showed improved cognitive performance. We also found an interaction between the patient groups and time which indicated that the MMT+M group's post-treatment improvement was better than that of the MMT+P group. Memantine, previously reported as neuroprotective may attenuate chronic opioid-dependence-induced cognitive decline. Using such low dose of memantine as adjuvant treatment for improving cognitive performance in opioid dependents; the dose of memantine might be a worthy topic in future studies. C1 [Chang, Yun-Hsuan] Asia Univ, Dept Psychol, Taichung, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Allied Hlth Sci, Div Clin Psychol, Tainan 70101, Taiwan. [Chang, Yun-Hsuan; Chen, Po See; Wang, Tzu-Yun; Lee, I. Hui; Chen, Kao Chin; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Dept Psychiat, Tainan 70101, Taiwan. [Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Behav Med, Tainan 70101, Taiwan. [Chen, Po See; Yang, Yen Kuang] Natl Cheng Kung Univ, Coll Med, Addict Res Ctr, Tainan 70101, Taiwan. [Lee, Sheng-Yu; Chen, Po See; Wang, Tzu-Yun; Lee, I. Hui; Chen, Kao Chin; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ Hosp, Dept Psychiat, Tainan 70428, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Zhunan, Miaoli County, Taiwan. [Lee, I. Hui] Natl Cheng Kung Univ Hosp, Dou Liou Branch, Dept Psychiat, Yunlin, Taiwan. [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, Kaohsiung, Taiwan. [Chen, Shiou-Lan] Kaohsiung Med Univ, Coll Med, Dept Neurol, Kaohsiung, Taiwan. [Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Coll Med, Inst Allied Hlth Sci, Div Clin Psychol, Tainan 70101, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC 98-2627-B-006-017]; National Cheng Kung University Project to Promote Academic Excellence and Develop a World Class Research Center FX This study was supported in part by grant NSC 98-2627-B-006-017 from the Taiwan National Science Council (to RBL), and by a grant from the National Cheng Kung University Project to Promote Academic Excellence and Develop a World Class Research Center. NR 48 TC 2 Z9 2 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 19 PY 2015 VL 5 AR 9708 DI 10.1038/srep09708 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ2CQ UT WOS:000355292200001 PM 25989606 ER PT J AU Lee, SY Chen, SL Chang, YH Chen, PS Huang, SY Tzeng, NS Wang, LJ Lee, IH Wang, TY Chen, KC Yang, YK Hong, JS Lu, RB AF Lee, Sheng-Yu Chen, Shiou-Lan Chang, Yun-Hsuan Chen, Po See Huang, San-Yuan Tzeng, Nian-Sheng Wang, Liang-Jen Lee, I. Hui Wang, Tzu-Yun Chen, Kao Chin Yang, Yen Kuang Hong, Jau-Shyong Lu, Ru-Band TI Low-dose memantine attenuated methadone dose in opioid-dependent patients: a 12-week double-blind randomized controlled trial SO SCIENTIFIC REPORTS LA English DT Article ID PSYCHIATRIC-DISORDERS; NEUROTROPHIC FACTOR; OPIUM TARYAK; TNF-ALPHA; MORPHINE; INFLAMMATION; HEROIN; ANTAGONIST; ACTIVATION; MECHANISMS AB Low-dose memantine might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. We investigated whether add-on memantine reduced cytokine levels and benefitted patients with opioid dependence undergoing methadone maintenance therapy (MMT) in a randomized, double-blind, controlled 12-week study. Patients were randomly assigned to a group: Memantine (5 mg/day) (n = 53) or Placebo (n = 75). The methadone dose required and retention in treatment were monitored. Plasma tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP), interleukin (IL)-6, IL-8, transforming growth factor (TGF)-beta 1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. General linear mixed models were used to examine therapeutic effect. After 12 weeks, Memantine-group required a somewhat lower methadone dose than did Placebo-group (P = 0.039). They also had significantly lower plasma TNF-alpha and significantly higher TGF-beta 1 levels. We provide evidence of the benefit of add-on memantine in opioid dependent patients undergoing MMT. C1 [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, Kaohsiung, Taiwan. [Lee, Sheng-Yu; Chen, Shiou-Lan; Chen, Po See; Lee, I. Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Dept Psychiat, Coll Med & Hosp, Tainan 70101, Taiwan. [Chen, Shiou-Lan] Kaohsiung Med Univ, Sch Med, Dept Neurol, Kaohsiung, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Def Med Ctr, Inst Allied Hlth Sci, Taipei, Taiwan. [Huang, San-Yuan; Tzeng, Nian-Sheng] Natl Def Med Ctr, Dept Psychiat, Tri Serv Gen Hosp, Taipei, Taiwan. [Wang, Liang-Jen] Kaohsiung Chang Gung Mem Hosp, Dept Child & Adolescent Psychiat, Kaohsiung, Taiwan. [Wang, Liang-Jen] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Hong, Jau-Shyong] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Lu, Ru-Band] Natl Cheng Kung Univ, Inst Behav Med, Coll Med & Hosp, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Dept Psychiat, Coll Med & Hosp, Tainan 70101, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3]; Taiwan Department of Health [DOH 95-TD-M-113-055]; Taiwan National Health Research Institute [NHRI-EX-97-9738NI]; National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers FX We thank Dr Liang-Jen Wang for his statistical advice, and Ms Hong-Yi Chang for her assistance in preparing this manuscript. This work was supported in part by grant NSC98-2314-B-006-022-MY3 (to RBL) from the Taiwan National Science Council, grant DOH 95-TD-M-113-055 (to RBL) from the Taiwan Department of Health, grant NHRI-EX-97-9738NI (to RBL) from the Taiwan National Health Research Institute, and the National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers. NR 36 TC 1 Z9 1 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 19 PY 2015 VL 5 AR 10140 DI 10.1038/srep10140 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ2DM UT WOS:000355294400001 PM 25988317 ER PT J AU Fenollar-Ferrer, C Forster, IC Patti, M Knoepfel, T Werner, A Forrest, LR AF Fenollar-Ferrer, Cristina Forster, Ian C. Patti, Monica Knoepfel, Thomas Werner, Andreas Forrest, Lucy R. TI Identification of the First Sodium Binding Site of the Phosphate Cotransporter NaPi-IIa (SLC34A1) SO BIOPHYSICAL JOURNAL LA English DT Article ID NA+/P-I COTRANSPORTER; DEPENDENT DICARBOXYLATE TRANSPORTER; FUNCTIONALLY IMPORTANT SITES; SUBSTRATE INTERACTIONS; VOLTAGE-DEPENDENCE; MEMBRANE-PROTEINS; CATION; ELECTROGENICITY; MECHANISM; RESIDUES AB Transporters of the SLC34 family (NaPi-IIa,b,c) catalyze uptake of inorganic phosphate (P-i) in renal and intestinal epithelia. The transport cycle requires three Na+ ions and one divalent P-i to bind before a conformational change enables translocation, intracellular release of the substrates, and reorientation of the empty carrier. The electrogenic interaction of the first Na+ ion with NaPi-IIa/b at a postulated Na1 site is accompanied by charge displacement, and Na1 occupancy subsequently facilitates binding of a second Na+ ion at Na2. The voltage dependence of cotransport and presteady-state charge displacements (in the absence of a complete transport cycle) are directly related to the molecular architecture of the Na1 site. The fact that Li+ ions substitute for Na+ at Na1, but not at the other sites (Na2 and Na3), provides an additional tool for investigating Na1 site-specific events. We recently proposed a three-dimensional model of human SLC34a1 (NaPi-IIa) including the binding sites Na2, Na3, and P-i based on the crystal structure of the dicarboxylate transporter VcINDY. Here, we propose nine residues in transmembrane helices (TM2, TM3, and TM5) that potentially contribute to Na1. To verify their roles experimentally, we made single alanine substitutions in the human NaPi-IIa isoform and investigated the kinetic properties of the mutants by voltage clamp and P-32 uptake. Substitutions at five positions in TM2 and one in TM5 resulted in relatively small changes in the substrate apparent affinities, yet at several of these positions, we observed significant hyperpolarizing shifts in the voltage dependence. Importantly, the ability of Li+ ions to substitute for Na+ ions was increased compared with the wild-type. Based on these findings, we adjusted the regions containing Na1 and Na3, resulting in a refined NaPi-IIa model in which five positions (T200, Q206, D209, N227, and S447) contribute directly to cation coordination at Na1. C1 [Fenollar-Ferrer, Cristina; Forrest, Lucy R.] NINDS, Porter Neurosci Res Ctr, Computat Struct Biol Sect, NIH, Bethesda, MD 20892 USA. [Forster, Ian C.; Patti, Monica; Knoepfel, Thomas] Univ Zurich, Inst Physiol, Zurich, Switzerland. [Forster, Ian C.; Patti, Monica; Knoepfel, Thomas] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Werner, Andreas] Newcastle Univ, Epithelial Res Grp, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Forrest, LR (reprint author), NINDS, Porter Neurosci Res Ctr, Computat Struct Biol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM iforster@access.uzh.ch; andreas.werner@newcastle.ac.uk; lucy.forrest@nih.gov FU Dunhill Medical Trust [AW SA10/0210]; Swiss National Science Foundation; Hartmann Muller Foundation; NIH, National Institute of Neurological Disorders and Stroke FX This work was supported by The Dunhill Medical Trust (AW SA10/0210), the Swiss National Science Foundation (I.C.F.), the Hartmann Muller Foundation (I.C.F.), and the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke (L.R.F.). NR 37 TC 5 Z9 5 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD MAY 19 PY 2015 VL 108 IS 10 BP 2465 EP 2480 DI 10.1016/j.bpj.2015.03.054 PG 16 WC Biophysics SC Biophysics GA CI5VF UT WOS:000354827200007 PM 25992725 ER PT J AU Norouzi, D Zhurkin, VB AF Norouzi, Davood Zhurkin, Victor B. TI Topological Polymorphism of the Two-Start Chromatin Fiber SO BIOPHYSICAL JOURNAL LA English DT Article ID HIGHER-ORDER STRUCTURE; NUCLEOSOME CORE PARTICLE; LINKING NUMBER; MOLECULAR-DYNAMICS; REPEAT LENGTH; LINKER LENGTH; DOUBLE HELIX; DNA; ORIENTATION; REVEALS AB Specific details concerning the spatial organization of nucleosomes in 30 nm fibers remain unknown. To investigate this, we analyzed all stereochemically possible configurations of two-start nucleosome fibers with short DNA linkers L = 13-37 bp (nucleosome repeat length (NRL) = 160-184 bp). Four superhelical parameters-inclination of nucleosomes, twist, rise, and diameter-uniquely describe a regular symmetric fiber. The energy of a fiber is defined as the sum of four terms: elastic energy of the linker DNA, steric repulsion, electrostatics, and a phenomenological (H4 tail-acidic patch) interaction between two stacked nucleosomes. By optimizing the fiber energy with respect to the superhelical parameters, we found two types of topological transition in fibers (associated with the change in inclination angle): one caused by an abrupt 360 degrees change in the linker DNA twisting (change in the DNA linking number, Delta Lk = 1), and another caused by overcrossing of the linkers (Delta Lk = 2). To the best of our knowledge, this topological polymorphism of the two-start fibers was not reported in the computations published earlier. Importantly, the optimal configurations of the fibers with linkers L = 10n and 10n + 5 bp are characterized by different values of the DNA linking number-that is, they are topologically different. Our results are consistent with experimental observations, such as the inclination 60 degrees to 70 degrees (the angle between the nucleosomal disks and the fiber axis), helical rise, diameter, and left-handedness of the fibers. In addition, we make several testable predictions, among them different degrees of DNA supercoiling in fibers with L = 10n and 10n + 5 bp, different flexibility of the two types of fibers, and a correlation between the local NRL and the level of transcription in different parts of the yeast genome. C1 [Norouzi, Davood; Zhurkin, Victor B.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zhurkin, VB (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM zhurkin@nih.gov FU NIH Intramural Research Program FX We are grateful to Wilma Olson and Sergei Grigoryev for sharing their unpublished observations and valuable discussions and to George Leiman for text editing. We appreciate constructive critical remarks by anonymous reviewers. The research was supported by the NIH Intramural Research Program. NR 55 TC 9 Z9 10 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD MAY 19 PY 2015 VL 108 IS 10 BP 2591 EP 2600 DI 10.1016/j.bpj.2015.04.015 PG 10 WC Biophysics SC Biophysics GA CI5VF UT WOS:000354827200019 PM 25992737 ER PT J AU Givertz, MM Anstrom, KJ Redfield, MM Deswal, A Haddad, H Butler, J Tang, WHW Dunlap, ME LeWinter, MM Mann, DL Felker, GM O'Connor, CM Goldsmith, SR Ofili, EO Saltzberg, MT Margulies, KB Cappola, TP Konstam, MA Semigran, MJ McNulty, SE Lee, KL Shah, MR Hernandez, AF AF Givertz, Michael M. Anstrom, Kevin J. Redfield, Margaret M. Deswal, Anita Haddad, Haissam Butler, Javed Tang, W. H. Wilson Dunlap, Mark E. LeWinter, Martin M. Mann, Douglas L. Felker, G. Michael O'Connor, Christopher M. Goldsmith, Steven R. Ofili, Elizabeth O. Saltzberg, Mitchell T. Margulies, Kenneth B. Cappola, Thomas P. Konstam, Marvin A. Semigran, Marc J. McNulty, Steven E. Lee, Kerry L. Shah, Monica R. Hernandez, Adrian F. CA NHLBI Heart Failure Clinical Res TI Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study SO CIRCULATION LA English DT Article DE allopurinol; clinical trial; heart failure; xanthine oxidase ID NITROSO-REDOX IMBALANCE; LEFT-VENTRICULAR MASS; URIC-ACID; OXIDATIVE STRESS; ALLOPURINOL USE; HEALTH-STATUS; OXYPURINOL; SURVIVAL; TRIAL; CARDIOMYOPATHY AB Background-Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results-We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction <= 40%, and serum uric acid levels >= 9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, -4.2 [-4.9, -3.5] mg/dL and -3.5 [-4.2, -2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol-and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36). Conclusions-In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. C1 [Givertz, Michael M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Anstrom, Kevin J.; Felker, G. Michael; O'Connor, Christopher M.; McNulty, Steven E.; Lee, Kerry L.; Hernandez, Adrian F.] Duke Univ, Med Ctr, Durham, NC USA. [Redfield, Margaret M.] Mayo Clin, Rochester, MN USA. [Deswal, Anita] Baylor Coll Med, Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Haddad, Haissam] Ottawa Heart Inst, Ottawa, ON, Canada. [Butler, Javed] Emory Univ, Atlanta, GA 30322 USA. [Tang, W. H. Wilson] Cleveland Clin, Cleveland, OH USA. [Dunlap, Mark E.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [LeWinter, Martin M.] Univ Vermont, Burlington, VT 05405 USA. [Mann, Douglas L.] Washington Univ, St Louis, MO USA. [Goldsmith, Steven R.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Saltzberg, Mitchell T.] Christiana Care Hlth Syst, Newark, DE USA. [Margulies, Kenneth B.; Cappola, Thomas P.] Univ Penn, Philadelphia, PA 19104 USA. [Konstam, Marvin A.] Tufts Med Ctr, Boston, MA USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shah, Monica R.] NHLBI, Bethesda, MD 20892 USA. RP Givertz, MM (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM mgivertz@partners.org RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU National Institutes of Health: NHLBI [U10HL084904, U01HL084861, U10HL110312, U109HL110337, U01HL084889, U01HL084890, U01HL084891, U10HL110342, U10HL110262, U01HL084931, U10HL110297, U10HL110302, U10 HL110309, U10HL110336, U10HL110338]; National Center for Advancing Translational Sciences [UL1TR000454, UL1TR000439]; National Institute on Minority Health and Health Disparities [8 U54 MD007588] FX This work was supported by grants from the National Institutes of Health: NHLBI (coordinating center: U10HL084904; regional clinical centers: U01HL084861, U10HL110312, U109HL110337, U01HL084889, U01HL084890, U01HL084891, U10HL110342, U10HL110262, U01HL084931, U10HL110297, U10HL110302, U10 HL110309, U10HL110336, U10HL110338); the National Center for Advancing Translational Sciences (UL1TR000454, UL1TR000439); and the National Institute on Minority Health and Health Disparities (8 U54 MD007588). NR 41 TC 34 Z9 34 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 19 PY 2015 VL 131 IS 20 BP 1763 EP 1771 DI 10.1161/CIRCULATIONAHA.114.014536 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CI2XC UT WOS:000354610300013 PM 25986447 ER PT J AU Mitra, S Ring, AM Amarnath, S Spangler, JB Li, P Ju, W Fischer, S Oh, J Spolski, R Weiskopf, K Kohrt, H Foley, JE Rajagopalan, S Long, EO Fowler, DH Waldmann, TA Garcia, KC Leonard, WJ AF Mitra, Suman Ring, Aaron M. Amarnath, Shoba Spangler, Jamie B. Li, Peng Ju, Wei Fischer, Suzanne Oh, Jangsuk Spolski, Rosanne Weiskopf, Kipp Kohrt, Holbrook Foley, Jason E. Rajagopalan, Sumati Long, Eric O. Fowler, Daniel H. Waldmann, Thomas A. Garcia, K. Christopher Leonard, Warren J. TI Interleukin-2 Activity Can Be Fine Tuned with Engineered Receptor Signaling Clamps SO IMMUNITY LA English DT Article ID GAMMA-CHAIN; IL-2 RECEPTOR; BETA-CHAIN; CARDIAC TRANSPLANTATION; CYTOPLASMIC DOMAINS; MONOCLONAL-ANTIBODY; ALPHA-RECEPTOR; T-LYMPHOCYTES; HOST-DISEASE; CELLS AB Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2R beta and gamma(c) receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 "superkine'' with enhanced affinity for IL-2R beta. Here, we describe next-generation IL-2 variants that function as "receptor signaling clamps.'' They retained high affinity for IL-2R beta, inhibiting binding of endogenous IL-2, but their interaction with gamma(c) was weakened, attenuating IL-2R beta-gamma(c) heterodimerization. These IL-2 analogs acted as partial agonists and differentially affected lymphocytes poised at distinct activation thresholds. Moreover, one variant, H9-RETR, antagonized IL-2 and IL-15 better than blocking antibodies against IL-2R alpha or IL-2R beta. Furthermore, this mutein prolonged survival in a model of graft-versus-host disease and blocked spontaneous proliferation of smoldering adult T cell leukemia (ATL) T cells. This receptor-clamping approach might be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation. C1 [Mitra, Suman; Li, Peng; Oh, Jangsuk; Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Mitra, Suman; Li, Peng; Oh, Jangsuk; Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Ring, Aaron M.; Spangler, Jamie B.; Fischer, Suzanne; Garcia, K. Christopher] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. [Ring, Aaron M.; Spangler, Jamie B.; Fischer, Suzanne; Garcia, K. Christopher] Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA. [Ring, Aaron M.; Spangler, Jamie B.; Fischer, Suzanne; Garcia, K. Christopher] Stanford Univ, Dept Biol Struct, Sch Med, Stanford, CA 94305 USA. [Amarnath, Shoba; Foley, Jason E.; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Ju, Wei; Waldmann, Thomas A.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Weiskopf, Kipp; Kohrt, Holbrook] Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA. [Rajagopalan, Sumati; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Garcia, KC (reprint author), Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. EM kcgarcia@stanford.edu; wjl@helix.nih.gov FU Divisions of Intramural Research, National Heart, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Diseases; Leukemia & Lymphoma Society; [NIH-R0AI51321]; [NIH-F30DK094541] FX This work was supported by the Divisions of Intramural Research, National Heart, Lung, and Blood Institute (S.M., P.L., J.O., R.S., and W.J.L.), National Cancer Institute (S.M., W.J., D.H.F., and T.A.W.), National Institute of Allergy and Infectious Diseases (S.R. and E.O.L), NIH-R0AI51321 (K.C.G.), and NIH-F30DK094541 (A.M.R.). K.C.G. is an investigator of the Howard Hughes Medical Institute. J.B.S. is the recipient of a Leukemia & Lymphoma Society Career Development Program fellowship. We thank Dr. Junji Yodoi, Kyoto University, for YT and YT-1 NK-like cells. NR 48 TC 14 Z9 14 U1 5 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAY 19 PY 2015 VL 42 IS 5 BP 826 EP 838 DI 10.1016/j.immuni.2015.04.018 PG 13 WC Immunology SC Immunology GA CI5VH UT WOS:000354827400010 PM 25992859 ER PT J AU Ritter, AT Asano, Y Stinchcombe, JC Dieckmann, NMG Chen, BC Gawden-Bone, C van Engelenburg, S Legant, W Gao, L Davidson, MW Betzig, E Lippincott-Schwartz, J Griffiths, GM AF Ritter, Alex T. Asano, Yukako Stinchcombe, Jane C. Dieckmann, N. M. G. Chen, Bi-Chang Gawden-Bone, C. van Engelenburg, Schuyler Legant, Wesley Gao, Liang Davidson, Michael W. Betzig, Eric Lippincott-Schwartz, Jennifer Griffiths, Gillian M. TI Actin Depletion Initiates Events Leading to Granule Secretion at the Immunological Synapse SO IMMUNITY LA English DT Article ID T-CELL-RECEPTOR; RETROGRADE FLOW; F-ACTIN; ACTIVATION; MICROCLUSTERS; ADHESION; DOMAIN; POLYMERIZATION; REORIENTATION; ACCUMULATION AB Cytotoxic T lymphocytes (CTLs) use polarized secretion to rapidly destroy virally infected and tumor cells. To understand the temporal relationships between key events leading to secretion, we used high-resolution 4D imaging. CTLs approached targets with actin-rich projections at the leading edge, creating an initially actin-enriched contact with rearward-flowing actin. Within 1 min, cortical actin reduced across the synapse, T cell receptors (TCRs) clustered centrally to form the central supramolecular activation cluster (cSMAC), and centrosome polarization began. Granules clustered around the moving centrosome within 2.5 min and reached the synapse after 6 min. TCR-bearing intracellular vesicles were delivered to the cSMAC as the centrosome docked. We found that the centrosome and granules were delivered to an area of membrane with reduced cortical actin density and phospholipid PIP2. These data resolve the temporal order of events during synapse maturation in 4D and reveal a critical role for actin depletion in regulating secretion. C1 [Ritter, Alex T.; Asano, Yukako; Stinchcombe, Jane C.; Dieckmann, N. M. G.; Gawden-Bone, C.; Griffiths, Gillian M.] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Ritter, Alex T.; van Engelenburg, Schuyler; Lippincott-Schwartz, Jennifer] NICHD, NIH, Bethesda, MD 20892 USA. [Chen, Bi-Chang; Legant, Wesley; Gao, Liang; Betzig, Eric] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32304 USA. [Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32304 USA. RP Lippincott-Schwartz, J (reprint author), NICHD, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov; gg305@cam.ac.uk RI Chen , Bi-Chang /F-3480-2014; OI Griffiths, Gillian/0000-0003-0434-5842 FU Wellcome Trust [075880, 103930]; Eunice Shriver National Institute of Child Health and Human Development; [100140] FX Funding was provided by the Wellcome Trust through Principal Research Fellowships (075880 and 103930) to G.M.G. and a Strategic Award (100140) to the Cambridge Institute for Medical Research (CIMR). A.T.R. is an NIH-OxCam scholar supported by funding to J.L.-S. from the Eunice Shriver National Institute of Child Health and Human Development. At the NIH, we thank Senta Kapnick and Pam Schwartzberg for assistance with CTL culture and helpful discussion, P. Sengupta for Farnesyl-EGFP, and Erin Fincher for assistance with the graphic illustration. At the CIMR, we thank Matthew Gratian and Mark Bowen for support with imaging and Alison Schuldt and John James for critical reading of the manuscript. The light-sheet technology used herein is covered by US patent 7,894,136 (issued to E.B. and assigned to Lattice Light LLC of Ashburn, VA), US patent 8,711,211 (issued to E.B. and assigned to the Howard Hughes Medical Institute [HHMI]), and US patent application 13/844,405 (filed by E.B. and assigned to the HHMI). NR 42 TC 28 Z9 28 U1 3 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAY 19 PY 2015 VL 42 IS 5 BP 864 EP 876 DI 10.1016/j.immuni.2015.04.013 PG 13 WC Immunology SC Immunology GA CI5VH UT WOS:000354827400013 PM 25992860 ER PT J AU Hirahara, K Onodera, A Villarino, AV Bonelli, M Sciume, G Laurence, A Sun, HW Brooks, SR Vahedi, G Shih, HY Gutierrez-Cruz, G Iwata, S Suzuki, R Mikami, Y Okamoto, Y Nakayama, T Holland, SM Hunter, CA Kanno, Y O'Shea, JJ AF Hirahara, Kiyoshi Onodera, Atsushi Villarino, Alejandro V. Bonelli, Michael Sciume, Giuseppe Laurence, Arian Sun, Hong-Wei Brooks, Stephen R. Vahedi, Golnaz Shih, Han-Yu Gutierrez-Cruz, Gustavo Iwata, Shigeru Suzuki, Ryo Mikami, Yohei Okamoto, Yoshitaka Nakayama, Toshinori Holland, Steven M. Hunter, Christopher A. Kanno, Yuka O'Shea, John J. TI Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity SO IMMUNITY LA English DT Article ID CD4(+) T-CELLS; INTERFERON-GAMMA; CUTTING EDGE; TH17 CELLS; IL-27; INTERLEUKIN-27; ACTIVATION; RECEPTOR; DIFFERENTIATION; INDUCTION AB Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins, but yet are ascribed unique and overlapping functions. To evaluate the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and chromatin immunoprecipitation- sequencing (ChIP-seq) approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action. C1 [Hirahara, Kiyoshi; Villarino, Alejandro V.; Bonelli, Michael; Sciume, Giuseppe; Laurence, Arian; Vahedi, Golnaz; Shih, Han-Yu; Iwata, Shigeru; Mikami, Yohei; Kanno, Yuka; O'Shea, John J.] NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Sun, Hong-Wei; Brooks, Stephen R.] NIAMS, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Gutierrez-Cruz, Gustavo] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Suzuki, Ryo] NIAMS, Lab Mol Immunogenet, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hunter, Christopher A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Hirahara, Kiyoshi] Chiba Univ, Grad Sch Med, Dept Adv Allergol Airway, Chiba 2608670, Japan. [Onodera, Atsushi; Nakayama, Toshinori] Chiba Univ, Grad Sch Med, Dept Immunol, Chiba 2608670, Japan. [Okamoto, Yoshitaka] Chiba Univ, Grad Sch Med, Dept Otorhinolaryngol, Chiba 2608670, Japan. [Nakayama, Toshinori] Core Res Evolut Sci & Technol, Japan Sci & Technol Agcy, Chiba, Chiba 2608670, Japan. RP Kanno, Y (reprint author), NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM kannoy@mail.nih.gov; osheaj@arb.niams.nih.gov RI Laurence, Arian/A-8770-2009; Sciume, Giuseppe/K-8985-2016; Nakayama, Toshinori/E-1067-2017; Hirahara, Kiyoshi/E-2460-2017; Onodera, Atsushi/E-3136-2017; OI Laurence, Arian/0000-0003-0942-8292; Sciume, Giuseppe/0000-0003-0131-512X; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319; Villarino, Alejandro/0000-0001-8068-2176 FU Intramural Research Programs of NIAMS; Ministry of Education, Culture, Sports, Science and Technology (Japan) [25893032]; Astellas Foundation for Research on Metabolic Disorders; Uehara Memorial Foundation; Osaka Foundation for Promotion of Fundamental Medical Research; Kanae Foundation for the Promotion of Medical Science; Takeda Science Foundation FX We thank J. Simone, J. Lay (Flow Cytometry Section, NIAMS), and the NIAMS LACU staff for their excellent technical support. This study utilized the high-performance computational capabilities of the Helix Systems at the NIH. This work was supported by the Intramural Research Programs of NIAMS, grant from the Ministry of Education, Culture, Sports, Science and Technology (Japan; Grants-in-Aid for Research Activity start-up #25893032), The Astellas Foundation for Research on Metabolic Disorders, The Uehara Memorial Foundation, Osaka Foundation for Promotion of Fundamental Medical Research, Kanae Foundation for the Promotion of Medical Science, and Takeda Science Foundation (K.H.). NR 50 TC 23 Z9 23 U1 5 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAY 19 PY 2015 VL 42 IS 5 BP 877 EP 889 DI 10.1016/j.immuni.2015.04.014 PG 13 WC Immunology SC Immunology GA CI5VH UT WOS:000354827400014 PM 25992861 ER PT J AU Butt, D Chan, TD Bourne, K Hermes, JR Nguyen, A Statham, A O'Reilly, LA Strasser, A Price, S Schofield, P Christ, D Basten, A Ma, CS Tangye, SG Phan, TG Rao, VK Brink, R AF Butt, Danyal Chan, Tyani D. Bourne, Katherine Hermes, Jana R. Nguyen, Akira Statham, Aaron O'Reilly, Lorraine A. Strasser, Andreas Price, Susan Schofield, Peter Christ, Daniel Basten, Antony Ma, Cindy S. Tangye, Stuart G. Tri Giang Phan Rao, V. Koneti Brink, Robert TI FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production SO IMMUNITY LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; SYSTEMIC-LUPUS-ERYTHEMATOSUS; T-CELLS; GENE-MUTATIONS; IN-VIVO; LIGAND; APOPTOSIS; MICE; DISEASE; ELIMINATION AB The mechanistic links between genetic variation and autoantibody production in autoimmune disease remain obscure. Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL, with autoantibodies thought to arise through failure of FAS-mediated removal of self-reactive germinal center (GC) B cells. Here we show that FAS is in fact not required for this process. Instead, FAS inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation, survived despite losing antigen reactivity, and differentiated into a large population of plasma cells that included autoantibody-secreting clones. IgE(+) plasma cell numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated "rogue GC B cells,'' are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease. C1 [Butt, Danyal; Chan, Tyani D.; Bourne, Katherine; Hermes, Jana R.; Nguyen, Akira; Statham, Aaron; Schofield, Peter; Christ, Daniel; Basten, Antony; Ma, Cindy S.; Tangye, Stuart G.; Tri Giang Phan; Brink, Robert] Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW 2010, Australia. [Butt, Danyal; Chan, Tyani D.; Christ, Daniel; Basten, Antony; Ma, Cindy S.; Tangye, Stuart G.; Tri Giang Phan; Brink, Robert] UNSW Australia, St Vincents Clin Sch, Darlinghurst, NSW 2010, Australia. [O'Reilly, Lorraine A.; Strasser, Andreas] Walter & Eliza Hall Inst Med Res, Mol Genet Canc Div, Parkville, Vic 3052, Australia. [O'Reilly, Lorraine A.; Strasser, Andreas] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. [Price, Susan; Rao, V. Koneti] NIAID, Mol Dev Sect, Immunol Lab, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Brink, R (reprint author), Garvan Inst Med Res, Div Immunol, 384 Victoria St, Darlinghurst, NSW 2010, Australia. EM r.brink@garvan.org.au RI Strasser, Andreas/C-7581-2013; OI Strasser, Andreas/0000-0002-5020-4891 FU Australian Postgraduate Award; National Health and Medical Research Council (NHMRC) [1054669, 1020363, 1050146, 1008820, 1042925, 1005097, 1002280]; Asthma Foundation NSW; R.G. Arnott Foundation; NHMRC [1044477, 1016953, 1009145, 1016701]; Leukemia and Lymphoma Society (SCOR) [7413, 7001-13]; National Institute of Allergy and Infectious Diseases; NIH Clinical Center FX We thank R. Salomon, C. Brownlee, and Garvan Institute Flow Facility staff for single-cell sorting and J. Kingham and the staff of Australian BioResources for animal husbandry. We also thank C. Goodnow, A. Collins, and J. Davies for their comments on the manuscript. D.B. is supported by an Australian Postgraduate Award and T.D.C., A. Strasser, D. C., C.S.M., S.G.T., T.G.P., and R.B. by National Health and Medical Research Council (NHMRC) fellowships 1054669, 1020363, 1050146, 1008820, 1042925, 1005097, and 1002280. This work was funded by Asthma Foundation NSW, R.G. Arnott Foundation, NHMRC Project Grant 1044477, and NHMRC Program Grant 1016953. Additional support came from NHMRC Project Grant 1009145, NHMRC Program Grant 1016701, Leukemia and Lymphoma Society (SCOR grants #7413 and #7001-13), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the NIH Clinical Center. NR 44 TC 11 Z9 11 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAY 19 PY 2015 VL 42 IS 5 BP 890 EP 902 DI 10.1016/j.immuni.2015.04.010 PG 13 WC Immunology SC Immunology GA CI5VH UT WOS:000354827400015 PM 25979420 ER PT J AU Devanathan, V Hagedorn, I Kohler, D Pexa, K Cherpokova, D Kraft, P Singh, M Rosenberger, P Stoll, G Birnbaumer, L Piekorz, RP Beer-Hammer, S Nieswandt, B Nurnberg, B AF Devanathan, Vasudharani Hagedorn, Ina Koehler, David Pexa, Katja Cherpokova, Deya Kraft, Peter Singh, Madhurendra Rosenberger, Peter Stoll, Guido Birnbaumer, Lutz Piekorz, Roland P. Beer-Hammer, Sandra Nieswandt, Bernhard Nuernberg, Bernd TI Platelet G(i) protein G alpha(i2) is an essential mediator of thrombo-inflammatory organ damage in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE G proteins; platelets; ischemia reperfusion injury; P2Y(12) receptor; thrombosis ID CARDIOVASCULAR-DISEASE; ARTERIAL THROMBOSIS; REPERFUSION INJURY; ISCHEMIC-STROKE; FAMILY MEMBERS; BLEEDING-TIME; ACTIVATION; RECEPTOR; P2Y(12); AGGREGATION AB Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The G(i) protein G alpha(i2) mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking G alpha(i2) exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking G alpha(i2) in megakaryocytes and platelets (Gnai2(fl/fl)/PF4-Cre mice) and found bleeding defects comparable to those in global G alpha(i2)-deficient mice. To examine the impact of platelet G alpha(i2) in postischemic thrombo-inflammatory infarct progression, Gnai2(fl/fl)/PF4-Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gnai2(fl/fl)/PF4-Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gnai2(fl/fl)/PF4-Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet G alpha(i2) not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo. C1 [Devanathan, Vasudharani; Beer-Hammer, Sandra; Nuernberg, Bernd] Univ Tubingen, Dept Pharmacol & Expt Therapy, D-72074 Tubingen, Germany. [Devanathan, Vasudharani; Beer-Hammer, Sandra; Nuernberg, Bernd] Univ Tubingen, Interfac Ctr Pharmacogen & Drug Res, D-72074 Tubingen, Germany. [Koehler, David; Rosenberger, Peter] Univ Tubingen, Dept Anesthesiol & Intens Care Med, D-72076 Tubingen, Germany. [Hagedorn, Ina; Cherpokova, Deya; Nieswandt, Bernhard] Univ Wurzburg, Univ Hosp, Dept Expt Biomed, D-97080 Wurzburg, Germany. [Cherpokova, Deya; Nieswandt, Bernhard] Univ Wurzburg, Rudolf Virchow Ctr, D-97080 Wurzburg, Germany. [Kraft, Peter; Stoll, Guido] Univ Wurzburg, Dept Neurol, D-97080 Wurzburg, Germany. [Pexa, Katja; Singh, Madhurendra; Piekorz, Roland P.] Univ Dusseldorf, Inst Biochem & Mol Biol 2, D-40225 Dusseldorf, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27009 USA. RP Birnbaumer, L (reprint author), NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27009 USA. EM birnbau1@gmail.com; bernd.nuernberg@uni-tuebingen.de FU Deutsche Forschungsgemeinschaft [Sonderforschungsbereich (SFB) 612, MO2252/1, SFB 688]; Forschungskommission (Medical Faculty) of the Dusseldorf University [9772327, 9772517]; Dusseldorf Entrepreneurs Foundation ("Qiagen-Stiftung"); Intramural Research Program of the National Institutes of Health Grant [Z01-ES101643] FX We thank Sandra Schwegmann, Michaela Hoch-Gutbrod, and Dr. Claudia Bernardo de Oliviera Franz for excellent technical assistance and Christian Harteneck for critical discussions. This work was supported by Deutsche Forschungsgemeinschaft Grants Sonderforschungsbereich (SFB) 612 (to R.P.P. and B. Nurnberg), MO2252/1 (to D.K.), and SFB 688 (to B. Nieswandt and G.S.); Forschungskommission (Medical Faculty) of the Dusseldorf University Grants 9772327 (to R.P.P. and B. Nurnberg) and 9772517 (to R.P.P.); a grant from the Dusseldorf Entrepreneurs Foundation ("Qiagen-Stiftung") (to K.P.); and the Intramural Research Program of the National Institutes of Health Grant Z01-ES101643 (to L.B.). NR 49 TC 4 Z9 4 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 19 PY 2015 VL 112 IS 20 BP 6491 EP 6496 DI 10.1073/pnas.1505887112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI4OD UT WOS:000354729500074 PM 25944935 ER PT J AU Jorgenson, LA Newsome, WT Anderson, DJ Bargmann, CI Brown, EN Deisseroth, K Donoghue, JP Hudson, KL Ling, GSF MacLeish, PR Marder, E Normann, RA Sanes, JR Schnitzer, MJ Sejnowski, TJ Tank, DW Tsien, RY Ugurbil, K Wingfield, JC AF Jorgenson, Lyric A. Newsome, William T. Anderson, David J. Bargmann, Cornelia I. Brown, Emery N. Deisseroth, Karl Donoghue, John P. Hudson, Kathy L. Ling, Geoffrey S. F. MacLeish, Peter R. Marder, Eve Normann, Richard A. Sanes, Joshua R. Schnitzer, Mark J. Sejnowski, Terrence J. Tank, David W. Tsien, Roger Y. Ugurbil, Kamil Wingfield, John C. TI The BRAIN Initiative: developing technology to catalyse neuroscience discovery SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE BRAIN Initiative; neural circuitry; neurotechnology ID RETINAL CELL-TYPES; NEURAL CIRCUITS; FUNCTIONAL ARCHITECTURE; SENSORY STIMULATION; CEREBRAL-CORTEX; VISUAL-CORTEX; RESOLUTION; NEURONS; RECONSTRUCTION; OPTOGENETICS AB The evolution of the field of neuroscience has been propelled by the advent of novel technological capabilities, and the pace at which these capabilities are being developed has accelerated dramatically in the past decade. Capitalizing on this momentum, the United States launched the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative to develop and apply new tools and technologies for revolutionizing our understanding of the brain. In this article, we review the scientific vision for this initiative set forth by the National Institutes of Health and discuss its implications for the future of neuroscience research. Particular emphasis is given to its potential impact on the mapping and study of neural circuits, and how this knowledge will transform our understanding of the complexity of the human brain and its diverse array of behaviours, perceptions, thoughts and emotions. C1 [Jorgenson, Lyric A.; Hudson, Kathy L.] NIH, Off Director, Bethesda, MD 20892 USA. [Newsome, William T.; Deisseroth, Karl; Schnitzer, Mark J.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Newsome, William T.] Stanford Univ, Stanford Neurosdences Inst, Stanford, CA 94305 USA. [Anderson, David J.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. [Anderson, David J.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Bargmann, Cornelia I.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Bargmann, Cornelia I.] Rockefeller Univ, Lulu & Anthony Wang Lab Neural Circuits & Behav, New York, NY 10065 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Deisseroth, Karl] Stanford Univ, Dept Psychiat & Behav Sci, Dept Bioengn, Stanford, CA 94305 USA. [Donoghue, John P.] Brown Univ, Brown Inst Brain Sci, Providence, RI 02912 USA. [Ling, Geoffrey S. F.] Def Adv Res Projects Agcy, Biol Technol Off, Arlington, VA 22203 USA. [MacLeish, Peter R.] Morehouse Sch Med, Neurosci Inst, Dept Neurobiol, Atlanta, GA 30310 USA. [Marder, Eve] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. [Marder, Eve] Brandeis Univ, Volen Ctr, Waltham, MA 02454 USA. [Normann, Richard A.] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. [Sanes, Joshua R.] Harvard Univ, Ctr Brain Sci, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Schnitzer, Mark J.] Stanford Univ, James H Clark Ctr Biomed Engn & Sci, CNC Program, Stanford, CA 94305 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA. [Tank, David W.] Princeton Univ, Princeton Neurosci Inst, Bezos Ctr Neural Circuit Dynam, Princeton, NJ 08544 USA. [Tank, David W.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Tsien, Roger Y.] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA. [Tsien, Roger Y.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Ugurbil, Kamil] Univ Minnesota, Ctr Magnet Resonance Res, Minneapolis, MN 55454 USA. [Wingfield, John C.] Natl Sci Fdn, Directorate Biol Sci, Arlington, VA 22230 USA. RP Jorgenson, LA (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM bnewsome@stanford.edu OI Bargmann, Cornelia/0000-0002-8484-0618 FU National Institutes of Health; Howard Hughes Medical Institute FX The authors thank the National Institutes of Health and the Howard Hughes Medical Institute for supporting the publication of this article. NR 82 TC 22 Z9 23 U1 5 U2 37 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAY 19 PY 2015 VL 370 IS 1668 BP 8 EP 19 AR UNSP 20140164 DI 10.1098/rstb.2014.0164 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CH5JH UT WOS:000354071400002 ER PT J AU Kim, S Rimando, J Sandler, DP AF Kim, Sangmi Rimando, Joseph Sandler, Dale P. TI Fruit and Vegetable Intake and Urinary Levels of Prostaglandin E-2 Metabolite in Postmenopausal Women SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID C-REACTIVE PROTEIN; NUTRITION EXAMINATION SURVEY; TOTAL ANTIOXIDANT CAPACITY; HEALTHY EATING INDEX; OXIDATIVE STRESS; CANCER RISK; ENDOTHELIAL ACTIVATION; COLORECTAL-CANCER; DIETARY PATTERNS; NATIONAL-HEALTH AB Prostaglandin E-2 (PGE(2)) is an inflammatory mediator that plays key roles in promoting tumor development and progression. Urinary concentration of a major PGE(2) metabolite (PGE-M) has been recently proposed as a promising cancer biomarker. Using dietary intake data from 600 postmenopausal women aged 50-74years, we examined cross-sectional relationships between fruit and vegetable intake and urinary levels of PGE-M, determined using liquid chromatography/tandem mass spectrometry. After multivariable adjustment, increasing consumption of fruits, but not vegetables, was associated with reduced levels of urinary PGE-M (P for linear trend = 0.02), with geometric means of 5.8 [95% confidence interval (CI): 5.2-6.6] in the lowest quintile versus 4.8 (95% CI: 4.3-5.4) in the highest quintile (Q5) of fruit consumption. A better quality diet, indicated by higher scores on the Healthy Eating Index, was also associated with decreased PGE-M (P for linear trend <0.01). The lack of association with vegetable intake may be related to variation in antioxidant capacities of the major dietary sources of fruits and vegetables for the study participants. Our findings suggest that urinary PGE-M may be modifiable by a healthy diet that follows current national dietary guideline. Further studies are warranted to assess potential utility of urinary PGE-M in assessing cancer prevention efficacy. C1 [Kim, Sangmi; Rimando, Joseph] Georgia Regents Univ, Med Coll Georgia, Ctr Canc, Dept Med,Sect Hematol Oncol, Augusta, GA 30912 USA. [Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Kim, S (reprint author), Georgia Regents Univ, Med Coll Georgia, Ctr Canc, Dept Med,Sect Hematol Oncol, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. EM sankim@gru.edu OI Sandler, Dale/0000-0002-6776-0018 FU Department of Defense Breast Cancer Postdoctoral Fellowship [BC0923202]; NIH, National Institute of Environmental Health Sciences [Z01 ES044005] FX This work was supported in part by Department of Defense Breast Cancer Postdoctoral Fellowship BC0923202 and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044005). NR 43 TC 1 Z9 1 U1 1 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PD MAY 19 PY 2015 VL 67 IS 4 BP 580 EP 586 DI 10.1080/01635581.2015.1011787 PG 7 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA CH1HC UT WOS:000353771000004 PM 25811232 ER PT J AU Munoz-Lopez, M Insausti, R Mohedano-Moriano, A Mishkin, M Saunders, RC AF Munoz-Lopez, M. Insausti, R. Mohedano-Moriano, A. Mishkin, M. Saunders, R. C. TI Anatomical pathways for auditory memory II: information from rostral superior temporal gyrus to dorsolateral temporal pole and medial temporal cortex SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE auditory; memory; superior temporal gyrus; primate; temporal pole; medial temporal cortex ID VISUAL RECOGNITION MEMORY; RHESUS-MONKEY; ENTORHINAL CORTEX; PARAHIPPOCAMPAL CORTICES; PERIRHINAL CORTEX; MACAQUE MONKEY; CONNECTIONS; REGION; ORGANIZATION; PROJECTIONS AB Auditory recognition memory in non-human primates differs from recognition memory in other sensory systems. Monkeys learn the rule for visual and tactile delayed matching-to-sample within a few sessions, and then show one-trial recognition memory lasting 10-20 min. In contrast, monkeys require hundreds of sessions to master the rule for auditory recognition, and then show retention lasting no longer than 30-40s. Moreover, unlike the severe effects of rhinal lesions on visual memory, such lesions have no effect on the monkeys' auditory memory performance. The anatomical pathways for auditory memory may differ from those in vision. Long-term visual recognition memory requires anatomical connections from the visual association area TE with areas 35 and 36 of the perirhinal cortex (PRC). We examined whether there is a similar anatomical route for auditory processing, or that poor auditory recognition memory may reflect the lack of such a pathway. Our hypothesis is that an auditory pathway for recognition memory originates in the higher order processing areas of the rostral superior temporal gyrus (rSTG), and then connects via the dorsolateral temporal pole to access the rhinal cortex of the medial temporal lobe. To test this, we placed retrograde (3% FB and 2% DY) and anterograde (10% BDA 10,000 mW) tracer injections in rSTG and the dorsolateral area 38(DL) of the temporal pole. Results showed that area 38(DL) receives dense projections from auditory association areas Ts1, TAa, TPO of the rSTG, from the rostral parabelt and, to a lesser extent, from areas Ts2-3 and PGa. In turn, area 38(DL) projects densely to area 35 of PRC, entorhinal cortex (EC), and to areas TH/TF of the posterior parahippocampal cortex. Significantly, this projection avoids most of area 36r/c of PRC. This anatomical arrangement may contribute to our understanding of the poor auditory memory of rhesus monkeys. C1 [Munoz-Lopez, M.; Mishkin, M.; Saunders, R. C.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Munoz-Lopez, M.; Insausti, R.; Mohedano-Moriano, A.] Univ Castilla La Mancha, Sch Med, Human Neuroanat Lab, Albacete 02006, Spain. [Munoz-Lopez, M.; Insausti, R.; Mohedano-Moriano, A.] Univ Castilla La Mancha, Sch Med, Reg Ctr Biomed Res CRIB, Albacete 02006, Spain. RP Munoz-Lopez, M (reprint author), Univ Castilla La Mancha, Sch Med, Ave Almansa 14, Albacete 02006, Spain. EM monica.munozlopez@uclm.es RI Mohedano-Moriano, Alicia/L-1121-2016; OI Mohedano-Moriano, Alicia/0000-0003-4904-6774; Munoz Lopez, Monica/0000-0002-5530-2394 FU NIMH/IRP [BFI 2003-09581]; Spanish Ministry of Science and Innovation [BFU 2006-12964] FX This study was supported by NIMH/IRP grant BFI 2003-09581 and the Spanish Ministry of Science and Innovation grant BFU 2006-12964. The Technical support of Elena Hernaez, Marta Fonollosa is greatly appreciated. NR 68 TC 7 Z9 7 U1 0 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD MAY 18 PY 2015 VL 9 AR 158 DI 10.3389/fnins.2015.00158 PG 21 WC Neurosciences SC Neurosciences & Neurology GA CS3NM UT WOS:000361981200001 PM 26041980 ER PT J AU Preusch, PC AF Preusch, Peter C. TI New grant programs offered by the National Institute of General Medical Sciences SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Preusch, Peter C.] Natl Inst Gen Med Sci, Div Cell Biol & Biophys, Bethesda, MD 20892 USA. EM preuschp@nigms.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 3 BP 1 EP 2 DI 10.1080/07391102.2015.1032629 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600004 PM 26103213 ER PT J AU Zhou, BR Jiang, JS Wang, R Feng, HQ Ghirlando, R Xiao, TS Bai, YW AF Zhou, Bing-Rui Jiang, Jiansheng Wang, Rui Feng, Hanqiao Ghirlando, Rodolfo Xiao, T. Sam Bai, Yawen TI Structural mechanisms of nucleosome recognition by linker histones SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Zhou, Bing-Rui; Wang, Rui; Feng, Hanqiao; Bai, Yawen] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [Jiang, Jiansheng; Xiao, T. Sam] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 5 BP 2 EP 3 DI 10.1080/07391102.2015.1032630 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600006 PM 26103215 ER PT J AU Shaytan, AK Armeev, GA Goncearenco, A Zhurkin, VB Landsman, D Panchenko, AR AF Shaytan, Alexey K. Armeev, Grigoriy A. Goncearenco, Alexander Zhurkin, Victor B. Landsman, David Panchenko, Anna R. TI Combined influence of linker DNA and histone tails on nucleosome dynamics as revealed by microsecond molecular dynamics simulations SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Shaytan, Alexey K.; Goncearenco, Alexander; Landsman, David; Panchenko, Anna R.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Armeev, Grigoriy A.] Moscow MV Lomonosov State Univ, Fac Biol, Moscow 119991, Russia. [Zhurkin, Victor B.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. EM alexey.shaytan@nih.gov RI Goncearenco, Alexander/M-3946-2015; Shaytan, Alexey/D-7306-2012 OI Goncearenco, Alexander/0000-0002-9738-7146; Shaytan, Alexey/0000-0003-0312-938X NR 0 TC 0 Z9 1 U1 2 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 6 BP 3 EP 3 DI 10.1080/07391102.2015.1032631 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600007 PM 26103217 ER PT J AU Norouzi, D Zhurkin, VB AF Norouzi, Davood Zhurkin, Victor B. TI Topological polymorphism of two-start nucleosome fibers SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Norouzi, Davood; Zhurkin, Victor B.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. EM davood.norouzi@nih.gov NR 3 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 7 BP 4 EP 4 DI 10.1080/07391102.2015.1032631 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600008 PM 26103219 ER PT J AU Naufer, MN Furano, AV Williams, MC AF Naufer, M. Nabuan Furano, Anthony V. Williams, Mark C. TI Oligomerization kinetics of ORF1p is correlated with LINE1 retrotransposition SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Naufer, M. Nabuan; Williams, Mark C.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Furano, Anthony V.] NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. EM ma.williams@neu.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 12 BP 7 EP 8 DI 10.1080/07391102.2015.1032553 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600013 PM 26103223 ER EF